Psychiatric Times May 2011 Vol XXVIII, No 5 by UBM Medica

Treatment Resistance Understanding Nonadherence

A UBM Medica Publication®

Special Report Clinical Psychopharmacology, Part 2

Category 1 CME Metabolic Risks of Antidepressants and Antipsychotics

May 2011 • Vol. XXVIII, No. 5

www.PsychiatricTimes.com

Psychiatry: Awaken and Return to the Path by James L. Knoll IV, MD

address a few subjects that may have the potential to create a more insidious and enduring form of misrepresentation—namely, the implications that psychiatrists must now “play the game” and resign themselves to a bleak future of harried pill dispensing. I’ll not soft peddle our dilemma. I do think a strong argument can be made that psychiatry is, in part, responsible for the circumstances in which it currently finds itself. In the recent past, psychiatric research has suffered humiliating dishonor in terms of allegations of fraud and selective publication of clinical trials.4 And now, some psychiatrists may find themselves terribly discouraged by the current state of the psychiatric union. In particular, they are saddened by the “business” of medicine, how it no longer pays as well, and how it has curtailed their very ability to listen to patients. My initial reaction to the article

. . . If the fight is for principle and justice, even when failure seems certain . . . cling to your ideal . . . and calmly await the conflict. Sir William Osler, MD1 It may seem difficult at first, but everything is difficult at Miyamoto Musashi first.2 he recent New York Times article by Harris3 presented some of the current challenges facing psychiatry, but did so amidst a distorted backdrop and to the melody of a phantom Greek chorus. I leave it to my colleagues to filter out the distortions according to their specialty and predilections. Instead of focusing on the more astonishing inaccuracies, such as there not being much to “master” in psychopharmacology, I should like to

(Please see Awaken, page 2)

The 2011 Psychiatric Times Ethics Survey: Moral Struggles by Cynthia M. A. Geppert, MD, PhD, MPH he pages of Psychiatric Times and other journals and newspapers both scholarly and popular are replete with stories about the ethical controversies of modern psychiatry and the crises of the profession. The overwhelming response among physicians in general to a recent Medscape ethics survey1 inspired me to work with Psychiatric Times to develop a survey uniquely geared toward psychiatrists and other mental health professionals. The goal of the survey was to go beyond ethical lessons, useful as these

may be, and to learn how Psychiatric Times’ readers—who are on the front line of psychiatric practice—handle a series of hypothetical ethical scenarios. The survey ran from January 13 through February 28, 2011. The responses were all anonymous and reported in aggregate. The thoughtfulness and courage of the psychiatrists who participated was impressive. They volunteered a window into their personal moral struggles regarding a host of sensitive ethical subjects as evident in this précis. Two questions dealt with emerging end-of(Please see Ethics Survey, page 7)

Issue Highlights Commentaries on Psychiatric Outpatient Care Volkswagen Psychopharmacology S. Nassir Ghaemi, MD, MPH

What’s in It for Psychiatrists? H. Steven Moffic, MD

A Missed Opportunity Paul Summergrad, MD

It’s Still Possible—Even in a Managed Care World James S. Goodman, MD COMPLETE CONTENTS, PAGE 8

P SY CH I AT R I C T I M ES www.psy c h i a t r i c t i m e s. c o m

Awaken Continued from page 1

was predictable: How sad. This is terrible. The psychiatric sky is falling. Yet after thinking about the big picture, speaking with psychiatric colleagues, and re-reading my prized copy of Aequanimitas, it occurred to me: this New York Times article is not a dirge—it’s a reveille. Why might it be published now? Could it be that after several decades, psychiatry is awakening from a long sleep? A sleep induced by straying from the path of focusing on patient care, and into the dark woods where a dense pharmaceutical miasma blinded our vision? Awakenings can be painful. We’ll be stiff and groggy as we look around and survey our current situation. But the pain will cause us to become wide awake. Psychiatry is becoming more conscious—it is setting limits and cutting inappropriate ties to Big Pharma. It is researching new treatments on its own, without biasing influences. It is saying—“we value all the psychotherapy we learned and wish to use it, because it helps our patients.” Good morning, Psychiatry! You’ve been asleep for some time now and you’ve been missed. But the good news is that your patients need you and your highly specialized training. But let me warn you— things have changed while you slumbered. . . . Many of our patients have been relocated. Jails now house more persons with serious mental illness than do psychiatric hospitals. 5-7 Perhaps we might consider a return to the original ideals of our path—the care and well-being of persons suffering with serious mental illness, and especially the many who are now in our “new asylums.” The fact is that such jobs are plentiful, lucrative, and rewarding. One can practice without any false partitions. Medical concerns, medications, psychotherapy—all may be attended to by the psychiatrist. The patients are grateful for competent care, and time constraints are far less of an issue. Here is a noble calling and return to psychiatry’s roots. There is great honor in following this path that was originally traveled by names such as Rush, Ray, Pinel, and Menninger. I liken our predicament to that of the ancient samurai of Japan. The original meaning of the word “samurai” was “to wait upon or accompany a person.” One had to serve a long apprenticeship and undergo arduous training. They followed a “code,” and held a prominent place in society for many hundreds of years. But as

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sure as all things are transient, modernization and changing societal politics dissolved the samurai’s power, value, and influence back into the ocean of Japanese society. However, many samurai assimilated themselves into the more modern naval training schools. Some went on to learn other skills and/or teach higher education. It is evident that their culture and philosophy still influence Japan. My point is that they ultimately adapted to inevitable

change without giving up on their ideals. It is not difficult to find highly successful Japanese businessmen who trace their lineage back to the samurai, and indeed refer to themselves as modern-day samurai. As for those who choose private practice—they, too, play a critical role. But note that in the Times article, Dr Lance answers to no one but her patients’ needs and her own calling.3 To continue my samurai analogy, she could be likened to a

Ronin—a masterless samurai. Ronin have an important role, and they refuse to relinquish their honor by lowering their practice standards. They practice to the best of their abilities, but they have adapted to the changing conditions. I personally know many such Ronin, who continue to remind me how satisfied they are with their chosen path. They could not “imagine seeing patients for just 15 minutes”—and so they (Please see Awaken, page 4)

INTUNIV® (guanfacine) Extended-Release Tablets

INTUNIV ® (guanfacine) Extended-Release Tablets

Rx Only BRIEF SUMMARY: Consult the Full Prescribing Information for complete product information. INDICATIONS AND USAGE INTUNIV® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. The efficacy of INTUNIV® was studied for the treatment of ADHD in two controlled monotherapy clinical trials (8 and 9 weeks in duration) and one controlled adjunctive trial with psychostimulants (9 weeks in duration) in children and adolescents ages 6-17 who met DSM-IV® criteria for ADHD [see Clinical Studies in Full Prescribing Information]. The effectiveness of INTUNIV® for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials. CONTRAINDICATIONS Patients with a history of hypersensitivity to INTUNIV®, its inactive ingredients [see Description in Full Prescribing Information], or other products containing guanfacine (e.g. TENEX®) should not take INTUNIV®. WARNINGS AND PRECAUTIONS Hypotension, Bradycardia, and Syncope Treatment with INTUNIV® can cause decreases in blood pressure and heart rate. In the monotherapy, pediatric, short-term (8-9 weeks), controlled trials, the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse were –5 mm Hg, –3 mm Hg, and –6 bpm, respectively, for all dose groups combined (generally one week after reaching target doses of 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day). These changes were dose dependent. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse event for 7% of the INTUNIV® group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the INTUNIV® group and none in the placebo group. In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with INTUNIV® as compared to none in the placebo group. In long-term, open label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric subjects in the clinical program. The majority of these cases occurred in the long-term, openlabel studies. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use INTUNIV® with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use INTUNIV® with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated. Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies (38% for INTUNIV® vs. 12% for placebo in monotherapy studies and 18% for INTUNIV® vs. 7% for placebo in the adjunctive study) in children and adolescents with ADHD, especially during initial use [see Adverse Reactions]. Before using INTUNIV® with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV®. Advise patients to avoid use with alcohol. Other Guanfacine-Containing Products Guanfacine, the active ingredient in INTUNIV®, is also approved as an antihypertensive. Do not use INTUNIV® in patients concomitantly taking other guanfacine-containing products (e.g., Tenex). ADVERSE REACTIONS Monotherapy Trials The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the monotherapy trials with INTUNIV® were: somnolence, fatigue, nausea, lethargy, and hypotension. Twelve percent (12%) of patients receiving INTUNIV® discontinued from the monotherapy clinical studies due to adverse events, compared to 4% in the placebo group. The most common adverse reactions leading to discontinuation of INTUNIV®-treated patients from the studies were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: hypotension, headache, and dizziness. Adjunctive Trial The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the adjunctive trial with INTUNIV® were: somnolence, fatigue, insomnia, dizziness, and abdominal pain. Three percent of patients receiving INTUNIV® discontinued from the adjunctive clinical study due to adverse events, compared to 1% in the placebo group. Clinical Trial Experience Short Term Monotherapy Clinical Studies Common Adverse Reactions - Two short-term, placebo-controlled, double-blind pivotal studies (Studies 1 and 2) were conducted in children and adolescents with ADHD, using fixed doses of INTUNIV® (1, 2, 3, and 4 mg/day). The most commonly reported adverse reactions (occurring in ≥2% of patients) that were considered drug-related and reported in a greater percentage of patients taking INTUNIV® compared to patients taking placebo were: somnolence, headache, fatigue, abdominal pain, hypotension, nausea, lethargy, dizziness, irritability, decreased appetite, dry mouth and constipation. Adverse reactions that were dose-related include: somnolence/sedation, abdominal pain, dizziness, hypotension, dry mouth and constipation. Short Term Adjunctive Clinical Study A 9-week, placebo-controlled, double-blind, dose-optimized pivotal study (Study 3) was conducted in children and adolescents aged 6-17 years with a diagnosis of ADHD who were identified as having a sub-optimal response to psychostimulants.

Patients received INTUNIV® (1, 2, 3, and 4 mg/day) or placebo, dosed in the morning or in the evening, in combination with their morning dose of psychostimulant. The most commonly reported adverse reactions (occurring in ≥ 2% of patients in the overall INTUNIV® group) that were reported in a greater percentage of patients taking INTUNIV® compared to patients taking placebo were: headache, somnolence, insomnia, fatigue, abdominal pain, dizziness, decreased appetite, nausea, diarrhea, hypotension, affect lability, bradycardia, constipation and dry mouth. Effects on Height, Weight, and Body Mass Index (BMI) Patients taking INTUNIV® demonstrated similar growth compared to normative data. Patients taking INTUNIV® had a mean increase in weight of 0.5 kg (1 lb) compared to those receiving placebo over a comparative treatment period. Patients receiving INTUNIV® for at least 12 months in open-label studies gained an average of 8 kg (17 lbs) in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV®. Laboratory Tests In short and long-term studies, no clinically important effects were identified on any laboratory parameters. Effects on Heart Rate and QT Interval The effect of two dose levels of immediate-release guanfacine (4 mg and 8 mg) on the QT interval was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in healthy adults. A dose-dependent decrease in heart rate was observed during the first 12 hours, at time of maximal concentrations. The mean change in heart rate was -13 bpm at 4 mg and -22 bpm at 8 mg. An apparent increase in mean QTc was observed for both doses. However, guanfacine does not appear to interfere with cardiac repolarization of the form associated with proarrhythmic drugs. This finding has no known clinical relevance. Other Adverse Reactions Observed in Clinical Studies Additional adverse reactions observed in short-term, placebo-controlled and long-term, open-label clinical studies not included elsewhere in this section include: atrioventricular block, sinus arrhythmia, dyspepsia, stomach discomfort, vomiting, asthenia, chest pain, hypersensitivity, increased alanine amino transferase, increased blood pressure, increased weight, convulsion, postural dizziness, syncope, agitation, anxiety, depression, nightmare, increased urinary frequency, enuresis, asthma, hypertension and pallor. DRUG INTERACTIONS CYP3A4/5 Inhibitors Use caution when INTUNIV® is administered to patients taking ketoconazole and other strong CYP3A4/5 inhibitors, since elevation of plasma guanfacine concentration increases the risk of adverse events such as hypotension, bradycardia, and sedation. CYP3A4 Inducers When patients are taking INTUNIV® concomitantly with a CYP3A4 inducer, an increase in the dose of INTUNIV® within the recommended dose range may be considered. Valproic Acid Co-administration of guanfacine and valproic acid can result in increased concentrations of valproic acid. Antihypertensive Drugs Use caution when INTUNIV® is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see Warnings and Precautions]. CNS Depressant Drugs Caution should be exercised when INTUNIV® is administered concomitantly with CNS depressant drugs (e.g. alcohol, sedative/hypnotics, benzodiazepines, barbiturates, and antipsychotics) due to the potential for additive pharmacodynamic effects (e.g., sedation, somnolence) [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B There are no adequate and well-controlled studies of guanfacine in pregnant women. INTUNIV® should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. Nursing Mothers: It is not known whether guanfacine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when INTUNIV® is administered to a nursing woman. Pediatric Use: The safety and efficacy of INTUNIV® in pediatric patients less than 6 years of age have not been established. For children and adolescents 6 years and older, efficacy beyond 9 weeks and safety beyond 2 years of treatment have not been established. Geriatric Use: The safety and efficacy of INTUNIV® in geriatric patients have not been established. Use in Patients with Renal or Hepatic Impairment: Dose reduction may be required in patients with clinically significant impairment of renal or hepatic function. OVERDOSAGE Symptoms Two cases of accidental overdose of INTUNIV® were reported in clinical trials in pediatric ADHD patients. These reports included adverse reactions of sedation and bradycardia in one patient and somnolence and dizziness in the other patient. During post-marketing surveillance of guanfacine, hypotension, initial hypertension, drowsiness, lethargy, and bradycardia have been observed following overdose. Treatment Consult a Certified Poison Control Center for up to date guidance and advice. Manufactured for Shire US Inc., Wayne, PA 19087. INTUNIV® is a registered trademark of Shire LLC. © 2011 Shire Pharmaceuticals Inc. Version: February 2011 INT-01788

P SY CH I AT R I C T I M ES www.psy c h i a t r i c t i m e s. c o m

Awaken Continued from page 2

don’t. This is their principle, and they stand by it. And in doing so, they help countless patients receive quality treatment. It is also not the case that these Ronin care only for the “worried well.” The Times piece notes that in “New York City . . . a select group of psychiatrists charges $600 or more per hour.”3 But the rarified atmosphere of a top dollar Manhattan psychiatrist’s office is hardly a realistic assessment of the state of private practice in psychiatry. There is much truth to the statement that “medicine is rapidly changing in the United States,” and that these changes have been associated with a “loss of intimacy between doctors and patients.”3 This is simply a fact for all of medicine, and so let’s examine this trend a little more closely. Trends in health care, generally, could be said to proceed in this fashion: • Te c h n o l o g y n e v e r s t o p s progressing. • As technology progresses, much of the evaluation/treatment process becomes more rapid, and just as importantly . . . • It becomes easier for people without specialized training to do. Again, a simple fact because the computer/new technology/etc can do the job more quickly, more consistently, and without a salary and health care benefits. • Thus, the business of health care becomes progressively segmented and compartmentalized • No area of health care is immune to the above process. Psychotherapy does not escape this sequence. Already, virtual psychotherapy is being developed and used. Soon, “avatar therapists” may be implemented.8 But until we develop true artificial intelligence, human beings will still be needed somewhere in the process. So in the interim, psychotherapy, too, will be distilled down to what “researchers” believe is its practical “essence.” Anything that cannot be accomplished in the 10- to 15-minute session can be given as a take-home assignment to the patient. At some point, third-party payers may decide that it is no longer feasible to pay even psychologists or social workers for what anyone with a bachelor’s degree can do. Does this sound familiar? If so, it is because some of it is already happening. But the question still remains: if we are not satisfied with this, must we accept it? Are we so genteel and apathetic as a profession that we will

M AY 2011

simply acquiesce? Will we passively assent to a lowering of what we believe is an acceptable standard of care for the patients we took an oath to treat? Some may argue that my points here are too idealistic. Others may quarrel: “It is easy to proclaim such ideals when one does not have to live with the restrictions of my position.” To them I would say—who is it that is keeping you imprisoned by these restrictions? Ultimately, this type of thinking provides no solutions and nurtures discontent. All that really matters are the answers to these questions: • Are your patients’ best interests being served? • Are you content practicing medicine according to the oath you took? If the answer to either of these questions is no, then it may be time to change your situation. If we still wish to pursue our medical calling, then we must seek out the set of circumstances that brings us closer to what matters, and settle for nothing less. Such circumstances do exist (albeit maybe not in a particular desired location), and it is still possible to practice this amazing profession provided one is willing to adapt, stand by one’s principles, and stick to the path. Psychiatry—it is time for you to awaken and return to your calling. If you went into psychiatry for the money, well . . . perhaps it is time to reevaluate that decision. If you went into psychiatry because you wanted to relieve suffering and explore the mystery of the human condition with (Please see Awaken, page 6)

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Help your adult patients with Major Depressive Disorder (MDD) toward their treatment goals

forward with Results from PRISTIQ 50 mg clinical studies: • An SNRI with proven efficacy1 • Improvement in functional outcomes in work, leisure, and home activities2* • Discontinuation rate due to adverse events comparable to placebo3 • No significant weight gain versus placebo3 and low incidence of sexual side effects The most commonly observed adverse reactions in patients taking PRISTIQ (incidence ≥5% and ≥2x the rate of placebo) were nausea, dizziness, hyperhidrosis, constipation, and decreased appetite. *As measured by the Sheehan Disability Scale total score.

To learn more about the benefits of PRISTIQ, go to www.pristiqhcp.com PRISTIQ is indicated for the treatment of major depressive disorder in adults.

Important Safety Information for PRISTIQ WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of PRISTIQ or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PRISTIQ is not approved for use in pediatric patients. Contraindications • PRISTIQ is contraindicated in patients with a known hypersensitivity to PRISTIQ or venlafaxine. • PRISTIQ must not be used concomitantly with an MAOI or within 14 days of stopping an MAOI. Allow 7 days after stopping PRISTIQ before starting an MAOI. Warnings and Precautions • All patients treated with antidepressants should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment and when changing the dose. Consider changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, or suicidality that are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants should be alerted about the need to monitor patients. • Development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome-like reactions have been reported with SNRIs and SSRIs alone, including PRISTIQ treatment, but particularly with concomitant use of serotonergic drugs, including triptans, with drugs that impair the metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. If concomitant use with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Concomitant use of PRISTIQ with serotonin precursors is not recommended. • Patients receiving PRISTIQ should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies. Pre-existing hypertension should be controlled before starting PRISTIQ. Caution should be exercised in treating patients with pre-existing hypertension or other underlying conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported. For patients who experience a sustained increase in blood pressure, either dose reduction or discontinuation should be considered. • SSRIs and SNRIs, including PRISTIQ, may increase the risk of bleeding events. Concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants may add to this risk.

• Mydriasis has been reported in association with PRISTIQ; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored. • PRISTIQ is not approved for use in bipolar depression. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine the risk of bipolar disorder. • As with all antidepressants, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania, or with a history of seizure disorder. • Caution is advised in administering PRISTIQ to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders. Increases in blood pressure and small increases in heart rate were observed in clinical studies with PRISTIQ. PRISTIQ has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. • Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) cholesterol, and triglycerides were observed in clinical studies. Measurement of serum lipids should be considered during PRISTIQ treatment. • On discontinuation, adverse events, some of which may be serious, have been reported with PRISTIQ and other SSRIs and SNRIs. Abrupt discontinuation of PRISTIQ has been associated with the appearance of new symptoms. Patients should be monitored for symptoms when discontinuing treatment. A gradual reduction in dose rather than abrupt cessation is recommended whenever possible. • The recommended dose in patients with severe renal impairment or end-stage renal disease (ESRD) is 50 mg every other day. The dose should not be escalated in patients with moderate or severe renal impairment or ESRD. • Products containing desvenlafaxine and products containing venlafaxine should not be used concomitantly with PRISTIQ. • Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including PRISTIQ. Discontinuation of PRISTIQ should be considered in patients with symptomatic hyponatremia. • Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of PRISTIQ) therapy have been rarely reported. Adverse Reactions • The most commonly observed adverse reactions in patients taking PRISTIQ vs placebo for MDD in short-term fixed-dose premarketing studies (incidence ≥5% and ≥2x the rate of placebo in the 50-mg dose group) were nausea (22% vs 10%), dizziness (13% vs 5%), hyperhidrosis (10% vs 4%), constipation (9% vs 4%), and decreased appetite (5% vs 2%). References: 1. Thase ME, Kornstein SG, Germain JM, Jiang Q, Guico-Pabia C, Ninan PT. An integrated analysis of the efficacy of desvenlafaxine compared with placebo in patients with major depressive disorder. CNS Spectr. 2009;14(3):144-154.2. Soares CN, Kornstein SG, Thase ME, Jiang Q, Guico-Pabia CJ. Assessing the efficacy of desvenlafaxine for improving functioning and well-being outcome measures in patients with major depressive disorder: a pooled analysis of 9 double-blind, placebo-controlled, 8-week clinical trials. J Clin Psychiatry. 2009;70(10):1365-1371. 3. Clayton AH, Kornstein SG, Rosas G, Guico-Pabia C, Tourian KA. An integrated analysis of the safety and tolerability of desvenlafaxine compared with placebo in the treatment of major depressive disorder. CNS Spectr. 2009;14(4):183-195. Please see brief summary of Prescribing Information on adjacent pages.

Extended-Release Tablets BRIEF SUMMARY. See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. WARNING: Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Pristiq or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Pristiq is not approved for use in pediatric patients [see Warnings and Precautions (5.1), Use in Specific Populations (8.4), and Patient Counseling Information (17.1 in the full prescribing information)]. INDICATIONS AND USAGE: Pristiq, a selective serotonin and norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder (MDD). CONTRAINDICATIONS: Hypersensitivity-Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the Pristiq formulation. Monoamine Oxidase Inhibitors-Pristiq must not be used concomitantly in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with SNRI or SSRI treatment or with other serotonergic drugs. Based on the half-life of desvenlafaxine, at least 7 days should be allowed after stopping Pristiq before starting an MAOI [see Dosage andAdministration (2.6) in the full prescribing information]. WARNINGS AND PRECAUTIONS: Clinical Worsening and Suicide Risk-Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 of the full prescribing information. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.9) and Dosage and Administration (2.3) in the full prescribing information for a description of the risks of discontinuation of Pristiq]. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Pristiq should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening patients for bipolar disorder- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Pristiq is not approved for use in treating bipolar depression. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions- The development of a potentially lifethreatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Pristiq treatment, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs that impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Serotonin syndrome in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Pristiq with MAOIs intended to treat depression is contraindicated [see Contraindications (4.2)]. If concomitant treatment of Pristiq with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Pristiq with serotonin precursors (such as tryptophan) is not recommended. Treatment with Pristiq and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated. Elevated Blood Pressure- Patients receiving Pristiq should have regular monitoring of blood pressure since dosedependent increases were observed in clinical studies. Pre-existing hypertension should be controlled before initiating treatment with Pristiq. Caution should be exercised in treating patients with pre-existing hypertension or other underlying conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with Pristiq. Sustained hypertension- Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving Pristiq, either dose reduction or discontinuation should be considered [see Adverse Reactions (6.1)]. Treatment with Pristiq in controlled studies was associated with sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits. In clinical studies, regarding the proportion of patients with sustained hypertension, the following rates were observed: placebo (0.5%), Pristiq 50 mg (1.3%), Pristiq 100 mg (0.7%), Pristiq 200 mg (1.1%), and Pristiq 400 mg (2.3%).

Analyses of patients in Pristiq controlled studies who met criteria for sustained hypertension revealed a dose-dependent increase in the proportion of patients who developed sustained hypertension. Abnormal Bleeding-SSRIs and SNRIs can increase the risk of bleeding events. Concomitant use of aspirin, other drugs that affect platelet function, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants can add to this risk. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Pristiq and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Narrow-angle Glaucoma-Mydriasis has been reported in association with Pristiq; therefore, patients with raised intraocular pressure or those at risk of acute narrowangle glaucoma (angle-closure glaucoma) should be monitored. Activation of Mania/Hypomania-During all MDD and VMS (vasomotor symptoms) phase 2 and phase 3 studies, mania was reported for approximately 0.1% of patients treated with Pristiq. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Pristiq should be used cautiously in patients with a history or family history of mania or hypomania. Cardiovascular/Cerebrovascular Disease-Caution is advised in administering Pristiq to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders [see Adverse Reactions (6.1)]. Increases in blood pressure and heart rate were observed in clinical studies with Pristiq. Pristiq has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were excluded from clinical studies. Serum Cholesterol and Triglyceride Elevation-Dose-related elevations in fasting serum total cholesterol, LDL (low-density lipoprotein) cholesterol, and triglycerides were observed in the controlled studies. Measurement of serum lipids should be considered during treatment with Pristiq [see Adverse Reactions (6.1)]. Discontinuation of Treatment with Pristiq- Discontinuation symptoms have been systematically and prospectively evaluated in patients treated with Pristiq during clinical studies in major depressive disorder. Abrupt discontinuation or dose reduction has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy. During marketing of SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors) and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (eg, paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Pristiq. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate [see Dosage and Administration (2.4) and Adverse Reactions (6.1) in full prescribing information]. Renal Impairment-In patients with moderate or severe renal impairment or end-stage renal disease (ESRD) the clearance of Pristiq was decreased, thus prolonging the elimination half-life of the drug. As a result, there were potentially clinically significant increases in exposures to Pristiq [see Clinical Pharmacology (12.6) in full prescribing information]. Dosage adjustment (50 mg every other day) is necessary in patients with severe renal impairment or ESRD. The doses should not be escalated in patients with moderate or severe renal impairment or ESRD [see Dosage and Administration (2.2) in full prescribing information]. Seizure-Cases of seizure have been reported in premarketing clinical studies with Pristiq. Pristiq should be prescribed with caution in patients with a seizure disorder. Hyponatremia- Hyponatremia can occur as a result of treatment with SSRIs and SNRIs, including Pristiq. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients can be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.6) in full prescribing information]. Discontinuation of Pristiq should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Coadministration of Drugs Containing Desvenlafaxine and Venlafaxine- Desvenlafaxine is the major active metabolite of venlafaxine. Products containing desvenlafaxine and products containing venlafaxine should not be used concomitantly with Pristiq. Interstitial Lung Disease and Eosinophilic Pneumonia- Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of Pristiq) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with Pristiq who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of Pristiq should be considered. ADVERSE REACTIONS: Clinical Studies Experience: The most commonly observed adverse reactions in Pristiq-treated MDD patients in short-term fixed-dose studies (incidence ≥5% and at least twice the rate of placebo in the 50- or 100-mg dose groups) were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders. Adverse reactions reported as reasons for discontinuation of treatment- The most common adverse reactions leading to discontinuation in at least 2% of the Pristiq-treated patients in the short-term studies, up to 8 weeks, were nausea (4%); dizziness, headache and vomiting (2% each); in the long-term study, up to 9 months, the most common was vomiting (2%). Common adverse reactions in placebo-controlled MDD studies- Table 3 in full PI shows the incidence of common adverse reactions that occurred in ≥2% of Pristiq-treated MDD patients at any dose in the 8-week, placebo-controlled, fixed-dose, premarketing clinical studies. In general, the adverse reactions were most frequent in the first week of treatment. Cardiac disorders: Palpitations, Tachycardia, Blood pressure increased; Gastrointestinal disorders: Nausea, Dry mouth, Diarrhea, Constipation, Vomiting; General disorders and administration site conditions: Fatigue, Chills, Feeling jittery, Asthenia; Metabolism and nutrition disorders: Decreased appetite, weight decreased; Nervous system disorders: Dizziness, Somnolence, Headache, Tremor, Paraesthesia, Disturbance in attention; Psychiatric Disorders: Insomnia, Anxiety, Nervousness, Irritability, Abnormal dreams; Renal and urinary disorders: Urinary hesitation; Respiratory, thoracic, and mediastinal disorders: Yawning; Skin and subcutaneous tissue disorders: Hyperhidrosis, Rash; Special Senses: Vision blurred; Mydriasis, Vertigo, Tinnitus, Dysgeusia; Vascular Disorders: Hot flush. Sexual function adverse reactions-Table 4 shows the incidence of sexual function adverse reactions that occurred in ≥2% of Pristiq-treated MDD patients in any fixed-dose group (8-week, placebo-controlled, fixed and flexible-dose, premarketing clinical studies). Men Only: Anorgasmia, Libido decreased, Orgasm abnormal, Ejaculation delayed, Erectile dysfunction, Ejaculation disorder, Ejaculation failure, Sexual dysfunction; Women Only: Anorgasmia; Other adverse reactions observed in premarketing clinical studies: Other infrequent adverse reactions occurring at an incidence of <2% in MDD patients treated with Pristiq were: Immune system disorders – Hypersensitivity. Investigations – Weight increased, liver function test abnormal, blood prolactin increased. Nervous system disorders – Convulsion, syncope, extrapyramidal disorder. Musculoskeletal and connective tissue disorders – Musculoskeletal stiffness. Psychiatric disorders – Depersonalization, hypomania. Respiratory, thoracic and mediastinal disorders – Epistaxis. Vascular disorders – Orthostatic hypotension. In clinical studies, there were uncommon reports of ischemic cardiac adverse events, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during Pristiq treatment as compared to placebo [see Warnings and Precautions (5.7)]. Discontinuation events-Adverse events reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical studies at a rate of ≥5% include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy [see Dosage and Administration (2.4) and Warnings and Precautions (5.9) in full prescribing information]. Laboratory, ECG and vital sign changes observed in MDD clinical studies-The following changes were observed in placebocontrolled, short-term, premarketing MDD studies with Pristiq. Lipids-Elevations in fasting serum total cholesterol, LDL (low-density lipoprotein) cholesterol, and triglycerides occurred in the controlled studies. Some of these abnormalities were considered potentially clinically significant [see Warnings and Precautions (5.8)]. Proteinuria-Proteinuria, greater than or equal to trace, was observed in the fixed-dose controlled studies (see Table 6 in full prescribing information). This proteinuria was not associated with increases in BUN or creatinine and was generally transient. ECG changes-Electrocardiograms were obtained from 1,492 Pristiq-treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between Pristiq-treated and placebotreated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval. Vital sign changes-Table 7 summarizes the changes that were observed in placebo-controlled, short-term, premarketing studies with Pristiq in patients with MDD (doses 50 to 400 mg). Relative to placebo, Pristiq was associated with mean increase of up to 2.1 mm Hg in systolic blood pressure, 2.3 mm Hg in diastolic blood pressure, and 4.1 bpm with supine pulse. At the final on-therapy assessment in the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Pristiq during the initial 12-week, open-label phase, there was no statistical difference in mean weight gain between Pristiq- and placebo-treated patients. Orthostatic hypotension- In the short-term, placebo-controlled clinical studies with doses of 50-400 mg, systolic orthostatic hypotension (decrease ≥30 mm Hg from supine to standing position) occurred more frequently in patients ≥65 years of age receiving Pristiq (8.0%, 7/87) versus placebo (2.5%, 1/40), compared to patients <65 years of age receiving Pristiq (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218). Adverse Reactions Identified During

Post-Approval Use- The following adverse reaction has been identified during post-approval use of Pristiq. Because post-approval reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Skin and subcutaneous tissue disorders – Angioedema. Adverse Reactions Reported With Other SNRIsAlthough the following are not considered adverse reactions for desvenlafaxine succinate, they are adverse reactions for other SNRIs and may also occur with desvenlafaxine succinate: gastrointestinal bleeding, hallucinations, photosensitivity reactions and severe cutaneous reactions (such as Steven-Johnson Syndrome, toxic epidermal necrolysis, and/or erythemia multiforme). DRUG INTERACTIONS: Central Nervous System (CNS)-Active Agents-The risk of using Pristiq in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when Pristiq is taken in combination with other CNS-active drugs [see Warnings and Precautions (5.13)]. Monoamine Oxidase Inhibitors (MAOIs)- Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on antidepressants with pharmacological properties similar to Pristiq (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI [see Contraindications (4.2)]. Serotonergic Drugs- Based on the mechanism of action of Pristiq and the potential for serotonin syndrome, caution is advised when Pristiq is coadministered with other drugs that may affect the serotonergic neurotransmitter systems [see Warnings and Precautions (5.2)]. Drugs that Interfere with Hemostasis (eg, NSAIDs, Aspirin, and Warfarin)Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Pristiq is initiated or discontinued. Ethanol- A clinical study has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking Pristiq. Potential for Other Drugs to Affect Desvenlafaxine-Inhibitors of CYP3A4 (ketoconazole)- CYP3A4 is a minor pathway for the metabolism of Pristiq. Concomitant use of Pristiq with potent inhibitors of CYP3A4 may result in higher concentrations of Pristiq. Inhibitors of other CYP enzymes- Based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of Pristiq. Potential for Desvenlafaxine to Affect Other Drugs- Drugs metabolized by CYP2D6 (desipramine)- In vitro studies showed minimal inhibitory effect of desvenlafaxine on CYP2D6. Clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. Concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 can result in higher concentrations of that drug. Drugs metabolized by CYP3A4 (midazolam)- In vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isozyme. Concomitant use of Pristiq with a drug metabolized by CYP3A4 can result in lower exposures to that drug. Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19- In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes. P-glycoprotein Transporter- In vitro, desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter. The pharmacokinetics of Pristiq are unlikely to be affected by drugs that inhibit the P-glycoprotein transporter, and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter. Electroconvulsive Therapy- There are no clinical data establishing the risks and/or benefits of electroconvulsive therapy combined with Pristiq treatment. USE IN SPECIFIC POPULATIONS: PregnancyPatients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Teratogenic effects– Pregnancy Category C- There are no adequate and well-controlled studies of Pristiq in pregnant women. Therefore, Pristiq should be used during pregnancy only if the potential benefits justify the potential risks. Non-teratogenic effects- Neonates exposed to SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. When treating a pregnant woman with Pristiq during the third trimester, the physician should carefully consider the potential risks and benefits of treatment [see Dosage and Administration (2.2)]. Labor and Delivery- The effect of Pristiq on labor and delivery in humans is unknown. Pristiq should be used during labor and delivery only if the potential benefits justify the potential risks. Nursing Mothers- Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Pristiq, a decision should be made whether or not to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Only administer Pristiq to breastfeeding women if the expected benefits outweigh any possible risk. Pediatric Use- Safety and effectiveness in the pediatric population have not been established [see Box Warning and Warnings and Precautions (5.1)]. Anyone considering the use of Pristiq in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use- Of the 3,292 patients in clinical studies with Pristiq, 5% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term, placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with Pristiq [see Adverse Reactions (6)]. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose [see Dosage and Administration (2.2) and Clinical Pharmacology (12.6)]. If Pristiq is poorly tolerated, every other day dosing can be considered. SSRIs and SNRIs, including Pristiq, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.12)]. Greater sensitivity of some older individuals cannot be ruled out. Renal Impairment- In subjects with renal impairment the clearance of Pristiq was decreased. In subjects with severe renal impairment (24-hr CrCl < 30 mL/min) and end-stage renal disease, elimination half-lives were significantly prolonged, increasing exposures to Pristiq; therefore, dosage adjustment is recommended in these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.6) in the full prescribing information]. Hepatic Impairment- The mean t1/2 changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with hepatic impairment is 50 mg/day. Dose escalation above 100 mg/day is not recommended [see Clinical Pharmacology (12.6) ]. OVERDOSAGE: Human Experience with Overdosage- There is limited clinical experience with desvenlafaxine succinate overdosage in humans. In premarketing clinical studies, no cases of fatal acute overdose of desvenlafaxine were reported. The adverse reactions reported within 5 days of an overdose >600 mg that were possibly related to Pristiq included headache, vomiting, agitation, dizziness, nausea, constipation, diarrhea, dry mouth, paresthesia, and tachycardia. Desvenlafaxine (Pristiq) is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of Pristiq) is presented below; the identical information can be found in the Overdosage section of the venlafaxine package insert. In postmarketing experience, overdose with venlafaxine (the parent drug of Pristiq) has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. Prescriptions for Pristiq should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage- Treatment should consist of those general measures employed in the management of overdosage with any SSRI/SNRI. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Induction of emesis is not recommended. Because of the moderate volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for desvenlafaxine are known. In managing an overdose, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians Desk Reference (PDR®). This brief summary is based on Pristiq Prescribing Information W10529C018, revised December 2010. 280518-01

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Awaken Continued from page 4

your fellow travelers/patients, then it is time to stand by the code and ideals of your profession. And if, at some point, you find yourself worn down by the tedium of your routine, consider returning to the source of your principles, where you will find that the beauty and mystery have been awaiting you.

February 2011

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Nothing will sustain you more potently than the power to recognize in your humdrum routine . . . the true poetry of life. . . . Sir William Osler, MD1 Dr Knoll is director of forensic psychiatry and associate professor of psychiatry at SUNY Upstate Medical University in Syracuse, NY. He is editor in chief of Psychiatric Times.

References: 1. Osler W. Aequanimitas. 3rd ed. Philadelphia: The Blakiston Company; 1947. 2. Tokitsu K. Miyamoto Musashi: His Life and Writings. Boston: Weatherhill; 2004. 3. Harris G. Talk doesn’t pay, so psychiatry turns instead to drug therapy. New York Times. March 5, 2011. http://www.nytimes.com/2011/03/06/health/ policy/06doctors.html. Accessed April 13, 2011. 4. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:252-260. 5. Bloom JD. “The incarceration revolution”: the

abandonment of the seriously mentally ill to our jails and prisons. J Law Med Ethics. 2010;38:727-734. 6. Torrey EF, Zdanowicz M. Prison and jails are no place for people with mental illness. The Idaho Statesman. November 25, 2002. http://www. treatmentadvocacycenter.org/index.php?option= com_content&task=view&id=452&Itemid=195. Accessed March 31, 2011. 7. Lamb HR, Weinberger LE. The shift of psychiatric inpatient care from hospitals to jails and prisons. J Am Acad Psychiatry Law. 2005;33:529-534. 8. Carey B. In cybertherapy, avatars assist with healing. New York Times. November 22, 2010. http:// www.nytimes.com/2010/11/23/science/23avatar. html. ❒

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w w w. psychi atr i cti mes. com

Ethics Survey Continued from page 1

life issues in psychiatry—involvement in physician-assisted suicide and whether patients with mental illness ever reach the state where continued care is futile. Three others focused on the more familiar boundary concerns of personal disclosure and romantic involvement. Two scenarios described patients with difficult behaviors and asked how the clinician would handle the problems. Respondents were asked how they would deal with the conflict between confidentiality and nonmaleficence when a patient threatens an identified victim and how they handle the increasingly common

dilemma of an elderly patient for whom driving preserves independence but threatens the public. There were also questions about the influence of third-party forces such as insurance companies, managed care, regulatory authorities, and the pharmaceutical industry on contemporary practice.

Survey overview I hope this brief description whets your appetite for future fare. Here I offer a tentative and broad interpretation of what the results tell us about how often psychiatrists grapple with complex ethical issues, whether those dilemmas have changed in recent years, and how prepared psychi-

Poetry of the Times

by Richard M. Berlin, MD

Note to Pablo Neruda I wake to dawn’s pink light and palm warblers twitching their tails as they feed in the pines and I recall your line: “I was only a tunnel. The birds fled from me.” I pull your book from the shelf, study your picture— a middle-aged man wearing a white shirt and British cap, hands clasped, warm, sad, knowing eyes looking into mine. I hear you ask, “Do birds fly from you, too,” and I answer, Long ago, when I became a doctor I heard the sounds of pheasants drumming in our chests, studied our eggs, our courtship flight, the paper and nails we use to build our nests, the long fall before we hit the ground. My first patients gathered like winter songbirds with their hungers and their fears, and late at night I would read your poems, flowing like an infinite black river, your words carrying me high as crows when they harvest morning stars in the heavens of their beaks. Dr Berlin is associate professor of psychiatry at the University of Massachusetts Medical School. E-mail: Richard.Berlin@gmail.com. He is the author of The Prophecy, published by Pudding House Press.

atrists feel they are to manage these challenging dilemmas. The survey asked participants to respond to a range of ethical dilemmas encountered in daily practice. The questions were multiple choice, with space provided for free text comments. The first 3 questions asked for basic demographic information such as age, whether the respondent was a physician, and his or her specialty. An amazing 708 psychiatrists took the time to respond to the survey along with other mental health professionals, including nurses, psychologists, and students, for a grand total of 1400 responses. The survey participants ranged in age from 20 years to 71 and older. Question 4 asked readers how often they encounter ethical dilemmas in their practice. Of the 640 participants who answered the question, 34% reported facing ethics issues once or twice a week, 43% once or twice a month, and 23% hardly ever. Question 6 asked readers about their level of comfort and preparedness when faced with ethical dilemmas in daily practice. The responses are an encouraging sign that psychiatrists recognize and reflect on ethical problems in the profession. Of the 633 participants who responded, 29.4% felt they had adequate skills and knowledge to analyze and resolve ethical dilemmas; a robust 47.2% said they occasionally needed ethical consultation but knew where to find such assistance; 23.4% said they occasionally needed help, but did not know who to turn to for an ethics consult. Question 7 asked to what extent participants would benefit from expert ethics consultation. Of the 644 respondents, 4.1% replied they would never benefit from consultation and 9.8% said they would often benefit. Many (35.7%) said they seldom needed an ethics consult and 50.4% said they could occasionally use a consultation. In our next survey, we plan to add a question further delineating the ethics resources and type of consultations psychiatrists turn to for guidance.

The current ethical climate Question 5—the focus of this article—asked readers whether the ethical issues in psychiatry are becoming more difficult or have not changed in the past decade. Most of the 624 respondents (59.1%) found that the ethical issues had not changed in the past decade. The 40.9% of respondents who believed

the ethical climate is more challenging were asked to give their opinion regarding the reasons for the difference. The 208 clinicians who took the time to give us their individual perspectives represent a microcosm of the moral distress and the moral seriousness of contemporary psychiatric culture. It is impossible to do justice to the richness and diversity of commentary, but we can glean some broad and overarching themes. The first is that the context in which psychiatrists are embedded is itself more complicated today than it was 10 years ago. As a psychiatrist put it: “The world is an increasingly complex place. Changes in society, technology, medicine add complexity. Psychiatrists should be increasingly active participants.” Several psychiatrists wrote that psychiatry in the 21st century “has many gray areas where there is nothing to follow” and “values are becoming broader and our ideology is no longer black and white.”

Information technology The information technology revolution was identified more often than any other cultural development as dramatically changing psychiatric practice—chiefly in 2 main areas. The first area is how electronic means of communication, such as e-mail and electronic medical records, generate unprecedented confidentiality and privacy concerns. The second area is that the Internet has enabled patients to become educated and empowered as never before, which psychiatrists saw as a double-edged sword. In the words of one clinician: “Patients have now a lot of information available from sources like the Web, and this issue makes some of them more inquisitive about the diagnosis and treatment they get. This means they have more information but this information is not always accurate.” The shrinking availability of care and expanding demands for treatment were another frequently cited source of ethical problems. “Resource constraints increasingly pose difficult problems of care and safety versus autonomy and patient choice. Referring patients is problematic in a broken, unfunded system.”

Conflicts of interest The struggle of clinicians trying to do what is right and best for patients in the face of a growing cadre of stakeholders with a panoply of often competing agendas was evident. (Please see Ethics Survey, page 8)

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Ethics Survey Continued from page 7

“Government, JCAHO [Joint Commission on the Accreditation of Healthcare Organizations ] , and insurance mandates are driving up costs and limiting treatment options. The dilemma is whether to treat the bureaucracy or the patient.” Multiple respondents commented on how politics, the power of the state, regulations, law, and business motives threaten the moral primacy of the good of the patient and the integrity of the psychiatrist. “Some of the ethical dilemmas have been created by the business model of medicine. Do you put the patient’s interest over institution protocol? Other times personal agendas of administrators are carried out at the expense and indifference to patients.” Many clinicians remarked that for-profit health care dominates in an era of scarce government resources and creates conditions ripe for moral compromise. “Systems-based and financial issues have removed the patient to a no. 2 at best focus in many areas of care. With systems’ needs and economics taking the first or second pressure in clinical settings. Cheap, available is replacing tailored and appropriate for the individual.” The Health Insurance Portability and Accountability Act ( HIPAA) and the patient rights movement were some of the most frequently cited changes that have intensified the historic tension between patient welfare and the approaches of law and medicine toward mental illness. Some of the most poignant responses were from forensic psychiatrists confronting a clash between ethical obligations and legal mandates: “I deal with forensic issues and the courts have become overly aggressive and less attentive to patient rights when patients encounter legal issues.”

Medication management The respondents singled out the ascendancy of psychopharmacology in an era of limited resources as the postmodern focus of many ethics conflicts between patient autonomy and the physician’s duty to do no harm. “Persons presenting on medication without clear symptomderived diagnoses. Over prescribing of potentially damaging medication. Persons requesting medication to solve lifestyle and nonpsychiatric issues.” Several practitioners mentioned the role of the pharmaceutical industry and managed care to explain why ethics questions more frequently

M AY 2011

come up in medication management. “Related to consumer marketing of medications, differences between docs on prescribing patterns—use of controlled substances.”

Ethics out in the open Psychiatrists are obviously frustrated with many of the countervailing movements in the social, economic, and legal sphere that jeopardize their efforts to provide efficacious and humanistic care for patients who have mental illness. Yet these physicians also speak with a clear and strong voice that the greater attention given to ethics is a salutary advance. “It’s a good thing. Ethical issues used to just get buried in denial, now they are out in the open.” In subsequent columns and podcasts, I plan to explore the wisdom of readers regarding specific survey topics along with the best current legal and ethical thinking regarding the subject. We hope to make the ethics survey an annual event as one small contribution to what the results of our survey show is a growing ethical awareness among psychiatrists, “Ethical dilemmas are becoming more nuanced as different issues are identified and brought to the fore of one’s consciousness.” You can find a summary of the survey online at http://www. surveymonkey.com/sr.aspx?sm= G7H5GdWLkqAwQdTzzqGBiXH_ 2bqoQtvdtaGIkxr_2fcyUiM_3d. Dr Geppert is chief of consultation psychiatry and ethics at the New Mexico Veterans Affairs Health Care System in Albuquerque. She is also associate professor in the department of psychiatry and director of ethics education at the New Mexico School of Medicine.

In This Issue CATEGORY 1 CME ARTICLE Metabolic Risks of Antidepressant and Antipsychotic Drugs W. Victor R. Vieweg, MD, Mehrul Hasnain, MD, Mark A. Wood, MD, Antony Fernandez, MD, Edward J. Lesnefsky, MD, and Ananda K. Pandurangi, MD

DEPARTMENTS COVER STORIES Psychiatry: Awaken and Return to the Path

James L. Knoll IV, MD

The 2011 Psychiatric Times Ethics Survey: Moral Struggles Cynthia M. A. Geppert, MD, PhD, MPH

NEWS A Psychiatrist’s Perspective on a Potentially Explosive Issue Susan Kweskin

COMMENTARIES Volkswagen Psychopharmacology What’s in It for Psychiatrists? A Missed Opportunity

S. Nassir Ghaemi, MD, MPH

H. Steven Moffic, MD

Paul Summergrad, MD

It’s Still Possible—Even in a Managed Care World The King’s Psychotherapy

James S. Goodman, MD

Lawrence D. Blum, MD

LETTERS TO THE EDITOR The Vote on Tutu: Fair Hearing? Bruce Hershfield, MD

With responses from Arline Kaplan and Jerome Rogoff, MD

Black Psychiatrists of America Speak About Desmond Tutu P.A. Newton, MD, MPH, MA

DEBATE Board Certification: Two Perspectives Kevin B. Weiss, MD and Larry R. Faulkner, MD With response from Sidney Weissman, MD

ARTICLES Treatment Resistance: Understanding the Psychodynamics of Nonadherence César A. Alfonso, MD A Literature Review of Videophone Use in Mental Health J. Edwin Nieves, MD, Gregory Briscoe, MD, Lucinda Edwards, MLS, and Aidith Flores-Carrera, DO

Cognitive Symptoms Lewis A. Opler, MD, PhD

Reference 1. Kane L. Exclusive Ethics Survey Results: Doctors Struggle With Tougher-Than-Ever Dilemmas. Medscape Medical Ethics. November 11, 2010. http:// www.medscape.com/viewarticle/731485. Accessed April 7, 2011. ❒

SPECIAL REPORT CLINICAL PSYCHOPHARMACOLOGY, PART 2 Does MDMA Have a Role in Clinical Psychiatry? Michael C. Mithoefer, MD Ethical Issues in Psychopharmacology Laura Weiss Roberts, MD, MA and Shaili Jain, MD

Pharmonitor Have you read something recently in Psychiatric Times or one of its supplements that you considered biased? We invite you to write and tell us why you think the author(s) either underemphasized or overemphasized the positive or negative effects of a pharmaceutical agent or a medical device. Log on to www.PsychiatricTimes.com and search for Pharmonitor for details. Please e-mail your comments to editor@ psychiatrictimes.com. ❒

COLUMNS POETRY OF THE TIMES Note to Pablo Neruda

Richard M. Berlin, MD

PAIN MANAGEMENT Analgesic Medications: Balancing Efficacy, Adverse Effects, and Convenience

Steven A. King, MD, MS

BOOK REVIEWS Recovery From Disability: Manual of Psychiatric Rehabilitation Reviewed by Michael Alan Schwartz, MD

MOLECULES OF THE MIND Lorenzo’s Oil and the Rehabilitation of Gene Therapy John J. Medina, PhD Cover Image © Hand Colored Photographic Image of fierce Samurai warrior from the Meiji Era Japan/Peabody

MAY 2011

COMMENTARIES ON PSYCHIATRIC OUTPATIENT CARE

Volkswagen Psychopharmacology

by S. Nassir Ghaemi, MD, MPH roundbreaking scientific studies get published, and I rarely hear from colleagues. But any article emanating from the Manhattan media sets e-mails abuzz; PDFs are forwarded and tut-tutting is heard. This is no way to learn. We don’t follow William Osler’s advice: “Read the old books and the journals,” he said.1 But we don’t read the journals, and we don’t even know about the old books. Instead, we all read The New York Times. Gardiner Harris’ recent look at psychiatry in The New York Times2 is not entirely disinterested. The journalist-author has a well-deserved, and in some ways admirable, muckraking reputation, criticizing the barons of Capitalism—whether they produce coal or Zyprexa. He now interviews for the Times a 68-year-old psychiatrist who used to do pure psychotherapy in the 1970s and 1980s and today provides pure medication treatment in 15-minute med checks. Much dissatisfaction is described. The psychiatrist interviewed calls himself a good Volkswagen mechanic, apparently unaware that our patients’ brains are Porsches. VW knowledge is not good enough. The metaphor dovetails with the final testament of a founder of psychopharmacology, the great Frank Ayd, a man whose wife brought the first haloperidol pills to the United States in her purse on a flight from Europe. In the era when Freudian talk was the rage, Frank realized that these medications actually did something helpful. Frank passed away in

his late 80s a few years ago, and in his last public interview (with Psychiatric Times), he bequeathed us a warning. We will have many medications in the future, he prophesied; that will not be a problem. Our challenge will be in teaching doctors how to use them, “otherwise it would be like giving a driver’s license to someone who can’t drive.”3 The problem with psychopharmacology today is precisely the notion that it is easy, that it doesn’t take much thought, that it can be handled in 15 minutes, and that (as the Times article states) a trained ape could do it. Most psychiatry residency programs boast many, many hours of psychotherapy training and much less time for psychopharmacology didactics. Some even explicitly proclaim that psychopharmacology can simply be learned from a book. I suppose we should just close all medical schools: all of medicine can be learned from books. Osler is gyrating underground; I can hear him moaning. Nature is the great teacher, Osler always taught; each patient is a book, teaching new lessons. But we still need books too, so it matters which books. It is not enough to read books, we have to have good books to read. Some popular texts of psychopharmacology, rather than relying on clinical knowledge, teach biological speculation. This drug affects that receptor; this neurotransmitter needs to be increased in this condition, that one decreased in that condition. It’s simple: imagine the synapse, memorize some facts about a couple dozen drugs, and you’re finished. Volkswagen psychopharmacology.

And what about the teaching, from Hippocrates via Osler, that we shouldn’t treat symptoms, but that we should primarily treat diseases? And what are the mental diseases? Schizophrenia and manic depression, I’d say; but you’ll have this objection or that. All the ideas can be found in the old books. Let’s discuss them. We don’t carefully identify diseases of the mind. We throw pills at the symptoms: penny-in-the-slot practice, Osler called it, guaranteed to produce a harmful polypharmacy. We don’t carefully follow the clinical research science supporting which drugs to use, and more importantly not to use, for which diseases. Listen to an old book, the 1806 text of Philippe Pinel4: “In diseases of the mind . . . it is an art of no little importance to administer medicines properly; but, it is an art of much greater importance and more difficult acqui-

sition to know when to suspend or altogether omit them.” All drugs are toxic; only their indication and dosage make them therapeutic. (You won’t find that in the morning paper. It’s in Osler’s Aequanimitas.) Maybe that’s why we went to medical school. Enough. My morning coffee’s still hot. Pass the newspaper. Dr Ghaemi is professor of psychiatry and pharmacology at Tufts University School of Medicine and director of the Mood Disorders Program at Tufts Medical Center, Boston. References 1. Osler W. Aequanimitas. 3rd ed. New York: McGraw-Hill; 1932. 2. Harris G. Talk doesn’t pay, so psychiatry turns instead to drug therapy. New York Times. March 5, 2011. 3. Kaplan A. Through the Times with Frank J. Ayd, Jr, MD. Psychiatr Times. 2005;22(1):17-24. 4. Pinel P. A Treatise on Insanity. Birmingham, AL: The Classics of Medicine Library; 1806. ❒

Take Our Poll

What percentage of your patients see you primarily for med checks? 5%? 15%? 80%?

A recent New York Times article “Talk Doesn’t Pay, So Psychiatry Turns Instead to Drug Therapy” www.nytimes.com/2011/03/06/health/policy/06doctors.html focuses on the practice of one psychiatrist who—for a variety of reasons—now provides only 15-minute “med checks” for his patients. Psychiatric Times would like to find out how accurately this depiction mirrors the way our readers practice outpatient psychiatry.

To that end, we invite you to answer our poll questions by clicking on www.PsychiatricTimes.com You can see the most current results of the poll on our Web site. Thanks for participating.

COMMENTARIES ON PSYCHIATRIC OUTPATIENT CARE

MAY 2011

What’s in It for Psychiatrists? by H. Steven Moffic, MD t could have been me. But I’m glad it wasn’t. It would not have passed my (late) mother’s sniff test. I’m referring to the recent New York Times article, “Talk Doesn’t Pay, So Psychiatry Turns Instead to Drug Therapy.”1 After all, the title implies that psychiatrists are motivated more by how much they make than by how much they help. If the title had been therapeutically reframed—as our best cognitive-behavioral therapists would do—to something like “Psychiatrists Turn to Therapeutic Med Checks,” then my mother would have been proud, as would I. However, psychiatrist bashing is popular with the public and the press, so the title is unfortunately consistent. But what about the article itself, for those who read beyond the headline? Although I don’t have a private practice run by my wife (though I’m sure she would like that) and I don’t look like Dr Levin, who was featured in the Times article, I do practice nowadays much like he does. And, from my wide knowledge of clinical psychiatrists around the country, many others do so to a great extent. Younger psychiatrists may actually not realize how different it once was. I’ve been a participant-observer of this trend for over 40 years. I’ve even led a not-for-profit behavioral health care system so I could be in the eye of these winds of change.2 It became clear to me that for-profit managed care and big Pharma were leading more and more psychiatrists along the biological path to the 15-minute med check. If the Times reporter had asked to observe my practice, I would have probably agreed as long as my confidentiality concerns were allayed. I would have had to accept that some of my comments would likely be taken out of context and therefore look worse than they were—as some of Dr Levin’s may have been—in order to support the newspaper’s agenda. Given such risks, Dr Levin was courageous to make his practice more transparent, and we owe him some thanks. Nevertheless, if I’d had the opportunity, here’s what I might have said differently than Dr Levin, who is quoted in the article as saying:

“I miss the mystery and intrigue of psychotherapy. Now I feel like a good Volkswagen mechanic.” I, too, did a lot of psychodynamic psychotherapy earlier in my career. It certainly was intriguing to learn about the mysteries of our secret thoughts, desires, and conflicts. Many patients did seem to improve once their secrets were unlocked, although it often took an awfully long time.

“I’m good at it, but there’s not a lot to master in medications.” True enough . . . it’s much easier to understand medications than our psychologies. Actually, we need a sophisticated psychological approach to help ensure the acceptance of medication for many patients. But why isn’t being “good at it” enough? What helped me was to remind myself that what we psychia-

ing and we are not living up to our potential. It is not too late to reclaim some of what we have lost as long as we are ready to focus on some—or all—of the following principles: • Be an expert diagnostician Given our extensive training and the medical considerations in the diagnosis of psychiatric disorders, the upcoming DSM-5 should convey the unique expertise of psychiatrists that would also justify higher evaluative reimbursement. • Be a unique clinician No other mental health clinicians can combine psychotherapy and medication—often the preferred treatment—as cost-effectively as psychiatrists. • Be an effective communicator We need to improve how we communicate with the public—and to do it as well as other businesses (yes, we are a business and a profession!). We need to be able to counter quickly and effectively any inaccuracies in stories like ones conveyed in the Times piece.5

Dr Donald Levin, like many psychiatrists, does not provide talk therapy because of insurance limits. © New York Times

I believe that the challenge to learn enough relevant information about a patient in brief medication (and evaluative) sessions still exists. And there is also the challenge of picking a medication that will be acceptable and valued—both from a symbolic and biological standpoint. Before we demonize managed care and/or Pharma for our pervasive current predicament, let’s remember that brief med checks have been omnipresent in community mental health settings since the 1960s because of financial priorities—well before managed care extended that to private insurance. Moreover, new clinical settings can add a lot of mystery and intrigue to the practice of psychiatry. In particular, my recent work with refugees, prison inmates, and the transgendered has me trying to learn so much about trauma, evil, and gender. Opportunities still abound for psychiatrists with these patients. Dr Levin also had this to say about psychopharmacology:

trists do is a sacred calling that goes back to the days of shamans, and each brief meeting can be a Buber-like Ithou interaction.3 We can help make it that way by always looking (and, hopefully, feeling) happy to see our patients, ascertaining their strengths, and finding out quickly how our treatment can help them fulfill whatever gives their life meaning. Nothing is wrong with apologizing for the limits of time, but we can add that we’re in this together and can still accomplish much. In a way, this challenge to do more with less time is akin to the paradox of talking with someone as they are dying, which was most movingly and successfully depicted in the bestselling book Tuesdays With Morrie.4 Time is short, but that necessitates discussing what is most important in the relationship and in life. Perhaps we can conclude, then, there’s still quite a bit in it for psychiatrists—certainly more than a 15-minute med check would imply. However, what we do is indeed diminish-

• Be a contributor to the community Our profession needs to be actively engaged in addressing health and mental health threats that range from gun control to climate change. • Be proud! Even if it is less than ideal, be not ashamed of what we can still do to help. Dr Moffic is a tenured professor in the departments of psychiatry and behavioral sciences and of family and community medicine at the Medical College of Wisconsin in Milwaukee. He is a regular contributor to the “Couch in Crisis” blog at Psychiatric Times. References 1. Harris G. Talk doesn’t pay so, psychiatry turns instead to drug therapy. New York Times. March 5, 2011. http://www.nytimes.com/2011/03/06/health/ policy/06doctors.html. Accessed April 1, 2011. 2. Moffic HS. The Ethical Way: Challenges and Solutions for Managed Behavioral Healthcare. San Francisco: Jossey-Bass Publishers; 1997. 3. Moffic HS. Therapeutic alliances: conveying our sacred calling. Curr Psychiatry. 2011;10:2. 4. Albom M. Tuesdays With Morrie. New York: Random House; 1997. 5. Luntz FI. Win: The Key Principles to Take Your Business From Ordinary to Extraordinary. New York: Hyperion; 2011. ❒

MAY 2011

COMMENTARIES ON PSYCHIATRIC OUTPATIENT CARE

A Missed Opportunity by Paul Summergrad, MD ardiner Harris’s1 recent article in The New York Times was, at best, a missed opportunity to look at the changing patterns of outpatient care by psychiatrists. Centered around a single psychiatrist in Pennsylvania whose practice is limited to diagnostic and medication management visits, Harris paints a picture of psychiatric outpatient care driven primarily by the distorted financial reimbursements built into our health care insurance system. Harris1 cites, with obvious concern, a 2005 federal survey that found that “just 11% of psychiatrists provided talk therapy to all patients.” How accurate is this picture, and what explains the changing patterns of psychiatric practice? First, the survey that Harris cites—the National Ambulatory Medical Care Survey— provides data that contradict the impressions in Harris’s article. As analyzed by Mojtabai and Olfson,2 psychotherapy visits to psychiatrists—defined as visits of longer than 30 minutes—occurred in 28.9% of visits in 2004 - 2005 compared with 44.4% of visits in 1996 - 1997. As they themselves noted, the authors used a “restrictive definition of psychotherapy that may have misclassified some visits.”2 Indeed, common practice and standard Current Procedural Terminology (CPT) codes specifically include 30-minute visits for psychotherapy, with or without pharmacotherapy—visits they excluded in their analysis. Even with the restrictive definition in the Mojtabai and Olfson study, 59% of psychiatrists in the sample provided some psychotherapy, although with regional variation. More important, there was significant variance in provision of 45-minute (or longer) psychotherapy visits, based on diagnosis: patients with schizophrenia were least likely to receive more intensive forms of psychotherapy, and patients with dysthymia and personality disorders were most likely, even after controlling for multiple other variables. These data suggest that the provision of more intensive psychotherapy by psychiatrists is highly sensitive to evidence-based studies and perhaps to circumstances in which well-documented pharmacotherapies are less available. If pay-

ment were the sole or primary determinant of care, it is unlikely that this more granular and specific provision of psychotherapy would be present.

In addition to his mischaracterization of the Mojtabai and Olfson study, Harris ignores contrary data. Thus, Reif and colleagues3 looked at types

of outpatient visits to a private national managed behavioral health plan. Based on their analysis of these 2004 (Please see Missed Opportunity, page 12)

When you treat Attention Deﬁcit/Hyperactivity Disorder (ADHD) with stimulants, for some patients, a question may be...

*Kapvay™ was FDA approved on September 28, 2010.

• When added to a stimulant, extended-release Kapvay™ demonstrated statistically signiﬁcant improvement of ADHD symptoms compared with a stimulant alone at the end of 5 weeks of treatment, as measured by the ADHD RS-IV total score

Indication Kapvay™ (clonidine hydrochloride) extended-release tablets are indicated for the treatment of attention deﬁcit/hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications in children and adolescents ages 6-17. The efﬁcacy of Kapvay™ is based on the results of 2 clinical trials in children and adolescents. Kapvay™ is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. The effectiveness of Kapvay™ for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials; therefore, the physician electing to use Kapvay™ for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Important Safety Information • Kapvay™ should not be used in patients with known hypersensitivity to clonidine • Kapvay™ can cause dose-related decreases in blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope • Somnolence/Sedation were commonly reported adverse reactions in clinical studies with Kapvay™. Potential for additive sedative effects with CNSdepressant drugs. Advise patients to avoid use with alcohol. Caution patients against operating heavy equipment or driving until they know how they respond to Kapvay™ • Patients should be instructed not to discontinue Kapvay™ therapy without consulting their physician due to the potential risk of withdrawal effects. Kapvay™ should be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days • In patients who have developed localized contact sensitization or other allergic reaction to clonidine in a transdermal system, substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash, urticaria, or angioedema. Use cautiously in patients with vascular disease, cardiac conduction disease, or chronic renal failure: Monitor carefully and uptitrate slowly • Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs • Use caution when Kapvay™ is administered concomitantly with antihypertensive drugs, due to the additive pharmacodynamic effects (e.g., hypotension, syncope) • Kapvay™ should not be used during pregnancy unless clearly needed. Since clonidine hydrochloride is excreted in human milk, caution should be exercised when Kapvay™ is administered to a nursing woman • Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers) due to a potential for additive effects, such as bradycardia and AV block • Clonidine, the active ingredient in Kapvay™, is also approved as an antihypertensive. Do not use Kapvay™ in patients concomitantly taking other clonidine-containing products, (e.g., Catapres® [clonidine hydrochloride], JENLOGA) • Common adverse reactions (incidence at least 5% and twice the rate of placebo) include: somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain Kapvay™ is a trademark of Shionogi Pharma, Inc. Catapres® is a registered trademark of Boehringer Ingelheim.

Please see Brief Summary of full Prescribing Information on the adjacent page.

Atlanta, Georgia.

KAP10-PAD-002-00

COMMENTARIES ON PSYCHIATRIC OUTPATIENT CARE

Missed Opportunity Continued from page 11

data, more than 67% of visits to psychiatrists involved either medication management and psychotherapy, or psychotherapy alone. This was despite the fact that the visits occurred in the type of insurance setting that has generally been viewed as least hospitable and remunerative to psychiatric practice. So in what ways was the Harris

piece a missed opportunity? First, one would not know, on the basis of the article, that psychiatry has been rapidly increasing the quality of its evidence base and the specificity of its treatments—verbal, behavioral, and psychopharmacological. Indeed, the growth in the use of pharmacotherapeutic agents—imperfect though they are, according to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and Se-

quenced Treatment Alternatives to Relieve Depression (STAR*D) efficacy studies—has been driven not merely by financial or marketing considerations, but by the efforts of generations of psychiatric researchers to find more effective treatments for fearsome and profoundly disabling illnesses. Second, Harris fails to note that it has been psychiatric clinicians and researchers, as well as colleagues in

KAPVAY (clonidine hydrochloride) extended-release tablets, oral, Rx only INDICATIONS AND USAGE KAPVAY™ is a centrally acting alpha2-adrenergic agonist indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications. (1) The efficacy of KAPVAY is based on the results of two clinical trials in children and adolescents. (14) Maintenance efficacy has not been systematically evaluated, and patients who are continued on longer-term treatment require periodic reassessment. (1) This extended-release formulation of clonidine hydrochloride is also approved for the treatment of hypertension under the trade name JENLOGA. (1) CONTRAINDICATIONS KAPVAY should not be used in patients with known hypersensitivity to clonidine. WARNINGS AND PRECAUTIONS Hypotension/Bradycardia Treatment with KAPVAY can cause dose related decreases in blood pressure and heart rate. In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -8.8 mmHg on KAPVAY 0.4 mg/day. The maximum placebosubtracted mean change in diastolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -7.3 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on KAPVAY 0.2 mg/day and -7.7 beats per minute on KAPVAY 0.4 mg/day. During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on KAPVAY 0.2 mg/day and -5.6 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on KAPVAY 0.2 mg/day and -5.4 mmHg on KAPVAY 0.4 mg/day. The maximum placebosubtracted mean change in heart rate was -0.6 beats per minute on KAPVAY 0.2 mg/day and -3.0 beats per minute on KAPVAY 0.4 mg/day. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use KAPVAY with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use KAPVAY with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated. Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day vs 7% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with KAPVAY+stimulant vs 8% treated with placebo+stimulant reported somnolence. Before using KAPVAY with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with KAPVAY. Advise patients to avoid use with alcohol. Abrupt Discontinuation No studies evaluating abrupt discontinuation of KAPVAY in children with ADHD have been conducted. In children and adolescents with ADHD, physicians should gradually reduce the dose of KAPVAY in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue KAPVAY therapy without consulting their physician due to the potential risk of withdrawal effects. In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety. In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. Allergic Reactions In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). Patients with Vascular Disease, Cardiac Conduction Disease, or Renal Failure Clonidine hydrochloride should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure. Other Clonidine-Containing Products Clonidine, the active ingredient in KAPVAY, is also approved as an antihypertensive. Do not use KAPVAY in patients concomitantly taking other clonidine-containing products, (e.g. Catapres®). ADVERSE REACTIONS Clinical Trial Experience Two KAPVAY ADHD clinical studies evaluated 256 patients who received active therapy, in one of the two placebo-controlled studies (Studies 1 and 2) with primary efficacy end-points at 5-weeks. Study 1: Fixed-dose KAPVAY Monotherapy Study 1 was a multi-center, randomized, double-blind, placebo-controlled study with primary efficacy endpoint at 5 weeks, of two fixed doses (0.2 mg/day or 0.4 mg/day) of KAPVAY in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2.

MAY 2011

psychology and other disciplines, who have argued for the use of combined treatments. These include forms of psychotherapy, such as cognitive-behavioral therapy, that can be provided outside the framework of hour-long visits. Third, there is no mention of the seminal work in neuroimaging, genetics, and animal models that has begun to reveal the importance of epigenesis—essentially, the influence

Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Treatment period (Study 1) Percentage of Patients Reporting Event KAPVAY KAPVAY Preferred Term Placebo 0.4 mg/day 0.2 mg/day (N=76) N=78 N=76 Somnolence1 Headache Upper Abdominal Pain Fatigue2 Upper Respiratory Tract Infection Irritability Throat Pain Nausea Nightmare Dizziness Insomnia Emotional Disorder Constipation Dry Mouth Nasal Congestion Body Temperature Increased Gastrointestinal Viral Diarrhea Ear Pain Nasopharyngitis Abnormal Sleep-Related Event Aggression Asthma Bradycardia Enuresis Inﬂuenza like Illness Tearfulness Thirst Tremor Epistaxis Lower Respiratory Tract Infection Pollakiuria Sleep Terror

31% 19% 13% 13% 6% 6% 6% 8% 9% 3% 6% 5% 6% 5% 5% 1% 0% 1% 0 3% 1% 1% 1% 4% 4% 3% 3% 3% 3% 0 0

38% 29% 20% 16% 11% 9% 8% 5% 3% 7% 4% 4% 1% 0 3% 5% 7% 4% 5% 3% 3% 3% 3% 0 0 1% 1% 1% 1% 3% 3%

5% 18% 17% 1% 4% 3% 3% 4% 0 5% 1% 1% 0 1% 1% 3% 4% 3% 1% 1% 0 1% 1% 0 0 1% 0 0 0 0 1%

0 0

3% 3%

0 0

1. Somnolence includes the terms “somnolence” and “sedation”. 2. Fatigue includes the terms “fatigue” and “lethargy”. Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3. Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Taper period* (Study 1) Percentage of Patients Reporting Event KAPVAY KAPVAY Preferred Term Placebo 0.4 mg/day 0.2 mg/day (N=76) N=78 N=76 Abdominal Pain Upper Headache Gastrointestinal Viral Somnolence Heart Rate Increased Otitis Media Acute

6% 2% 5% 3% 3% 0

0 5% 0 2% 0 3%

3% 3% 0 0 0 0

*Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8 Study 2: Flexible-dose KAPVAY as Adjunctive Therapy to Psychostimulants Study 2 was a multi-center, randomized, double-blind, placebo-controlled study, with primary efﬁcacy endpoint at 5 weeks, of a ﬂexible dose of KAPVAY as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. KAPVAY was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most KAPVAY treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day. Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4.

MAY 2011

COMMENTARIES ON PSYCHIATRIC OUTPATIENT CARE

of environmental and psychological events on the expression of the genetic code. Epigenesis has important “permissive” effects on the development of both psychiatric and medical illnesses and helps us understand why psychotherapeutic work has important neurobiological correlates and effects. None of these fundamental developments in psychiatry, or their impact on clinical practice, were evident in Harris’ article.

Finally, Harris did not go deep enough in understanding how payment schemes in the health care insurance environment do drive the provision of care. For example, we have known for decades that primary care and non-psychiatric specialty physicians provide more than 50% of all ambulatory psychiatric care. They also write 70% of the prescriptions for antidepressants. Yet, partly because of the development of “carve outs”—

Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Treatment Period (Study 2) Preferred Term Somnolence1 Fatigue2 Abdominal Pain Upper Nasal Congestion Throat Pain Decreased Appetite Body Temperature Increased Dizziness Insomnia Epistaxis Rhinorrhea Abdominal Pain Anxiety Pain in Extremity

Percentage of Patients Reporting Event KAPVAY+STM PBO+STM (N=102) (N=96) 19% 8% 16% 4% 12% 7% 6% 5% 6% 3% 5% 4% 4% 2% 4% 2% 4% 2% 3% 0 3% 0 2% 1% 2% 0 2% 0

1. Somnolence includes the terms: “somnolence” and “sedation”. 2. Fatigue includes the terms “fatigue” and “lethargy”. Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5. Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Taper Period* (Study 2)

Preferred Term

Percentage of Patients Reporting Event KAPVAY+STM PBO+STM (N=102) (N=96) 4% 2% 3% 1% 3% 2% 3% 1% 2% 0 2% 0

Nasal Congestion Headache Irritability Throat Pain Gastroenteritis Viral Rash *Taper Period: weeks 6-8. Most common adverse reactions, deﬁned as events that were reported in at least 5% of drugtreated patients and at least twice the rate as in placebo patients, during the treatment period were somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain. The most common adverse reactions that were reported during the taper phase were upper abdominal pain and gastrointestinal virus. Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving KAPVAY discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of KAPVAY monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: formication, vomiting, prolonged QT, increased heart rate, and rash. In the pediatric adjunctive treatment to stimulants study, one patient discontinued from KAPVAY + stimulant group because of bradyphrenia. Effects on Laboratory Tests, Vital Signs, and Electrocardiograms KAPVAY treatment was not associated with any clinically important effects on any laboratory parameters in either of the placebo-controlled studies. Mean decreases in blood pressure and heart rate were seen [see Warnings and Precautions (5.1)]. There were no changes on ECGs to suggest a drug-related effect. DRUG INTERACTIONS No drug interaction studies have been conducted with KAPVAY in children. The following have been reported with other oral immediate release formulations of clonidine. Interactions with CNS-depressant Drugs Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. Interactions with Tricyclic Antidepressants If a patient is receiving clonidine hydrochloride and also taking tricyclic antidepressants the hypotensive effects of clonidine may be reduced. Interactions with Drugs Known to Affect Sinus Node Function or AV Nodal Conduction Due to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers). Use with other products containing clonidine Do not use KAPVAY concomitantly with other products containing clonidine (e.g. Catapres®). Antihypertensive Drugs Use caution when KAPVAY is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see Warnings and Precautions (5.2)].

specialized, fourth-party mental health insurance plans—general physicians rarely code psychiatric diagnoses because payment for these illnesses is often limited if provided by these practitioners. This makes it harder to understand the scope and quality of mental health care in the general medical sector. Similarly, if the patient already sees a nonmedical therapist, many psychiatrists will avoid using psy-

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m2 basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. No adequate and wellcontrolled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed. Nursing Mothers Since clonidine hydrochloride is excreted in human milk, caution should be exercised when KAPVAY is administered to a nursing woman. Pediatric Use A study was conducted in which young rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood at doses of up to 300 mcg/kg/day, which is approximately 3 times the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. A slight delay in onset of preputial separation was seen in males treated with the highest dose (with a no-effect dose of 100 mcg/kg/day, which is approximately equal to the MRHD), but there were no drug effects on fertility or on other measures of sexual or neurobehavioral development.

chotherapy codes to “protect” the patient’s limited number of psychotherapy visits. Consequently, actual psychotherapy provision by psychiatrists may be underestimated in some studies. Moreover, with rare exceptions, insurers prohibit psychiatrists from billing the standard medical evaluation and management codes used by all other physicians (the so-called 99xxx E&M codes). These codes allow for stratified medical visits by complexity and time based on patients’ needs. As a consequence, patients may be squeezed into brief medication visits that become caricatures of psychiatric practice. Gardiner Harris and The New York Times were near these important stories and missed them. Hopefully, Harris will find a way to return to these insurance issues—and to the real growth in psychiatric neuroscience—and tell both in a more balanced and accurate fashion. Dr Summergrad is Dr Frances S. Arkin Professor and Chairman, department of psychiatry, Professor of Medicine at Tufts University School of Medicine, and Psychiatrist-in-Chief

KAPVAY has not been studied in children with ADHD less than 6 years old. Patients with Renal Impairment The impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of KAPVAY should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental KAPVAY following dialysis. Adult Use in ADHD KAPVAY has not been studied in adult patients with ADHD. DRUG ABUSE AND DEPENDENCE Controlled Substance KAPVAY is not a controlled substance and has no known potential for abuse or dependence. OVERDOSAGE Symptoms Clonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. Treatment Consult with a Certified Poison Control Center for up-to-date guidance and advice. © 2010 Shionogi Pharma, Inc. Florham Park, NJ 07932 Last modified 10/2010

of Tufts Medical Center, Boston. References 1. Harris G. Talk doesn’t pay, so psychiatry turns instead to drug therapy. New York Times. March 5, 2011. http://www.nytimes.com/2011/03/06/health/ policy/06doctors.html. Accessed March 31, 2011. 2. Mojtabai R, Olfson M. National trends in psychotherapy by office-based psychiatrists. Arch Gen Psychiatry. 2008;65:962-970. 3. Reif S, Horgan C, Torres M, Merrick E. Economic grand rounds: types of practitioners and outpatient visits in a private managed behavioral health plan. Psychiatr Serv. 2010;61:1066-1068. ❒

QUESTIONS? COMMENTS? We welcome your questions or comments about any articles or columns in Psychiatric Times. Send to Editor, Psychiatric Times, 535 Connecticut Avenue, Suite 300, Norwalk, CT 06854; or e-mail editor@psychiatrictimes. com. Letters may be referred to authors and correspondence may be edited and published for the benefit of our readers.

COMMENTARIES ON PSYCHIATRIC OUTPATIENT CARE

MAY 2011

It’s Still Possible—Even in a Managed Care World by James S. Goodman, MD n “Talk Doesn’t Pay, So Psychiatry Turns to Drug Therapy,”1 The New York Times chronicled Dr Donald

Levin’s change from a psychotherapy practice to a very different kind of practice in which he sees 4 follow-up patients an hour—and makes more money. The story is, unfortunately,

both sad and true. My practice is similar to that of Dr Lance, the “former colleague of Dr Levin [who] practices the old style of psychiatry from an office next to her

NEWS BRIEF A Psychiatrist’s Perspective on a Potentially Explosive Issue by Susan Kweskin Had the National Rifle Association (NRA) had its way and Bill 432 had been voted into law in Florida, physicians in that state would have been prohibited from asking their patients whether they have access to firearms.1 That bill—the details of which can be read at www.flsenate.gov/session/bill/2011/0432/

gun-related suicide and homicide, as well as un-

BillText/Filed/HTML—would have made it a felony to

intentional gun-related harm to others.

ask about access to guns or even to include details

“The constitutionality of legal possession of

about such access in a patient’s medical record. Doc-

firearms is emphatically not the issue here. The

tors found guilty of doing so could have been impris-

issue is the physician’s professional right and

oned for up to 5 years and/or fined up to $5 million.

duty to inquire into risk factors for harm to self

According to Psychiatric News, the NRA introduced

or others, including but not limited to possession

Bill 432 into the Florida House and Senate in an effort

of firearms. Indeed, failure to so inquire—par-

to “prevent intrusion” into the constitutional right to

ticularly in cases involving suicidal or homicidal

bear arms.2

individuals seen in emergency department set-

An article that appeared in the March 29, 2011, Sun-

tings—would pose a serious threat to the safety

shine News (http://www.sunshinestatenews.com/print/

and well-being of both the patient and, poten-

2524846) reports that a compromise has been reached

tially, society. It would also expose the physician

between the backers of the bill and the Florida Medi-

to tremendous liability in the event a patient with

cal Association (FMA), which strongly opposed it. Un-

violent tendencies left the medical setting and

der that compromise, questions about gun ownership

inflicted harm on himself or herself or others.

would generally be permissible—as long as the physi-

“No law that has a chilling effect on pertinent

cian doesn’t “harass” the patient and doesn’t include

medical assessment of risk factors for violence

information about guns in the medical record without

should be tolerated by any state or any citizen.

“good reason.” According to that article, both the FMA

I would urge all legislators to ensure that any

and the NRA now support the measure.

law written to protect the privacy of patients in-

The NRA appears to be maneuvering similar bills in

cludes language stating that ‘nothing in this leg-

other states, so the issue may become one of national

islation shall be construed as restricting a physi-

importance. It is a legislative battle that could affect

cian’s right and duty to carry out a thorough and

all physicians—but it has serious forensic and liability

professional assessment of the patient’s safety

implications for psychiatrists in particular.

vis-a-vis self and others. No liability shall be

house”1—except that my office is not next to my house and I participate in a few insurance networks. In fact, a substantial portion of my patients see me “in network.” My patients range from business owners and highly accomplished professionals to individuals who struggle to get by on paltry disability payments. Here in Albuquerque, where there are well over 100 psychiatrists, my wife, Mary L. De Luca, MD, and I are among just a handful who do not take on patients only for “med checks.” As the Times reporter correctly states, we would earn more money if we practiced like Dr Levin. However, the far greater disparity in fees is between those allowed for talking and listening to patients (and even for examining them) and those allowed for procedures. This is true whether it is a psychotherapistpsychiatrist, med-check psychiatrist, or primary care physician who is doing the talking, listening, or examining. I estimate that colleagues who put a rubber band on a hemorrhoid or perform a colonoscopy (both truly valuable services) are allowed fees that amount to 3 to 7 times what I am paid per hour, even after figuring in much higher overhead for such medical procedures. The good news is that while our numbers are dwindling, it is still possible for a psychiatrist to have a successful and very gratifying practice that provides psychotherapy (along with medication to those who need both)—even “in a managed care environment.” Many patients prefer to see a single clinician, with whom they develop a close relationship, for both psychotherapy and pharmacotherapy. And I believe that in many cases, knowing patients’ psyches more intimately and having more time to inquire into their symptoms and history lead to better recommendations regarding medication.

Psychiatric Times editor in chief emeritus, Ronald

attached to a physician’s inquiries re: firearms

Pies, MD, offers his thoughts on this issue. Dr Pies is

possession, when such inquiry occurs in the

Dr Goodman is a psychiatric member of the

professor in the psychiatry departments of SUNY Up-

course of the professional medical assessment

American Academy of Psychoanalysis and

state Medical University, Syracuse, NY, and Tufts Uni-

of a patient’s safety.’”

Dynamic Psychiatry in Albuquerque.

versity School of Medicine, Boston. “It is the physician’s moral, legal, and clinical responsibility to inquire into all relevant risk factors related to a patient’s safety, both with respect to self-harm and potential harm to others. The possession of firearms in the home—legal or otherwise—markedly increases the risk of both

References 1. Doctors to go to jail for asking patients about guns in the home. http:// psychiatrist-blog.blogspot.com/2011/03/doctors-to-go-to-jail-for-asking. html. Accessed April 1, 2011. 2. Guldin B. Bill would put silencer on gun talk between doctors, patients. Psychiatric News. March 4, 2011. http://pn.psychiatryonline.org/content/ 46/5/16.3.full. Accessed April 1, 2011. ■

Reference 1. Harris G. Talk doesn’t pay, so psychiatry turns instead to drug therapy. New York Times. March 5, 2011. http://www.nytimes.com/2011/03/06/health/ policy/06doctors.html. Accessed April 1, 2011. ❒

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PSYCHIATRIC TIMES www.psy c h i a t r i c t i m e s. c o m

MAY 2011

LETTERS TO THE EDITOR

better to have checked with others who were present to get a more balanced story than to rely on the limited sources she did. To imply that the Assembly takes serious concerns, honestly aired, either lightly or dishonestly does a disservice to our profession and feeds the dangerous myth that authority is always corrupt. Bruce Hershfield, MD Speaker of the APA Assembly Reference 1. Kaplan A. Boycotts and protests to meet APA keynote speaker, Desmond Tutu. Psychiatric Times. 2011;28(3):1-4.

Arline Kaplan Responds: © World Economic Forum swiss-image.ch/Photo by Remy Steinegger

The Vote on Tutu: Fair Hearing? I am concerned that the front-page article in the March issue of Psychiatric Times, “Boycotts and Protests to Meet APA Keynote Speaker, Desmond Tutu,”1 strongly implies that in November the Assembly failed to fairly consider Dr Jerome Rogoff’s Action Paper (AP) urging President Bernstein to rescind her invitation. It does no service to Dr Rogoff and others who had something to say about the invitation to suggest that they did not get a fair hearing before an Assembly that is designed to give them exactly that―and did. The Assembly is run strictly according to Alice Sturgis’s The Standard Code of Parliamentary Procedure, with a Parliamentarian sitting directly next to the Speaker. I was particularly determined to ensure that Assembly Representatives who were upset about the invitation would have a chance to make their position clear. For example, I offered to try to make 30 minutes available for discussion of this AP under “New Business” at the end of the meeting. (“New Business” is not “an interesting phenomenon itself,” [as the reporter, Arline Kaplan, had written] but is the place where APs submitted after the deadline are to be considered.) Dr Rogoff and I agreed beforehand that a half hour should be sufficient for a thorough discussion. At 10:30—exactly 30 minutes before the room had to be vacated—Dr Rogoff moved the paper, and took 12 minutes to speak in favor of it. After another member spoke, Dr Rogoff responded, then 5 more members spoke―4 in favor and 1 opposed. The question was “called” from the

floor and 2 voice votes on the motion to call were taken. It was determined that the two-thirds requirement for calling a question had been met. No one disputed that ruling, so a voice vote was taken on the motion itself. That vote was resoundingly “nay”― not “close” at all. (My impression was that it was about a two-thirds nay). No one even asked that a second voice vote take place or called for a standing vote (which, as Dr Peele points out in the Psychiatric Times article, is the usual procedure when there is a close voice vote.) There were 7 minutes remaining, which would have been sufficient to count a standing vote if one were needed. The reason that no one asked for a standing vote was that the voice vote was so resoundingly clear. Nowhere in “Sturgis” does it state that every person who wants to speak on a subject must be heard. However, the Code does specify that someone in favor and someone opposed should get a chance to present the 2 sides of an issue. The Tutu invitation had been discussed at length in several venues before the Assembly met, as it has been since. It is inconceivable that Assembly members had not had time before a vote was taken to form an opinion about whether or not the invitation should be rescinded. I have no problem with APA members airing their dissatisfaction with the invitation. However, I am very troubled by the article’s insinuation that the Assembly leadership endeavored to block them from getting a fair hearing. If I had wanted to interfere with their rights―which I most definitely did not―others on the dais who are fair and who are experienced in parliamentary proce-

dure, such as our Parliamentarian, Speaker-elect, Recorder, and Past Speakers, would have seen to it that I followed the Assembly rules. Your reporter would have done

I appreciate the additional clarity and detail that Dr Hershfield brings to this controversial issue. Regarding the fair hearing question surrounding the AP, Dr Peele—the APA’s newly (Please see Vote on Tutu, page 20)

Black Psychiatrists of America Speak About Desmond Tutu

On behalf of the Black Psychiatrists of America, we are writing to the

American

chiatric

Psy-

Association

regarding the recent “issues”

that

have

been raised by some members of your association with respect to Archbishop Tutu being this year’s convocation speaker at your annual meeting in Hawaii in May. We have prepared a consensus document that is wholly endorsed by our entire membership with regards to this most unfortunate issue. While we acknowledge that it is rather lengthy, it is felt by our members that in order to do justice to the matter, nothing short of our expressed feelings in detail could suffice. We are requesting your attention to this document and distribution as you see fit. Please be aware that this document is appearing on our Web site today and is being sent to our distribution list as well as to other key media outlets and persons critical to the matter. P. A. Newton, MD, MPH, MA President [Editor’s note: This letter was sent to the American Psychiatric Association as well as to Psychiatric Times. The consensus document is posted on our Web site—www.psychiatrictimes.com.] ■

BIPOLAR I MAINTENANCE TREATMENT

GEODON is indicated for acute treatment as monotherapy of manic or mixed episodes associated with bipolar I disorder and for maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate. For full symptoms and diagnostic criteria, see the DSM-IV-TR ® (2000). IMPORTANT SAFETY INFORMATION Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo. GEODON is not approved for the treatment of patients with dementia-related psychosis. GEODON is contraindicated in patients with a known history of QT prolongation, recent acute myocardial infarction, or uncompensated heart failure, and should not be used with certain other QT-prolonging drugs. GEODON has a greater capacity to prolong the QTc interval than several antipsychotics. In some drugs, QT prolongation has been associated with torsade de pointes, a potentially fatal arrhythmia. In many cases this would lead to the conclusion that other drugs should be tried ﬁrst. Hypokalemia may increase the risk of QT prolongation and arrhythmia. As with all antipsychotic medications, a rare and potentially fatal condition known as neuroleptic malignant syndrome (NMS) has been reported with GEODON. NMS can cause hyperpyrexia, muscle rigidity, diaphoresis, tachycardia, irregular pulse or blood pressure, cardiac dysrhythmia, and altered mental status. If signs and symptoms appear, immediate discontinuation, treatment, and monitoring are recommended. Prescribing should be consistent with the need to minimize tardive

dyskinesia (TD), a potentially irreversible dose- and durationdependent syndrome. If signs and symptoms appear, discontinuation should be considered since TD may remit partially or completely. Hyperglycemia-related adverse events, sometimes serious, have been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia or diabetes in patients treated with GEODON, and it is not known if GEODON is associated with these events. Patients treated with an atypical antipsychotic should be monitored for symptoms of hyperglycemia. Precautions include the risk of rash, orthostatic hypotension, and seizures. Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery. GEODON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Breast feeding is not recommended. The most common adverse events (≥5%) associated with GEODON in the bipolar maintenance study were tremor and insomnia. Please see brief summary of prescribing information on adjacent page. For more information, please visit www.pfizerpro.com/GEODON

GEODON® (ziprasidone HCl) Capsules GEODON® (ziprasidone mesylate) injection for intramuscular use BRIEF SUMMARY: See package insert for full prescribing information. INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS—Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the ﬁndings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. GEODON (ziprasidone) is not approved for the treatment of patients with Dementia-Related Psychosis (see WARNINGS).

INDICATIONS GEODON is indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder. GEODON intramuscular is indicated for acute agitation in schizophrenic patients. DOSAGE AND ADMINISTRATION Schizophrenia GEODON Capsules should be administered at an initial daily dose of 20 mg twice daily with food. In some patients, daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady-state is achieved within 1 to 3 days. In order to ensure use of the lowest effective dose, patients should ordinarily be observed for improvement for several weeks before upward dosage adjustment. Efficacy in schizophrenia was demonstrated in a dose range of 20 mg to 100 mg twice daily in short-term, placebocontrolled clinical trials. There were trends toward dose response within the range of 20 mg to 80 mg twice daily, but results were not consistent. An increase to a dose greater than 80 mg twice daily is not generally recommended. The safety of doses above 100 mg twice daily has not been systematically evaluated in clinical trials. Maintenance Treatment—While there is no body of evidence available to answer the question of how long a patient treated with ziprasidone should remain on it, a maintenance study in patients who had been symptomatically stable and then randomized to continue ziprasidone or switch to placebo demonstrated a delay in time to relapse for patients receiving GEODON. No additional benefit was demonstrated for doses above 20 mg twice daily. Patients should be periodically reassessed to determine the need for maintenance treatment. Bipolar I Disorder Acute Treatment of Manic or Mixed Episodes—Dose Selection: Oral ziprasidone should be administered at an initial daily dose of 40 mg twice daily with food. The dose may then be increased to 60 mg or 80 mg twice daily on the second day of treatment and subsequently adjusted on the basis of tolerance and efficacy within the range 40 mg to 80 mg twice daily. In the flexible-dose clinical trials, the mean daily dose administered was approximately 120 mg. Maintenance Treatment (as an adjunct to lithium or valproate)—Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40 mg to 80 mg twice daily with food. Patients should be periodically reassessed to determine the need for maintenance treatment. Acute Treatment of Agitation in Schizophrenia Intramuscular Dosing —The recommended dose is 10 mg to 20 mg administered as required up to a maximum dose of 40 mg per day. Doses of 10 mg may be administered every two hours; doses of 20 mg may be administered every four hours up to a maximum of 40 mg/day. Intramuscular administration of ziprasidone for more than three consecutive days has not been studied. If long-term therapy is indicated, oral ziprasidone hydrochloride capsules should replace the intramuscular administration as soon as possible. Since there is no experience regarding the safety of administering ziprasidone intramuscular to schizophrenic patients already taking oral ziprasidone, the practice of co-administration is not recommended. Ziprasidone intramuscular is intended for intramuscular use only and should not be administered intravenously. Intramuscular Preparation for Administration GEODON for Injection (ziprasidone mesylate) should only be administered by intramuscular injection and should not be administered intravenously. Single-dose vials require reconstitution prior to administration. Add 1.2 mL of Sterile Water for Injection to the vial and shake vigorously until all the drug is dissolved. Each mL of reconstituted solution contains 20 mg ziprasidone. To administer a 10 mg dose, draw up 0.5 mL of the reconstituted solution. To administer a 20 mg dose, draw up 1.0 mL of the reconstituted solution. Any unused portion should be discarded. Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final solution. This medicinal product must not be mixed with other medicinal products or solvents other than Sterile Water for Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dosing in Special Populations Oral: Dosage adjustments are generally not required on the basis of age, gender, race, or renal or hepatic impairment. GEODON is not approved for use in children or adolescents. Intramuscular: Ziprasidone intramuscular has not been systematically evaluated in elderly patients or in patients with hepatic or renal impairment. As the cyclodextrin excipient is cleared by renal filtration, ziprasidone intramuscular should be administered with caution to patients with impaired renal function. Dosing adjustments are not required on the basis of gender or race. CONTRAINDICATIONS QT Prolongation Because of ziprasidone’s dose-related prolongation of the QT interval and the known association of fatal arrhythmias with QT prolongation by some other drugs, ziprasidone is contraindicated in patients with a known history of QT prolongation (including congenital long QT syndrome), with recent acute myocardial infarction, or with uncompensated heart failure (see WARNINGS). Pharmacokinetic/ pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded. Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class Ia and III antiarrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. Ziprasidone is also contraindicated with other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning [see WARNINGS]. Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product. WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. GEODON is not approved for the treatment of dementia-related psychosis (see BOXED WARNING). QT Prolongation and Risk of Sudden Death Ziprasidone use should be avoided in combination with other drugs that are known to prolong the QTc interval. Additionally, clinicians should be alert to the identification of other drugs that have been consistently observed to prolong the QTc interval. Such drugs should not be prescribed with ziprasidone. Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias (see CONTRAINDICATIONS). QT Prolongation in Clinical Trials A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers. The mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was approximately

14 msec less than the prolongation observed for thioridazine. In this study, the effect of ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice daily). In placebo-controlled trials, oral ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. In clinical trials the electrocardiograms of 2/2988 (0.06%) patients who received GEODON and 1/440 (0.23%) patients who received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 msec. In the ziprasidone-treated patients, neither case suggested a role of ziprasidone. QT Prolongation and Torsade De Pointes Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsade de pointes and with sudden unexplained death. The relationship of QT prolongation to torsade de pointes is clearest for larger increases (20 msec and greater) but it is possible that smaller QT/QTc prolongations may also increase risk, or increase it in susceptible individuals. Although torsade de pointes has not been observed in association with the use of ziprasidone in premarketing studies and experience is too limited to rule out an increased risk, there have been rare post-marketing reports (in the presence of multiple confounding factors) (see ADVERSE REACTIONS). A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with intramuscular haloperidol as a control, was conducted in patient volunteers. In the trial, ECGs were obtained at the time of maximum plasma concentration following two injections of ziprasidone (20 mg then 30 mg) or haloperidol (7.5 mg then 10 mg) given four hours apart. Note that a 30 mg dose of intramuscular ziprasidone is 50% higher than the recommended therapeutic dose. The mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone was 4.6 msec following the first injection and 12.8 msec following the second injection. The mean increase in QTc from baseline for haloperidol was 6.0 msec following the first injection and 14.7 msec following the second injection. In this study, no patients had a QTc interval exceeding 500 msec. As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking ziprasidone at recommended doses. The premarketing experience for ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo, but the extent of exposure was limited, especially for the drugs used as active controls and placebo. Nevertheless, ziprasidone’s larger prolongation of QTc length compared to several other antipsychotic drugs raises the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs for treating schizophrenia. This possibility needs to be considered in deciding among alternative drug products. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. Electrolyte Disturbances May Increase The Risk of QT Prolongation It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances, hypokalemia in particular, have baseline serum potassium and magnesium measurements. Hypokalemia (and/ or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. Hypokalemia may result from diuretic therapy, diarrhea, and other causes. Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment. Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec. Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. If signs and symptoms of tardive dyskinesia appear in a patient on ziprasidone, drug discontinuation should be considered. Hyperglycemia and Diabetes Mellitus Hyperglycemia-related adverse events, sometimes serious, have been reported in patients treated with atypical anti-psychotics. There have been few reports of hyperglycemia or diabetes in patients treated with GEODON, and it is not known if GEODON is associated with these events. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. PRECAUTIONS Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis (including fatal cases) have been reported temporally related to antipsychotic agents. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue GEODON at the first sign of decline in WBC in the absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue GEODON and have their WBC followed until recovery. Rash In premarketing trials with ziprasidone, about 5% of patients developed rash and/or urticaria, with discontinuation of treatment in about one-sixth of these cases. The occurrence of rash was related to dose of ziprasidone, although the finding might also be explained by the longer exposure time in the higher dose patients. Several patients with rash had signs and symptoms of associated systemic illness, e.g., elevated WBCs. Most patients improved promptly with adjunctive treatment with antihistamines or steroids and/or upon discontinuation of ziprasidone, and all patients experiencing these reactions were reported to recover completely. Upon appearance of rash for which an alternative etiology cannot be identified, ziprasidone should be discontinued. Orthostatic Hypotension Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia, and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its a -adrenergic antagonist properties. Syncope was reported in 0.6% of the patients treated with ziprasidone. Ziprasidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). Seizures In clinical trials, seizures occurred in 0.4% of patients treated with ziprasidone. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. As with other antipsychotic drugs, ziprasidone should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia, and ziprasidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia (see BOXED WARNING and Increased Mortality in Elderly Patients with Dementia-Related Psychosis in WARNINGS). Hyperprolactinemia As with other drugs that antagonize dopamine D2 receptors, ziprasidone elevates prolactin levels in humans. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is 1

contemplated in a patient with previously detected breast cancer. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction in patients treated with ziprasidone. In the 4- and 6-week placebo-controlled trials, somnolence was reported in 14% of patients on ziprasidone compared to 7% of placebo patients. Somnolence led to discontinuation in 0.3% of patients in short-term clinical trials. Since ziprasidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that ziprasidone therapy does not affect them adversely. Priapism One case of priapism was reported in the premarketing database. Body Temperature Regulation Although not reported with ziprasidone in premarketing trials, disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Suicide The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ziprasidone should be written for the smallest quantity of capsules consistent with good patient management in order to reduce overdose risk. Patients With Concomitant Illnesses Clinical experience with ziprasidone in patients with certain concomitant systemic illnesses is limited. Ziprasidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of QTc prolongation and orthostatic hypotension with ziprasidone, caution should be observed in cardiac patients (see QT Prolongation and Risk of Sudden Death in WARNINGS and Orthostatic Hypotension in PRECAUTIONS). Information for Patients To assure safe and effective use of GEODON, the information and instructions provided in the patient information should be discussed with patients. Laboratory Tests Patients being considered for ziprasidone treatment who are at risk of significant electrolyte disturbances should have baseline serum potassium and magnesium measurements. Low serum potassium and magnesium should be replaced before proceeding with treatment. Patients who are started on diuretics during Ziprasidone therapy need periodic monitoring of serum potassium and magnesium. Discontinue ziprasidone in patients who are found to have persistent QTc measurements >500 msec (see WARNINGS). DRUG INTERACTIONS (1) Ziprasidone should not be used with any drug that prolongs the QT interval. (2) Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs. (3) Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents. (4) Ziprasidone may antagonize the effects of levodopa and dopamine agonists. Effect of Other Drugs on Ziprasidone Carbamazepine, 200 mg bid for 21 days, resulted in a decrease of approximately 35% in the AUC of ziprasidone. Ketoconazole, a potent inhibitor of CYP3A4, 400 mg qd for 5 days, increased the AUC and Cmax of ziprasidone by about 35-40%. Cimetidine, 800 mg qd for 2 days, did not affect ziprasidone pharmacokinetics. Co-administration of 30 mL of Maalox® did not affect ziprasidone pharmacokinetics. Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has not revealed evidence of any clinically significant pharmacokinetic interactions with benztropine, propranolol, or lorazepam. Effect of Ziprasidone on Other Drugs In vitro studies revealed little potential for ziprasidone to interfere with the metabolism of drugs cleared primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and little potential for drug interactions with ziprasidone due to displacement. Ziprasidone 40 mg bid administered concomitantly with lithium 450 mg bid for 7 days did not affect the steady-state level or renal clearance of lithium. In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of estrogen or progesterone components. Ziprasidone 20 mg bid did not affect the pharmacokinetics of concomitantly administered oral contraceptives, ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg). Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Lifetime carcinogenicity studies were conducted with ziprasidone in Long Evans rats and CD-1 mice. In male mice, there was no increase in incidence of tumors relative to controls. In female mice, there were dose-related increases in the incidences of pituitary gland adenoma and carcinoma, and mammary gland adenocarcinoma at all doses tested. Increases in serum prolactin were observed in a 1-month dietary study in female, but not male, mice. Ziprasidone had no effect on serum prolactin in rats in a 5-week dietary study at the doses that were used in the carcinogenicity study. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown (see Hyperprolactinemia in PRECAUTIONS). Mutagenesis: There was a reproducible mutagenic response in the Ames assay in one strain of S. typhimurium in the absence of metabolic activation. Positive results were obtained in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes. Impairment of Fertility: Ziprasidone increase time to copulation in SpragueDawley rats in two fertility and early embryonic development studies at doses of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD of 200 mg/day on a mg/m2 basis). Fertility rate was reduced at 160 mg/kg/day (8 times the MRHD on a mg/m2 basis). There was no effect on fertility at 40 mg/kg/day (2 times the MRHD on a mg/m2 basis). The fertility of female rats was reduced. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Ziprasidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The effect of ziprasidone on labor and delivery in humans is unknown. Nursing Mothers It is not known whether ziprasidone or its metabolites are excreted in human milk. It is recommended that women receiving ziprasidone should not breastfeed. Pediatric Use The safety and effectiveness of ziprasidone in pediatric patients have not been established. Geriatric Use Of the total number of subjects in clinical studies of ziprasidone, 2.4 percent were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Nevertheless, the presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for some elderly patients. ADVERSE REACTIONS Adverse Findings Observed in Short-term, Placebo-Controlled Trials The following findings are based on the short-term placebo-controlled premarketing trials for schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials) and bipolar mania (a pool of two 3-week flexible-dose trials) in which GEODON was administered in doses ranging from 10 to 200 mg/day. Adverse Events Associated With Discontinuation Schizophrenia: Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 2.2% (6/273) on placebo. The most common reaction associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients (see PRECAUTIONS). Bipolar Mania: Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 3.7% (5/136) on placebo. The most common reactions associated with dropout in the ziprasidone-treated patients were akathisia, anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of these reactions among ziprasidone patients (1%) compared to one placebo patient each for dystonia and rash (1%) and no placebo patients for the remaining adverse events. Adverse Events at an Incidence of ≥5% and at Least Twice the Rate of Placebo The most commonly observed adverse events associated with GEODON in schizophrenia trials were somnolence (14%) and respiratory tract infection (8%). The most commonly observed adverse events associated with the use of GEODON in bipolar mania trials were somnolence (31%), extrapyramidal symptoms (31%), dizziness (16%),

akathisia (10%), abnormal vision (6%), asthenia (6%), and vomiting (5%). The following list enumerates the treatment-emergent adverse events that occurred during acute therapy, including only those events that occurred in 2% of GEODON patients and at a greater incidence than in placebo. Schizophrenia: Body as a Whole—asthenia, accidental injury, chest pain. Cardiovascular—tachycardia. Digestive—nausea, constipation, dyspepsia, diarrhea, dry mouth, anorexia. Nervous—extrapyramidal symptoms, somnolence, akathisia, dizziness. Respiratory—respiratory tract infection, rhinitis, cough increased. Skin and Appendages—rash, fungal dermatitis. Special Senses—abnormal vision. Bipolar Mania: Body as a Whole—headache, asthenia, accidental injury. Cardiovascular—hypertension. Digestive—nausea, diarrhea, dry mouth, vomiting, increased salivation, tongue edema, dysphagia. Musculoskeletal—myalgia. Nervous—somnolence, extrapyramidal symptoms, dizziness, akathisia, anxiety, hypesthesia, speech disorder. Respiratory—pharyngitis, dyspnea. Skin and Appendages—fungal dermatitis. Special Senses—abnormal vision. Dose Dependency An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of adverse reaction to dose for the following reactions: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision. Extrapyramidal Symptoms (EPS) The incidence of reported EPS for ziprasidone patients in the short-term, placebo-controlled schizophrenia trials was 14% vs. 8% for placebo. Objectively collected data from those trials on the SimpsonAngus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. Elevated risk of acute dystonia is observed in males and younger age groups. Vital Sign Changes Ziprasidone is associated with orthostatic hypotension (see PRECAUTIONS). Weight Gain In short-term schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of body weight were compared, revealing a statistically significantly greater incidence of weight gain for ziprasidone (10%) compared to placebo (4%). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no median weight change in placebo patients. Weight gain was reported as an adverse event in 0.4% of both ziprasidone and placebo patients. During long-term therapy with ziprasidone, a categorization of patients at baseline on the basis of body mass index (BMI) revealed the greatest mean weight gain and highest incidence of clinically significant weight gain (>7% of body weight) in patients with low BMI (<23) compared to normal (23-27) or overweight patients (>27). There was a mean weight gain of 1.4 kg for those patients with a “low” baseline BMI, no mean change for patients with a “normal” BMI, and a 1.3 kg mean weight loss for patients who entered the program with a “high” BMI. ECG Changes Ziprasidone is associated with an increase in the QTc interval (see WARNINGS). In the schizophrenia trials, ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients. Other Adverse Events Observed During the Premarketing Evaluation of Ziprasidone in Schizophrenia Frequent adverse events are those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare adverse events are those occurring in fewer than 1/1000 patients. Body as a Whole—Frequent: abdominal pain, flu syndrome, fever, accidental fall, face edema, chills, photosensitivity reaction, flank pain, hypothermia, motor vehicle accident. Cardiovascular System—Frequent: tachycardia, hypertension, postural hypotension. Infrequent: bradycardia, angina pectoris, atrial fibrillation. Rare: first degree AV block, bundle branch block, phlebitis, pulmonary embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis. Digestive System—Frequent: anorexia, vomiting. Infrequent rectal hemorrhage, dysphagia, tongue edema. Rare: gum hemorrhage, jaundice, fecal impaction, gamma glutamyl trans-peptidase increased, hematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena. Endocrine—Rare: hypothyroidism, hyperthyroidism, thyroiditis. Hemic and Lymphatic System—Infrequent: anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy. Rare: thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia. Metabolic and Nutritional Disorders—Infrequent: thirst, transaminase increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased, albuminuria, hypokalemia. Rare: BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemic reaction, hypomagnesemia, ketosis, respiratory alkalosis. Musculoskeletal System—Frequent: myalgia. Infrequent: tenosynovitis. Rare: myopathy. Nervous System—Frequent: agitation, extrapyramidal syndrome, tremor, dystonia, hypertonia, dyskinesia, hostility, twitching, paresthesia, confusion, vertigo, hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis, hypesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal syndrome, buccoglossal syndrome, choreoathetosis, diplopia, incoordination, neuropathy. Infrequent: paralysis. Rare: myoclonus, nystagmus, torticollis, circumoral paresthesia, opisthotonos, reflexes increased, trismus. Respiratory System—Frequent: dyspnea Infrequent pneumonia, epistaxis. Rare: hemoptysis, laryngismus. Skin and Appendages—Infrequent: maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash. Special Senses— Frequent: fungal dermatitis. Infrequent: conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia. Rare: eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis. Urogenital System—Infrequent: impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention, metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria. Rare: gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage. Adverse Findings Observed in Trials of Intramuscular Ziprasidone In these studies, the most commonly observed adverse reactions associated with the use of intramuscular ziprasidone (≥5%) and observed at a rate on intramuscular ziprasidone (in the higher dose groups) at least twice that of the lowest intramuscular ziprasidone group were headache (13%), nausea (12%), and somnolence (20%). Adverse Events at an Incidence of ≥1% in Short-Term Fixed-Dose Intramuscular Trials The following list enumerates the treatment-emergent adverse events that occurred in ≥1% of patients during acute therapy with intramuscular ziprasidone: Body as a Whole— headache, injection site pain, asthenia, abdominal pain, flu syndrome, back pain. Cardiovascular—postural hypotension, hypertension, bradycardia, vasodilation. Digestive—nausea, rectal hemorrhage, diarrhea, vomiting, dyspepsia, anorexia, constipation, tooth disorder, dry mouth. Nervous—dizziness, anxiety, insomnia, somnolence, akathisia, agitation, extrapyramidal syndrome, hypertonia, cogwheel rigidity, paresthesia, personality disorder, psychosis, speech disorder. Respiratory—rhinitis. Skin and Appendages—furunculosis, sweating. Urogenital—dysmenorrhea, priapism. Other Events Observed During Post-marketing Use Adverse reaction reports not listed above that have been received since market introduction include rare occurrences of the following—Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors), (see WARNINGS); Digestive System Disorders: Swollen Tongue; Reproductive System and Breast Disorders: Galactorrhea, priapism; Nervous System Disorders: Facial Droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash; Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope. DRUG ABUSE AND DEPENDENCE Controlled Substance Class Ziprasidone is not a controlled substance. OVERDOSAGE In premarketing trials in over 5400 patients, accidental or intentional overdosage of oral ziprasidone was documented in 10 patients. All patients survived without sequelae. In the patient taking the largest confirmed amount (3240 mg), the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95). GZU00989E

Revised January 2011

PSYCHIATRIC TIMES www.psy c h i a t r i c t i m e s. c o m

Vote on Tutu Continued from page 16

elected secretary—also indicated that he felt the “debate was closed prematurely.” During our telephone interview, Dr Rogoff told me that the issue was put on the agenda for the “very end of the Assembly, which is an interesting phenomenon in and of itself. The Assembly at the Marriott in Washington, DC, ends at 11 am on Sunday, because they use it for something else.” Dr Rogoff said that in actuality only about 20 minutes was available for the presentation of the AP and subsequent discussion and that some 20 people had lined up at the microphones to speak. Certainly, many aspects of this controversy deserve thorough exploration. I did what I could within a limited word count to present the key concerns and responses, and I also provided some references in my article to place Archbishop Emeritus Tutu’s comments in context. I am hopeful that the APA’s leadership and membership will continue the dialogue within the organization and through letters to the editor of Psychiatric Times. Arline Kaplan

Dr Rogoff Responds: I first want to make absolutely clear that I in no way intended to impugn Dr Hershfield’s running of the November APA Assembly Sunday meeting. Dr Hershfield did what he could to give the 25 of us who signed the AP a chance to present it. As I recall it, however, we did not agree that a half hour would be sufficient; rather, when Dr Hershfield told me that given the full Assembly agenda a half hour was the most he could free up, I accepted and agreed to make the best possible use of the available time. During the event, the time was very inadequate. There were about 20 Assembly representatives lined up at the floor microphones to speak when discussion was terminated and a vote was called, but that was no fault of Dr Hershfield’s. Also, bearing in mind that I had a very clear bias toward adoption of the AP, from where I sat just below Dr Hershfield, the voice vote on the AP sounded very close to me. Had there been time, I, as well as others, would certainly have called for a standing vote. Only a few minutes were left after the question was

MAY 2011

LETTERS TO THE EDITOR called—not enough time to mount and carry out a standing vote. This was very frustrating to the AP’s supporters and to all those left stranded at the mikes, but it was within parliamentary rules, as Dr Hershfield states—and again, no fault of his. Dr Hershfield notes that I took 12 minutes to speak in favor of the paper. I took 12 minutes to merely present it. Most of the people present had no idea of Mr Tutu’s nefarious activities for the 25 years since his admirable work in South Africa. This information had to be presented or the AP would have made no sense. Moreover, background material— including numerous quotations from Mr Tutu’s speeches—also had to be presented because it could not be included in the format of an AP. The implication that my speaking in favor of the AP was partially or mostly responsible for others not having the chance to speak is simply not so. Without the full presentation of the facts, there would have been little to speak about. Two things made me tell Arline Kaplan that the episode at the Assembly was “interesting”: 1. The AP was given to the staff for printing with the names of all of the 25 signers. However, the AP that was actually distributed to the Assembly did not include any of those names—many of whom are quite influential. APs always include the names of the authors. 2. Dr Carol Bernstein, around whose choice of Desmond Tutu the whole matter swirled, was present for most of the Assembly meeting but absent for this presentation and discussion. I later saw her in a conference room just after the close of the meeting, so she was still present in the building. It seems to me and to my fellow cosigners of the AP and of the ad that later appeared in the February issue of Psychiatric Times that when the APA spends $39,000 out of the Annual Meeting Budget on an honorarium for a Convocation Speaker—that is what Desmond Tutu will be paid—funded at least in part by members’ dues (which account for approximately a third of the entire APA annual budget), that the person who chose that speaker would make it a priority to be present and to explain and defend that choice at this forum. This is particularly important when the invited speaker is a serious problem for a number of those members. Jerome Rogoff, MD ❒

Book Review Recovery From Disability: Manual of Psychiatric Rehabilitation by Robert Paul Liberman, MD; Washington, DC: American Psychiatric Publishing, 2008 624 pages • $65 (paperback)

Reviewed by Michael Alan Schwartz, MD Caring for patients with persisting and disabling mental illnesses now means keeping Robert Liberman’s Recovery From Disability close at hand—the guidebook that you have been waiting for has arrived! Your copy may get dog-eared; it will undoubtedly also be used by your patients, your colleagues, your team, and others—but it’s a sturdy volume and well worth its cost. Robert Paul Liberman, MD, is a founder of modern psychiatric rehabilitation; a masterful teacher; and, with his colleagues, a hands-on, paradigm-developing researcher. During a 40-year career, he has conceived many of the terms, concepts, and empirically validated tools and treatments used in present-day psychiatric rehabilitation—eg, social skills training, social learning therapy, and behavioral family management. Recovery From Disability brings all of this and decades of experience together in a remarkably useful compendium. Neither a conventional textbook nor a volume meant to gather dust in one’s library, the book is a user-friendly handbook for active practice. As the author himself clarifies, it is a guidebook for “those working in mental health centers, clinics and hospitals, day treatment centers, psychosocial clubhouses, community support and self-help programs, and even private offices.” Recovery From Disability is organized into 10 sections, beginning with the principles and prac-

tices of psychiatric rehabilitation as “the Road to Recovery,” and going on to illness management, functional assessment, social skills training, family involvement, vocational rehabilitation, methods and modalities of service delivery, and special services for special populations. I especially welcomed Dr Liberman’s straightforward language, his emphasis on empirical validation, and his focus on recovery from mental disorders as a practical and attainable goal. Highlights include an emphasis on empirically validated treatments and constructs; useful illustrations and diagrams; clear descriptions of all terms (remarkably helpful and even necessary in a rapidly changing field replete with agencies, transdisciplinary approaches, and no shortage of bureaucratese); and generous end-ofchapter tables of “key points.” Dr Liberman’s skill as a master educator is clear throughout the book. What I might wish for in his next edition is an additional chapter on engaging the patient who is unmotivated and unaware. Liberman’s book focuses on collaboration, but how do we collaborate in these circumstances? Given Dr Liberman’s remarkable productivity and his amazing capacity to keep his finger on the pulse of the field, I expect to find practical guidance in such circumstances in the next edition of Recovery From Disability. Currently at Austin State Hospital in Texas, Dr Schwartz was professor of psychiatry at St Vincent’s Hospital and Medical Center, New York, and at Case Western Reserve University, Cleveland. In 1998, he received the Swiss Dr Margrit Égnér Prize, and in 2000, he was named an Exemplary Psychiatrist by the National Alliance on Mental Illness. He is cofounding editor of Philosophy, Ethics, and Humanities in Medicine; founding president of the Association for the Advancement of Philosophy and Psychiatry; and, since its inception, associate editor of Philosophy, Psychiatry, Psychology. ❒

Removable Daytrana controls ADHD symptoms… ®

You control the duration of effect.

AM APPLY PATCH*

PM REMOVE PATCH*

*The maximum wear time for Daytrana is 9 hours. Efficacy observed at two hours after application. The effects from the patch continue for up to three hours after removal.1

Daytrana is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children (ages 6-12) and adolescents (ages 13-17). The efficacy of Daytrana was established in controlled clinic studies: two 7-week trials in children and one 7-week trial in adolescents. Daytrana is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social). Important Safety Information WARNING: DRUG DEPENDENCE Daytrana should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. Contraindications: The Daytrana patch should not be used by patients who have an allergy to methylphenidate or other patch components; marked anxiety, tension, and agitation; glaucoma; motor tics or with a diagnosis or a family history of Tourette’s syndrome; seizures; are being treated (or within 14 days after treatment) with monoamine oxidase inhibitors (MAOIs). Serious Cardiovascular Effects: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. A careful patient history, including family history, and physical exam should be performed to assess the presence of cardiac disease. Stimulant products generally should not be used in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems. Patients who develop symptoms (i.e., exertional chest pain, unexplained syncope) suggestive of cardiac disease while using or wearing the Daytrana patch should be promptly evaluated. Use with caution in patients whose underlying medical condition might be affected by increases in blood pressure or heart rate. Use cautiously with pressor agents. Hematologic monitoring is advised during prolonged treatment. Psychiatric and Long-Term Suppression of Growth: Use with caution in patients with a history of psychosis, EEG abnormalities, bipolar disorder, and depression. New psychosis, mania, aggression, visual disturbances, and growth suppression have been associated with the use of stimulants. Growth should be monitored in children during treatment with stimulants, and patients who are not growing (gaining height or weight) as expected may need to have their treatment interrupted. Contact Sensitization: Use of the Daytrana patch may lead to contact sensitization. Erythema has been commonly reported and is not by itself an indication of sensitization. If contact sensitization is suspected (erythema with edema, papules and/or vesicles spread beyond the patch site and/or lack of improvement within 48 hours), treatment should be discontinued. Patients should avoid applying external heat to the Daytrana patch; application of heat can increase the extent and rate of absorption. Most Common Adverse Events: The most common adverse reactions associated with the Daytrana patch (at least 5% and twice the rate of placebo-treated patients) in clinical trials were: children – decreased appetite, insomnia, nausea, vomiting, decreased weight, tics, affect lability, and anorexia; adolescents – decreased appetite, nausea, insomnia, decreased weight, dizziness, abdominal pain, and anorexia. In addition, the majority of subjects in these studies had minimal to definite skin erythema at the patch application site. Leaving the patch on for longer than the recommended 9 hours has resulted in an increased incidence of adverse events.

Reference: 1. Daytrana package insert. Miami, FL: Noven Pharmaceuticals Inc; 11/2010.

Please read Brief Summary of Full Prescribing Information on adjacent page.

www.Daytrana.com

PSYCHIATRIC TIMES www.psy c h i a t r i c t i m e s. c o m

TREATMENT RESISTANCE

MAY 2011

Understanding the Psychodynamics of Nonadherence by CĂŠsar A. Alfonso, MD onadherence to treatment by patients represents one of the most prevalent and important

challenges to the practice of psychiatry. Despite treatment advances and efforts to elucidate the determinants of noncompliance to medical care, nonadherence remains ubiquitous in

DAYTRANA - methylphenidate patch Noven Therapeutics, LLC Brief Summary. Consult Package Insert for complete Prescribing Information. WARNING: DRUG DEPENDENCE Daytrana should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. INDICATIONS AND USAGE Daytrana (methylphenidate transdermal system) is indicated for the treatment of Attention DeďŹ cit Hyperactivity Disorder (ADHD). The efďŹ cacy of Daytrana in patients diagnosed with ADHD was established in two 7-week controlled clinical trials in children (ages 6-12) and one 7-week, controlled clinical trial in adolescents (ages 13-17). CONTRAINDICATIONS Hypersensitivity to Methylphenidate - Daytrana is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product (polyester/ethylene vinyl acetate laminate ďŹ lm backing, acrylic adhesive, silicone adhesive, and ďŹ&#x201A;uoropolymer-coated polyester). Agitation - Daytrana is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. Glaucoma - Daytrana is contraindicated in patients with glaucoma. Tics - Daytrana is contraindicated in patients with motor tics or with a family history or diagnosis of Touretteâ&#x20AC;&#x2122;s syndrome [see Adverse Reactions (6.1)]. Monoamine Oxidase Inhibitors - Daytrana is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result). WARNINGS and PRECAUTIONS Serious Cardiovascular Events Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Adults: Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. Hypertension and Other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia [see Adverse Reactions (6.1)]. Assessing Cardiovascular Status in Patients Being Treated With Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if ďŹ ndings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. Psychiatric Adverse Events Pre-Existing Psychosis: Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Bipolar Illness: Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms: Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to none in placebo-treated patients. Aggression: Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. Seizures - There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. Long-Term Suppression of Growth - Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Visual Disturbance - DifďŹ culties with accommodation and blurring of vision have been reported with stimulant treatment. Contact Sensitization - In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with Daytrana using a 9-hour wear time, one subject (0.3%) was conďŹ rmed by patch testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at Daytrana application sites with concurrent urticarial lesions on the abdomen and legs resulting in treatment discontinuation. This subject was not transitioned to methylphenidate. Use of Daytrana may lead to contact sensitization. Daytrana should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of Daytrana and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not signiďŹ cantly improve within 48 hours or spreads beyond the patch site. ConďŹ rmation of a diagnosis of contact sensitization (allergic contact dermatitis) may require further diagnostic testing. Patients sensitized from use of Daytrana, as evidenced by development of an allergic contact dermatitis, may develop systemic sensitization or other systemic reactions if methylphenidatecontaining products are taken via other routes, e.g., orally. Manifestations of systemic sensitization may include a ďŹ&#x201A;are-up of previous dermatitis or of prior positive patch-test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting. No cases of systemic sensitization have been observed in clinical trials of Daytrana. Patients who develop contact sensitization to Daytrana and require oral treatment with methylphenidate should be initiated on oral medication under close medical supervision. It is possible that some patients sensitized to methylphenidate by exposure to Daytrana may not be able to take methylphenidate in any form. Patients Using External Heat - Patients should be advised to avoid exposing the Daytrana application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the patch. When heat is applied to Daytrana after patch application, both the rate and extent of absorption are signiďŹ cantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold. This increased absorption can be clinically signiďŹ cant and can result in overdose of methylphenidate [see Overdosage (10)]. Hematologic Monitoring - Periodic CBC, differential, and platelet counts are advised during prolonged therapy. ADVERSE REACTIONS Detailed information on serious and adverse reactions of particular importance is provided in the "OXED 7ARNING AND 7ARNINGS AND 0RECAUTIONS SECTIONS s $RUG DEPENDENCE ;SEE "OXED 7ARNING= s (YPERSENSITIVITY TO -ETHYLPHENIDATE ;SEE #ONTRAINDICATIONS = s -ARKED ANXIETY TENSION OR AGITATION ;SEE #ONTRAINDICATIONS = s 'LAUCOMA ;SEE #ONTRAINDICATIONS = s 4ICS OR A FAMILY HISTORY OF 4OURETTE S SYNDROME ;SEE #ONTRAINDICATIONS = s -ONOAMINE /XIDASE )NHIBITORS ;SEE #ONTRAINDICATIONS AND $RUG )NTERACTIONS = s 3ERIOUS #ARDIOVASCULAR %VENTS ;SEE 7ARNINGS AND 0RECAUTIONS = s )NCREASE IN "LOOD 0RESSURE ;SEE 7ARNINGS AND 0RECAUTIONS = s 0SYCHIATRIC !DVERSE %VENTS ;SEE 7ARNINGS AND 0RECAUTIONS = s 3EIZURES ;SEE 7ARNINGS AND 0RECAUTIONS = s ,ONG 4ERM 3UPPRESSION OF 'ROWTH ;SEE 7ARNINGS AND 0RECAUTIONS = s 6ISUAL $ISTURBANCE ;SEE 7ARNINGS AND 0RECAUTIONS = s #ONTACT 3ENSITIZATION ;SEE 7ARNINGS AND 0RECAUTIONS = s %XTERNAL (EAT ;SEE 7ARNINGS AND 0RECAUTIONS = s (EMATOLOGIC -ONITORing [see Warnings and Precautions (5.8)] The most commonly reported (frequency * 5% and twice the rate of placebo) adverse reactions in a controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. The most commonly reported (frequency * 5% and twice the rate of placebo) adverse reactions in a controlled trial in adolescents aged 13-17 were appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain and anorexia [see Adverse Reactions (6.1)]. The most common (* 2% of subjects) adverse reaction associated with discontinuations in double-blind clinical trials in children or adolescents was application site reactions15 [see Adverse Reactions (6.3)]. The overall Daytrana development program included exposure to Daytrana in a total of 2,152 participants in clinical trials, including 1,529 children aged 6-12, 223 adolescents aged 13-17, and 400 adults. The 1,752 child and adolescent subjects aged 6-17 years were evaluated in 10 controlled clinical studies, 7 open-label clinical studies, and 5 clinical pharmacology studies. In a combined studies pool of children using Daytrana with a wear time of 9 hours, 212 subjects were exposed for * 6 months and 115 were exposed for * 1 year; 85 adolescents have been exposed for * 6 months. Most patients studied were exposed to Daytrana patch sizes of 12.5 cm2, 18.75 cm2, 25 cm2 or 37.5 cm2, with a wear time of 9 hours. In the data presented below, the adverse reactions reported during exposure were obtained primarily by general inquiry at each visit, and were recorded by the clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without ďŹ rst grouping similar types of events into a smaller number of standardized event categories. Throughout this section adverse reactions reported are events that were considered to be reasonably associated with the use of Daytrana based on comprehensive assessment of the available adverse event

persons with chronic medical conditions (with average adherence rates of 43% to 78%) and in psychiatric cohorts (with average adherence rates of 50% to 62%).1-3 Researchers in cogni-

information. A causal association for Daytrana often cannot be reliably established in individual cases. Further, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reďŹ&#x201A;ect the rates observed in clinical practice. Clinical Trials Experience Adverse Reactions Associated With Discontinuation of Treatment In a 7-week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting, 7.1% (7/98) of patients treated with Daytrana discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The most commonly reported (* 1% and twice the rate of placebo) adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%), tics (1%), headache (1%), and irritability (1%). In a 7-week double-blind, parallel-group, placebo-controlled study in adolescents with ADHD conducted in the outpatient setting, 5.5% (8/145) of patients treated with Daytrana discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%) and decreased appetite/anorexia (1.4%). Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Trials Skin Irritation and Application Site Reactions: Daytrana is a dermal irritant. In addition to the most commonly reported adverse reactions preTable 2 - Number (%) of Subjects with Commonly Reported Adverse sented in Table 2, the majority of subjects in Reactions (* 1% in the Daytrana Group) in 7-Week Placebo-controlled those studies had minimal to deďŹ nite skin Studies in Either Children or Adolescents - Safety Population erythema at the patch application site. This erythema generally caused no or minimal Adolescents Children discomfort and did not usually interfere System Organ Class Placebo Daytrana Placebo Daytrana with therapy or result in discontinuation Preferred term N = 72 N = 145 N = 85 N = 98 from treatment. Erythema is not by itself Cardiac Disorders a manifestation of contact sensitization. However, contact sensitization should be 0 (0) 1 (0.7) 0 (0) 1 (1.0) Tachycardia suspected if erythema is accompanied by Gastrointestinal evidence of a more intense local reaction disorders (edema, papules, vesicles) that does Abdominal pain 0 (0) 7 (4.8) 5 (5.9) 7 (7.1) not signiďŹ cantly improve within 48 hours Nausea 2 (2.8) 14 (9.7) 2 (2.4) 12 (12.2) or spreads beyond the patch site [see 6OMITING 1 (1.4) 5 (3.4) 4 (4.7) 10 (10.2) Warnings and Precautions (5.6)]. Most Investigations Commonly Reported Adverse Reactions: Weight decreased 1 (1.4) 8 (5.5) 0 (0) 9 (9.2) Table 2 lists treatment-emergent adverse Metabolism and reactions reported in * 1% Daytranadisorders treated children or adolescents with ADHD nutrition Anorexia 1 (1.4) 7 (4.8) 1 (1.2) 5 (5.1) in two 7 week double-blind, parallel-group, Decreased appetite 1 (1.4) 37 (25.5) 4 (4.7) 25 (25.5) placebo-controlled studies conducted in Nervous system the outpatient setting. Overall, in these disorders studies, 75.5% of children and 78.6% Dizziness 1 (1.4) 8 (5.5) 1 (1.2) 0 (0) of adolescents experienced at least 1 Headache 9 (12.5) 18 (12.4) 10 (11.8) 15 (15.3) adverse event. Adverse Reactions With the Long-Term Use of Daytrana: In a long-term Psychiatric disorders Affect lability 6 (6.1)* 0 (0) 0 (0) 1 (1.4) open-label study of up to 12 months Insomnia 13 (13.3) 4 (4.7) 9 (6.2) 2 (2.8) duration in 326 children wearing Daytrana Irritability 7 (7.1) 4 (4.7) 16 (11) 5 (6.9) 9 hours daily, the most common (* 10%) Tic 7 (7.1) 0 (0) 0 (0) 0 (0) adverse reactions were decreased appetite, headache, and weight decreased. A * Six subjects had affect lability, all judged as mild and descibed as increased total of 30 subjects (9.2%) were withdrawn emotionally sensitive, emotionality, emotional instability, emotional lability, and from the study due to adverse events and intermittent emotional 22 additional subjects (6.7%) discontinued treatment as the result of an application site reaction. Other than application site reactions, affect lability (5 subjects, 1.5%) was the only additional adverse reaction leading to discontinuation reported with a frequency of greater than 1%. In a long-term open-label study of up to 6 months duration in 162 adolescents wearing Daytrana 9 hours daily, the most common (* 10%) adverse reactions were decreased appetite and headache. A total of 9 subjects (5.5%) were withdrawn from the study due to adverse events and 3 additional subjects (1.9%) discontinued treatment as the result of an application site reaction. Other adverse reactions leading to discontinuation that occurred with a frequency of greater than 1% included affect lability and irritability (2 subjects each, 1.2%). Postmarketing Experience In addition, the following adverse reactions have been identiďŹ ed during the post-approval use of Daytrana. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to Daytrana exposure. Cardiac Disorders: palpitation. Eye Disorders: visual disturbances, blurred vision, mydriasis, accommodation disorder. General Disorders and Administration Site Disorders: application site reactions such as bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, erythema, excoriation, exfoliation, ďŹ ssure, hyperpigmentation, hypopigmentation, induration, infection, inďŹ&#x201A;ammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth. Immune System Disorders: hypersensitivity reactions including generalized erythematous and urticarial rashes, allergic contact dermatitis, angioedema, and anaphylaxis. Investigations: blood pressure increased. Nervous System Disorders: convulsion, dyskinesia. Psychiatric Disorders: transient depressed mood, hallucination, nervousness. Skin and Subcutaneous Tissue Disorders: alopecia Adverse Reactions With Oral Methylphenidate Products Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. Other reactions include: Cardiac: angina, arrhythmia, pulse increased or decreased. Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological ďŹ ndings of necrotizing vasculitis, and thrombocytopenic purpura. Metabolism/Nutrition: anorexia, weight loss during prolonged therapy. Nervous System: drowsiness, rare reports of Touretteâ&#x20AC;&#x2122;s syndrome, toxic psychosis. 6ASCULAR blood pressure increased or decreased, cerebral arteritis and/or occlusion. Although a deďŹ nite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood/lymphatic: leukopenia and/or anemia. Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma. Psychiatric: transient depressed mood. Skin/Subcutaneous: scalp hair loss. Neuroleptic Malignant Syndrome: 6ERY RARE reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his ďŹ rst dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. DRUG INTERACTIONS MAO Inhibitors - Daytrana should not be used in patients being treated (currently or within the preceding two weeks) with monoamine oxidase inhibitors [see Contraindications (4.5)]. Vasopressor Agents - Because of a possible effect on blood pressure, Daytrana should be used cautiously with pressor agents. Hypotension Agents - Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors - Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and some tricyclic drugs (e.g., imipramine, clomipramine, desipramine) and selective serotonin reuptake inhibitors. Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C - Animal reproduction studies with transdermal methylphenidate have not been performed. In a study in which oral methylphenidate was given to pregnant rabbits during the period of organogenesis at doses up to 200 mg/kg/day no teratogenic effects were seen, although an increase in the incidence of a variation, dilation of the lateral ventricles, was seen at 200 mg/kg/day; this dose also produced maternal toxicity. A previously conducted study in rabbits showed teratogenic effects of methylphenidate at an oral dose of 200 mg/kg/day. In a study in which oral methylphenidate was given to pregnant rats during the period of organogenesis at doses up to 100 mg/kg/day, no teratogenic effects were seen although a slight delay in fetal skeletal ossiďŹ cation was seen at doses of 60 mg/kg/day and above; these doses caused some maternal toxicity. In a study in which oral methylphenidate was given to rats throughout pregnancy and lactation at doses up to 60 mg/kg/day, offspring weights and survival were decreased at 40 mg/kg/day and above; these doses caused some maternal toxicity. Adequate and well-controlled studies in pregnant women have not been conducted. Daytrana should be used during pregnancy only if the potential beneďŹ t justiďŹ es the potential risk to the fetus. Labor and Delivery - The effect of Daytrana on labor and delivery in humans is unknown. Nursing Mothers - It is not known whether methylphenidate is excreted in human milk. Daytrana should be administered to a nursing woman only if the potential beneďŹ t justiďŹ es the potential risk to the child. Pediatric Use - Daytrana should not be used in children under six years of age, since safety and efďŹ cacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established. Studies with transdermal methylphenidate have not been performed in juvenile animals. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day or greater, and a deďŹ cit in the acquisition of a speciďŹ c learning task was seen in females exposed to the highest dose. The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day. The clinical signiďŹ cance of the long-term behavioral effects observed in rats is unknown. Geriatric Use: Daytrana has not been studied in patients greater than 65 years of age. DRUG ABUSE AND DEPENDENCE Controlled Substance - Daytrana is classiďŹ ed as a Schedule II controlled substance by federal regulation. Abuse - See warning containing drug abuse information [see Boxed Warning]. Dependence - See warning containing drug dependence information [see Boxed Warning]. Manufactured for: Noven Therapeutics, LLC, Miami, FL 33186 By: Noven Pharmaceuticals, Inc., Miami, FL 33186. For more information call 1-877-567-7857 or visit WWW.DAYTRANA.COM. Dot Matrixâ&#x201E;˘ is a trademark of Noven Pharmaceuticals, Inc. DaytranaÂŽ is a registered trademark of Noven Therapeutics, LLC. ÂŠ 2009, 2010 Noven Pharmaceuticals, Inc. This product is covered by US patents including for use with 6,905,016. Last ModiďŹ ed: 11/2010 102086-12 Revised: 11/2010 Noven Therapeutics, LLC DAY-2011-A 03/11

tive-behavioral therapy, psychoeducation, and motivational interviewing have made significant contributions to understanding nonadherence and tailoring interventions to improve treatment adherence.4 A psychodynamic theoretical framework is another approach to understanding and improving adherence. Psychodynamic theory is a framework that could be helpful in clarifying our understanding of nonadherence. In particular, looking at the contributions of attachment theory and research has allowed us to deepen our understanding of nonadherence.5 Strengthening the therapeutic alliance and fostering collaborative physician-patient relationships may result in improved adherence.

Psychological and psychodynamic antecedents of nonadherence Cohen and colleagues6 have written extensively on the connection between early childhood trauma and nonadherence or resistance to care in adult patients with posttraumatic stress disorder and comorbid depression. They postulated that traumatized patientsâ&#x20AC;&#x2122; sense of a foreshortened future may be related to failure to engage in or accept medical treatment, which suggests that early childhood trauma is a psychological risk factor for adult nonadherence. Psychodynamic determinants and adaptive (and maladaptive) defenses related to nonadherence in psychiatric patients include5,7-9: â&#x20AC;˘ Limited understanding of the illness â&#x20AC;˘ Denial, rationalization, and isolation of affect â&#x20AC;˘ Feeling coerced, disrespected, or infantilized by the physician â&#x20AC;˘ Feeling deceived or manipulated â&#x20AC;˘ Sensing that the psychiatrist is tentative or ambivalent when presenting the information As prescribers, our failure of empathy often stems from an unconscious need to feel separate from our patientsâ&#x20AC;&#x201D;to defend ourselves against overwhelming distress and maintain a safe space and emotional distanceâ&#x20AC;&#x201D; consequently, abstinence and neutrality are overemphasized.10 A collaborative stance promotes adherence, while paternalistic or categorical medication advice could be perceived as coercive and could result in partial or nonadherence.

MAY 2011

Attachment theory and nonadherence A recent focus on the interface between attachment theory and psychoanalytical theory has deepened our understanding of the psychodynamics of nonadherence. Attachment theory is based on the premise that early life experiences with caregivers are internalized and determine how individuals relate to others in adulthood. Attachment concepts were originally conceived to understand the evolutionary, adaptive, and biological aspects of parent-infant care giving. Most recently, clinical research has validated the usefulness of attachment concepts in understanding nonadherence.11-13 The disruption in attachment bonds by separation, rejection, loss, inconsistent attunement, or fear can lead to problematic behavior during childhood and possibly across the life span. Research has demonstrated that the caregiver’s sensitivity to the infant’s needs (availability and responsiveness) is essential to ensure secure attachments and lead to an empirically based classification of motherinfant dyads. Ainsworth and colleagues14 observed in their laboratories infants’ reactions to separation from the mother, exposure to a stranger, and reunion with the mother. They initially described 3 types of attachment interactions: secure, avoidant, and ambivalent. Secure infants are consoled by reunion and reconnection with the mother; infants with avoidant attachment are indifferent and avoid the mother when reunited; and infants with ambivalent attachment, although preoccupied with the mother’s whereabouts during separation, are inconsolable during reunion. Secure infants have sensitive and attuned parents; avoidant infants have parents who are emotionally constricted and uncomfortable with physical contact; and ambivalent infants have parents who oscillate in their stance from available and responsive to insensitive and rageful.14 Wallin15 reports that a level of consistency was found between behavior observed in infancy and attachment styles in adulthood in up to 75% of subjects studied longitudinally. More important, research has demonstrated that many adults with histories that would predict insecure attachment behaviors have reparative experiences later in life with significant others that allow for “earned secure” attachments. Sensitivity, availability, and responsiveness are at the core of all psychotherapeutic interventions and enduring life-enhancing

TREATMENT RESISTANCE relationships.5,15,16 Ciechanowski and colleagues11-13 examined correlations between attachment styles and treatment adherence and hypothesized that certain adult attachment styles correlate with treatment adherence in the medically ill. They studied cohorts of diabetic patients in primary care clinic settings, a high-risk population because nonadherence to treatment among diabetic patients is associated with significant morbidity and mortality. The initial hypothesis was that only those with secure attachments would be treatment-adherent. However, the findings were surprising and indicate

caregiving parents, while adults with dismissing attachment had avoidant parents who were consistently emotionally unresponsive. Adults with secure attachment are comfortable depending on others and are readily comforted by them. Adults with dismissing style become compulsively self-reliant, describe themselves as independent and self-sufficient, and are uncomfortable being close to or trusting of others. Dismissing patients, while initially unable to remember, describe, emote, or reconstruct experiences, can be gradually exposed to these processes by a psychodynamically informed therapist.

What is already known about the psychodynamics of nonadherence? Classical psychoanalytic theory, with emphasis on concepts of resistance, transference, and countertransference, has shed some light and guided clinicians who work with patients who are nonadherent. Some helpful psychodynamic concepts include clinicians’ failure of empathy that stems from an unconscious need to feel separate from our patients’ distress, and their use of defenses of denial, rationalization, and isolation of affect.

What new information does this article add? In this article, emphasis shifts to understanding nonadherence using the paradigm of attachment theory.

What are the implications for psychiatric practice? Identifying adults with dismissing attachment style can be predictive of nonadherence to care. Dismissing individuals are compulsively self-reliant and tend to idealize or devalue with facility, but they can be easily engaged in psychotherapy and are open to the possibility of “earned attachment” through collaborative, nonconfrontational psychotherapeutic interventions.

that 1 attachment style correlates with nonadherence, 1 correlates with adherence, and 2 are not significant. They found that persons with dismissing attachment style had significantly worse glucose control than those with secure, preoccupied, or fearful attachment styles. Dismissing individuals, such as infants who do not protest when separated from parents and who are indifferent to their return and are inhibited at play, as adults become compulsively self-reliant and are uncomfortable being close to or trusting of others. Narratives of dismissing individuals are characterized by a very brief discourse, gross generalizations, a paucity of examples, unsupported claims (even active contradictions), and an insistence on absence of childhood memories. They idealize or devalue one or both parents but are usually unable to substantiate their claims. Adults with secure attachment experienced consistently responsive

Therapeutic implications Awareness of dismissing attachment behaviors in our nonadherent patients can help us reframe our psychotherapeutic work. Wallin15 describes the process of therapeutic interventions with dismissing individuals as “moving from isolation to intimacy.” In the early stages of treatment, he encourages a keen awareness of subtle affective cues and nonverbal communication, and judicious sharing of countertransference, to help patients be comfortable in letting others in and in being treatment collaborators. The dynamics of power struggles and control need to be clearly understood by the therapist, and a warm, collaborative, and cooperative stance is preferred to an authoritarian and detached attitude. Attachment theory and research provides a useful framework for understanding the impact of parent-infant caregiving on development and subsequent adult patterns of relationships. Psychotherapy interventions based on attachment theory

PSYCHIATRIC TIMES

w w w. psychi atr i cti mes. com

for parents with insecure caregiving styles can promote parental sensitivity and secure attachment organization. Similarly, psychotherapy interventions informed by the contributions of attachment theory could help adults with dismissing attachment behaviors who are nonadherent to treatment by stressing the importance of collaborative relationships, relinquishing excessive self-reliance and control, and promoting trust. Dr Alfonso is president (2010-2012) of the American Academy of Psychoanalysis and Dynamic Psychiatry (AAPDP). The AAPDP’s 55th Annual Meeting will take place May 1214, 2011, in Honolulu. The meeting’s theme is “Psychodynamic Approaches to Treatment Resistance and Therapeutic Obstacles.” Dr Alfonso reports that he has no conflicts of interest concerning the subject matter of this article. References 1. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497. 2. Lacro JP, Dunn LB, Dolder CR, et al. Prevalence and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry. 2002;63:892909. 3. Jónsdóttir H, Opjordsmoen S, Birkenaes AB, et al. Medication adherence in outpatients with severe mental disorders: relation between self-reports and serum level. J Clin Psychopharmacol. 2010;30:169175. 4. Julius RJ, Novitsky MA Jr, Dubin WR. Medication adherence: a review of the literature and implications for clinical practice. J Psychiatr Pract. 2009; 15:34-44. 5. Alfonso CA. Dynamic psychopharmacology and treatment adherence. J Am Acad Psychoanal Dyn Psychiatry. 2009;37:269-285. 6. Cohen MA, Alfonso CA, Hoffman RG, et al. The impact of PTSD on treatment adherence in persons with HIV infection. Gen Hosp Psychiatry. 2001;23: 294-296. 7. Mintz D. Psychodynamic psychopharmacology: addressing the underlying causes of treatment resistance. Psychiatric Times. 2009. http://www. psychiatrictimes.com/display/article/10168/ 1430600. Accessed April 4, 2011. 8. Gabbard GO. Psychodynamic Psychiatry in Clinical Practice. 3rd ed. Washington, DC: American Psychiatric Press, Inc; 2000. 9. Gutheil TG. The psychology of psychopharmacology. Bull Menninger Clin. 1982;46:321-330. 10. Perry SW. Undermedication for pain on a burn unit. Gen Hosp Psychiatry. 1984;6:308-316. 11. Ciechanowski PS, Katon WJ, Russo JE, Walker EA. The patient-provider relationship: attachment theory and adherence to treatment in diabetes. Am J Psychiatry. 2001;158:29-35. 12. Ciechanowski P, Russo J, Katon W, et al. Influence of patient attachment style on self-care and outcomes in diabetes. Psychosom Med. 2004;66:720728. 13. Ciechanowski P, Russo J, Katon W, et al. Where is the patient? The association of psychosocial factors and missed primary care appointments in patients with diabetes. Gen Hosp Psychiatry. 2006;28:9-17. 14. Ainsworth MDS, Blehar MC, Waters E, Wall S. Patterns of Attachment: A Psychological Study of the Strange Situation. Hillsdale, NJ: Erlbaum; 1978. 15. Wallin DJ. Attachment in Psychotherapy. New York: Guilford Press; 2007. 16. Ricart F, Cohen MA, Alfonso CA, et al. Understanding the psychodynamics of non-adherence to medical treatment in persons with HIV infection. Gen Hosp Psychiatry. 2002;24:176-180. ❒

PSYCHIATRIC TIMES www.psy c h i a t r i c t i m e s. c o m

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CLINICAL

A Literature Review of Videophone Use in Mental Health A Tool That Can Enhance Patient Convenience, Safety, and Satisfaction by J. Edwin Nieves, MD, Gregory Briscoe, MD, Lucinda Edwards, MLS, and Aidith Flores-Carrera, DO

he delivery of mental health care via electronic devices— also called telemental health—

has gradually become an established alternative to improve access to mental health services. Telemental health services routinely include psychotherapy, psychological testing, medication management, and forensic evaluations. Most of these services

are provided through videoconferencing using a “hub and spoke” model. In this model, the care provider, or consultant, is at the medical center (or “hub”) while the patient is at a distant location, usually a satellite clinic (or tip of the “spoke”).

This model of care has effectively brought care closer to patients, but it still requires that patients travel to the “spoke” tip location, which may not be practical for those with chronic mental or physical illness. Videoconferencing equipment tends to be

Studies on the use of videophones for mental health service

Table

Study

Number of participants

Discipline

Application

Clinical

Technical difficulties

Nieves1

24 patients

Mental health

Adjunct case management services

Supplement case management home visits with nonemergency access to team psychiatrist as adjuvant to face-to-face visits

Picture freezing up with movements

Yes

Oliver2

2 patientcaregiver dyads

Mental health, hospice

Provide education, support to in-home hospice caregivers

Administer anxiety and quality-oflife rating scales to in-home caregivers, assess feasibility and satisfaction with in-home caregiving

None noted

Yes, anxiety and quality-of-life scales were completed; caregivers were satisfied with use of videophones

Oliver3

2 patients

Hospice

Psychoeducation

Compare psychoeducational interventions via videophone with face-to-face

None listed

Yes

Passik4

8 patients

Mental health, hospice

Deliver dignity psychotherapy to terminally ill patients at home

None listed

Yes

Cluver5

10 patients

Mental health

Compare face-to-face cognitive-behavioral therapy with remote therapy via low-bandwidth equipment

Deliver cognitive-behavioral therapy

None listed, 1 patient concerned about confidentiality

Patients satisfied with both face-to-face and videophones

WittenbergLyles6

12 patients

Hospice

Interdisciplinary team participation

Allow caregivers to participate in care coordination and medication/ pain management

None listed

Yes

Rivera7

61 patientcaregiver dyads

Spinal cord injury, mental health

Pressure ulcer in spinal cord injury patients; depression prevention in caregivers

Support caregivers of spinal cord injury patients in distant areas

Power fluctuations may have damaged some of the units

Yes

May8

22 patients

Primary care, mental health

Primary care–mental health consultation

Allow primary care physicians to obtain diagnosis and management advice on depressed or anxious patients

“Frame tension” (freeze frame) with movement

Yes, comments on patient relationship

Nieves9

24 patients

Mental health, pharmacy

Access to clinical pharmacist

Refill authorization, formulary, and other access to team pharmacist

“Frame tension” (freeze frame) with movement

Yes

Menon10

24 patients

Geriatric mental health

Compare diagnostic reliability using Geriatric Depression Scale and Hamilton Depression Rating Scale

Demonstrates comparable reliability between Geriatric Depression Scale and Hamilton Depression Rating Scale scores, face-to-face and via videophone

Movement artifact

3 patients not satisfied; preferred face-to-face

Jacobsen11

32 patients

Psychology

Compare neuropsychometric testing administered via videophones

Administer neuropsychometric testing to patients remotely to determine services required

None listed

No preference; 1 patient described experience as “impersonal”

Hensel12

10 pairs of nursing home patients and family members

Geriatric mental health

Use videophones to provide image contact between nursing home residents and families

Provide increased “social presence” and enhanced affective communication

None listed

Yes

Satisfaction

bulky (about the size of a living room television set) and requires dedicated space and information technology support staff. Both may limit technical deployment. Telemental health alternatives with video capability that make the patient’s home the point of service are scarce. Videophones are a reasonable alternative that bring access to care directly into the patient’s home, provided the patient has a telephone line and a power source. Although limited by image size (6 to 8 inches wide) and bandwidth (25 to 50 kHz), videophones are easy to use and are readily accepted by patients and staff.1 While these limitations may restrict videophones as first-line telemental health delivery devices, videophones could serve as an adjunctive means to mental health services for special populations, such as the severely mentally ill or those living in rural areas. We set out to systematically review the medical literature to determine the usefulness of this simple telemental health alternative tool. We conducted a comprehensive search in electronic bibliographical databases using PubMed citations

What is already known about videophone use in mental health? Videophones are a telehealth alternative that can provide adjunct health care services right in the patient’s home. They are easy to use and are accepted by staff, patients, and caregivers.

What new information does this article add? The article provides insight into how videophones can provide preventive, supportive, and other services to special populations (eg, the terminally ill, highly rural patients) that otherwise would not be able to receive these services face-toface.

What are the implications for psychiatric practice? Videophones can assist clinicians in providing “patient-centric” care by bringing a wide array of hospitalbased services into the patient’s home. While the popularity of cellular telephones may be a barrier to the deployment of “first-generation” videophones, the newer-generation videophones promise to make the patient, wherever he or she may be, truly the center of care.

PSYCHIATRIC TIMES

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from 1960 to July 2010, Cumulative Index to Nursing and Allied Health Literature citations from 1981 to July 2010, and PsycINFO. The following keywords were used: videophones, videophony, video-phone, videotelephone, telephone, and telephony. The search was further refined with such terms as mental health, mental health services, psychotherapy, telepsychiatry, and psychology. The total results from all databases were 39 citations.

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We included only those studies that described the use of videophones for mental health services, such as mental health disease prevention, psychotherapy, and testing. Twelve studies fulfilled these criteria and are included in the Table.

Palliative care The 12 studies included a total of 97 patients. Of the 12 studies, 5 (41.7%) were applications of a videophone in

palliative care with up to 34 patients (35%).2-5 One study described 2 case reports of terminally ill patients where a videophone was used to provide each patient and his or her caregiver access to a hospital-based hospice care staff.2 The goal was to decrease caregiver anxiety and maintain both the patient’s and caregiver’s quality of life while assessing the use(Please see Videophone Use, page 26)

AVOID MEDICATION ERRORS Medication errors involving LAMICTAL have occurred. To reduce the potential for medication errors, please write and say “LAMICTAL” clearly. LAMICTAL® (lamotrigine) Chewable Dispersible Tablets

2 mg

5 mg

25 mg

LAMICTAL® (lamotrigine) Tablets

25 mg

100 mg

150 mg

200 mg

berry-flavored chewable dispersible tablets

scored tablets

LAMICTAL® XR™ (lamotrigine) Extended-Release Tablets

LAMICTAL® ODT™ (lamotrigine) Orally Disintegrating Tablets

25 mg

50 mg

100 mg

200 mg

once-daily round tablets with white center

25 mg

50 mg

100 mg

200 mg

cherry-flavored disintegrating tablets

• The name LAMICTAL or lamotrigine can be confused with the names of other commonly used medications including Lamisil,* lamivudine, Ludiomil,* labetalol, and Lomotil* – Patients who do not receive LAMICTAL would be inadequately treated and could experience serious consequences – Conversely, patients erroneously receiving LAMICTAL, especially high initial doses, would be unnecessarily subjected to a risk of serious side effects • Medication errors may also occur between formulations of LAMICTAL – Patients who do not receive the appropriate formulation of LAMICTAL may receive the incorrect dose or incorrect timing of dose and could experience inadequate treatment or side effects that, in some instances, may lead to potentially serious consequences – In some cases, these potential medication errors could result in a patient receiving a sub-therapeutic dose (ie, half the dose) or an excessive dose (ie, double the dose) of lamotrigine • To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are receiving LAMICTAL, as well as the correct formulation of LAMICTAL, each time they fill their prescription If you become aware of an adverse event or prescription dispensing error involving these products, please contact GlaxoSmithKline at 1-800-334-4153; the USP Medication Errors Reporting Program at 1-800-233-7767 (for medication errors only); or the MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, by the Internet at www.fda.gov/medwatch, or by mail at MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787.

* Lamisil (terbinafine HCI tablets) and Ludiomil (maprotiline HCI) are registered trademarks of Novartis Pharmaceuticals Corporation. Lomotil (diphenoxylate HCI, atropine sulfate) is a registered trademark of G.D. Searle LLC.

Please see Brief Summary, including Boxed Warning, for LAMICTAL XR and Brief Summary, including Boxed Warning, for LAMICTAL Tablets, LAMICTAL Chewable Dispersible Tablets, and LAMICTAL ODT Orally Disintegrating Tablets on adjacent pages.

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Videophone Use Continued from page 25

fulness of the technology. The patients lived in a remote rural location that would have made access to hospice care staff difficult. In both cases, the videophone was readily accepted and no technical problems were described. Anxiety levels measured by the S-Anxiety Inventory (a self-report instrument) remained low and quality of life was not diminished

CLINICAL secondary to technical issues related to the videophone. In another study, Oliver and Demiris3 compared how useful videophones were in delivering psychoeducational material with face-toface sessions. One caregiver-patient dyad received the educational material face-to-face, the other received it via videophone. Both were equally satisfied. Curiously, the investigators noticed an increase in the number of

verbal interactions between hospice staff and caregivers in the dyad when a videophone was used. Furthermore, the caregiver who used a videophone noted increased satisfaction because of not having to worry about leaving her business to meet face-to-face. In another study, by Passik and associates,4 dignity psychotherapy was delivered via videophone to 8 terminally ill patients in an effort to prevent depression. These patients lived in a

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rural area far from the local medical center.4 Although there were some minor technical problems with the videophone, patients’mood remained stable (measured by Zung scale) throughout the sessions for an average of 31 days. The patients showed an overall preference for using the videophone compared with face-toface sessions because of the ability to participate from their own homes. Cluver and colleagues5 compared

LAMICTAL® XR™ (lamotrigine) Extended-Release Tablets BRIEF SUMMARY of adult patients who received the immediate-release formulation of LAMICTAL in The following is a brief summary only; see full prescribing information for complete premarketing clinical trials of epilepsy. In worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to product information. permit a precise estimate of the rate. WARNING: SERIOUS SKIN RASHES Among the rashes leading to hospitalization were Stevens-Johnson syndrome, LAMICTAL ® XR™ can cause serious rashes requiring toxic epidermal necrolysis, angioedema, and a rash associated with a variable hospitalization and discontinuation of treatment. The incidence number the following systemic manifestations: fever, lymphadenopathy, facial of these rashes, which have included Stevens-Johnson syndrome, is swelling,ofand hematologic and hepatologic abnormalities. approximately 0.8% (8 per 1,000) in pediatric patients (2 to 16 years There is evidence that the inclusion of valproate in a multidrug regimen of age) receiving the immediate-release formulation of LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on increases the risk of serious, potentially life-threatening rash in adults. Specifically, adjunctive therapy for epilepsy. In a prospectively followed cohort of of 584 patients administered the immediate-release formulation of LAMICTAL 1,983 pediatric patients (2 to 16 years of age) with epilepsy taking the with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association adjunctive immediate-release formulation of LAMICTAL, there was 1 rash- with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers related death. LAMICTAL XR is not approved for patients under the age administered the immediate-release formulation of LAMICTAL in the absence of of 13 years. In worldwide postmarketing experience, rare cases of toxic valproate were hospitalized. Patients With History of Allergy or Rash to Other Antiepileptic Drugs (AEDs): epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of LAMICTAL is exceeded and in patients with a estimate of the rate. The risk of serious rash caused by treatment with LAMICTAL XR is history of allergy or rash to other AEDs. not expected to differ from that with the immediate-release formulation of LAMICTAL. However, the relatively limited treatment experience with 5.2 Hypersensitivity Reactions: Hypersensitivity reactions, some fatal or life LAMICTAL XR makes it difficult to characterize the frequency and risk of threatening, have also occurred. Some of these reactions have included clinical serious rashes caused by treatment with LAMICTAL XR. features of multiorgan failure/dysfunction, including hepatic abnormalities and Other than age, there are as yet no factors identified that are known to evidence of disseminated intravascular coagulation. It is important to note that early predict the risk of occurrence or the severity of rash caused by LAMICTAL XR. manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present There are suggestions, yet to be proven, that the risk of rash may also be even though a rash is not evident. If such signs or symptoms are present, the increased by (1) coadministration of LAMICTAL XR with valproate (includes patient should be evaluated immediately. LAMICTAL XR should be discontinued if valproic acid and divalproex sodium), (2) exceeding the recommended an alternative etiology for the signs or symptoms cannot be established. initial dose of LAMICTAL XR, or (3) exceeding the recommended dose escalation for LAMICTAL XR. However, cases have occurred in the absence Prior to initiation of treatment with LAMICTAL XR, the patient should be of these factors. instructed that a rash or other signs or symptoms of hypersensitivity (e.g., Nearly all cases of life-threatening rashes caused by the immediate- fever, lymphadenopathy) may herald a serious medical event and that the release formulation of LAMICTAL have occurred within 2 to 8 weeks of patient should report any such occurrence to a physician immediately. treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied 5.3 Acute Multiorgan Failure: Multiorgan failure, which in some cases has upon as means to predict the potential risk heralded by the first appearance been fatal or irreversible, has been observed in patients receiving the immediateof a rash. release formulation of LAMICTAL. Fatalities associated with multiorgan failure and Although benign rashes are also caused by LAMICTAL XR, it is not possible to predict reliably which rashes will prove to be serious or life various degrees of hepatic failure have been reported in 2 of 3,796 adult patients threatening. Accordingly, LAMICTAL XR should ordinarily be discontinued and 4 of 2,435 pediatric patients who received the immediate-release formulation at the first sign of rash, unless the rash is clearly not drug related. of LAMICTAL in epilepsy clinical trials. Rare fatalities from multiorgan failure have Discontinuation of treatment may not prevent a rash from becoming life been reported in compassionate plea and postmarketing use. The majority of these threatening or permanently disabling or disfiguring [see Warnings and deaths occurred in association with other serious medical events, including status epilepticus and overwhelming sepsis, and hantavirus, making it difficult to identify Precautions (5.1)]. the initial cause. Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl) developed multiorgan dysfunction and disseminated intravascular 1 INDICATIONS AND USAGE coagulation 9 to 14 days after the immediate-release formulation of LAMICTAL LAMICTAL XR is indicated as adjunctive therapy for primary generalized tonic-clonic was added to their AED regimens. Rash and elevated transaminases were also (PGTC) seizures and partial onset seizures with or without secondary generalization in present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were receiving concomitant therapy with valproate, while the adult patient patients *13 years of age. Safety and effectiveness of LAMICTAL XR for use in patients less than 13 years of age was being treated with carbamazepine and clonazepam. All patients subsequently recovered with supportive care after treatment with the immediate-release have not been established. formulation of LAMICTAL was discontinued. 4 CONTRAINDICATIONS 5.4 Blood Dyscrasias: There have been reports of blood dyscrasias with the LAMICTAL XR is contraindicated in patients who have demonstrated hypersensitivity immediate-release formulation of LAMICTAL that may or may not be associated to the drug or its ingredients [see Boxed Warning, Warnings and Precautions (5.1), (5.2)]. with the hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia. 5 WARNINGS AND PRECAUTIONS 5.5 Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including 5.1 Serious Skin Rashes [see Boxed Warning]: The risk of serious rash LAMICTAL XR, increase the risk of suicidal thoughts or behavior in patients taking caused by treatment with LAMICTAL XR is not expected to differ from that with these drugs for any indication. Patients treated with any AED for any indication the immediate-release formulation of LAMICTAL [see Boxed Warning]. However, should be monitored for the emergence or worsening of depression, suicidal the relatively limited treatment experience with LAMICTAL XR makes it difficult to thoughts or behavior, and/or any unusual changes in mood or behavior. characterize the frequency and risk of serious rashes caused by treatment with Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and LAMICTAL XR. adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of Pediatric Population: The incidence of serious rash associated with hospitalization the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, and discontinuation of the immediate-release formulation of LAMICTAL in a 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. prospectively followed cohort of pediatric patients (aged 2 to 16 years) with In these trials, which had a median treatment duration of 12 weeks, the estimated epilepsy receiving adjunctive therapy with immediate-release lamotrigine was incidence of suicidal behavior or ideation among 27,863 AED-treated patients was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing expert dermatologists, there was considerable disagreement as to their proper an increase of approximately 1 case of suicidal thinking or behavior for every 530 classification. To illustrate, one dermatologist considered none of the cases to be patients treated. There were 4 suicides in drug-treated patients in the trials and Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There none in placebo-treated patients, but the number of events is too small to allow any was 1 rash-related death in this 1,983-patient cohort. Additionally, there have been conclusion about drug effect on suicide. rare cases of toxic epidermal necrolysis with and without permanent sequelae and/ The increased risk of suicidal thoughts or behavior with AEDs was observed as or death in US and foreign postmarketing experience. early as 1 week after starting treatment with AEDs and persisted for the duration There is evidence that the inclusion of valproate in a multidrug of treatment assessed. Because most trials included in the analysis did not extend regimen increases the risk of serious, potentially life-threatening rash beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could in pediatric patients. In pediatric patients who used valproate concomitantly, not be assessed. 1.2% (6 of 482) experienced a serious rash compared with 0.6% The risk of suicidal thoughts or behavior was generally consistent among drugs (6 of 952) patients not taking valproate. in the data analyzed. The finding of increased risk with AEDs of varying mechanism LAMICTAL XR is not approved in patients less than 13 years of age. of action and across a range of indications suggests that the risk applies to all AEDs Adult Population: Serious rash associated with hospitalization and discontinuation used for any indication. The risk did not vary substantially by age (5 to 100 years) of the immediate-release formulation of LAMICTAL occurred in 0.3% (11 of 3,348) in the clinical trials analyzed.

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the efficacy of cognitive therapy delivered via videophone with that of face-to-face therapy in 10 terminally ill patients. A total of 53 sessions were carried out alternating randomly between face-to-face and videophone. Of these, 21 sessions (39.6%) used videophone and 32 sessions (60.4%) were face-to-face. Patients reported being “highly satisfied” with both videophone technology and videoconferencing.

The studies by the Passik group4 and the Cluver group5 report easy acceptance and satisfaction with videophone technology by both patients and caregivers. These studies highlight the value of videophone technology in bringing access to services right into the patient’s home.

Caregiver support Videophones have also been used successfully to offer 12 caregivers of

terminally ill patients access to an institutionally based hospice interdisciplinary team.6 The caregivers were able to participate in treatment team meetings and to discuss medications (refills/dosages) and pain management. It also allowed the treatment team members visual confirmation of patient health status (disease progression and whether or not death was imminent).6 Caregiver support and psychiatric

morbidity prevention have also been accomplished using videophones in a cohort of 61 patients with spinal cord injuries and their caregivers in rural areas of 3 southeastern states.7 Caregivers were supported with problemsolving interventions via videophones. The goal was to prevent caregivers from becoming distressed and depressed and also to help them

LAMICTAL® XR™ (lamotrigine) Extended-Release Tablets Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur. Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis 5.9 Withdrawal Seizures: As with other AEDs, LAMICTAL XR should not be Risk Difference: abruptly discontinued. In patients with epilepsy there is a possibility of increasing Relative Risk: Additional Drug seizure frequency. Unless safety concerns require a more rapid withdrawal, Incidence of the dose of LAMICTAL XR should be tapered over a period of at least 2 weeks Indication Patients With Events in Drug Placebo Patients Drug Patients (approximately 50% reduction per week) [see Dosage and Administration (2.1) of Events Per With Events Per With Events Per Patients/Incidence 1,000 Patients 1,000 Patients in Placebo Patients 1,000 Patients full prescribing information]. Epilepsy Psychiatric Other Total

1.0 5.7 1.0 2.4

3.4 8.5 1.8 4.3

3.5 1.5 1.9 1.8

2.4 2.9 0.9 1.9

5.10 Status Epilepticus: Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with immediate-release lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, The relative risk for suicidal thoughts or behavior was higher in clinical trials for a number of reports of variably defined episodes of seizure exacerbation (e.g., epilepsy than in clinical trials for psychiatric or other conditions, but the absolute seizure clusters, seizure flurries) were made. risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing LAMICTAL XR or any other AED must 5.11 Sudden Unexplained Death in Epilepsy (SUDEP): During the balance the risk of suicidal thoughts or behavior with the risk of untreated illness. premarketing development of the immediate-release formulation of LAMICTAL, 20 Epilepsy and many other illnesses for which AEDs are prescribed are themselves sudden and unexplained deaths were recorded among a cohort of 4,700 patients associated with morbidity and mortality and an increased risk of suicidal thoughts with epilepsy (5,747 patient-years of exposure). and behavior. Should suicidal thoughts and behavior emerge during treatment, the of these could represent seizure-related deaths in which the seizure prescriber needs to consider whether the emergence of these symptoms in any wasSome not observed, e.g., at night. This represents an incidence of 0.0035 deaths given patient may be related to the illness being treated. per patient-year. Although this rate exceeds that expected in a healthy population Patients, their caregivers, and families should be informed that AEDs increase matched for age and sex, it is within the range of estimates for the incidence the risk of suicidal thoughts and behavior and should be advised of the need to be of sudden unexplained death in patients with epilepsy not receiving lamotrigine alert for the emergence or worsening of the signs and symptoms of depression, (ranging from 0.0005 for the general population of patients with epilepsy, to any unusual changes in mood or behavior, or the emergence of suicidal thoughts, 0.004 for a recently studied clinical trial population similar to that in the clinical behavior, or thoughts about self-harm. Behaviors of concern should be reported development program for immediate-release lamotrigine, to 0.005 for patients immediately to healthcare providers. with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon 5.6 Aseptic Meningitis: Therapy with LAMICTAL increases the risk of to the cohort receiving immediate-release lamotrigine and the accuracy of the developing aseptic meningitis. Because of the potential for serious outcomes of estimates provided. Probably most reassuring is the similarity of estimated SUDEP untreated meningitis due to other causes, patients should also be evaluated for rates in patients receiving immediate-release lamotrigine and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar other causes of meningitis and treated as appropriate. Postmarketing cases of aseptic meningitis have been reported in pediatric populations. Importantly, that drug is chemically unrelated to lamotrigine. This and adult patients taking LAMICTAL for various indications. Symptoms upon evidence suggests, although it certainly does not prove, that the high SUDEP rates presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. reflect population rates, not a drug effect. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to 5.12 Addition of LAMICTAL XR to a Multidrug Regimen That Includes one and a half months following the initiation of treatment. In most cases, symptoms Valproate: Because valproate reduces the clearance of lamotrigine, the dosage were reported to resolve after discontinuation of LAMICTAL. Re-exposure resulted of lamotrigine in the presence of valproate is less than half of that required in its in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation absence. of treatment) that were frequently more severe. Some of the patients treated with LAMICTAL who developed aseptic meningitis had underlying diagnoses of 5.13 Binding in the Eye and Other Melanin-Containing Tissues: Because systemic lupus erythematosus or other autoimmune diseases. lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported This raises the possibility that lamotrigine may cause toxicity in these tissues after cases was characterized by a mild-to-moderate pleocytosis, normal glucose levels, extended use. Although ophthalmological testing was performed in 1 controlled and mild-to-moderate increase in protein. CSF white blood cell count differentials clinical trial, the testing was inadequate to exclude subtle effects or injury occurring showed a predominance of neutrophils in a majority of the cases, although a after long-term exposure. Moreover, the capacity of available tests to detect predominance of lymphocytes was reported in approximately one third of the potentially adverse consequences, if any, of lamotrigine binding to melanin is cases. Some patients also had new onset of signs and symptoms of involvement unknown [see Clinical Pharmacology (12.2) of full prescribing information]. of other organs (predominantly hepatic and renal involvement), which may suggest Accordingly, although there are no specific recommendations for periodic that in these cases the aseptic meningitis observed was part of a hypersensitivity ophthalmological monitoring, prescribers should be aware of the possibility of longreaction [see Warnings and Precautions (5.2)]. term ophthalmologic effects. 5.7 Potential Medication Errors: Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL XR clearly. Depictions of the LAMICTAL XR Extended-Release Tablets can be found in the Medication Guide [see Patient Counseling Information (17.10) of full prescribing information]. Each LAMICTAL XR tablet has a distinct color and white center, and is printed with “LAMICTAL XR” and the tablet strength. These distinctive features serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. LAMICTAL XR is supplied in round, unit-of-use bottles with orange caps containing 30 tablets. The label on the bottle includes a depiction of the tablets that further communicates to patients and pharmacists that the medication is LAMICTAL XR and the specific tablet strength included in the bottle. The unit-of-use bottle with a distinctive orange cap and distinctive bottle label features serves to identify the different presentations of the drug and thus may help to reduce the risk of medication errors. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL XR each time they fill their prescription.

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5.14 Laboratory Tests: The value of monitoring plasma concentrations of lamotrigine in patients treated with LAMICTAL XR has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs including AEDs (see Table 2), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary. Treatment with LAMICTAL XR caused an increased incidence of subnormal (below the reference range) values in some hematology analytes (e.g., total white blood cells, monocytes). The treatment effect (LAMICTAL XR % - Placebo %) incidence of subnormal counts was 3% for total white blood cells and 4% for monocytes. 6 ADVERSE REACTIONS The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Serious skin rashes [see Warnings and Precautions (5.1)], Hypersensitivity reactions [see Warnings and Precautions (5.2)], Acute multiorgan failure [see Warnings and Precautions (5.3)], Blood dyscrasias [see Warnings and Precautions (5.4)], Suicidal behavior and ideation [see Warnings and Precautions (5.5)], Aseptic meningitis [see Warnings and Precautions (5.6)], Withdrawal seizures [see Warnings and Precautions (5.9)], Status epilepticus [see Warnings and Precautions (5.10)], Sudden unexplained death in epilepsy [see Warnings and Precautions (5.11)]

5.8 Concomitant Use With Oral Contraceptives: Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology (12.3) of full prescribing information]. Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL XR [see Dosage and Administration (2.1) of full prescribing information]. During the week of 6.1 Clinical Trial Experience With LAMICTAL XR for Treatment of Primary inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma Generalized Tonic-Clonic and Partial Onset Seizures: Because clinical trials are lamotrigine levels are expected to rise, as much as doubling at the end of the week. conducted under widely varying conditions, adverse reaction rates observed in the

(Please see Videophone Use, page 28)

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forestall pressure ulcers and other complications in their patients. Videophones provided visual access to health care information services and support to caregivers.

Remote mental health care access May and colleagues8 explored the use of the videophone as a means to expe-

CLINICAL dite primary care clinic referrals from a distant location to a mental health center in the United Kingdom. In this study, primary care providers used a videophone to refer anxious or depressed patients to a mental health provider. Mental health providers evaluated the patient using a videophone, made an initial diagnosis and management recommendations, and then subsequently saw the patients face-to-face.

The researchers reported initial enthusiasm by both primary care and mental health providers following the trial period of 6 months. However, some mental health providers were concerned about the potential impact of the technology on the physicianpatient relationship. There were no patient complaints about the technology. Other than occasional “image freeze” (delay), no other technical limitations were noted. Some patients

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saw the benefits of accessing specialty care through a videophone, while others saw the use of the technology itself as “unremarkable.” We have used the videophone to augment access to medical and psychiatric services by a case management team that serves a severely mentally ill patient population.1,9 Case managers carry a videophone while making patient home visits and use it to discuss nonemergency clinical

LAMICTAL® XR™ (lamotrigine) Extended-Release Tablets clinical trials of a drug cannot be directly compared with rates in the clinical trials of Adverse reactions are further classified within body system categories and another drug and may not reflect the rates observed in practice. enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients; LAMICTAL XR has been evaluated for safety in patients ≥13 years of age with PGTC and partial onset seizures. The most commonly observed adverse infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; reactions (≥4% for LAMICTAL XR and more common on drug than placebo) in rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body these 2 double-blind, placebo-controlled trials of adjunctive therapy with LAMICTAL XR as a Whole: Infrequent: Allergic reaction, chills, and malaise. Cardiovascular were, in order of decreasing treatment difference (LAMICTAL XR % - Placebo %) System: Infrequent: Flushing, hypertension, palpitations, postural hypotension, syncope, tachycardia, and vasodilation. Dermatological: Infrequent: Acne, incidence: dizziness, tremor/intention tremor, vomiting, and diplopia. In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the hirsutism, maculopapular rash, skin discoloration, and urticaria. Rare: Angioedema, group receiving placebo and 10 (5%) patients in the group receiving LAMICTAL erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, XR. Dizziness was the most common reason for withdrawal in the group receiving multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, LAMICTAL XR (5 patients [3%]). The next most common adverse reactions and vesiculobullous rash. Digestive System: Infrequent: Dysphagia, eructation, leading to withdrawal in 2 patients each (1%) were rash, headache, nausea, and gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, nystagmus. gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, The following listing provides the incidence of adverse reactions in these two melena, stomach ulcer, stomatitis, and tongue edema. Endocrine System: Rare: 19-week, double-blind, placebo-controlled studies of patients with PGTC and partial onset Goiter and hypothyroidism. Hematologic and Lymphatic System: Infrequent: seizures. Ecchymosis and leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen Treatment-Emergent Adverse Reaction Incidence in Double-Blind, Placebo- decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, Controlled Adjunctive Trials of Patients With Epilepsy (Adverse Reactions petechia, and thrombocytopenia. Metabolic and Nutritional Disorders: Infrequent: ≥2% of Patients Treated With LAMICTAL XR and Numerically More Frequent Aspartate transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase Than in the Placebo Group). Adverse reactions are listed by body system with the increase, alanine transaminase increase, bilirubinemia, general edema, gamma percent incidence of LAMICTAL XR (n=190) followed by placebo (n=195): Ear and glutamyl transpeptidase increase, and hyperglycemia. Musculoskeletal System: labyrinth disorders: vertigo (3,<1); Eye disorders: Diplopia (5,<1), Vision blurred Infrequent: Arthritis, leg cramps, myasthenia, and twitching. Rare: Bursitis, (3,2); Gastrointestinal disorders: Nausea (7,4), Vomiting (6,3), Diarrhea (5,3), muscle atrophy, pathological fracture, and tendinous contracture. Nervous Constipation (2,<1), Dry mouth (2,1); General disorders and administration site System: Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy, conditions: Asthenia and fatigue (6,4); Infections and infestations: Sinusitis aphasia, central nervous system (CNS) depression, depersonalization, dysarthria, (2,1); Metabolic and nutritional disorders: Anorexia (3,2); Musculoskeletal and dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido connective tissue disorder: Myalgia (2,0); Nervous system: Dizziness (14,6), decreased, memory decrease, mind racing, movement disorder, myoclonus, Tremor and intention tremor (6,1), Somnolence (5,3), Cerebellar coordination and panic attack, paranoid reaction, personality disorder, psychosis, stupor, and balance disorder (3,0), Nystagmus (2,<1); Psychiatric disorders: Depression suicidal ideation. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, (3,<1), Anxiety (3,0); Respiratory, thoracic, and mediastinal disorders: extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, Pharyngolaryngeal pain (3,2); Vascular disorder: Hot flush (2,0). hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression Note: In these trials the incidence of nonserious rash was 2% for LAMICTAL XR reaction, muscle spasm, neuralgia, neurosis, paralysis, and peripheral and 3% for placebo. In clinical trials evaluating the immediate-release formulation neuritis. Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation. of LAMICTAL, the rate of serious rash was 0.3% in adults on adjunctive therapy for Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation, epilepsy [see Boxed Warning]. conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Adverse reactions were also analyzed to assess the incidence of the onset of an Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, event in the titration period, and in the maintenance period, and if adverse reactions taste loss, uveitis, and visual field defect. Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, and urinary incontinence. occurring in the titration phase persisted in the maintenance phase. The incidence for many adverse reactions caused by LAMICTAL XR treatment Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, was increased relative to placebo (i.e., LAMICTAL XR % - Placebo % = treatment creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, difference ≥2%) in either the titration or maintenance phases of the study. During kidney pain, nocturia, urinary retention, and urinary urgency. the titration phase, an increased incidence (shown in descending order of % treatment difference) was observed for diarrhea, nausea, vomiting, somnolence, 6.3 Postmarketing Experience with the Immediate-Release Formulation of vertigo, myalgia, hot flush, and anxiety. During the maintenance phase, an LAMICTAL: The following adverse events (not listed above in clinical trials or other increased incidence was observed for dizziness, tremor, and diplopia. Some sections of the prescribing information) have been identified during postapproval adverse reactions developing in the titration phase were notable for persisting (>7 use of the immediate-release formulation of LAMICTAL. Because these events are days) into the maintenance phase. These “persistent” adverse reactions included reported voluntarily from a population of uncertain size, it is not always possible to somnolence and dizziness. reliably estimate their frequency or establish a causal relationship to drug exposure. There were inadequate data to evaluate the effect of dose and/or concentration Blood and Lymphatic: Agranulocytosis, hemolytic anemia, lymphadenopathy on the incidence of adverse reactions because although patients were randomized not associated with hypersensitivity disorder. Gastrointestinal: Esophagitis. to different target doses based upon concomitant AED, the plasma exposure was Hepatobiliary Tract and Pancreas: Pancreatitis. Immunologic: Lupus-like reaction, expected to be generally similar among all patients receiving different doses. vasculitis. Lower Respiratory: Apnea. Musculoskeletal: Rhabdomyolysis has However, in a randomized, parallel study comparing placebo and 300 and 500 been observed in patients experiencing hypersensitivity reactions. Neurology: mg/day of immediate-release formulation of LAMICTAL, the incidence of the most Exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s common adverse reactions (≥5%) such as ataxia, blurred vision, diplopia, and disease, tics. Non-site Specific: Progressive immunosuppression. dizziness were dose-related. Less common adverse reactions (<5%) were not assessed for dose-response relationships. There were insufficient data to evaluate the effect of gender, age, and race on 7 DRUG INTERACTIONS Significant drug interactions with lamotrigine are summarized in Table 2. the adverse reaction profile for LAMICTAL XR. Additional details of these drug interaction studies, which were conducted using the immediate-release formulation of LAMICTAL, are provided in the Clinical 6.2 Other Adverse Reactions Observed During the Clinical Development Pharmacology section [see Clinical Pharmacology (12.3) of full prescribing of the Immediate-Release Formulation of LAMICTAL: All reported reactions information]. are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated Table 2. Established and Other Potentially Significant Drug Interactions with the use of the drug. Adjunctive Therapy in Adults With Epilepsy: In addition to the adverse reactions Effect on Concentration reported above from the development of LAMICTAL XR, the following adverse Clinical Comment Concomitant Drug of Lamotrigine or reactions with an uncertain relationship to lamotrigine were reported during the Concomitant Drug clinical development of the immediate-release formulation of LAMICTAL for treatment of epilepsy in adults. These reactions occurred in ≥2% of patients Π lamotrigine Decreased lamotrigine levels receiving the immediate-release formulation of LAMICTAL and more frequently Estrogen-containing oral approximately 50%. than in the placebo group. Body as a Whole: Flu syndrome, fever, abdominal pain, contraceptive preparations Π levonorgestrel Decrease in levonorgestrel neck pain. Musculoskeletal: Arthralgia. Nervous: Insomnia, convulsion, irritability, containing 30 mcg component by 19%. speech disorder, concentration disturbance. Respiratory: Rhinitis, pharyngitis, ethinylestradiol and cough increased. Skin and Appendages: Rash, pruritus. Urogenital: (female 150 mcg levonorgestrel patients only) Vaginitis, amenorrhea, dysmenorrhea. Carbamazepine (CBZ) Π lamotrigine Addition of carbamazepine Other Clinical Trial Experience: The immediate-release formulation of LAMICTAL and CBZ epoxide decreases lamotrigine concentration has been administered to 6,694 individuals for whom complete adverse reaction approximately 40%. data was captured during all clinical trials, only some of which were placebo May increase CBZ epoxide levels. ? CBZ epoxide controlled. During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful Π lamotrigine Decreased lamotrigine estimate of the proportion of individuals having adverse reactions, similar types Phenobarbital/Primidone concentration approximately 40%. of reactions were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who experienced (cont’d) an event of the type cited on at least 1 occasion while receiving LAMICTAL.

needs with the team psychiatrist and other team members. These needs include medication follow-up, monitoring clinical improvement, adverseeffect evaluations, and family support. The videophones have increased the involvement of family members in treatment planning and access to team members (eg, clinical pharmacists).9 This has helped with medication refill authorization and preparation questions. Although it

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has not been measured, we believe this has resulted in improved treatment adherence. This application has also resulted in better resource utilization and has reduced the need for patient travel and has improved case managers’ productivity by saving time and travel expenses.

Testing Menon and colleagues10 demonstrated that videophones are a valuable

tool for evaluating patients remotely. No differences were found between face-to-face and videophone results when 24 geriatric patients were evaluated using the Geriatric Depression Scale and Hamilton Depression Rating Scale. In addition, most patients preferred a videophone interview because of the convenience of avoiding unnecessary travel. The researchers noted the additional benefit of avoiding falls or accidents that may occur

LAMICTAL® XR™ (lamotrigine) Extended-Release Tablets 8.3 Nursing Mothers: Preliminary data indicate that lamotrigine passes into Table 2. Established and Other Potentially Significant Drug Interactions (cont’d) human milk. Because the effects on the infant exposed to lamotrigine by this route Effect on Concentration are unknown, breastfeeding while taking LAMICTAL XR is not recommended. Concomitant Drug of Lamotrigine or Clinical Comment Concomitant Drug 8.4 Pediatric Use: LAMICTAL XR is indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) and partial onset seizures with or without Phenytoin (PHT) Π lamotrigine Decreased lamotrigine secondary generalization in patients ≥13 years of age. Safety and effectiveness concentration approximately 40%. of LAMICTAL XR for any use in patients less than 13 years of age have not been established. Rifampin Π lamotrigine Decreased lamotrigine AUC The immediate-release formulation of LAMICTAL is indicated for adjunctive approximately 40%. therapy in patients ≥2 years of age for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures. Valproate Ξ lamotrigine Increased lamotrigine Safety and efficacy of the immediate-release formulation of LAMICTAL, concentrations slightly more than used as adjunctive treatment for partial seizures, were not demonstrated in a 2-fold. small randomized, double-blind, placebo-controlled, withdrawal study in very ? valproate Decreased valproate young pediatric patients (1 to 24 months). The immediate-release formulation of concentrations an average of LAMICTAL was associated with an increased risk for infectious adverse reactions 25% over a 3-week period then stabilized in healthy volunteers; no (LAMICTAL 37%, placebo 5%), and respiratory adverse reactions (LAMICTAL change in controlled clinical trials 26%, placebo 5%). Infectious adverse reactions included: bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and in epilepsy patients. viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea. Π = Decreased (induces lamotrigine glucuronidation). 8.5 Geriatric Use: Clinical studies of LAMICTAL XR for epilepsy did not include Ξ = Increased (inhibits lamotrigine glucuronidation). sufficient numbers of subjects 65 years of age and over to determine whether they ? = Conflicting data. respond differently from younger subjects or exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater 8 USE IN SPECIFIC POPULATIONS frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.1 Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was found in mice, rats, or rabbits when 8.6 Patients With Hepatic Impairment: Experience in patients with hepatic lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on impairment is limited. Based on a clinical pharmacology study with the immediatea mg/m2 basis, the highest usual human maintenance dose (i.e., release formulation of LAMICTAL in 24 patients with mild, moderate, and severe liver 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing impairment [see Clinical Pharmacology (12.3) of full prescribing information], the following reduced fetal weight and/or delayed ossification were seen in mice and rats, but general recommendations can be made. No dosage adjustment is needed in patients not in rabbits at these doses. Teratology studies were also conducted using bolus with mild liver impairment. Initial, escalation, and maintenance doses should generally intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. be reduced by approximately 25% in patients with moderate and severe liver In rat dams administered an intravenous dose at 0.6 times the highest usual impairment without ascites and 50% in patients with severe liver impairment with human maintenance dose, the incidence of intrauterine death without signs of ascites. Escalation and maintenance doses may be adjusted according to clinical response [see Dosage and Administration (2.1) of full prescribing information]. teratogenicity was increased. A behavioral teratology study was conducted in rats dosed during the period of 8.7 Patients With Renal Impairment: Lamotrigine is metabolized mainly by organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg/day or higher displayed a significantly longer latent period for open field exploration and glucuronic acid conjugation, with the majority of the metabolites being recovered a lower frequency of rearing. In a swimming maze test performed on days 39 to in the urine. In a small study comparing a single dose of immediate-release 44 postpartum, time to completion was increased in offspring of dams receiving 25 lamotrigine in patients with varying degrees of renal impairment with healthy mg/kg/day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m2 volunteers, the plasma half-life of lamotrigine was significantly longer in the patients with renal impairment [see Clinical Pharmacology (12.3) of full prescribing basis, respectively. Lamotrigine did not affect fertility, teratogenesis, or postnatal development when information]. Initial doses of LAMICTAL XR should be based on patients’ AED regimens; rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during mg/m2 basis. When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest chronic treatment with lamotrigine. Because there is inadequate experience in human maintenance dose (on a mg/m2 basis) during the latter part of gestation this population, LAMICTAL XR should be used with caution in these patients [see (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food Dosage and Administration (2.1) of full prescribing information]. consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose group. Postnatal 10 OVERDOSAGE death was also seen, but only in the 2 highest doses, and occurred between days 10.1 Human Overdose Experience: Overdoses involving quantities up to 15 g 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A no-observed-effect level (NOEL) could not be determined have been reported for the immediate-release formulation of LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, increased for this study. Although lamotrigine was not found to be teratogenic in the above studies, seizures, decreased level of consciousness, coma, and intraventricular conduction lamotrigine decreases fetal folate concentrations in rats, an effect known to be delay. associated with teratogenesis in animals and humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies 10.2 Management of Overdose: There are no specific antidotes for lamotrigine. are not always predictive of human response, this drug should be used during Following a suspected overdose, hospitalization of the patient is advised. pregnancy only if the potential benefit justifies the potential risk to the fetus. General supportive care is indicated, including frequent monitoring of vital signs Non-Teratogenic Effects: As with other AEDs, physiological changes during and close observation of the patient. If indicated, emesis should be induced; pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There usual precautions should be taken to protect the airway. It is uncertain whether have been reports of decreased lamotrigine concentrations during pregnancy and hemodialysis is an effective means of removing lamotrigine from the blood. In 6 restoration of pre-partum concentrations after delivery. Dosage adjustments may renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be necessary to maintain clinical response. Pregnancy Exposure Registry: To provide information regarding the be contacted for information on the management of overdosage of LAMICTAL XR. effects of in utero exposure to LAMICTAL XR, physicians are advised to recommend that pregnant patients taking LAMICTAL XR enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Physicians are also encouraged to register patients in the Lamotrigine Pregnancy Registry; enrollment in this registry must be done prior to any prenatal diagnostic tests and before fetal outcome is known. Physicians can obtain information by calling the Lamotrigine Pregnancy Registry at 1-800-336-2176 (tollfree). LAMICTAL XR is a trademark of GlaxoSmithKline. 8.2 Labor and Delivery: The effect of LAMICTAL XR on labor and delivery in ©2010, GlaxoSmithKline. All rights reserved. October 2010 humans is unknown.

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as unintended consequences of travel. This is especially significant in a geriatric population. As in a previous study, there was image delay (movement artifact).8 Jacobsen and colleagues11 conducted a series of neuropsychological tests in a cohort of 32 patients in Norway. Patients were evaluated both face-to-face and by videophone. The (Please see Videophone Use, page 30)

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Videophone Use Continued from page 29

image size on the videophone was augmented with a connection to a Tandberg screen. Results were consistent and reliable for both videophone and face-to-face testing. It is notable that the group did not express a preference for videophone. The researchers concluded that videophones are a reasonable alternative

means of specialized testing. This is especially significant when weather and geographical barriers limit treatment alternatives where specialized trained staff are at a premium.

Other uses Videophones have also been used successfully to provide access and “virtual visits” to nursing home residents from distant family members in an effort to prevent isolation and

depression.12 This visual access, although limited to small screen size, provided enough “social presence” to allow family members to “visit” with a nursing home resident and alleviate some of the isolation these residents often experience.13 The videophone also allowed family members to participate in treatment team decisions and thus decreased guilt and may have prevented their own onset of depressive symptoms.12

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Summary In our survey, we found videophones a surprisingly understudied and underutilized tool in spite of the fact that they are easy to use and do not require any technical support. One reason may be that most clinicians prefer higher-bandwidth technologies, such as videoconferencing, and are not familiar with videophones as a potential adjunct treatment alternative in patients whose functional mobility limi-

LAMICTAL® (lamotrigine) Tablets LAMICTAL® (lamotrigine) Chewable Dispersible Tablets LAMICTAL® ODT™ (lamotrigine) Orally Disintegrating Tablets BRIEF SUMMARY There is evidence that the inclusion of valproate in a multidrug regimen increases the risk The following is a brief summary only; see full prescribing information for complete product of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; information. in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered LAMICTAL in the WARNING: SERIOUS SKIN RASHES absence of valproate were hospitalized. LAMICTAL® can cause serious rashes requiring hospitalization and discontinuation Patients With History of Allergy or Rash to Other Antiepileptic Drugs (AEDs): The risk of of treatment. The incidence of these rashes, which have included Stevens-Johnson nonserious rash may be increased when the recommended initial dose and/or the rate of dose syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (2 to 16 years escalation of LAMICTAL is exceeded and in patients with a history of allergy or rash to other AEDs. of age) receiving LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per 5.2 Hypersensitivity Reactions: Hypersensitivity reactions, some fatal or life threatening, 1,000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8 per 1,000) in adult have also occurred. Some of these reactions have included clinical features of multiorgan failure/ patients receiving LAMICTAL as initial monotherapy and 0.13% (1.3 per 1,000) dysfunction, including hepatic abnormalities and evidence of disseminated intravascular coagulation. in adult patients receiving LAMICTAL as adjunctive therapy. In a prospectively It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may followed cohort of 1,983 pediatric patients (2 to 16 years of age) with epilepsy taking be present even though a rash is not evident. If such signs or symptoms are present, the patient adjunctive LAMICTAL, there was 1 rash-related death. In worldwide postmarketing should be evaluated immediately. LAMICTAL should be discontinued if an alternative etiology for the experience, rare cases of toxic epidermal necrolysis and/or rash-related death have signs or symptoms cannot be established. Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash been reported in adult and pediatric patients, but their numbers are too few to permit or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a a precise estimate of the rate. Other than age, there are as yet no factors identified that are known to predict the serious medical event and that the patient should report any such occurrence to a physician risk of occurrence or the severity of rash caused by LAMICTAL. There are suggestions, immediately. 5.3 Acute Multiorgan Failure: Multiorgan failure, which in some cases has been fatal or yet to be proven, that the risk of rash may also be increased by (1) coadministration of LAMICTAL with valproate (includes valproic acid and divalproex sodium), irreversible, has been observed in patients receiving LAMICTAL. Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation for LAMICTAL. However, cases have occurred in the patients and 4 of 2,435 pediatric patients who received LAMICTAL in epilepsy clinical trials. No such fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan absence of these factors. Nearly all cases of life-threatening rashes caused by LAMICTAL have occurred failure have also been reported in compassionate plea and postmarketing use. The majority of these within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred deaths occurred in association with other serious medical events, including status epilepticus and after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot overwhelming sepsis, and hantavirus, making it difficult to identify the initial cause. Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old be relied upon as means to predict the potential risk heralded by the first appearance girl) developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after of a rash. Although benign rashes are also caused by LAMICTAL, it is not possible to predict LAMICTAL was added to their AED regimens. Rash and elevated transaminases were also present reliably which rashes will prove to be serious or life threatening. Accordingly, in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were receiving LAMICTAL should ordinarily be discontinued at the first sign of rash, unless the rash concomitant therapy with valproate, while the adult patient was being treated with carbamazepine is clearly not drug related. Discontinuation of treatment may not prevent a rash from and clonazepam. All patients subsequently recovered with supportive care after treatment with becoming life threatening or permanently disabling or disfiguring [see Warnings and LAMICTAL was discontinued. 5.4 Blood Dyscrasias: There have been reports of blood dyscrasias that may or may not be Precautions (5.1)]. associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia, 1 INDICATIONS AND USAGE anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia. 1.1 Epilepsy 5.5 Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including LAMICTAL, increase Adjunctive Therapy: LAMICTAL is indicated as adjunctive therapy for the following seizure types the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients in patients *2 years of age: treated with any AED for any indication should be monitored for the emergence or worsening of • partial seizures depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. • primary generalized tonic-clonic (PGTC) seizures Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) • generalized seizures of Lennox-Gastaut syndrome of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice Monotherapy: LAMICTAL is indicated for conversion to monotherapy in adults (*16 years of age) the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was primidone, or valproate as the single antiepileptic drug (AED). Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy; (2) 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. concomitant AEDs. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week 1.2 Bipolar Disorder starting treatment with AEDs and persisted for the duration of treatment assessed. Because LAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to after trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (*18 years most beyond 24 weeks could not be assessed. of age) treated for acute mood episodes with standard therapy. The effectiveness of LAMICTAL in behavior The risk of suicidal thoughts or behavior was generally consistent among drugs in the data the acute treatment of mood episodes has not been established. analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo- range of indications suggests that the risk applies to all AEDs used for any indication. The risk did controlled trials in patients with Bipolar I Disorder as deﬁned by DSM-IV [see Clinical Studies not vary substantially by age (5 to 100 years) in the clinical trials analyzed. (14.2) of full prescribing information]. The physician who elects to prescribe LAMICTAL for periods Table 1 shows absolute and relative risk by indication for all evaluated AEDs. extending beyond 16 weeks should periodically re-evaluate the long-term usefulness of the drug for Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis the individual patient. Relative Risk: Risk Difference: 4 CONTRAINDICATIONS Incidence of Additional Drug LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug or Placebo Patients Drug Patients Events in Drug Patients With Indication its ingredients [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]. With Events Per With Events Per Patients/Incidence Events Per 5 WARNINGS AND PRECAUTIONS 1,000 Patients 1,000 Patients in Placebo Patients 1,000 Patients 5.1 Serious Skin Rashes [see Boxed Warning]: Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of LAMICTAL in a prospectively Epilepsy 1.0 3.4 3.5 2.4 followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy Psychiatric 5.7 8.5 1.5 2.9 was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert 1.0 1.8 1.9 0.9 dermatologists, there was considerable disagreement as to their proper classification. To illustrate, Other one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another Total 2.4 4.3 1.8 1.9 assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983-patient cohort. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent than in clinical trials for psychiatric or other conditions, but the absolute risk differences were sequelae and/or death in US and foreign postmarketing experience. similar for the epilepsy and psychiatric indications. There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate Anyone considering prescribing LAMICTAL or any other AED must balance the risk of suicidal concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk not taking valproate. Adult Population: Serious rash associated with hospitalization and discontinuation of LAMICTAL of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in premarketing clinical the prescriber needs to consider whether the emergence of these symptoms in any given patient trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was may be related to the illness being treated. 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of Patients, their caregivers, and families should be informed that AEDs increase the risk of 1,538) of adult patients who received LAMICTAL as adjunctive therapy. No fatalities occurred among suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, have been reported, but their numbers are too few to permit a precise estimate of the rate. or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal should be reported immediately to healthcare providers. necrolysis, angioedema, and a rash associated with a variable number of the following systemic 5.6 Use in Patients With Bipolar Disorder: Acute Treatment of Mood Episodes: Safety and manifestations: fever, lymphadenopathy, facial swelling, and hematologic and hepatologic abnormalities.

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tations maybe an issue. Another reason may be that most clinicians tend to think about “nonimage” technologies, such as home messaging, when they think about telehealth services delivered to the home. Videophones may be an ideal tool to bridge these 2 technical levels of care; videophones provide both imaging and in-home access to clinical care, albeit with some limitations. Videophones are an ideal tele-

CLINICAL health alternative for delivering “patient-centric” care. They are well accepted by patients, caregivers, and staff for their simplicity of use. They are affordable, portable, and durable and can be used to provide an array of adjunct care services to patients with barriers to treatment—whether geographical, functional, or otherwise. Videoconferencing equipment, on the other hand, is more expensive, requires dedicated space, and is not mo-

bile; also, it requires technical support and incurs infrastructure expenses. The second generation of videophones (ie, smartphones, super phones) will allow even more patient access and have the potential to be the ultimate patient-centric telehealth alternative. Software in these affordable phones allows for the exchange of high-resolution image and nonimage exchange modalities (such as electronic mail), ideal for appoint-

LAMICTAL® (lamotrigine) Tablets LAMICTAL® (lamotrigine) Chewable Dispersible Tablets LAMICTAL® ODT™ (lamotrigine) Orally Disintegrating Tablets effectiveness of LAMICTAL in the acute treatment of mood episodes have not been established. 5.13 Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate: Because Children and Adolescents (Less Than 18 Years of Age): Safety and effectiveness of LAMICTAL in valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of patients less than 18 years of age with mood disorders have not been established [see Suicidal valproate is less than half of that required in its absence. Behavior and Ideation (5.5)]. Clinical Worsening and Suicide Risk Associated With Bipolar Disorder: 5.14 Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological for bipolar disorder. Patients should be closely monitored for clinical worsening (including testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle development of new symptoms) and suicidality, especially at the beginning of a course of treatment effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to or at the time of dose changes. detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown [see In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a Clinical Pharmacology (12.2) of full prescribing information]. significant degree of suicidal ideation prior to commencement of treatment, and young adults are Accordingly, although there are no specific recommendations for periodic ophthalmological at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects. during treatment [see Suicidal Behavior and Ideation (5.5)]. 5.15 Laboratory Tests: The value of monitoring plasma concentrations of lamotrigine Consideration should be given to changing the therapeutic regimen, including possibly in patients treated with LAMICTAL has not been established. Because of the possible discontinuing the medication, in patients who experience clinical worsening (including development pharmacokinetic interactions between lamotrigine and other drugs including AEDs [see Table 15 of new symptoms) and/or the emergence of suicidal ideation/behavior especially if these symptoms under Pharmacokinetics (12.3) of full prescribing information], monitoring of the plasma levels of are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent with general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine good patient management in order to reduce the risk of overdose. Overdoses have been reported and other drugs and whether or not dosage adjustments are necessary. for LAMICTAL, some of which have been fatal [see Overdosage (10.1)]. 6 ADVERSE REACTIONS 5.7 Aseptic Meningitis: Therapy with LAMICTAL increases the risk of developing aseptic The following adverse reactions are described in more detail in the Warnings and Precautions meningitis. Because of the potential for serious outcomes of untreated meningitis due to other section of the label: Serious skin rashes [see Warnings and Precautions (5.1)], Hypersensitivity causes, patients should also be evaluated for other causes of meningitis and treated as appropriate. reactions [see Warnings and Precautions (5.2)], Acute multiorgan failure [see Warnings and Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking Precautions (5.3)], Blood dyscrasias [see Warnings and Precautions (5.4)], Suicidal behavior and LAMICTAL for various indications. Symptoms upon presentation have included headache, fever, ideation [see Warnings and Precautions (5.5)], Aseptic meningitis [see Warnings and Precautions nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, (5.7)], Withdrawal seizures [see Warnings and Precautions (5.10)], Status epilepticus [see Warnings and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 and Precautions (5.11)], Sudden unexplained death in epilepsy [see Warnings and Precautions day to one and a half months following the initiation of treatment. In most cases, symptoms were (5.12)]. reported to resolve after discontinuation of LAMICTAL. Re-exposure resulted in a rapid return of 6.1 Clinical Trials: Because clinical trials are conducted under widely varying conditions, adverse symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the more severe. Some of the patients treated with LAMICTAL who developed aseptic meningitis had clinical trials of another drug and may not reflect the rates observed in practice. underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases. LAMICTAL has been evaluated for safety in patients with epilepsy and in patients with Bipolar Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was I Disorder. Adverse reactions reported for each of these patient populations are provided below. characterized by a mild-to-moderate pleocytosis, normal glucose levels, and mild-to-moderate Excluded are adverse reactions considered too general to be informative and those not reasonably increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in attributable to the use of the drug. a majority of the cases, although a predominance of lymphocytes was reported in approximately one Epilepsy: Most Common Adverse Reactions in All Clinical Studies: Adjunctive Therapy in Adults third of the cases. Some patients also had new onset of signs and symptoms of involvement of other With Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than organs (predominantly hepatic and renal involvement), which may suggest that in these cases the placebo) adverse reactions seen in association with LAMICTAL during adjunctive therapy in adults aseptic meningitis observed was part of a hypersensitivity reaction [see Warnings and Precautions and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, (5.2)]. somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, 5.8 Potential Medication Errors: Medication errors involving LAMICTAL have occurred. ataxia, blurred vision, nausea, and vomiting were dose-related. Dizziness, diplopia, ataxia, and In particular, the names LAMICTAL or lamotrigine can be confused with the names of other blurred vision occurred more commonly in patients receiving carbamazepine with LAMICTAL than commonly used medications. Medication errors may also occur between the different formulations in patients receiving other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly. including serious rash, in patients receiving concomitant valproate than in patients not receiving Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating valproate [see Warnings and Precautions (5.1)]. Tablets can be found in the Medication Guide that accompanies the product to highlight the Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy distinctive markings, colors, and shapes that serve to identify the different presentations of the drug in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse and thus may help reduce the risk of medication errors. To avoid the medication error of using the reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to headache (2.5%). verify that they are LAMICTAL, as well as the correct formulation of LAMICTAL, each time they fill In a dose-response study in adults, the rate of discontinuation of LAMICTAL for dizziness, ataxia, their prescription. diplopia, blurred vision, nausea, and vomiting was dose-related. 5.9 Concomitant Use With Oral Contraceptives: Some estrogen-containing oral contraceptives Monotherapy in Adults With Epilepsy: The most commonly observed (≥5% for LAMICTAL have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology and more common on drug than placebo) adverse reactions seen in association with the (12.3) of full prescribing information]. Dosage adjustments will be necessary in most patients use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at who start or stop estrogen-containing oral contraceptives while taking LAMICTAL [see an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, Dosage and Administration (2.1) of full prescribing information]. During the week of inactive hormone nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to dysmenorrhea. The most commonly observed (≥5% for LAMICTAL and more common on drug rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels than placebo) adverse reactions associated with the use of LAMICTAL during the conversion to of lamotrigine, such as dizziness, ataxia, and diplopia, could occur. monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate5.10 Withdrawal Seizures: As with other AEDs, LAMICTAL should not be abruptly discontinued. treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, patients with Bipolar Disorder, two patients experienced seizures shortly after abrupt withdrawal of diarrhea, lymphadenopathy, pruritus, and sinusitis. LAMICTAL; however, there were confounding factors that may have contributed to the occurrence of Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in seizures in these bipolar patients. Unless safety concerns require a more rapid withdrawal, the dose premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse of LAMICTAL should be tapered over a period of at least 2 weeks (approximately 50% reduction per reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and week) [see Dosage and Administration (2.1) of full prescribing information]. asthenia (2.4%). 5.11 Status Epilepticus: Valid estimates of the incidence of treatment-emergent status Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly observed (≥5% for epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters LAMICTAL and more common on drug than placebo) adverse reactions seen in association with participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, the use of LAMICTAL as adjunctive treatment in pediatric patients 2 to 16 years of age and not 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, clusters, seizure flurries) were made. flu syndrome, and diplopia. 5.12 Sudden Unexplained Death in Epilepsy (SUDEP): During the premarketing development In 339 patients 2 to 16 years of age with partial seizures or generalized seizures of Lennoxof LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo discontinued with epilepsy (5,747 patient-years of exposure). due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation Some of these could represent seizure-related deaths in which the seizure was not observed, of LAMICTAL was rash. e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate Approximately 11.5% of the 1,081 pediatric patients 2 to 16 years of age who received LAMICTAL exceeds that expected in a healthy population matched for age and sex, it is within the range of as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse estimates for the incidence of sudden unexplained death in patients with epilepsy not receiving reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for reaction aggravated (1.7%), and ataxia (0.6%). a recently studied clinical trial population similar to that in the clinical development program for Controlled Adjunctive Clinical Studies in Adults With Epilepsy: Listed below are treatmentLAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are emergent adverse reactions that occurred in at least 2% of adult patients with epilepsy treated reassuring or suggest concern depends on the comparability of the populations reported upon to the with LAMICTAL in placebo-controlled trials and were numerically more common in the patients cohort receiving LAMICTAL and the accuracy of the estimates provided. Probably most reassuring is treated with LAMICTAL. In these studies, either LAMICTAL or placebo was added to the patient’s the similarity of estimated SUDEP rates in patients receiving LAMICTAL and those receiving other current AED therapy. Adverse reactions were usually mild to moderate in intensity. LAMICTAL AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. was administered as adjunctive therapy to 711 patients; 419 patients received adjunctive placebo. Importantly, that drug is chemically unrelated to LAMICTAL. This evidence suggests, although it Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant AEDs certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect. (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL or placebo.

PSYCHIATRIC TIMES

w w w. psychi atr i cti mes. com

ment confirmation, laboratory results notification, etc. These devices have about the same screen size as the firstgeneration videophone, but their portability is greatly improved. On the other hand, patient privacy and the expectation of unlimited real-time access to care are items to be considered in the future clinical deployment of these devices. (Please see Videophone Use, page 32)

PSYCHIATRIC TIMES www.psy c h i a t r i c t i m e s. c o m

Videophone Use Continued from page 31

Most of the studies of telemedicine have been small. Larger, more systematic investigations of telemental health via videophones, particularly in the areas of patient and caregiver satisfaction and treatment response, are needed. Areas of utilization listed in our review (special populations and/or caregiver support) are understudied and underserved telemental

CLINICAL health populations. The ability of videophones to provide increased access to higher levels of care, such as hospital-based resources, at minimal cost is apparent, especially in cases in which mobility to “spoke” locations served by videoconferencing may be impractical because of illness or geographical barriers. Videophones enable clinicians and caregivers to maximize patient convenience, safety, and satisfaction.

Dr Nieves is associate chief of staff for education and associate professor of psychiatry and behavioral sciences at the Eastern Virginia Medical School in Norfolk. Dr Briscoe is professor of psychiatry and behavioral sciences at the Eastern Virginia Medical School and staff psychiatrist at the Veterans Administration Hospital in Hampton, Va. Ms Edwards is medical librarian in the department of education at the Veterans Administration Hospital. Dr Flores-Carrera is a psy-

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chiatry resident at the Naval Medical Center in Portsmouth, Va. The authors report no conflicts of interest concerning the subject matter of this article.

Disclaimer—The contents of this article do not represent the views of the Department of Veterans Affairs, the Department of the Navy, or of the government of the United States.

LAMICTAL® (lamotrigine) Tablets LAMICTAL® (lamotrigine) Chewable Dispersible Tablets LAMICTAL® ODT™ (lamotrigine) Orally Disintegrating Tablets Patients may have reported multiple adverse reactions during the study or at discontinuation; thus, Digestive: Nausea (14,11), Constipation (5,2), Vomiting (5,2); Nervous System: Insomnia (10,6), patients may be included in more than 1 category. Somnolence (9,7), Xerostomia (dry mouth) (6,4); Respiratory: Rhinitis (7,4), Exacerbation of Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Adjunctive Trials cough (5,3), Pharyngitis (5,4); Skin: Rash (nonserious) (7,5). In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received in Adult Patients With Epilepsy (Adverse reactions in at least 2% of patients treated with LAMICTAL and numerically more frequent than in the placebo group are listed by LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL body system with the incidence for LAMICTAL followed by placebo): Body as a whole: as adjunctive therapy [see Warnings and Precautions (5.1)]. Adverse reactions that occurred in Headache (29,19), Flu syndrome (7,6), Fever (6,4), Abdominal pain (5,4), Neck pain (2,1), Reaction at least 5% of patients and were numerically more common during the dose-escalation phase aggravated (seizure exacerbation) (2,1); Digestive: Nausea (19,10), Vomiting (9,4), Diarrhea (6,4), of LAMICTAL in these trials (when patients may have been receiving concomitant medications) Dyspepsia (5,2), Constipation (4,3), Anorexia (2,1); Musculoskeletal: Arthralgia (2,0); Nervous: compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), Dizziness (38,13), Ataxia (22,6), Somnolence (14,7), Incoordination (6,2), Insomnia (6,2), Tremor diarrhea (8%), dream abnormality (6%), and pruritus (6%). (4,1), Depression (4,3), Anxiety (4,3), Convulsion (3,1), Irritability (3,2), Speech disorder (3,0), During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’ Concentration disturbance (2,1); Respiratory: Rhinitis (14,9), Pharyngitis (10,9), Cough increased duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190 patients (8,6); Skin and appendages: Rash (10,5), Pruritus (3,2); Special senses: Diplopia (28,7), who received placebo, and 23% of 166 patients who received lithium discontinued therapy because Blurred vision (16,5), Vision abnormality (3,1); Urogenital (female patients only, n = 365, n = 207): of an adverse reaction. The adverse reactions which most commonly led to discontinuation Dysmenorrhea (7,6), Vaginitis (4,1), Amenorrhea (2,1). of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Dose-Related Adverse Reactions From a Randomized, Placebo-Controlled Adjunctive Approximately 16% of 2,401 patients who received LAMICTAL (50 to 500 mg/day) for Bipolar Trial in Adults With Epilepsy: In a randomized, parallel study comparing placebo (n = 73) and Disorder in premarketing trials discontinued therapy because of an adverse reaction, most 300 mg/day (n = 71) and 500 mg/day (n = 72) of LAMICTAL, some of the more common commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%). drug-related adverse reactions were dose-related. The following adverse reactions are listed The overall adverse reaction profile for LAMICTAL was similar between females and males, by incidence (%) in placebo first, LAMICTAL 300 mg dose second, and LAMICTAL 500 between elderly and nonelderly patients, and among racial groups. mg dose third: Ataxia (10,10,28ab), Blurred vision (10,11,25ab), Diplopia (8,24a,49ab), These adverse reactions were usually mild to moderate in intensity. Other reactions that occurred Dizziness (27,31,54ab), Nausea (11,18,25a), Vomiting (4,11,18a). aSigniﬁcantly greater in 5% or more patients but equally or more frequently in the placebo group included: dizziness, than placebo group (p<0.05). bSigniﬁcantly greater than group receiving LAMICTAL mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia. 300 mg (p<0.05). Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of patients The overall adverse reaction profile for LAMICTAL was similar between females and males, receiving LAMICTAL and numerically more frequent than placebo were: General: Fever, neck pain. and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of Cardiovascular: Migraine. Digestive: Flatulence. Metabolic and Nutritional: Weight gain, edema. patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to support a Musculoskeletal: Arthralgia, myalgia. Nervous System: Amnesia, depression, agitation, emotional statement regarding the distribution of adverse reaction reports by race. Generally, females receiving lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia. Respiratory: Sinusitis. either LAMICTAL as adjunctive therapy or placebo were more likely to report adverse reactions than Urogenital: Urinary frequency. males. The only adverse reaction for which the reports on LAMICTAL were greater than 10% more Adverse Reactions Following Abrupt Discontinuation: In the 2 maintenance trials, there was no frequent in females than males (without a corresponding difference by gender on placebo) was increase in the incidence, severity, or type of adverse reactions in Bipolar Disorder patients after dizziness (difference = 16.5%). There was little difference between females and males in the rates abruptly terminating therapy with LAMICTAL. In clinical trials in patients with Bipolar Disorder, two of discontinuation of LAMICTAL for individual adverse reactions. patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were Controlled Monotherapy Trial in Adults With Partial Seizures: Listed below are treatment- confounding factors that may have contributed to the occurrence of seizures in these bipolar patients emergent adverse reactions that occurred in at least 5% of patients with epilepsy treated [see Warnings and Precautions (5.10)]. with monotherapy with LAMICTAL in a double-blind trial following discontinuation Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in in Bipolar I Disorder in which patients were converted to monotherapy with LAMICTAL (100 to the control group. Forty-three patients received monotherapy with LAMICTAL up to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic 500 mg/day; 44 received low-dose valproate monotherapy at 1,000 mg/day. Patients in these or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated studies were converted to LAMICTAL or valproate monotherapy from adjunctive therapy with with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated carbamazepine or phenytoin. Patients may have reported multiple adverse experiences during the with placebo (n = 190). In all bipolar controlled trials combined, adverse reactions of mania (including study; thus, patients may be included in more than 1 category. hypomania and mixed mood episodes) were reported in 5% of patients treated with LAMICTAL Treatment-Emergent Adverse Reaction Incidence in Adults With Partial Seizures in a (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803). Controlled Monotherapy Trial (Adverse reactions in at least 5% of patients treated with 6.2 Other Adverse Reactions Observed in All Clinical Trials: LAMICTAL has been LAMICTAL and numerically more frequent than in the valproate group are listed by body administered to 6,694 individuals for whom complete adverse reaction data was captured during system with the incidence for LAMICTAL followed by valproate): Body as a whole: Pain (5,0), all clinical trials, only some of which were placebo controlled. During these trials, all adverse Infection (5,2), Chest pain (5,2); Digestive: Vomiting (9,0), Dyspepsia (7,2), Nausea (7,2); Metabolic reactions were recorded by the clinical investigators using terminology of their own choosing. To and nutritional: Weight decrease (5,2); Nervous: Coordination abnormality (7,0), Dizziness (7,0), provide a meaningful estimate of the proportion of individuals having adverse reactions, similar Anxiety (5,0), Insomnia (5,2); Respiratory: Rhinitis (7,2); Urogenital (female patients only, n=21, types of adverse reactions were grouped into a smaller number of standardized categories using n=28): Dysmenorrhea (5 ,0). modified COSTART dictionary terminology. The frequencies presented represent the proportion of Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of the 6,694 individuals exposed to LAMICTAL who experienced an event of the type cited on at least patients receiving LAMICTAL and numerically more frequent than placebo were: Body as a one occasion while receiving LAMICTAL. All reported adverse reactions are included except those Whole: Asthenia, fever. Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer. Metabolic already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and Nutritional: Peripheral edema. Nervous System: Amnesia, ataxia, depression, hypesthesia, and those not reasonably associated with the use of the drug. libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation. Adverse reactions are further classified within body system categories and enumerated in order Respiratory: Epistaxis, bronchitis, dyspnea. Skin and Appendages: Contact dermatitis, dry skin, of decreasing frequency using the following definitions: frequent adverse reactions are defined sweating. Special Senses: Vision abnormality. as those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy: Listed below are in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 adverse reactions that occurred in at least 2% of 339 pediatric patients with partial seizures or patients. Body as a Whole: Infrequent: Allergic reaction, chills, and malaise. Cardiovascular generalized seizures of Lennox-Gastaut syndrome, who received LAMICTAL up to 15 mg/kg/day or a System: Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, maximum of 750 mg/day. Reported adverse reactions were classified using COSTART terminology. syncope, tachycardia, and vasodilation. Dermatological: Infrequent: Acne, alopecia, hirsutism, LAMICTAL was administered as adjunctive therapy to 168 patients; 171 patients received adjunctive maculopapular rash, skin discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative placebo. dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Adjunctive Trials pustular rash, Stevens-Johnson syndrome, and vesiculobullous rash. Digestive System: Infrequent: in Pediatric Patients With Epilepsy (Adverse reactions in at least 2% of patients treated Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests with LAMICTAL and numerically more frequent than in the placebo group are listed by abnormal, and mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, body system with the incidence for LAMICTAL followed by placebo): Body as a whole: gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, Infection (20,17), Fever (15,14), Accidental injury (14,12), Abdominal pain (10,5), Asthenia (8,4), Flu and tongue edema. Endocrine System: Rare: Goiter and hypothyroidism. Hematologic and syndrome (7,6), Pain (5,4), Facial edema (2,1), Photosensitivity (2,0); Cardiovascular: Hemorrhage Lymphatic System: Infrequent: Ecchymosis and leukopenia. Rare: Anemia, eosinophilia, fibrin (2,1); Digestive: Vomiting (20,16), Diarrhea (11,9), Nausea (10,2), Constipation (4,2), Dyspepsia decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic (2,1), Hemic and lymphatic: Lymphadenopathy (2,1); Metabolic and nutritional: Edema (2,0) anemia, petechia, and thrombocytopenia. Metabolic and Nutritional Disorders: Infrequent: Aspartate Nervous system: Somnolence (17,15), Dizziness (14,4), Ataxia (11,3), Tremor (10,1), Emotional transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase increase, alanine lability (4,2), Gait abnormality (4,2), Thinking abnormality (3,2), Convulsions (2,1), Nervousness (2,1), transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, Vertigo (2,1); Respiratory: Pharyngitis (14,11), Bronchitis (7,5), Increased cough (7,6), Sinusitis and hyperglycemia. Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, (2,1), Bronchospasm (2,1); Skin: Rash (14,12), Eczema (2,1), Pruritus (2,1); Special senses: and twitching. Rare: Bursitis, muscle atrophy, pathological fracture, and tendinous contracture. Diplopia (5,1), Blurred vision (4,1), Visual abnormality (2,0); Urogenital: (male and female patients) Nervous System: Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy, aphasia, Urinary tract infection (3,0). central nervous system (CNS) depression, depersonalization, dysarthria, dyskinesia, euphoria, Bipolar Disorder: The most commonly observed (≥5%) treatment-emergent hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, adverse reactions seen in association with the use of LAMICTAL as monotherapy (100 to movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, 400 mg/day) in adult patients (≥18 years of age) with Bipolar Disorder in the 2 double- sleep disorder, stupor, and suicidal ideation. Rare: Choreoathetosis, delirium, delusions, dysphoria, blind, placebo-controlled trials of 18 months’ duration, and numerically more frequent than in dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, placebo-treated patients are: Treatment-Emergent Adverse Reaction Incidence in 2 Placebo- hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, Controlled Trials in Adults With Bipolar I Disorder (Adverse reactions in at least 5% of neurosis, paralysis, and peripheral neuritis. Respiratory System: Infrequent: Yawn. Rare: Hiccup and patients treated with LAMICTAL (n=227) as monotherapy and numerically more frequent hyperventilation. Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation, than in the placebo group (n=190) are listed by body system with the incidence for conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness, LAMICTAL followed by placebo.) Patients in these studies were converted to LAMICTAL (100 to lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. defect. Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, Patients may have reported multiple adverse reactions during the study; thus, patients may be polyuria, and urinary incontinence. Rare: Acute kidney failure, anorgasmia, breast abscess, breast included in more than 1 category. General: Back pain (8,6); Fatigue (8,5), Abdominal pain (6,3); neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney

MAY 2011

References 1. Nieves JE, Godleski, LS, Stack KM, Zinanni T. Videophones for intensive case management of psychiatric outpatients. J Telemed Telecare. 2009;15:5154. 2. Oliver DR, Demiris G, Day M, et al. Telehospice support for elder caregivers of hospice patients: two case studies. J Palliat Med. 2006;9:264-267. 3. Oliver DP, Demiris G. Comparing face-to-face and telehealth-mediated delivery of a psychoeducational intervention: a case comparison study in hospice. Telemed J E Health. 2010;16:751-753. 4. Passik SD, Kirsh KL, Leibee S, et al. A feasibility

CLINICAL study of dignity psychotherapy delivered via telemedicine. Palliat Support Care. 2004;2:149-155. 5. Cluver JS, Schuyler D, Frueh BC, et al. Remote psychotherapy for terminally ill cancer patients. J Telemed Telecare. 2005;11:157-159. 6. Wittenberg-Lyles E, Oliver DP, Demiris G, et al. Question asking by family caregivers in hospice interdisciplinary team meetings. Res Gerontol Nurs. 2010;3:82-88. 7. Rivera PA, Shewchuck R, Elliott T. Project FOCUS: using videophones to provide problem-solving training to family caregivers of persons with spinal cord injuries. Top Spinal Cord Injury Rehabil.

2000;9:53-62. 8. May C, Gask L, Atkinson T, et al. Resisting and promoting new technologies in clinical practice: the case of telepsychiatry. Soc Sci Med. 2001;52:18891901. 9. Nieves JE, Stack KM, Cruz M. Telepharmacy in mental health outpatient case management. J Pharm Technol. 2007;23:281-283. 10. Menon AS, Kondapavalru P, Krishna P, et al. Evaluation of a portable low cost videophone system in the assessment of depressive symptoms and cognitive function in elderly medically ill veterans. J Nerv Ment Dis. 2001;189:399-401.

LAMICTAL® (lamotrigine) Tablets LAMICTAL® (lamotrigine) Chewable Dispersible Tablets LAMICTAL® ODT™ (lamotrigine) Orally Disintegrating Tablets pain, nocturia, urinary retention, and urinary urgency. Non-Teratogenic Effects: As with other AEDs, physiological changes during pregnancy may 6.3 Postmarketing Experience: The following adverse events (not listed above in clinical trials affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased or other sections of the prescribing information) have been identified during postapproval use of lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after LAMICTAL. Because these events are reported voluntarily from a population of uncertain size, delivery. Dosage adjustments may be necessary to maintain clinical response. it is not always possible to reliably estimate their frequency or establish a causal relationship to Pregnancy Exposure Registry: To provide information regarding the effects of in utero drug exposure. Blood and Lymphatic: Agranulocytosis, hemolytic anemia, lymphadenopathy not exposure to LAMICTAL, physicians are advised to recommend that pregnant patients associated with hypersensitivity disorder. Gastrointestinal: Esophagitis. Hepatobiliary Tract and taking LAMICTAL enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Pancreas: Pancreatitis. Immunologic: Lupus like reaction, vasculitis. Lower Respiratory: Apnea. Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing hypersensitivity done by patients themselves. Information on the registry can also be found at the website reactions. Neurology: Exacerbation of Parkinsonian symptoms in patients with pre-existing http://www.aedpregnancyregistry.org/. Physicians are also encouraged to register patients in the Lamotrigine Pregnancy Registry; Parkinson’s disease, tics. Non-site Specific: Progressive immunosuppression. enrollment in this registry must be done prior to any prenatal diagnostic tests and before fetal 7 DRUG INTERACTIONS outcome is known. Physicians can obtain information by calling the Lamotrigine Pregnancy Significant drug interactions with lamotrigine are summarized in Table 2. Additional details of Registry at 1-800-336-2176 (toll-free). these drug interaction studies are provided in the Clinical Pharmacology subsection [see Clinical 8.2 Labor and Delivery: The effect of LAMICTAL on labor and delivery in humans is unknown. Pharmacology (12.3) of full prescribing information]. 8.3 Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk. Table 2. Established and Other Potentially Significant Drug Interactions Because the effects on the infant exposed to lamotrigine by this route are unknown, breastfeeding while taking LAMICTAL is not recommended. Effect on Concentration 8.4 Pediatric Use: LAMICTAL is indicated for adjunctive therapy in patients ≥2 years of age for Clinical Comment Concomitant Drug of Lamotrigine or partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized Concomitant Drug tonic-clonic seizures. Π lamotrigine Decreased lamotrigine levels Estrogen-containing oral Safety and efficacy of LAMICTAL, used as adjunctive treatment for partial seizures, were not approximately 50%. contraceptive preparations demonstrated in a small randomized, double-blind, placebo-controlled, withdrawal study in very Π levonorgestrel Decrease in levonorgestrel containing 30 mcg young pediatric patients (1 to 24 months). LAMICTAL was associated with an increased risk for component by 19%. ethinylestradiol and infectious adverse reactions (LAMICTAL 37%, placebo 5%), and respiratory adverse reactions (LAMICTAL 26%, placebo 5%). Infectious adverse reactions included: bronchiolitis, bronchitis, 150 mcg levonorgestrel ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Carbamazepine (CBZ) Π lamotrigine Addition of carbamazepine Respiratory adverse reactions included nasal congestion, cough, and apnea. and CBZ epoxide decreases lamotrigine Safety and effectiveness in patients less than 18 years of age with Bipolar Disorder has not been concentration approximately 40%. established. ? CBZ epoxide May increase CBZ epoxide levels. 8.5 Geriatric Use: Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not include sufficient numbers of subjects aged 65 years of age and over to determine whether they respond differently from younger subjects or exhibit a different safety profile than that of Phenobarbital/Primidone Π lamotrigine Decreased lamotrigine patients. In general, dose selection for an elderly patient should be cautious, usually starting concentration approximately 40%. younger at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Patients With Hepatic Impairment: Experience in patients with hepatic impairment is Phenytoin (PHT) Π lamotrigine Decreased lamotrigine concentration approximately 40%. limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Clinical Pharmacology (12.3) of full prescribing information], the following general recommendations can be made. No dosage adjustment is needed in patients with mild Rifampin Π lamotrigine Decreased lamotrigine AUC liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 40%. approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be Valproate Ξ lamotrigine Increased lamotrigine adjusted according to clinical response [see Dosage and Administration (2.1) of full prescribing concentrations slightly more than information]. 2-fold. 8.7 Patients With Renal Impairment: Lamotrigine is metabolized mainly by glucuronic acid ? valproate Decreased valproate conjugation, with the majority of the metabolites being recovered in the urine. In a small study concentrations an average of comparing a single dose of lamotrigine in patients with varying degrees of renal impairment with 25% over a 3-week period then healthy volunteers, the plasma half-life of lamotrigine was significantly longer in the patients with stabilized in healthy volunteers; renal impairment [see Clinical Pharmacology (12.3) of full prescribing information]. no change in controlled clinical Initial doses of LAMICTAL should be based on patients’ AED regimens; reduced maintenance trials in epilepsy patients. doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be used with caution in these patients [see Dosage and Administration (2.1) of full prescribing information]. Π= Decreased (induces lamotrigine glucuronidation). 10 OVERDOSAGE Ξ= Increased (inhibits lamotrigine glucuronidation). 10.1 Human Overdose Experience: Overdoses involving quantities up to 15 g have been ? = Conflicting data. reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia, 8 USE IN SPECIFIC POPULATIONS nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular 8.1 Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of conduction delay. teratogenicity was found in mice, rats, or rabbits when lamotrigine was orally administered 10.2 Management of Overdose: There are no specific antidotes for lamotrigine. Following a to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, times, respectively, on a mg/m2 basis, the highest usual human maintenance dose (i.e., including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight should be induced; usual precautions should be taken to protect the airway. It should be kept in mind and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology that lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3) of full prescribing information]. studies were also conducted using bolus intravenous administration of the isethionate salt of It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information was increased. on the management of overdosage of LAMICTAL. A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg/day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg/day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m2 basis, respectively. Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis. When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and LAMICTAL Tablets and Chewable Dispersible Tablets are manufactured by fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation DSM Pharmaceuticals, Inc., Greenville, NC 27834 or period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in GlaxoSmithKline, Research Triangle Park, NC 27709 all 3 drug-treated groups with the highest number in the high-dose group. Postnatal death was also LAMICTAL Orally Disintegrating Tablets are manufactured by seen, but only in the 2 highest doses, and occurred between days 1 and 20. Some of these deaths Eurand, Inc., Vandalia, OH 45377 appear to be drug-related and not secondary to the maternal toxicity. A no-observed-effect level LAMICTAL is a registered trademark of GlaxoSmithKline. (NOEL) could not be determined for this study. Although lamotrigine was not found to be teratogenic in the above studies, lamotrigine decreases ©2010, GlaxoSmithKline. All rights reserved. LMT:4BRS fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and October 2010 humans. There are no adequate and well-controlled studies in pregnant women. Because animal ©2011 The GlaxoSmithKline Group of Companies All rights reserved. reproduction studies are not always predictive of human response, this drug should be used during Printed in USA. LBP952R0 February 2011 pregnancy only if the potential benefit justifies the potential risk to the fetus.

PSYCHIATRIC TIMES

w w w. psychi atr i cti mes. com

11. Jacobsen SE, Sprenger T, Andersson S, Krogstad JM. Neuropsychological assessment and telemedicine: a preliminary study examining the reliability of neuropsychology services performed via telecommunication. J Int Neuropsychol Soc. 2003;9:472478. 12. Hensel BK, Parker-Oliver D, Demiris G. Videophone communication between residents and family: a case study. J Am Med Dir Assoc. 2007;8:123127. 13. Cukor P, Baer L, Willis BS, et al. Use of videophones and low-cost standard telephone lines to provide a social presence in telepsychiatry. Telemed J. 1998;4:313-321. ❒

MAY 2011

COMMENTARY

The Kingâ&#x20AC;&#x2122;s Psychotherapy by Lawrence D. Blum, MD n The Kingâ&#x20AC;&#x2122;s Speech, Prince Albert gets the royal treatmentâ&#x20AC;&#x201D;by being treated the same as everyone else. Like the commoners who consult Lionel Logue, Prince Albert is helped to confront his avoidances, to tolerate his feelings, and to understand his fears and fantasies. A humane respect for emotional problems may be uncommon among humans but is captivating in this movie that has proved more popular than anyone expected. Albertâ&#x20AC;&#x2122;s good fortune, his path toward emotional liberation, is that his speech therapy incorporates so many features of psychoanalytic therapy. When Prince Albert turns to Logue for help with his debilitating, humiliating stutter, Logue promptly refuses special requestsâ&#x20AC;&#x201D;house callsâ&#x20AC;&#x201D;for royalty, insisting on â&#x20AC;&#x153;my house, my rules.â&#x20AC;? He also makes the provocative demand that he and the prince should

call each other by first names. Logue thus indicates to the prince that he will have to struggle with his shame and anxiety as anyone else wouldâ&#x20AC;&#x201D;royalty offers no protection from human emotions. He also immediately shows his patient that the relationship between them is a matter for observation and discussion. This setting of a framework that will allow the therapist and patient to examine and discuss the relationship that develops between them is a fundamental psychoanalytic principle. It gives patients a new window on their own minds and how they relate to other people. Logue next devotes much effort to showing â&#x20AC;&#x153;Bertieâ&#x20AC;? that his stuttering is aggravated by his anxiety: it is diminished when he is distracted by music, and he has less inhibition of speech when he can curse or sing. This recognition paves the way to help Bertie look more deeply at the substance of

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Colin Firth plays King George VI, who, to overcome his stammer, sees Lionel Logue, an unorthodox Australian speech therapist played by Geoffrey Rush.

the emotional struggles that interfere with his speech. In psychoanalysis, this process of clarifying present concerns to reveal more hidden matters is called analyzing defenses or â&#x20AC;&#x153;resistances.â&#x20AC;? When he has successfully overcome some of his initial objections and feels less ashamed, Bertie can gradually see that as an adult he is continuing the fearful mental battles of his childhood. Bertie then tests out some of his long-suppressed challenges to his old adversaries, his father and brother, in his relationship with his therapist. As Logue tolerates these challenges without being injured and without criticizing or attacking his patient, Bertie starts to feel free to find his own voice. Unconscious, leftover struggles from childhood influence all of us. The opportunity to play out, observe, and alter them in relation to the therapist is one of the most important contributions of psychoanalysis. If youâ&#x20AC;&#x2122;ve ever wondered what psychoanalytic treatments are like, The Kingâ&#x20AC;&#x2122;s Speech provides an unusually good cinematic representation of a psychoanalytic therapy. Thereâ&#x20AC;&#x2122;s no magic to the iconic couch; the key is what goes on between the two people. We live in a quick-fix society. We focus on what people do but donâ&#x20AC;&#x2122;t look inside at why they do it. This is the kind of approachâ&#x20AC;&#x201D;just try to change the behaviorâ&#x20AC;&#x201D;that did not work for Prince Albert and that left

him discouraged about himself and about any prospect for help. But no matter the behavior, it is still wise to remember the mind, with all the complex feelings, thoughts, and emotional conflicts to which humans are subject. Treatments such as the one that helped Bertie require intense emotional involvement and much time. They arenâ&#x20AC;&#x2122;t for everyone, and they donâ&#x20AC;&#x2122;t follow a script. While most therapists are not trained to do them, psychoanalysts are. The royal treatment is still available to those who seek it out. It is not a coincidence that such an affecting movie as The Kingâ&#x20AC;&#x2122;s Speech depicts a treatment that is so psychoanalytic. No one goes to the movies to watch a formulaic treatmentâ&#x20AC;&#x201D;or a prescription for Prozac. We go to be involved in the full play of human emotionsâ&#x20AC;&#x201D;love, hate, fear, lust, envy, joy, greed, the hidden and forbidden yearnings. Even a stiff-upper-lip royal needs a home for the heart. The final joy of The Kingâ&#x20AC;&#x2122;s Speech is seeing the kingâ&#x20AC;&#x2122;s hard-won ability to speak from his heart. Dr Blum is a psychiatrist and psychoanalyst in private practice in Philadelphia and in Cherry Hill, NJ. He is on the faculty of the Psychoanalytic Center of Philadelphia and is clinical assistant professor of psychiatry at the University of Pennsylvania, Philadelphia. â?&#x2019;

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Charles Raison, MD Jon W. Draud, MS, MD

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Jon W. Draud, MS, MD Rakesh Jain, MD, MPH 5:00 PM - 5:30 PM

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MAY 2011

CLINICAL PSYCHOPHARMACOLOGY Does MDMA Have a Role in Clinical Psychiatry? by Michael C. Mithoefer, MD ike every drug or technology that has therapeutic value, MDMA (3,4-methylenedioxymethamphetamine) has potential risks and benefits. Unlike most other drugs under clinical investigation, MDMA has a complex and controversial history that has delayed dispassionate scientific investigation into its therapeutic use. Fortunately, research efforts are now overcoming the liabilities of this history, and rigorous research that explores whether MDMA has a role in psychopharmacology is under way. MDMA was synthesized as an intermediate chemical, and it was patented in 1912 by Merck.1 The first published report of MDMA given to patients appeared in 1978, long after the Merck patent had expired. Shulgin and Nichols2 described the effect of MDMA as “an easily controlled altered state of consciousness with emotional and sensual overtones.” Shulgin introduced the compound to colleagues who were therapists, and the use of MDMA as a catalyst to psychotherapy was taken up by a number of psychiatrists and other therapists in the United States. A few favorable reports of its use appeared in the literature, although there were no controlled clinical trials.3,4 MDMA was neither an approved medication nor an illegal substance, but as it was increasingly marketed under the name “ecstasy” and as recreational use grew, it eventually drew the attention of lawmakers. In 1985, the Drug Enforcement Administration (DEA) deemed MDMA a Schedule 1 substance despite the testimony of physicians and the recommendation of an administrative law judge who sug-

gested that it be a Schedule 3 substance.5 Following this decision, clinical research with MDMA was severely curtailed, but in the past several years it has been gaining momentum.

Recent research A number of phase 1 safety studies have been done in the United States and Europe, and a phase 2 trial was started in Spain but halted for political reasons unrelated to drug safety.6-15 Additional phase 2 trials are under way in the United States and Switzerland and will soon begin in Israel, Jordan, and Canada. With the exception of 1 study of anxiety associated with advanced stage cancer in the United States, these trials are all directed at studying MDMAassisted psychotherapy for posttraumatic stress disorder (PTSD). It is noteworthy that all of these clinical trials are using MDMA as an adjunct to psychotherapy, rather than as a stand-alone medication. The drug is administered on only 2 or 3 occasions under direct supervision by a psychiatrist and a cotherapist during prolonged psychotherapy sessions, and treatment effects are compared with those of the same therapy without MDMA. The hypothesis that MDMA catalyzes psychotherapy, now being tested with these rigorous study designs, is derived from earlier © Sandra Dionisi/theiSpot.com published reports of the clinical use of MDMA and is consistent with the current understanding of the pharmacology of MDMA. In 1986, Greer and Tolbert3 published a report on 29 volunteers to whom MDMA had been administered in the presence of a male and a female thera-

Special Report Chairperson: Thomas L. Schwartz, MD

ALSO IN THIS SPECIAL REPORT:

50 Ethical Issues in Psychopharmacology Laura Weiss Roberts, MD, MA Shaili Jain, MD

Additional articles in this Special Report on Clinical Psychopharmacology can be found in the April 2011 issue of Psychiatric Times or at www.psychiatrictimes.com.

MAY 2011

CLINICAL PSYCHOPHARMACOLOGY

pist. The participants reported benefits such as “enhanced self-understanding [and] insight into personal patterns or problems, greater selfconfidence or self-acceptance, lowered defenses [while] undergoing a therapeutic emotional process,” and “less negative thoughts or feelings.”

A study of MDMA We recently published the first completed phase 2 pilot study of MDMA as a therapeutic agent.16 This was a double-blind placebo-controlled pilot study of MDMA-assisted psychotherapy in 20 patients with chronic, treatment-resistant PTSD. MDMA was administered to carefully screened participants under direct supervision during two 8-hour psychotherapy sessions with male and female cotherapists, using a nondirective method of therapy that is currently being manualized.17 Nondrug psychotherapy sessions prepared participants for the MDMA sessions, and follow-up psychotherapy sessions helped them integrate their experiences.

sion. All had a similar improvement. This was a pilot study with a small total number of participants designed to test proof of concept and safety in a patient population. Despite this low power, the results did reach statistical significance. The results of a recently completed long-term follow-up showed that 2 patients experienced symptom relapse. However, most maintained symptomatic improvement for a mean of 3.5 years.18 This study was not designed to determine the mechanism of action of MDMA-assisted psychotherapy; however, our clinical observations, as well as our formal results, can be partially explained on the basis of the current understanding of the pharmacology of MDMA. Although we observed a wide range of individual variation in the nature of participants’ experiences during and following MDMA sessions, much of the beneficial effect fell into 1 of 2 categories, both of which were experienced at various times by most patients.

What is already known about MDMA (3,4-methylenedioxymethamphetamine) and its role in clinical psychiatry? Anecdotal reports of clinical use before it was placed in Schedule 1 have suggested that MDMA may have clinical utility.

What new information does this article add? This article discusses the promising results of the first completed clinical trial of MDMA as a potential psychiatric treatment.

What are the implications for psychiatric practice? Pending further research, MDMA may have a role as an adjunct to psychotherapy for posttraumatic stress disorder and other psychiatric disorders.

Standard outcome measures of PTSD symptoms—the ClinicianAdministered PTSD Scale (CAPS) was the primary measure—showed that the MDMA group had statistically clinically significant improvement compared with the placebo group, which had received the same psychotherapy (CAPS improvement, P = .015; clinical improvement, greater than 30%; CAPS reduction of 83% in MDMA group vs 25% in placebo group). Figure 1 shows the CAPS results at 2-month follow-up. Seven of the 8 placebo recipients elected to enter an open-label crossover continuation phase in which they received MDMA on 2 occasions with the same schedule of psychotherapy before and after each ses-

Overcoming obstacles to therapeutic processing of trauma. MDMA appeared to lower fear levels while increasing access to emotions in general—including painful emotions. This created an opportunity for patients to process painful, traumatic experiences while avoiding the extremes of either being overwhelmed by emotions or experiencing emotional numbing (both common features of PTSD). One of our study participants said: Without the study I don’t think I could have ever dug down deep, I was so afraid of the fear. In the sessions there was just no fear; that builds your confidence. When I tried in therapy before, it would send me into a tailspin.

After an MDMA-assisted session, another participant told us: It’s like night and day for me compared to other methods of therapy. Without MDMA, I didn’t even know where I needed to go. Maybe one of the things the drug does is let your mind relax and get out of the way because the mind is so protective about the injury. Corrective positive experiences. During MDMA sessions, the experiences of the participants were often emotionally challenging, but in addition to these challenging, painful experiences, most participants, at other times in the sessions, also had positive, affirming experiences. They often experienced a sense of comfort and joy that they may not have felt for years, and they were frequently left with a more positive perspective about the world. Consequently, the cognitive distortions and unrealistic fears that had accompanied PTSD were corrected. For example, one man who had been sexually abused as a child told us that he had spent his adult life observing that other people were having an experience that he presumed must be what they called “happiness”—something he had not experienced and had always assumed he was incapable of experiencing. During his MDMA session, he felt happy for the first time in memory. Hopelessness was replaced by the conviction that happiness was no longer beyond his reach, and indeed, he then discovered the ability to feel happiness without MDMA. Many other participants felt this way as well. One woman said: I feel like I’m walking in a place I’ve needed to go for so long and just didn’t know how to get there. I feel like I know myself better than I ever have before. Now I know I’m a normal person. I’ve been through some bad stuff, but . . . those are things that happened to me, not who I am. . . . This is me, the medicine helps, but this is in me.

Possible mechanisms While the format of MDMA-assisted psychotherapy and the nondirective therapeutic approach we used are (Please see MDMA, page 38)

PSYCHIATRIC TIMES www.psy c h i a t r i c t i m e s. c o m

MDMA Continued from page 37

quite different from many existing treatments for PTSD, some elements of what occurs in MDMA-assisted therapy would be easily recognizable to many therapists. The first category of effects discussed above, in which MDMA appears to remove obstacles to effective trauma processing, can be understood in terms used by Foa and colleagues19 to describe obstacles to prolonged exposure therapy: overengagement and underengagement. To be effective, exposure must be accompanied by a degree of emotional engagement or fear activation while avoiding dissociation or overwhelming emotion.20 This has been referred to as working within the optimal arousal zone, or window of tolerance.21-23 During MDMA sessions, we observed that patients with PTSD

MAY 2011

CLINICAL PSYCHOPHARMACOLOGY MDMA administration has been associated with greater sociability and more gregarious behavior.24 MDMA has recently been shown to decrease perception of negative emotions in others and perception of threat-related signals, such as fear, which might increase social approach behavior.40 It has been postulated that prolactin release following MDMA administration may contribute to a postorgasmic-like sense of relaxation and receptivity.41 The neurocircuitry model of PTSD postulates a deficit in extinction of fear conditioning mediated by the amygdala and the ventromedial prefrontal cortex, a model supported by findings of reduced hippocampal activity and volume, increased activity in the amygdala, and decreased activation of the medial prefrontal cortex in persons with PTSD.42,43 Gamma and colleagues 44 used positron emission tomography to

cially when the drug first took effect. Often in the days after an MDMA session, patients had second thoughts about what they had discussed dur-

ing the session. With proper support, participants could successfully process these doubts and any accompanying emotions and could come

CAPS mean scores by group for Time 1 to Time 4

Figure 1

Placebo M = 69.9 SE = 6.9

MDMA M = 43.0 SE = 5.7

60 50

Mean CAPS

40 30 20 10 0

spontaneously engaged in “imaginal exposure,” and MDMA appeared to allow them to remain within an optimal arousal zone while doing so. The pharmacological effects of MDMA include serotonin release; serotonin type 2 receptor stimulation; and an increase in levels of the neurohormones oxytocin, prolactin, and cortisol.24-29 Serotonin release plays an important role in producing the subjective effects of MDMA.30-33 Pretreatment with SSRIs reduces most acute subjective and physiological effects of MDMA, including effects on mood and perception. Serotonin release directly or indirectly leads to an elevation in oxytocin levels, possibly by stimulating serotonin type 1A receptors.24,28,34 Studies suggest that oxytocin plays an important role in stress response, reduces the fear response, and increases social affiliation and trust35-39; thus, elevated oxytocin levels might help patients form a therapeutic alliance and revisit traumatic experiences in an emotionally engaged state. Elevation in oxytocin levels after

measure cerebral blood flow 75 minutes after MDMA was given to healthy volunteers. Their findings showed increases in cerebral blood flow in the ventromedial frontal and occipital cortex and decreases in the left amygdala. MDMA may produce some of its effects through these acute changes in brain activity, which may reverse abnormalities associated with PTSD and thereby allow effective processing of traumatic memories. The nature of the effects is consistent with much of what we observed in our clinical trial.

Risks of MDMA MDMA administration carries psychological risks, such as increased anxiety, confusion, ruminations, and dissociation.9,26,45 Our findings suggest that at the doses we used, these risks can be mitigated with proper preparation, a supportive setting during MDMA sessions, and good follow-up to facilitate integration. Some patients in our study had intense anxiety and needed reassurance during MDMA sessions, espe-

Time Time 1: baseline < 4 weeks before first experimental session and after discontinuing any psychotropic medications Placebo = 79.6 (8.1); MDMA = 79.2 (6.6) Time 2: 3 - 5 days after first experimental session Placebo = 74.1 (10.3); MDMA = 37.8 (8.4) Time 3: 3 - 5 days after second experimental session Placebo = 66.8 (8.0); MDMA = 29.3 (6.5) Time 4: 2 months after second experimental session Placebo = 59.1 (9.4); MDMA = 25.5 (7.7) CAPS, Clinician-Administered PTSD Scale; M, mean; SE, standard error; MDMA, 3,4-methylenedioxymethamphetamine. Reprinted from Mithoefer MC et al16 with permission from Sage Publishing © 2010.

Figure 2

RBANS scores before and after MDMA and placebo administration Placebo MDMA

140 120 100 RBANS score

Further trials will determine whether the study results will evolve into clinical applications . . . it is likely that MDMA may find an important place in the future of psychopharmacology.

80 60 40 20 0 Baseline

2-month follow-up

MAY 2011

to recognize these challenges as a meaningful part of healing. The fact that this close follow-up was necessary to address psychological difficulties underscores the potential problems that may be associated with MDMA in recreational settings. In illicit settings, in addition to these psychological risks, the primary acute risks of ecstasy (which may contain varying amounts of MDMA and other substances) involve hyperthermia and dehydration or overhydration, with resulting water intoxication and cerebral edema. These complications are highly unlikely in a controlled research setting. MDMA predictably causes increases in pulse rate and blood pressure that could be dangerous for persons with underlying cardiovascular disease. We excluded patients with any serious medical problems and psychiatric problems such as psychosis, bipolar disorder type 1, and active addiction, and we did not encounter any drug-related serious adverse events. Some controversy remains about adverse long-term neurocognitive effects in ecstasy users. Following their meta-analysis of cognitive functions of ecstasy users, Rogers and colleagues46 cautiously concluded that the drug may significantly affect verbal memory, with a lesser effect on visual memory. However, results from other meta-analyses were somewhat contradictory.47,48 A definitive conclusion about the adverse effects of MDMA remains elusive because of the considerable methodological challenges involved in studying illicit drug users; however, a very recent study by Halpern and colleagues49 that was designed to minimize these methodological problems “found little evidence of decreased cognitive performance in ecstasy users save for poorer strategic self-regulation, possibly reflecting impulsivity . . . which may have been a pre-morbid attribute of ecstasy users.” More germane to an assessment of the risks of clinical administration is the fact that there has been no evidence of memory loss or other adverse neuropsychological effects after administration of a few doses of pure MDMA in medical settings in phase 1 or phase 2 studies. In our 20 participants, we measured neurocognitive function before and after 2 doses of MDMA or 2 doses of placebo and found no indication of adverse effects.16 This is represented by the Repeatable Battery for the Assessment of Neuropsycholog-

CLINICAL PSYCHOPHARMACOLOGY ical Status (RBANS) scores shown in Figure 2. It is important to point out that our safety data should not be taken to imply that there are no psychological and physical risks accompanying the use of ecstasy, or even pure MDMA in other settings, at higher and more frequent doses, and when used in an addictive pattern,

which can be highly problematic. Like many of the drugs we use in medicine, MDMA can be dangerous when it is used inappropriately or when it is abused.

The future of MDMA in psychiatry These early results provide encouragement that MDMA-assisted psy-

PSYCHIATRIC TIMES

chotherapy may prove to be a valuable treatment for PTSD. However, there is still a long way to go from promising phase 2 trials to the demonstration of safety and efficacy in much larger phase 3 studies, which would be required for FDA approval of MDMA as a prescription medicine. (Please see MDMA, page 49)

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• The management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain (CLBP) and chronic pain due to osteoarthritis (OA).

• The treatment of generalized anxiety disorder • The management of diabetic peripheral neuropathic pain (DPNP). (GAD). The efficacy of Cymbalta was established in 3 short-term trials and • The management of fibromyalgia (FM). 1 maintenance trial. DD69562 0511

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Important Safety Information About Cymbalta Warning: Suicidality and Antidepressant Drugs—Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients.

(cont.) See Important Safety Information, including Boxed Warning, above and on next page, and Brief Summary of Prescribing Information on following pages.

Important Safety Information About Cymbalta (Cont.) Contraindications • Concomitant use in patients taking Monoamine Oxidase Inhibitors (MAOIs) is contraindicated due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions may include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI. • Cymbalta was associated with an increased risk of mydriasis; therefore, it should not be used in patients with uncontrolled narrow-angle glaucoma and used cautiously in patients with controlled narrow-angle glaucoma. Warnings and Precautions • Clinical Worsening and Suicide Risk All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially within the first few months of treatment and when changing the dose. Consider changing the therapeutic regimen, including possibly discontinuing the medication in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, or suicidality that are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If discontinuing treatment, the medication should be tapered. Families and caregivers of patients being treated with antidepressants for any indication should be alerted about the need to monitor patients. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

• Hepatic failure, sometimes fatal, has been reported in patients treated with Cymbalta. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. • Because it is possible that Cymbalta and alcohol may interact to cause liver injury or that Cymbalta may aggravate pre-existing liver disease, Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. • Orthostatic hypotension and syncope have been reported with therapeutic doses of Cymbalta. This tends to occur within the first week of therapy but can occur at any time during Cymbalta treatment, particularly after dose increases. Consideration should be given to discontinuing Cymbalta in patients who experience symptomatic orthostatic hypotension and/or syncope. • The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Cymbalta treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. Concomitant use with serotonin precursors (e.g., tryptophan) is not recommended. Treatment with duloxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. (cont.)

Important Safety Information About Cymbalta (Cont.) Warnings and Precautions (Cont.) • SSRIs and SNRIs, including Cymbalta, may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with concomitant use of Cymbalta and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation. • On abrupt or tapered discontinuation, spontaneous reports of adverse events, some of which may be serious, have been reported during the marketing of SSRIs and SNRIs. A gradual reduction in dose rather than abrupt cessation is recommended when possible.

• As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes. In the extension phases (up to 52 weeks) of the DPNP studies, an increase in HbA1c in both the Cymbalta (0.5%) and the routine care groups (0.2%) was noted. • Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during Cymbalta treatment, this effect may be drug-related. In postmarketing experience, urinary retention has been observed. Use in Specific Populations

• Cymbalta should be used cautiously in patients with a history of mania or with a history of a seizure disorder.

• Pregnancy and Nursing Mothers: Use only if the potential benefit justifies the potential risk to the fetus or child.

• In clinical trials across indications relative to placebo, treatment with Cymbalta was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.4 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment.

• The most commonly reported adverse events (≥5% and at least twice placebo) for Cymbalta vs placebo in controlled clinical trials (N=6020 vs 3962) were: nausea (24% vs 8%), dry mouth (13% vs 5%), somnolence* (10% vs 3%), fatigue (10% vs 5%), constipation* (10% vs 4%), dizziness (10% vs 5%), decreased appetite* (8% vs 2%), and increased sweating (7% vs 2%).

• Co-administration of Cymbalta with potent CYP1A2 inhibitors or thioridazine should be avoided. • SSRIs and SNRIs, including Cymbalta, have been associated with cases of clinically significant hyponatremia that appeared to be reversible when Cymbalta was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. • The effect that alterations in gastric motility may have on the stability of the enteric coating of Cymbalta is unknown. As duloxetine is rapidly hydrolyzed in acidic media to naphthol, caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). • Cymbalta should ordinarily not be administered to patients with any hepatic insufficiency or patients with end-stage renal disease (requiring dialysis) or severe renal impairment (creatinine clearance <30 mL/min).

Most Common Adverse Events

* Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies that did not have a placebo lead-in period or dose titration. • In placebo-controlled clinical trials, the overall discontinuation rates due to adverse events were: MDD: 9% vs 5%; GAD: 15% vs 4%; DPNP: 13% vs 5%; FM: 20% vs 12%; OA: 16% vs 6%; CLBP: 17% vs 6%. The common adverse events reported as a reason for discontinuation and considered to be drug related were: MDD: nausea (1.3% vs 0.5%). GAD: nausea (3.7% vs 0.2%), vomiting (1.3% vs 0%), dizziness (1.0% vs 0.2%). DPNP: nausea (3.5% vs 0.7%), dizziness (1.2% vs 0.4%), somnolence (1.1% vs 0%). FM: nausea (1.9% vs 0.7%), somnolence (1.5% vs 0%), fatigue (1.3% vs 0.2%). OA: nausea (2.9% vs 0.8%), asthenia (1.3% vs 0%). CLBP: nausea (3.0% vs 0.7%), somnolence (1.0% vs 0%).

For more safety information, please see Brief Summary of Prescribing Information, including Boxed Warning, on following pages. DD HCP ISI 4NOV10 DD69562 0511

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The Cymbalta Promise Program provides resources to help appropriate patients at the start of and throughout their treatment plan with Cymbalta. Your patients can sign up to receive ongoing information and educational materials and tools during treatment. If eligible, they can also enroll in the 60-day money-back offer. If you and your patients new to Cymbalta aren’t satisfied, patients may be reimbursed up to 100% of their out-ofpocket prescription costs for the first 60 days on Cymbalta.* To get your patients started in the Cymbalta Promise Program, have them visit cymbalta.com/ promiseprogram, call 1-877-CYMBALTA, or complete and return the enrollment reply card in the Getting Started With Cymbalta brochure. * Restrictions apply. See full Terms and Conditions. The 60-day money-back offer is not a guarantee of efficacy. It provides a trial period that may help you and your patients assess the efficacy, safety, and tolerability of Cymbalta.

Reimbursement offered for up to 60 days of Cymbalta therapy to a maximum of $700. Prescriptions for more than 2 capsules per day are not eligible for reimbursement. Limit one reimbursement per person. Offer void where prohibited by law. Valid only in the United States for US residents. Offer not valid for patients whose prescription claims for Cymbalta are reimbursed, in whole or in part, by (1) any governmental program, including, without limitation, Medicaid, Medicare, or any other federal or state program, such as Champus, the VA, TRICARE, or a state pharmaceutical assistance program, or (2) any third-party payer in the state of Massachusetts. By accepting this offer, patient agrees to notify his/her insurance carrier of reimbursement if required to do so by law or under the terms of coverage. Additional exclusions may apply and this offer may be terminated, rescinded, revoked, or amended by Lilly USA, LLC, at any time without notice. Cymbalta® and the Cymbalta logo are registered trademarks of Eli Lilly and Company.

Select Important Safety Information About Cymbalta • Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with major depressive disorder (MDD) and other psychiatric disorders. • Patients of all ages started on therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. • Cymbalta is not approved for use in pediatric patients. See Important Safety Information, including Boxed Warning, on previous pages, and Brief Summary of Prescribing Information on following pages.

INDICATIONS AND USAGE: Major Depressive Disorder—Cymbalta is indicated for the acute and maintenance treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in four short-term trials and one maintenance trial in adults. Generalized Anxiety Disorder—Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD). The efficacy of Cymbalta was established in three short-term trials and one maintenance trial in adults. Diabetic Peripheral Neuropathic Pain—Cymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy. Fibromyalgia—Cymbalta is indicated for the management of fibromyalgia (FM). Chronic Musculoskeletal Pain—Cymbalta is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain (CLBP) and chronic pain due to osteoarthritis. CONTRAINDICATIONS: Monoamine Oxidase Inhibitors—Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions may include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome [see Warnings and Precautions]. Uncontrolled Narrow-Angle Glaucoma—In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS: Clinical Worsening and Suicide Risk— Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Warnings and Precautions for descriptions of the risks of discontinuation of Cymbalta]. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder—A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Cymbalta (duloxetine) is not approved for use in treating bipolar depression. Hepatotoxicity—There have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (89/29,435) of Cymbalta-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.37% (132/9611) of Cymbalta-treated patients compared to 0.49% (35/7182) of placebo-treated patients. In placebocontrolled studies using a fixed-dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. Orthostatic Hypotension and Syncope—Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine treatment, particularly after dose increases. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions and Drug Interactions] and in patients taking duloxetine at doses above 60 mg daily. Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during duloxetine therapy. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions—The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Cymbalta treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant

syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Cymbalta with MAOIs intended to treat depression is contraindicated [see Contraindications]. If concomitant treatment of Cymbalta with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions]. The concomitant use of Cymbalta with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions]. Treatment with duloxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Abnormal Bleeding—SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation. Discontinuation of Treatment with Cymbalta—Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, fatigue, vomiting, irritability, insomnia, diarrhea, anxiety, and hyperhidrosis. During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration]. Activation of Mania/Hypomania—In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (2/2489) of duloxetine-treated patients and 0.1% (1/1625) of placebo-treated patients. No activation of mania or hypomania was reported in GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Cymbalta should be used cautiously in patients with a history of mania. Seizures—Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials, seizures/convulsions occurred in 0.03% (3/10,524) of patients treated with duloxetine and 0.01% (1/7699) of patients treated with placebo. Cymbalta should be prescribed with care in patients with a history of a seizure disorder. Effect on Blood Pressure—In placebo-controlled clinical trials across indications from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.4 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see Adverse Reactions]. Clinically Important Drug Interactions—Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potential for Other Drugs to Affect Cymbalta CYP1A2 Inhibitors—Co-administration of Cymbalta with potent CYP1A2 inhibitors should be avoided [see Drug Interactions]. CYP2D6 Inhibitors—Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine [see Drug Interactions]. Potential for Cymbalta to Affect Other Drugs Drugs Metabolized by CYP2D6—Co-administration of Cymbalta with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines, and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Cymbalta. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Cymbalta and thioridazine should not be co-administered [see Drug Interactions].

CYMBALTA® (duloxetine hydrochloride)

CYMBALTA (duloxetine hydrochloride) Delayed-Release Capsules Brief Summary: Consult the package insert for complete prescribing information. WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. [See Warnings and Precautions and Use in Speciﬁc Populations.]

PV 7213 AMP

Other Clinically Important Drug Interactions Alcohol—Use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions and Drug Interactions]. CNS Acting Drugs—Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see Warnings and Precautions and Drug Interactions]. Hyponatremia—Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Cymbalta. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Cymbalta was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations]. Discontinuation of Cymbalta should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. Use in Patients with Concomitant Illness—Clinical experience with Cymbalta in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Cymbalta’s enteric coating. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Cymbalta has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing. Hepatic Insufficiency—Cymbalta should ordinarily not be used in patients with hepatic insufficiency [see Warnings and Precautions and Use in Specific Populations]. Severe Renal Impairment—Cymbalta should ordinarily not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min). Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see Use in Specific Populations]. Controlled Narrow-Angle Glaucoma—In clinical trials, Cymbalta was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma [see Contraindications]. Glycemic Control in Patients with Diabetes—As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12week acute treatment phase of these studies, Cymbalta was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Cymbalta group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the Cymbalta group and by 0.2% in the routine care groups. Urinary Hesitation and Retention—Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related. In postmarketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed. Laboratory Tests—No specific laboratory tests are recommended. ADVERSE REACTIONS: Clinical Trial Data Sources—The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=2489), GAD (N=910), OA (N=239), CLBP (N=600), DPNP (N=906), and FM (N=876). The population studied was 17 to 91 years of age; 65.5%, 62.5%, 61.5%, 42.9%, and 94.9% female; and 86.5%, 81.2%, 86.2%, 74.0%, and 88% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies (14)]. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials—Major Depressive Disorder— Approximately 9% (209/2327) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.7% (68/1460) of the patients receiving placebo. Nausea (duloxetine 1.3%, placebo 0.5%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drugrelated (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo). Generalized Anxiety Disorder—Approximately 15.3% (102/668) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 4.0% (20/495) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.7%, placebo 0.2%), and vomiting (duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine 1.0%, placebo 0.2%).

Diabetic Peripheral Neuropathic Pain—Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%). Fibromyalgia—Approximately 19.6% (172/876) of the patients who received duloxetine in 3- to 6-month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 11.8% (63/535) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 1.9%, placebo 0.7%), somnolence (duloxetine 1.5%, placebo 0.0%), and fatigue (duloxetine 1.3%, placebo 0.2%). Chronic Pain due to Osteoarthritis—Approximately 16.3% (39/239) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 5.6% (14/248) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.9%, placebo 0.8%) and asthenia (duloxetine 1.3%, placebo 0.0%). Chronic Low Back Pain—Approximately 16.5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%). Most Common Adverse Reactions—Pooled Trials for all Approved Indications—The most commonly observed adverse reactions in Cymbaltatreated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis. Diabetic Peripheral Neuropathic Pain—The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Fibromyalgia—The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation. Chronic Pain due to Osteoarthritis—The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, fatigue, and constipation. Chronic Low Back Pain—The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue. Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials—Table 2 in full PI gives the incidence of treatment-emergent adverse reactions in placebocontrolled trials (N=6020 Cymbalta; N=3962 placebo) for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo. These adverse events were: nausea, headache, dry mouth, fatigue (includes asthenia), somnolence* (includes hypersomnia and sedation), insomnia* (includes middle insomnia, early morning awakening, and initial insomnia), dizziness, constipation*, diarrhea, decreased appetite* (includes anorexia), and hyperhidrosis. *Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials—Pooled MDD and GAD Trials—Table 3 in full PI gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials (N=2995 Cymbalta; N=1955 placebo) for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo. These adverse events were: Cardiac Disorders—palpitations; Eye Disorders—vision blurred; Gastrointestinal Disorders—nausea, dry mouth, diarrhea, constipation*, abdominal pain (includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain), vomiting; General Disorders and Administration Site Conditions—fatigue (includes asthenia); Investigations—weight decreased*; Metabolism and Nutrition Disorders—decreased appetite (includes anorexia); Nervous System Disorders—dizziness, somnolence (includes hypersomnia and sedation), tremor; Psychiatric Disorders—insomnia (includes middle insomnia, early morning awakening, and initial insomnia), agitation (includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation), anxiety, libido decreased (includes loss of libido), orgasm abnormal (includes anorgasmia), abnormal dreams (includes nightmare); Reproductive System and Breast Disorders—erectile dysfunction, ejaculation delayed*, ejaculation disorder (includes ejaculation failure and ejaculation dysfunction); Respiratory, Thoracic, and Mediastinal Disorders—yawning; Skin and Subcutaneous Tissue Disorders—hyperhidrosis; Vascular Disorders—hot flush. *Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. DPNP, FM, OA, and CLBP—Table 4 in full PI gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled trials (N=2621 Cymbalta; N=1672 placebo) and with an incidence greater than placebo. These adverse events were: Gastrointestinal Disorders—nausea, dry mouth*, constipation*, diarrhea, abdominal pain (includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain), vomiting, dyspepsia (includes stomach discomfort); General Disorders and Administration Site Conditions—fatigue (includes asthenia); Infections and Infestations—nasopharyngitis, upper respiratory tract infection, influenza; Metabolism and Nutrition Disorders—decreased appetite* (includes anorexia); Musculoskeletal and Connective Tissue Disorders—musculoskeletal pain* (includes myalgia and neck pain), muscle spasm; Nervous System Disorders— headache, somnolence* (includes hypersomnia and sedation), dizziness, paraesthesia (includes hypoaesthesia, hypoaesthesia facial, and paraethesia

oral), tremor*; Psychiatric Disorders—insomnia* (includes middle insomnia, early morning awakening, and initial insomnia), agitation (includes feeling jittery, nervousness, restlessness, tension, and psychomotor hyperactivity); Reproductive System and Breast Disorders—erectile dysfunction*, ejaculation disorder; Respiratory, Thoracic, and Mediastinal Disorders—cough, oropharyngeal pain*; Skin and Subcutaneous Tissue Disorders—hyperhidrosis; Vascular Disorders—flushing (includes hot flush). *Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day. Effects on Male and Female Sexual Function—Changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score. Physicians should routinely inquire about possible sexual side effects. (See Table 5 in full PI for specific ASEX results.) Vital Sign Changes—In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.07 mm Hg in systolic blood pressure and 0.62 mm Hg in diastolic blood pressure compared to mean decreases of 1.31 mm Hg systolic and 0.73 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions]. Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.40 beats per minute. Weight Changes—In placebo-controlled clinical trials, MDD and GAD patients treated with Cymbalta for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In studies of DPNP, FM, OA, and CLBP, patients treated with Cymbalta for up to 26 weeks experienced a mean weight loss of approximately 0.6 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In one long-term fibromyalgia 60-week uncontrolled study, duloxetine patients had a mean weight increase of 0.7 kg. In one long-term CLBP 54-week study (13-week, placebo-controlled acute phase and 41-week, uncontrolled extension phase), duloxetine patients had a mean weight decrease of 0.6 kg in 13 weeks of acute phase compared to study entry, then a mean weight increase of 1.4 kg in 41 weeks of extension phase compared to end of acute phase. Laboratory Changes—Cymbalta treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Cymbalta-treated patients when compared with placebo-treated patients [see Warnings and Precautions]. Electrocardiogram Changes—Electrocardiograms were obtained from duloxetine-treated patients and placebo-treated patients in clinical trials lasting up to 13 weeks. No clinically significant differences were observed for QTc, QT, PR, and QRS intervals between duloxetine-treated and placebotreated patients. There were no differences in clinically meaningful QTcF elevations between duloxetine and placebo. In a positive-controlled study in healthy volunteers using duloxetine up to 200 mg twice daily, no prolongation of the corrected QT interval was observed. Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine—Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 29,435 patients were treated with duloxetine. Of these, 30.4% (8953) took duloxetine for at least 6 months, and 14.7% (4317) for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Cardiac Disorders—Frequent: palpitations; Infrequent: myocardial infarction and tachycardia. Ear and Labyrinth Disorders—Frequent: vertigo; Infrequent: ear pain and tinnitus. Endocrine Disorders—Infrequent: hypothyroidism. Eye Disorders—Frequent: vision blurred; Infrequent: diplopia and visual disturbance. Gastrointestinal Disorders—Frequent: flatulence; Infrequent: eructation, gastritis, halitosis, and stomatitis; Rare: gastric ulcer, hematochezia, and melena. General Disorders and Administration Site Conditions—Frequent: chills/rigors; Infrequent: feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance. Infections and Infestations—Infrequent: gastroenteritis and laryngitis. Investigations— Frequent: weight increased; Infrequent: blood cholesterol increased. Metabolism and Nutrition Disorders—Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia. Musculoskeletal and Connective Tissue Disorders—Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching. Nervous System Disorders—Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria. Psychiatric Disorders— Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide. Renal and Urinary Disorders—Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal. Reproductive System and Breast Disorders—Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, and sexual dysfunction. Respiratory, Thoracic and Mediastinal Disorders—Frequent: yawning; Infrequent: throat tightness. Skin and Subcutaneous Tissue Disorders—Infrequent:

CYMBALTA® (duloxetine hydrochloride)

PV 7213 AMP

cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis. Vascular Disorders—Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness. Postmarketing Spontaneous Reports—The following adverse reactions have been identified during postapproval use of Cymbalta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, erythema multiforme, extrapyramidal disorder, galactorrhea, glaucoma, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria. Serious skin reactions including Stevens-Johnson Syndrome that have required drug discontinuation and/or hospitalization have been reported with duloxetine. DRUG INTERACTIONS: Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Inhibitors of CYP1A2—When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions]. Inhibitors of CYP2D6—Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions]. Dual Inhibition of CYP1A2 and CYP2D6—Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)—Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see Warnings and Precautions]. Lorazepam—Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration. Temazepam—Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. Drugs that Affect Gastric Acidity—Cymbalta has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of Cymbalta with aluminum- and magnesium-containing antacids (51 mEq), or Cymbalta, with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption [see Warnings and Precautions]. Drugs Metabolized by CYP1A2—In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily). Drugs Metabolized by CYP2D6—Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions]. Drugs Metabolized by CYP2C9—Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated, although clinical studies have not been performed. Drugs Metabolized by CYP3A—Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed. Drugs Metabolized by CYP2C19—Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed. Monoamine Oxidase Inhibitors—[See Contraindications and Warnings and Precautions.] Switching Patients to or from a Monoamine Oxidase Inhibitor—At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI [see Contraindications and Warnings and Precautions]. Serotonergic Drugs—Based on the mechanism of action of SNRIs and SSRIs, including Cymbalta, and the potential for serotonin syndrome, caution is

advised when Cymbalta is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort. The concomitant use of Cymbalta with other SSRIs, SNRIs, or tryptophan is not recommended [see Warnings and Precautions]. Triptans—There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions]. Alcohol—When Cymbalta and ethanol were administered several hours apart so that peak concentrations of each would coincide, Cymbalta did not increase the impairment of mental and motor skills caused by alcohol. In the Cymbalta clinical trials database, three Cymbalta-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions]. CNS Drugs—[See Warnings and Precautions.] Drugs Highly Bound to Plasma Protein—Because duloxetine is highly bound to plasma protein, administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. USE IN SPECIFIC POPULATIONS: Pregnancy—Teratogenic Effects, Pregnancy Category C—In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the human dose of 120 mg/day on a mg/m2 basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m2 basis in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and ≈1 times the human dose of 120 mg/day on a mg/m2 basis in rats; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects—Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. When treating pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cymbalta in the third trimester. Lilly maintains a pregnancy registry to monitor the pregnancy outcomes of women exposed to Cymbalta while pregnant. Healthcare providers are encouraged to register any patient who is exposed to Cymbalta during pregnancy by calling the Cymbalta Pregnancy Registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com. Labor and Delivery—The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers—Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics. (See Nursing Mothers section in full PI for additional information.) Pediatric Use—Safety and effectiveness in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions]. Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use—Of the 2418 patients in premarketing clinical studies of Cymbalta for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the 1761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or over. Premarketing clinical studies of GAD did not include sufficient numbers of subjects age 65 or over to determine whether they respond differently from younger subjects. In the MDD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Cymbalta, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. (See Geriatric Use section in full PI for additional information.)

Gender—Duloxetine’s half-life is similar in men and women. Dosage adjustment based on gender is not necessary. Smoking Status—Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers. Race—No specific pharmacokinetic study was conducted to investigate the effects of race. Hepatic Insufficiency—[See Warnings and Precautions-Use in Patients with Concomitant Illness.] (See Use in Patients with Concomitant IllnessHepatic Insufficiency section in full PI for additional information.) Severe Renal Impairment—[See Warnings and Precautions-Use in Patients with Concomitant Illness.] (See Use in Patients with Concomitant Illness-Severe Renal Impairment section in full PI for additional information.) DRUG ABUSE AND DEPENDENCE: Abuse—In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential. While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Cymbalta (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). Dependence—In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats. OVERDOSAGE: Signs and Symptoms—In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. Management of Overdose—There is no specific antidote to Cymbalta, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. (See Management of Overdose section in full PI for additional information.) NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility—Carcinogenesis—Duloxetine was administered in the diet to mice and rats for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis). In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors. Mutagenesis—Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo. Impairment of Fertility—Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility. PATIENT COUNSELING INFORMATION: See FDA-approved Medication Guide and Patient Counseling Information section of full PI. Additional information can be found at www.Cymbalta.com.

CYMBALTA® (duloxetine hydrochloride)

PV 7213 AMP

Literature revised: November 8, 2010

MAY 2011

MDMA Continued from page 39

Additional rigorous clinical trials will determine whether interesting early results will evolve into clinical applications. Nevertheless, given the considerable clinical experience with MDMA before it was deemed a schedule 1 substance, the robust results in the first controlled trial, and the intriguing—perhaps unique— qualities of MDMA administered in the context of psychotherapy, it is likely that MDMA may find an important place in the future of psychopharmacology. Dr Mithoefer is in private practice of psychiatry and clinical research in Mount Pleasant, SC. Dr Mithoefer reports that he receives funding from the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit organization for conducting research, protocol development, and training of other researchers, and for acting as medical monitor for other studies. Acknowledgment—The author thanks Lisa Jerome, MD, for her thoughtful suggestions about the manuscript as well as her work on the research, and his other fellow researchers, Mark Wagner, PhD, Ann Mithoefer, BSN, and Rick Doblin, PhD. References 1. Freudenmann RW, Oxler F, Bernschneider-Reif S. The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction. 2006;101:1241-1245. 2. Shulgin AT, Nichols DE. Characterization of Three New Psychotomimetics. 1978. http://www. ero wid.org/references/refs_view.php?A= ShowDocPartFrame&ID=961&DocPartID=832. Accessed February 23, 2011. 3. Greer G, Tolbert R. Subjective reports of the effects of MDMA in a clinical setting. J Psychoactive Drugs. 1986;18:319-327. 4. Holland J. The history of MDMA. In: Holland J, ed. Ecstasy: The Complete Guide. Rochester, VT: Inner Traditions; 2001:11-20. 5. Beck J, Rosenbaum M. The scheduling of MDMA (“Ecstasy”). In: Inciardi J, ed. Handbook of Drug Control in the United States. Westport, CT: Greenwood Press; 1990:303-316. 6. Vollenweider FX, Gamma A, Liechti M, Huber T. Psychological and cardiovascular effects and shortterm sequelae of MDMA (“ecstasy”) in MDMA-naïve healthy volunteers. Neuropsychopharmacology. 1998;19:241-251. 7. Dumont GJ, Verkes RJ. A review of acute effects of 3,4-methylenedioxymethamphetamine in healthy volunteers. J Psychopharmacol. 2006;20:176-187. 8. Freedman RR, Johanson CE, Tancer ME. Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl). 2005;183:248-256. 9. Liechti ME, Gamma A, Vollenweider FX. Gender

CLINICAL PSYCHOPHARMACOLOGY differences in the subjective effects of MDMA. Psychopharmacology (Berl). 2001;154:161-168. 10. Hasler F, Studerus E, Lindner K, et al. Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA. J Psychopharmacol. 2009;23:923-935. 11. Kuypers KP, Ramaekers JG. Transient memory impairment after acute dose of 75mg 3.4-methylene-dioxymethamphetamine. J Psychopharmacol. 2005;19:633-639. 12. Kolbrich EA, Goodwin RS, Gorelick DA, et al. Physiological and subjective responses to controlled oral 3,4-methylenedioxymethamphetamine administration. J Clin Psychopharmacol. 2008;28:432440. 13. Ramaekers JG, Kuypers KP, Samyn N. Stimulant effects of 3,4-methylenedioxymethamphetamine (MDMA) 75 mg and methylphenidate 20 mg on actual driving during intoxication and withdrawal. Addiction. 2006;101:1614-1621. 14. Randall S, Johanson CE, Tancer M, Roehrs T. Effects of acute 3,4-methylenedioxymethamphetamine on sleep and daytime sleepiness in MDMA users: a preliminary study. Sleep. 2009;32:15131519. 15. Bouso JC, Doblin R, Farré M, et al. MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. J Psychoactive Drugs. 2008;40:225-236. 16. Mithoefer MC, Wagner MT, Mithoefer AT, et al. The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol. 2011;25:439-452. 17. Ruse JM, Mithoefer MC, Jerome L, Doblin R, Gibson E. MDMA-Assisted Psychotherapy for the Treatment of Posttraumatic Stress Disorder, A Revised Teaching Manual Draft. 2010. http://www.maps.org/ research/MDMA_treatment_manual_10_23_ 2010_.pdf. Accessed March 1, 2011. 18. Mithoefer MC, Wagner MT, Mithoefer AT, et al. Long term follow-up of subjects who completed a clinical trial of (MDMA)-assisted psychotherapy for treatment-resistant posttraumatic stress disorder (PTSD). Poster presented at: International Society for Traumatic Stress Studies 27th Annual Meeting; 2010; Montreal. 19. Foa EB, Keane TM, Friedman MJ, Cohen JA. Effective Treatments for PTSD: Practice Guidelines From the International Society for Traumatic Stress Studies. 2nd ed. New York: Guilford Press; 2009. 20. Foa EB, Hembree EA, Rothbaum BO. Prolonged Exposure Therapy for PTSD: Emotional Processing of Traumatic Experiences: Therapist Guide. New York: Oxford University Press; 2007. 21. Wilbarger P, Willbarger J. Sensory Defensiveness and Related Social/Emotional and Neurological Problems. Van Nuys, CA: Wilbarger; 1997. 22. Siegel DJ. The Developing Mind: Toward a Neurobiology of Interpersonal Experience. New York: Guilford Press; 1999. 23. Ogden P, Kekuni M, Pain C. Trauma and the Body: A Sensorimotor Approach to Psychotherapy. New York: WW Norton & Company; 2006. 24. Dumont GJ, Sweep FC, van der Steen R, et al. Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration. Soc Neurosci. 2009;4:359-366. 25. Grob CS, Poland RE, Chang L, Ernst T. Psychobiologic effects of 3,4-methylenedioxymethamphetamine in humans: methodological considerations and preliminary observations. Behav Brain Res. 1996;73:103-107.

26. Harris DS, Baggott M, Mendelson JH, et al. Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl). 2002;162:396-405. 27. Mas M, Farré M, de la Torre R, et al. Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans. J Pharmacol Exp Ther. 1999;290:136-145. 28. Thompson MR, Callaghan PD, Hunt GE, et al. A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine (“ecstasy”). Neuroscience. 2007;146:509514. 29. Wolff K, Tsapakis EM, Winstock AR, et al. Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population. J Psychopharmacol. 2006;20:400-410. 30. Farré M, Abanades S, Roset PN, et al. Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther. 2007;323:954-962. 31. Liechti ME, Saur MR, Gamma A, et al. Psychological and physiological effects of MDMA (“Ecstasy”) after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans. Neuropsychopharmacology. 2000;23:396-404. 32. Liechti ME, Vollenweider FX. The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine (“Ecstasy”) in healthy volunteers. J Psychopharmacol. 2000;14:269-274. 33. Tancer M, Johanson CE. The effects of fluoxetine on the subjective and physiological effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl). 2007;189:565573. 34. Baggott MJ, Galloway G, Jang M, et al. 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) and prazosin interactions in humans. Paper presented at: 70th Annual Meeting of the College on Problems of Drug Dependence; June 14-19, 2008; San Juan, Puerto Rico. 35. Zak PJ, Kurzban R, Matzner WT. Oxytocin is associated with human trustworthiness. Horm Behav. 2005;48:522-527. 36. Domes G, Heinrichs M, Gläscher J, et al. Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry. 2007;62: 1187-1190. 37. Kosfeld M, Heinrichs M, Zak PJ, et al. Oxytocin increases trust in humans. Nature. 2005;435:673676. 38. Baumgartner T, Heinrichs M, Vonlanthen A, et al. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron. 2008;58:639-650. 39. Olff M, Carter S, Heim C, et al. The role of oxytocin in traumatic stress. Paper presented at: 26th Annual Meeting of the International Society for Traumatic Stress Studies; November 3-6, 2010; Montreal. 40. Bedi G, Hyman D, de Wit H. Is ecstasy an “empathogen”? Effects of ±3,4-methylenedioxymethamphetamine on prosocial feelings and identification of emotional states in others. Biol Psychiatry. 2010; 68:1134-1140. 41. Passie T, Hartmann U, Schneider U, et al. Ecstasy (MDMA) mimics the post-orgasmic state: impairment of sexual drive and function during acute MDMA-effects may be due to increased prolactin secretion. Med Hypotheses. 2005;64:899-903. 42. Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research—past, present, and future. Biol Psychiatry. 2006;60:376-382. 43. Kirsch P, Esslinger C, Chen Q, et al. Oxytocin

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modulates neural circuitry for social cognition and fear in humans. J Neurosci. 2005;25:11489-11493. 44. Gamma A, Buck A, Berthold T, et al. 3,4-methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H(2)(15)O]-PET in healthy humans [published correction appears in Neuropsychopharmacology. 2000;23:following 598]. Neuropsychopharmacology. 2000;23:388-395. 45. Cami J, Farré M, Mas M, et al. Human pharmacology of 3,4-methylenedioxymethamphetamine (“ecstasy”): psychomotor performance and subjective effects. J Clin Psychopharmacol. 2000;20:455466. 46. Rogers G, Elston J, Garside R, et al. The harmful health effects of recreational ecstasy: a systematic review of observational evidence. Health Technol Assess. 2009;13:iii-iv, ix-xii, 1-315. 47. Laws KR, Kokkalis J. Ecstasy (MDMA) and memory function: a meta-analytic update. Hum Psychopharmacol. 2007;22:381-388. 48. Zakzanis KK, Campbell Z, Jovanovski D. The neuropsychology of ecstasy (MDMA) use: a quantitative review. Hum Psychopharmacol. 2007;22:427-435. 49. Halpern JH, Sherwood AR, Hudson JI, et al. Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs. Addiction. 2011;106:777-786. ❒

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CLINICAL PSYCHOPHARMACOLOGY

Ethical Issues in Psychopharmacology Considerations for Clinical Practice by Laura Weiss Roberts, MD, MA and Shaili Jain, MD ental illnesses affect men and women, children and the elderly, and communities and entire nations. Neuropsychiatric disorders, moreover, are the second-leading cause of disability throughout the world. Psychiatry centers on the care of people living with these severe and burdensome illnesses, and over the past 3 decades in particular, our profession has sought advances both in the neuroscience of these illnesses and in the development of novel, evidencebased treatments—including psychopharmacological interventions.1 Psychotropics are now among the most commonly prescribed of all medications, and the widened use of these agents has improved the lives of millions of individuals living with mental illness. Nevertheless, greater reliance on psychotropics has created ethical and societal concerns. Some concerns relate to the risks of pharmacological interventions, such as the paradoxical finding that depressed children who take antidepressants may have an increased risk of suicidal behavior relative to those receiving placebo. Moreover, there are potentially serious adverse metabolic effects (eg, hyperglycemia, diabetes) associated with atypical antipsychotics. There are also concerns about the widespread application (some would say overprescription)

of psychotropics—a controversy that is further fueled by the fact that nonpsychiatric providers are the source of most psychotropic prescriptions in the United States. New ethical issues have arisen around the use of psychotropics (such as stimulants) to enhance the cognitive performance of healthy individuals. Readers are referred to a recent review of the “cosmetic” use of neuroenhancers by Geppert and Taylor.2 Psychopharmacological compe-

nostic evaluation and careful review of the patient’s history (including past symptoms and response to treatment) are essential. Learning what the patient’s hopes, greatest concerns, and motivations are is essential to developing an appropriate therapeutic strategy that may include the use of psychopharmacological agents to address specific target symptoms. The goal is to prescribe psychotropic medications only when they are clearly indicated and when

There is no consensus that cosmetic psychopharmacology is absolutely unethical, and parallels have been drawn with plastic surgery for physical enhancement. tency necessitates a sensitivity to ethical considerations (Figure 1).3 Our aim here is to provide a brief overview of how psychiatrists may approach psychopharmacological treatment in an ethical manner. We first describe the basis for prescribing these agents in sound clinical practice; we then briefly cover a handful of key topics on psychopharmacological ethics.

Basis for ethical prescribing Before a patient is offered a psychotropic medication, a thorough diag-

What is already known about the ethical use of psychopharmacology? Psychotropic medications are among the most commonly prescribed of all pharmacological agents. Psychotropics have improved the lives of millions of individuals living with mental illness. Significant controversy exists surrounding ethical best practices in the prescription of psychotropics.

What new information does this article add? This article provides an overview of the salient ethical issues that practitioners encounter.

What are the implications for psychiatric practice? Psychiatrists who develop and refine their ethics “skill set” will be in a better position to anticipate and respond to ethical dilemmas as they arise in the course of their practice.

there is a strong evidence base. In many circumstances, combined biological and psychosocial interventions may offer the greatest therapeutic benefit. The ethical practitioner needs to keep up-to-date with empirical findings on all somatic and psychosocial treatments, including their indications, adverse effects, and contraindications. Moreover, clinicians who prescribe medications should be prepared to recommend relevant data-driven psychotherapies and psychosocial interventions that may be indicated as first-line treatment or as important adjunctive treatments—even if these must be provided by another practitioner. An ethical practitioner will also be able to engage in a trusting and grounded informed consent dialogue with the patient. If the diagnosis is uncertain, the goals of treatment are unclear, or the clinician is not confident of what steps to take next, then consultation with another individual with relevant expertise is prudent. This is particularly true with patients who have multiple problems and perhaps multiple possible diagnoses or with those who are especially difficult interpersonally. Be prepared to document the patient’s response to treatment in a manner that may be helpful in the fu-

ture and, with the patient’s permission, to communicate in a collaborative manner with others who are involved in the patient’s care—such as a psychotherapist, a primary care provider, or family members.

Informed consent Informed consent is the legal and ethical foundation of ethical health care.4 It is predicated on the therapeutic relationship and involves the provision of information, the decision-making capabilities of the patient, and authentic voluntarism.5 The therapeutic relationship is deeply respectful of the patient and places primacy on promoting health and alleviating suffering as the basis for any treatment recommendation. It is dedicated to beneficence and nonmaleficence (ie, seeking good and avoiding harm in the patient’s care). The information-sharing element of informed consent stresses the importance of communicating accurate, appropriate, and balanced information regarding the risks and benefits of treatment and treatment alternatives—including the risks and benefits of no treatment. Moreover, information sharing should incorporate the attitudes and values of the patient to the fullest extent possible. It can be difficult to know how much information to bring into the discussion with the patient. More often than not, the “reasonable person” standard guides how much information to share—in other words, what would a reasonable person need or wish to know to make a decision? If the likelihood of benefit is great and the adverse effects are limited and far less burdensome than the illness itself, then the information to be shared will be far less than if the promise of benefit is small and the adverse effects are extensive, very burdensome, or severe. In particular, if adverse effects of treatment are rare but are life-threatening, they should be made explicit in the consent dialogue. Furthermore, informed consent requires that the patient have sufficient decisional capacity to understand the question at hand. The assessment of decisional capacity is a clinical judgment of the patient’s

MAY 2011

ability to provide an informed, voluntary decision. The evaluation of decisional capacity involves careful exploration of 4 elements: • The patient’s capacity to communicate and thus his or her ability to express a preference • The patient’s capacity to understand relevant information • The patient’s capacity to think through choices in a rational manner • The patient’s capacity to appreciate the nature of his illness and the recommended treatment in the context of his life The final element of informed consent is voluntarism, ie, the patient’s ability to act in accordance with an authentic sense of what is right for him, in light of his own life context and belief system.6 Voluntarism is contingent on the patient’s developmental level; consider whether his illness affects his ability to discern his preferences, whether there are psychological or cultural factors that shape his sense of being free to make the decision, and whether the context supports autonomous decision making. A child, for instance, will be less able to offer an authentic, uncoerced decision than an adult, and a prisoner with mental illness who resides in a locked facility will be less able to offer an authentic, uncoerced decision than an outpatient with mental illness who resides in a community setting. The capacity to provide consent is always measured in relation to a specific decision. High-stakes decisions—those that involve risk to the patient or to the community, for example—are held to a higher, more rigorous standard. A distressed inpatient with psychotic symptoms and a history of self-harm who demands to leave the hospital should meet an exceptionally high standard for informed refusal of treatment in comparison with the patient who declines to have his blood drawn for a routine cholesterol check. The consequences of the first patient’s decision could be grave, whereas the second patient’s decision is unlikely to threaten life and well-being. Other aspects of the informed consent process and criteria for ethical involuntary treatment are discussed extensively elsewhere.3,5 High-risk pharmacotherapy clearly necessitates a very careful informed consent process. The clinician must understand all clinical alternatives and the emerging empirical literature that may have bear-

PSYCHIATRIC TIMES

CLINICAL PSYCHOPHARMACOLOGY ing on the patient’s case. Before talking with the patient about the treatment decision, it may be prudent to consult with expert colleagues. The decision needs to be presented to the patient in a balanced manner. The patient needs to be allowed to weigh the risks and benefits in the context of his life. Facilitating collaborative decision making—such as involving the patient’s loved ones

and discussing all options, including the risks of not treating—is key. Frequent follow-up and monitoring are also necessary.3,7 A pregnant woman potentially in need of psychotropic therapy presents an example of high-risk pharmacotherapy; the psychiatrist must consider the well-being of the mother and the risk to her fetus if therapy is undertaken or discontinued. The

principles of autonomy—beneficence, nonmaleficence, and justice—can guide clinicians in finding ethical approaches to providing care under such circumstances.8 Miller8 emphasizes the importance of relational ethics, ie, an emphasis on the perspective that the well-being of the patient and her baby are intertwined rather than at odds. (Please see Ethical Issues, page 54)

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Introducing the first and only FDA-approved treatment for pseudobulbar affect (PBA)1

About NUEDEXTA NUEDEXTATM is the first and only FDA-approved treatment for pseudobulbar affect (PBA). NUEDEXTA is an innovative combination of two well-characterized components; dextromethorphan hydrobromide (20 mg), the ingredient active in the central nervous system, and quinidine sulfate (10 mg), a metabolic inhibitor enabling therapeutic dextromethorphan concentrations. NUEDEXTA acts on sigma-1 and NMDA receptors in the brain, although the mechanism by which NUEDEXTA exerts therapeutic effects in patients with PBA is unknown. NUEDEXTA is indicated for the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurological conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the patientâ&#x20AC;&#x2122;s underlying emotional state. Studies to support the effectiveness of NUEDEXTA were performed in patients with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NUEDEXTA has not been shown to be safe and effective in other types of emotional lability

that can commonly occur, for example, in Alzheimerâ&#x20AC;&#x2122;s disease and other dementias. The primary outcome measure, laughing and crying episodes, was significantly lower in the NUEDEXTA arm compared to placebo. The secondary outcome measure, the Center for Neurologic Studies Lability Scale (CNS-LS), demonstrated a significantly greater mean decrease in CNS-LS score from baseline for the NUEDEXTA arm compared to placebo.

NUEDEXTA Important Safety Information NUEDEXTA can interact with other medications causing significant changes in blood levels of those medications and/or NUEDEXTA. NUEDEXTA is contraindicated in patients receiving drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine and pimozide) and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine. NUEDEXTA is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days.

™

Reconnect affect to emotion—with NUEDEXTA Significant relief from involuntary outbursts of crying and/or laughing1-3 • Reductions from baseline may be seen within the first week of treatment • Efficacy was sustained over the course of 12 weeks • The need for continued treatment should be reassessed periodically, as spontaneous improvement of PBA symptoms occurs in some patients

Helps patients achieve episode remission2 • Half of all patients taking NUEDEXTA were episode-free over their final 14 days in the study

Visit NUEDEXTA.com for more information

NUEDEXTA is contraindicated in patients with a known hypersensitivity to its components. NUEDEXTA may cause serious side effects, including possible changes in heart rhythm. NUEDEXTA is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome or a history suggestive of torsades de pointes, in patients with heart failure as well as patients with, or at risk of, complete atrioventricular (AV) block, unless the patient has an implanted pacemaker. NUEDEXTA causes dose-dependent QTc prolongation. When initiating NUEDEXTA in patients at risk of QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation of QT interval should be conducted at baseline and 3-4 hours after the first dose. The most common adverse reactions in patients taking NUEDEXTA are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma-glutamyltransferase, and flatulence.

NUEDEXTA may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls. Patients should take NUEDEXTA exactly as prescribed. Patients should not take more than 2 capsules in a 24-hour period, make sure that there is an approximate 12-hour interval between doses, and not take a double dose after they miss a dose. These are not all the risks from use of NUEDEXTA. For additional important safety information about NUEDEXTA, please see the full Prescribing Information at www.NUEDEXTA.com.

Please see Brief Summary of full Prescribing Information on adjacent page. References: 1. NUEDEXTA Prescribing Information, Avanir Pharmaceuticals. 2. Pioro EP, Brooks BR, Cummings J, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010;68(5):693-702. 3. Data on file, Avanir Pharmaceuticals, Inc. © 2011 Avanir Pharmaceuticals, Inc. All Rights Reserved. NUE-0157-ADV-0112

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CLINICAL PSYCHOPHARMACOLOGY

Ethical Issues

Clinical innovation

Continued from page 51

In psychiatric practice, patients commonly present with symptoms for which there are few or no FDAapproved treatments.2 Clinical innovation is needed to help patients. By definition, clinical innovation poses an ethical risk because it involves the application of interventions that have not been well or sufficiently proved in a research setting.9

Clinicians also need to anticipate and reduce the risks of ethical dilemmas that arise at the onset of care. Preventive ethics includes proactive discussions about family planning when treating women of childbearing age, before they become pregnant.8

NUEDEXTA™ (dextromethorphan HBr and quinidine sulfate) Capsules Brief Summary of Prescribing Information See package insert for full Prescribing Information INDICATIONS AND USAGE NUEDEXTA is indicated for the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurological conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the underlying emotional state. Studies to support the effectiveness of NUEDEXTA were performed in patients with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NUEDEXTA has not been shown to be safe and effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias. DOSAGE AND ADMINISTRATION The recommended starting dose of NUEDEXTA (20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate) is one capsule daily by mouth for the initial seven days of therapy. On the eighth day of therapy and thereafter, the daily dose should be a total of two capsules a day, given as one capsule every 12 hours. The need for continued treatment should be reassessed periodically, as spontaneous improvement of PBA occurs in some patients. CONTRAINDICATIONS Quinidine and related drugs: NUEDEXTA contains quinidine, and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine. Hypersensitivity: NUEDEXTA is contraindicated in patients with a history of NUEDEXTA, quinine, mefloquine or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome; also in patients with known hypersensitivity to dextromethorphan [see Warnings and Precautions (5.1 in full PI)]. MAOIs: NUEDEXTA is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. Allow at least 14 days after stopping NUEDEXTA before starting an MAOI [see Drug Interactions (7.1 in full PI)]. Cardiovascular: NUEDEXTA is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome or a history suggestive of torsades de pointes, and in patients with heart failure [see Warnings and Precautions (5.3 in full PI)]. NUEDEXTA is contraindicated in patients receiving drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine and pimozide), as effects on QT interval may be increased [see Drug Interactions (7.2 in full PI)]. NUEDEXTA is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or in patients who are at high risk of complete AV block. WARNINGS AND PRECAUTIONS Thrombocytopenia and Other Hypersensitivity Reactions: Quinidine can cause immunemediated thrombocytopenia that can be severe or fatal. Non-specific symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, can precede or occur with thrombocytopenia. NUEDEXTA should be discontinued immediately if thrombocytopenia occurs, unless the thrombocytopenia is not drug-related, as continued use increases the risk for fatal hemorrhage. Likewise, NUEDEXTA should not be restarted in sensitized patients, because of the risk of more rapid and more severe thrombocytopenia. NUEDEXTA should not be used if immune-mediated thrombocytopenia from structurally related drugs including quinine and mefloquine is suspected, as cross-sensitivity can occur. Quinidineassociated thrombocytopenia usually resolves within a few days of discontinuation of the sensitizing drug. Quinidine has also been associated with a lupus-like syndrome involving polyarthritis, sometimes with a positive ANA. Other associations include rash, bronchospasm, adenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, the sicca syndrome, myalgia, elevated serum levels of skeletal muscle enzymes, and pneumonitis. Hepatotoxicity: Hepatitis has been reported in patients receiving quinidine, generally during the first few weeks of therapy. Cardiac Effects: NUEDEXTA causes dose-dependent QTc prolongation [see Clinical Pharmacology (12.2 in full PI)]. QT prolongation can cause torsades de pointes-type ventricular tachycardia, with the risk increasing as prolongation increases. When initiating NUEDEXTA in at risk patients, ECG evaluation of QT interval should be done at baseline and 3-4 hours after the first dose. This includes patients concomitantly taking drugs that prolong the QT interval or that are strong or moderate CYP3A4 inhibitors, and patients with left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD). LVH and LVD are more likely to be present in patients with chronic hypertension, known coronary artery disease, or history of stroke. LVH and LVD can be diagnosed utilizing echocardiography or another suitable cardiac imaging modality. Reevaluate ECG if risk factors for arrhythmia change during the course of treatment. Risk factors include concomitant use of drugs associated with QT prolongation, electrolyte abnormality (hypokalemia, hypomagnesemia), bradycardia, and family history of QT abnormality. Hypokalemia and hypomagnesemia should be corrected prior to initiation of therapy with NUEDEXTA, and should be monitored during treatment. If patients experience symptoms that could indicate cardiac arrhythmias, e.g., syncope or palpitations, NUEDEXTA should be discontinued and the patient further evaluated. Concomitant use of CYP2D6 Substrates: The quinidine in NUEDEXTA inhibits CYP2D6 in patients in whom CYP2D6 is not otherwise genetically absent or its activity otherwise pharmacologically inhibited [see CYP2D6 Poor Metabolizers (5.8 in full PI), Pharmacokinetics (12.3 in full PI), Pharmacogenomics (12.5 in full PI)]. Because of this effect on CYP2D6, accumulation of parent drug and/or failure of active metabolite formation may decrease the safety and/or the efficacy of drugs used concomitantly with NUEDEXTA that are metabolized by CYP2D6 [see Drug Interactions (7.5 in full PI)]. Dizziness: In a controlled trial of NUEDEXTA, 10% of patients on NUEDEXTA and 5% on placebo experienced dizziness. Serotonin Syndrome: When used with SSRIs or tricyclic antidepressants, NUEDEXTA may cause serotonin syndrome, including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor [see Drug Interactions (7.4 in full PI), Overdosage (10 in full PI)]. Anticholinergic Effects of Quinidine: Monitor for worsening clinical condition in diseases that may be adversely affected by anticholinergic effects. CYP2D6 Poor Metabolizers: The quinidine component of NUEDEXTA is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone [see Concomitant use of CYP2D6 substrates (5.4 in full PI), Pharmacokinetics (12.3 in full PI), Pharmacogenomics (12.5 in full PI)]. Approximately 7-10% of Caucasians and 3-8% of African Americans are poor metabolizers (PMs) lacking capacity to metabolize CYP2D6. In patients who may be at risk of significant toxicity due to quinidine, consider genotyping to determine if they are PMs prior to treating with NUEDEXTA.

Turning to innovation and, on some level, deviating from usual standards of care, entails careful thought and a clear rationale, as described in the ethical decision tree in Figure 2. This approach is in keeping with that of Ghaemi and Goodwin,9 who have emphasized that clinical innovation in psychiatry should not be discouraged but, rather, should oc-

ADVERSE REACTIONS A total of 946 patients participated in four Phase 3 controlled and uncontrolled PBA studies and received at least one dose of the combination product of dextromethorphan hydrobromide/quinidine sulfate in various strengths at the recommended or higher than the recommended dose. In a 12-week, placebo-controlled study (N=326), the most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) that led to discontinuation were muscle spasticity (3%), respiratory failure (1%), abdominal pain (2%), asthenia (2%), dizziness (2%), fall (1%), and muscle spasms (2%). The most common adverse reactions (≥ 3% and ≥ 2X placebo) were diarrhea (13%), dizziness (10%), cough (5%), vomiting (5%), asthenia (5%), edema (5%), urinary tract infection (4%), influenza (4%), flatulence (3%) and increased GGT (3%). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Safety Experience of Individual Components: Dextromethorphan: Drowsiness, dizziness, nervousness or restlessness, nausea, vomiting, and stomach pain. Quinidine: Cinchonism (nausea, vomiting, diarrhea, headache, tinnitus, hearing loss, vertigo, blurred vision, diplopia, photophobia, confusion, and delirium) is most often a sign of chronic quinidine toxicity, but it may appear in sensitive patients after a single moderate dose of several hundred milligrams. Other adverse reactions occasionally reported with quinidine therapy include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photosensitivity, keratopathy, and abnormalities of skin pigmentation. DRUG INTERACTIONS MAOIs: Do not use NUEDEXTA with monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days [see Contraindications (4.3 in full PI)]. Drugs that Prolong QT and are Metabolized by CYP2D6: Do not use with drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide) [see Contraindications (4.4 in full PI)]. Drugs that Prolong QT and Concomitant CYP3A4 Inhibitors: Recommend ECG in these patients who are taking NUEDEXTA [see Warnings and Precautions (5.3 in full PI)]. SSRIs and Tricyclic Antidepressants: Use of NUEDEXTA with SSRIs or tricyclic antidepressants increases the risk of serotonin syndrome [see Warnings and Precautions (5.6 in full PI)]. CYP2D6 Substrate: The co-administration of NUEDEXTA with drugs that undergo extensive CYP2D6 metabolism may result in altered drug effects [see Warnings and Precautions (5.4 in full PI)]. Desipramine (CYP2D6 substrate): This tricyclic antidepressant is metabolized primarily by CYP2D6. A drug interaction study was conducted between a higher combination dose of dextromethorphan (dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg) and desipramine 25 mg. This dose increased steady state desipramine levels approximately 8-fold. If NUEDEXTA and desipramine are prescribed concomitantly, the initial dose of desipramine should be markedly reduced. The dose of desipramine can then be adjusted based on response, but a dose above 40 mg/day is not recommended. Paroxetine (CYP2D6 inhibitor and substrate): When the combination dose of dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg was added to paroxetine at steady state, paroxetine exposure (AUC0-24) increased by 1.7 fold and Cmax increased by 1.5 fold. Consider initiating treatment with a lower dose of paroxetine if given with NUEDEXTA. The dose of paroxetine can then be adjusted based on response, but dosage above 35 mg/ day is not recommended. Digoxin: Quinidine is an inhibitor of P-glycoprotein. Prescribing quinidine with digoxin, a P-glycoprotein substrate, results in serum digoxin levels that may be as much as doubled. Alcohol: As with any other CNS drug, caution should be used when NUEDEXTA is taken in combination with other centrally acting drugs and alcohol. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate studies of NUEDEXTA in pregnant women. Labor and Delivery: The effects of NUEDEXTA on labor and delivery are unknown. Nursing Mothers: It is not known whether dextromethorphan and/or quinidine are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NUEDEXTA is given to a nursing mother. Pediatric and Geriatric Use: The safety and effectiveness of NUEDEXTA in these populations has not been determined. Renal and Hepatic Impairment: Dose adjustment of NUEDEXTA is not required in patients with mild to moderate renal or hepatic impairment. Increases in dextromethorphan and/or quinidine levels are likely to be observed in patients with severe renal or hepatic impairment. DRUG ABUSE AND DEPENDENCE NUEDEXTA contains dextromethorphan, and dextromethorphan abuse has been reported, predominately in adolescents. These observations were not systematic and it is not possible to predict on the basis of this experience the extent to which NUEDEXTA will be misused once marketed. Therefore, patients with a history of drug abuse should be observed closely. OVERDOSAGE Evaluation and treatment of NUEDEXTA overdose is based on experience with the individual components. Treatment of dextromethorphan overdosage should be directed at symptomatic and supportive measures. Treatment of quinidine overdosage requires monitoring the QTc interval and should involve a healthcare provider experienced in cardiac arrhythmia prevention and treatment and Ơ-blockade-induced hypotension. Because of the theoretical possibility of QT prolongation that might be additive to those of quinidine, antiarrhythmics with Class I (procainamide) or Class III activities should (if possible) be avoided. PATIENT COUNSELING INFORMATION Physicians should discuss the following topics with patients when prescribing NUEDEXTA: Hypersensitivity: [see Contraindications (4.2 in full PI), Warnings and Precautions (5.1 in full PI)]. Cardiac effects: Consult their healthcare provider immediately if they feel faint or lose consciousness. Inform their healthcare provider if they have any personal or family history of QTc prolongation [see Contraindications (4.4 in full PI), Warnings and Precautions (5.3 in full PI) Drug Interactions (7 in full PI)]. Dizziness: [see Warnings and Precautions (5.5 in full PI), Adverse Reactions (6.1 in full PI)]. Drug Interactions: [see Drug Interactions (7 in full PI)]. Dosing: Instruct patients to take NUEDEXTA exactly as prescribed, not to take more than 2 capsules in a 24-hour period, to be sure that there is an approximate 12-hour interval between doses, and not to take a double dose after a missed dose. General: Contact their healthcare provider if their PBA symptoms persist or worsen. Advise patients to keep this and all medications out of reach of children and pets. Marketed by Avanir™ Pharmaceuticals, Inc., Aliso Viejo, CA 92656 1-855-4NUEDEX (468-3339) www.NUEDEXTA.com © 2011 Avanir Pharmaceuticals, Inc. Part No. 2000003072 / Rev. Date January 2011

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cur under ethical conditions. Clinical innovation should be based on a scientific hypothesis. In addition, clinicians should report their observations, such as unexpected psychotropic effects, so that they can be evaluated by the scientific community. Throughout treatment, a high standard of informed consent— along with other safeguards essential to clinical practice—should be maintained. Much of pediatric psychopharmacology is inherently innovative because children’s mental health issues have received little attention or research. Moreover, there is often a limited scientific database to guide evidence-based use of medications in children with mental illness. The neurodevelopmental impact of exposure to psychotropic medications is as yet unknown. However, not treating the symptoms of mental illness, especially when they are severe and interfere with healthy development and sustenance of emotionally important relationships, has potentially devastating consequences for the child. The prescription of psychotropics for children and adolescents includes key safeguards that should be carefully documented. First, the patient should have an appropriate evaluation that encompasses psychiatric and medical areas and that includes basic considerations, such as measures of physical growth, as well as laboratory testing. This evaluation may be performed through a team approach with a pediatrician. Before undertaking treatment, the practitioner should engage the parents and, to the extent possible, the child in an informed consent process that explains the illness, the proposed treatment and the alternatives, and the anticipated outcomes of each. The consent information must include FDA black box warnings. Beyond the parents’ consent, the youngster should be informed about the basics of the illness and treatment options, and assent should be sought. This assent can be revisited as the young person matures. The treatment approach may require revision if the patient no longer provides assent. In recent years, the rights of the “mature minor” who possesses sufficient cognitive and emotional ability to provide informed consent for mental health and substance abuse treatments have been emphasized.10 Over time, diligent collaboration with the primary care provider and parent for close monitoring of adverse effects and drug interactions is critically important.6

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CLINICAL PSYCHOPHARMACOLOGY

Enhancement therapies The historical premise of clinical care is to heal, relieve suffering, and aid in the remission of symptoms. As in other specialties of medicine, psychiatrists are now faced with the ethical considerations that accompany the use of psychotropic medications with the intent of enhancement, rather than treatment. Socalled cosmetic psychopharmacology has drawn much criticism.11,12 There is less controversy in using psychotropic agents to treat minor depression or subclinical anxiety that may evolve into more severe illness.

However, the use of medications to address symptoms such as fatigue or tension in individuals in highdemand roles or to improve cognitive performance in noncognitively impaired individuals is under scrutiny. Across all disciplines of medicine, there is no consensus that this is absolutely unethical, and parallels have been drawn with plastic surgery for physical enhancement. New ethical standards for enhancement therapies are necessary if the use of psychotropic medications for enhancement is to become accepted practice. These new standards

Examples of ethical issues in psychopharmacology

Figure 1

Informed consent Therapeutic boundaries

External influences

Ethical issues in psychopharmacology The difficult patient

Clinical innovation

Enhancement pharmacotherapy

High-risk pharmacotherapy

will necessarily entail, at a minimum, a thorough exploration of the patient’s expectations of medication benefits, the known benefits and risks of the proposed treatment, and a clear understanding of available information based on clinical and research experience. The clinician should understand the previous treatments used (including psychotherapy) and should define the overall goals for the intervention. Wherever possible, look for an evidence base to support the use of psychotropics for the condition at hand and monitor patients closely for the risks and benefits associated with such approaches.13 Note that the logic behind clinical innovation is not quite met under the circumstance of enhancement therapy because of the first precondition—establishing a true clinical need. Moreover, the risks and burdens that accompany the intervention may be far greater than the baseline state of the individual. For instance, stimulant use may unmask latent bipolar disease or disrupt normal physical development in a child or adolescent. Similarly, use of anxiolytics for tension may give rise to addiction and harmful drug interactions. For these reasons, many believe that the mainstream practice of psychiatry has no place for enhancement therapies and that “cosmetic” treatment approaches produce excessive and ineffective polypharmacy and the associated negative sequelae for patients.1

Ethical decision tree for clinical innovation

Figure 2

Yes Is there a clinical need?

Yes Have standard treatments been exhausted without success?

Is there some scientific evidence in support of innovation in providing unique benefit?

Yes

Is this risk of the intervention significantly less than the risk of living with treatment-resistant illness?

Proceed with safeguards: • Consultation with a colleague • Monitor for adverse effects • Evaluate efficacy

Yes

PSYCHIATRIC TIMES

w w w. psychi atr i cti mes. com

This position is less firmly held with psychosocial interventions, such as cognitive-behavioral therapies to enhance performance in, for example, sports or examinations. Well-informed patient “consumers” are increasingly likely to advocate for the application of these therapies in everyday life. Consequently, the use of psychopharmacological agents beyond historical clinical indications is predictable and efforts should be undertaken to develop appropriate, clinically and ethically sound guidelines for this emerging practice.

Caring for “difficult” patients Clinical care is complex and challenging under the best of circumstances, and it becomes much harder when treating patients who express self-destructive, hostile, overly dependent, or acting-out behaviors.14 Other patients become nonadherent when their underlying illnesses are refractory to treatment or when treatment is accompanied by severe adverse effects.3 Psychopharmacotherapy may be essential for patients with multiple problems but also may pose new and unexpected ethical concerns. Even when focused on somatic treatments, mental health clinicians must understand fundamental intrapsychic and interpersonal dynamics that may shape the care of the patient.15,16 Psychiatrists must have a sophisticated awareness of the antecedents of maladaptive behaviors and be able to respond to the “difficult” behaviors in a manner that places patient well-being first. The ability to respond in this way requires that psychiatrists perceive the difficult behavior as a clinical sign, not unlike a skin lesion or high blood pressure. By viewing whatever is “difficult” about the patient in this way, the clinician is more likely to be compassionate and less likely to react without thinking or to inadvertently collude with or enable the pathological condition of the patient.17,18 Mintz19 has described different personality styles and offers suggestions on how to adapt prescribing styles accordingly. For example, the patient who has a dismissive attachment style or is quick to reject others will benefit from a prescribing physician who pays greater attention to explicit communication about the treatment, sets clear treatment expectations, invites the patient to (Please see Ethical Issues, page 56)

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Ethical Issues Continued from page 55

identify personal treatment goals, and prioritizes the establishment of a robust therapeutic alliance before offering psychotropic medication. Finally, the very act of prescribing medications may serve a myriad of defensive functions for the psychopharmacologist. For example, it may establish a sense of control, manage feelings of helplessness, control a patient’s affect, and subtly promote a patient’s dependency to avoid an experience of loss.20 Ongoing consultation and supervision for such difficult cases are key.3

Maintaining professional boundaries Boundaries that separate professional conduct from behaviors inappropriate for a professional relationship (eg, ones that gratify the clinician rather than serve the patient) have important clinical and legal implications. Boundary violations are destructive to the beneficent aims of therapy and cause foreseeable harm to patients.21 The role of therapeutic boundaries is usually viewed in the context of psychotherapy but has relevance to other forms of psychiatric practice. Gabbard16 and Hoop and colleagues3 have highlighted the importance of paying similar attention to therapeutic boundaries in the context of medication management. An overt focus on somatic issues may obscure intense psychological and boundary issues. For example, in some patients, psychopathology may manifest in attempts to disrupt treatment. Being late for appointments, missing appointments, and requesting special favors demand the same consideration by the prescribing psychiatrist as the psychotherapist. Neglecting such clinical signs and failure to evaluate them further could put the relationship at risk for boundary crossings and violations.21 Perhaps where boundary issues are most relevant is in the split treatment relationship, where a patient is seeing a therapist for ongoing psychotherapy and a psychiatrist for medication management. Gabbard16 has described such treatment as a “fertile field for splitting” and other primitive defenses that may be damaging to the patient’s care. Frequent, open, and respectful communication with the psychotherapist helps ensure that the patient receives optimal care and that therapeutic goals are aligned.18

MAY 2011

CLINICAL PSYCHOPHARMACOLOGY External influences on treatment choices Everyday practice rarely resembles textbook medicine, and there are numerous external factors that influence medical decision making. In rural settings, practitioners may of necessity lean more heavily on psychotropic medications when other care options do not exist. In other contexts, the fact that government or commercial insurers offer limited benefit coverage may cause psychiatrists to implement care quickly and to organize treatment around only the most severe symptoms rather than optimizing all aspects of the patient’s care. In recent years, other factors that may distort the choice of treatment have been increasingly recognized. Perhaps the most topical and controversial is the influence of the pharmaceutical industry in sculpting the practice and science of psychopharmacology, with consequences for patients, physicians, and society.22 Interactions of physicians with the pharmaceutical industry have been widely reported in the literature and lay press. Advertising, gift giving, providing incentives for the use of certain medications, and research funding have all been identified as ethically problematic. Psychiatric educators have discussed problems that arise when commercial interests play a role in educating trainees about pharmacology and the pervasive influence of industry-sponsored faculty and research on the practice of psychiatry.23 It is becoming well-established that gifts given in the context of intensive advertising campaigns may create an unconscious bias in prescribing practices. Wazana24 analyzed more than 20 published studies and found that receipt of gifts adversely affected physicians’ prescribing behavior in several ways (eg, incorrect information about a medication, rapid application of a new drug, requests for newer medications that rarely hold an advantage over existing ones). The scientific and ethical caliber of industry-funded research is also under scrutiny. In their pharmacoeconomic examination of published data, Baker and colleagues25 found that studies sponsored by drug manufacturers favored newer antidepressants over older antidepressants. Conflicts of interest naturally occur in all of medicine because of the societal imperative for physicians to participate not only in patient care but also in research and as leaders and educators. These dual roles have

inherent tensions that produce conflicts, because the goals of one role typically do not align exactly with the goals of the other. Thompson26 described a conflict of interest as “a set of conditions in which professional judgment concerning a primary interest (eg, patient’s welfare) tends to be unduly influenced by a secondary interest (such as financial gain).” Thompson emphasized that it is not necessary to eliminate financial gain incentives but to prevent secondary factors from dominating the relevant primary interest in the making of professional decisions. It follows that psychiatrists who receive income from industry have, at a minimum, a potential conflict of interest in their relationship with patients and, at worst, a disruption of their ethical duty of fidelity and obligation to the primacy of patient welfare. There have been greater efforts to explicitly manage conflicts of interest related to interactions with industry.27 Since 2004, many steps have been taken at institutional, state, and national levels to limit such relationships. Gifts and incentives physicians have received from the pharmaceutical industry have been significantly reduced.28

Conclusion Excellence in psychopharmacology demands sensitivity to the associated ethical considerations. The key considerations of psychiatry are both complex and dynamic, and psychiatrists who develop and refine their ethics skill set will be in a better position to anticipate and respond to ethical dilemmas as they arise in their practice. Dr Roberts is Katharine Dexter McCormick and Stanley McCormick Memorial Professor and chairman and Dr Jain is a postdoctoral medical fellow in the department of psychiatry and behavioral sciences at the Stanford University School of Medicine. Dr Roberts reports that she is the owner of Terra Nova Learning Systems (TNLS); she has received federal funding for competitive, peerreviewed research grants and competitive, peer-reviewed small-business grants and contracts; she serves as a consultant for federally funded scientific projects with collaborators across the United States. She does not receive direct funding from pharmaceutical companies for her work. Dr Jain reports no conflicts of interest concerning the subject matter of this article.

References 1. Ghaemi SN. Toward a Hippocratic psychopharmacology. Can J Psychiatry. 2008;53:189-196. 2. Geppert CMA, Taylor PJ. Should psychiatrists prescribe neuroenhancers for mentally healthy patients? Psychiatr Times. 2011;28(3):1, 6-9. 3. Hoop JG, Layde J, Roberts LW. Ethical considerations in psychopharmacological treatment and research. In: Schatzberg AF, Nemeroff CB, eds. The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed. Arlington, VA: American Psychiatric Publishing, Inc; 2009:1477-1495. 4. Kuther TL. Medical decision-making and minors: issues of consent and assent. Adolescence. 2003; 38:343-358. 5. Roberts LW, Dyer AR. A Concise Guide to Ethics in Mental Health Care. Arlington, VA: American Psychiatric Publishing; 2004. 6. Roberts LW. Informed consent and the capacity for voluntarism. Am J Psychiatry. 2002;159:705-712. 7. Dell ML, Vaughan BS, Kratochvil CJ. Ethics and the prescription pad. Child Adolesc Psychiatr Clin N Am. 2008;17:93-111, ix. 8. Miller LJ. Ethical issues in perinatal mental health. Psychiatr Clin North Am. 2009;32:259-270. 9. Ghaemi SN, Goodwin FK. The ethics of clinical innovation in psychopharmacology: challenging traditional bioethics. Philos Ethics Humanit Med. 2007; 2:26. 10. Belitz J, Bailey RA. Clinical ethics for the treatment of children and adolescents: a guide for general psychiatrists. Psychiatr Clin North Am. 2009; 32:243-257. 11. Kramer PD. Listening to Prozac. New York: Penguin; 1997. 12. Cerullo MA. Cosmetic psychopharmacology and the President’s Council on Bioethics. Perspect Biol Med. 2006;49:515-523. 13. Stein DJ. Cosmetic psychopharmacology of anxiety: bioethical considerations. Curr Psychiatry Rep. 2005;7:237-238. 14. Groves JE. Taking care of the hateful patient. N Engl J Med. 1978;298:883-887. 15. Mohl PC, Lomax J, Tasman A, et al. Psychotherapy training for the psychiatrist of the future. Am J Psychiatry. 1990;147:7-13. 16. Gabbard GO. Deconstructing the “med check.” Psychiatr Times. 2009;26(9):48. http://www. psychiatrictimes.com/display/article/10168/ 1444238. Accessed March 11, 2011. 17. Gabbard GO: Psychodynamic Psychiatry in Clinical Practice. 3rd ed. Washington, DC: American Psychiatric Press; 2000:134-143. 18. Roberts LW, Hoop JG, Dunn LB, et al. Ethics and Professionalism: An Overview for Mental Health Clinicians, Researchers, and Learners. Arlington, VA: American Psychiatric Publishing; 2008. 19. Mintz DL. Teaching the prescriber’s role: the psychology of psychopharmacology. Acad Psychiatry. 2005;29:187-194. 20. Brockman R. Medication and transference in psychoanalytically orientated psychotherapy of the borderline patient. Psychiatr Clin North Am. 1990; 13:287-295. 21. Jain S, Roberts LW. Ethics in psychotherapy: a focus on professional boundaries and confidentiality practices. Psychiatr Clin North Am. 2009;32:299314. 22. Jain S. Understanding Physician-Pharmaceutical Industry Interactions: A Concise Guide. New York: Cambridge University Press; 2007. 23. Jain S. Key aspects of physician and pharmaceutical industry relationships for trainees. Acad Psychiatry. 2010;34:98-101. 24. Wazana A. Physicians and the pharmaceutical industry: is a gift ever just a gift? JAMA. 2000;283: 373-380. 25. Baker CB, Johnsrud MT, Crismon ML, et al. Quantitative analysis of sponsorship bias in economic studies of antidepressants. Br J Psychiatry. 2003; 183:498-506. 26. Thompson DF. Understanding financial conflicts of interest. N Engl J Med. 1993;329:573-576. 27. American Board of Internal Medicine; American College of Physicians-American Society of Internal Medicine; European Federation of Internal Medicine. Medical professionalism in the new millennium: a physician charter. Ann Intern Med. 2002;136:243246. 28. Campbell EG, Rao SR, DesRoches CM, et al. Physician professionalism and changes in physicianindustry relationships from 2004 to 2009 [published correction appears in Arch Intern Med. 2010;170: 1966]. Arch Intern Med. 2010;170:1820-1826. 29. Haroun AM. Ethical discussion of informed consent. J Clin Psychopharmacol. 2005;25:405-406. ❒

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MOLECULES OF THE MIND

Lorenzo’s Oil and the Rehabilitation of Gene Therapy admit to having 2 mixed responses when I rented the 1992 movie Lorenzo’s Oil. The first reaction didn’t concern the film at all, but something I had read about in a science magazine earlier that day. Eighteen-year-old Jesse Gelsinger had just died, the first person to succumb during a human gene therapy trial. Gene therapy (sometimes called gene replacement therapy) attempts to ameliorate genetic-based disorders by introducing corrected genes into affected patients. Jesse suffered from ornithine transcarbamylase deficiency, an X-linked genetic disorder that results in the inability to metabolize ammonia. It is invariably fatal.

An adenovirus carrying a corrected OT gene had been injected into Jesse’s bloodstream, with hopes of restoring this metabolic activity. Unfortunately, he mounted a catastrophic immune response to the modified adenovirus and died of multiple organ failure. A flurry of investigations ensued, the trial was halted, and the family was eventually paid an undisclosed amount of money. Having worked with gene therapy technologies early in my career, I felt this disappointment acutely. But back to the movie, and my second mixed reaction. Lorenzo’s Oil was based on the true story of Lorenzo Odone, a boy suffering from a different X-linked genetic disease—adrenoleukodystrophy (ALD). ALD is a severe neurodegenerative disorder with no cure and, at the time, no successful treatment options. The movie concerned the efforts of Lorenzo’s parents to find an effective treatment for their son. They eventually hit upon a dietary supplement derived from olive oil— hence the title—a combination of 2 long-chain fatty acids. They had reason to believe it would help their son, and the film documents their struggle trying to convince skeptical scientists, friends, and clinicians. The bad news was that the establishment initially resisted their attempts to obtain a therapeutic distillate of the oil for their child. The good news was that the parents eventually found a professional who would create the distillate. Astonishingly, the compound halted the progression of the disease (the actual Lorenzo died last year of aspiration pneumonia, having lived to an incredible age of 30 years). In this film, members of the scientific commu-

nity were portrayed as churlish, narrow-minded, and subject to groupthink. We can be all these things, of course—research is a very human

Figure

enterprise—but coming on the same day as the report of Jesse’s death, it didn’t feel like a very good day to be a scientist. Happily, gene therapy technologies have undergone a powerful revolution. Since Jesse’s failed trial, additional safety procedures and oversight activities have been put into play. Existing experimental protocols have been modified. Combined with technical advances in gene replacement strategies, the changes have resulted in a number of clinical success stories. One extraordinary achievement occurred this fall and involved ALD, Lorenzo’s disorder. The achievement brought back a reminder not only of the day I saw the movie but also of how far we’ve come since then. I want to tell you

by John J. Medina, PhD

about what happened. I start with some background information about ALD, then move to an experiment that, at this writing, shows enormous promise.

Relevant biology ALD is a demyelinating disease of the CNS. The mutations responsible for the disorder occur in a gene called ABCD1, which encodes an adenosine triphosphate–binding transporter protein. The protein normally hangs out in the membranes of peroxisomes of both oligodendrocytes (Please see Lorenzo’s Oil, page 58)

Gene therapy for ALD A therapy using gene replacement technology has been developed for adrenoleukodystrophy (ALD). It is described in 3 steps below.

Demyelination arrested in 1 year

Reintroduction Modified cells are reintroduced into the patient. After 20 months, the progeny of gene-corrected HSCs are distributed throughout the body.

Addition of ABCD1 gene Using modified HIV1 viruses, healthy ABCD1 genes are transduced into the HSCs.

HSC extraction Hematopoietic stem cells (HSCs) are extracted from a patient suffering from ALD.

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PSYCHIATRIC TIMES www.psy c h i a t r i c t i m e s. c o m

Lorenzo’s Oil Continued from page 57

and microglial cells. In its role as a peroxisomal transporter, it happily degrades very long-chain fatty acids in these cells. A loss of this function inhibits normal myelination maintenance by these cells. Not surprisingly, active multifocal brain demyelination occurs in affected children, with an active degradation phase that manifests around age 6 years. Death usually occurs before puberty. It is a remarkable tribute to Lorenzo’s parents that their son lived so long. Once there is onset of the lesion phase, it is impossible to stop the degradation, which is why therapeutic interventions are best initiated at the earliest ages possible. The only effective treatment to date is hematopoietic stem cell (HSC) therapy, classic stem cell transplantation therapy. It works by supplying replacement microglial cells derived from donor bone marrow myelomonocytic sources. There are limitations to this therapy, of course, ranging from the limited pool of compatible donors to its high fatality rate.

MOLECULES OF THE MIND centage will express whatever foreign gene is on board, setting up a long-term presence of gene product in HSC lineages. The question, however, remains: Would this work for patients suffering from ALD? Seemingly simple—the introduction of the foreign gene into HSCs— the initial leg of this journey is a cautious one. If integration is successful,

the next step is to determine what happens after transplantation. Once the cells stabilize in the patient, then one would start looking for clinical effects. That’s exactly what teams of researchers—some from Europe, some from the United States—have undertaken to do. They were given permission to treat 2 ALD-affected boys, aged 7 and 7.5 years. The children had no

MAY 2011

matched donor available or cord blood for a ready sources of HSCs, which made them ideal candidates for a gene therapy trial. In the laboratory, autologous HSCs were transduced with an HIV-1 vector genetically engineered to express healthy ABCD1 genes. After myeloablative treatment, these HSCs were reintroduced into the patients. The boys were followed up over

RISPERDAL® CONSTA® (risperidone) FOR THE MAINTENANCE TREATMENT OF BIPOLAR I DISORDER

Gene therapy strategies Obviously, replacing a mutated ABCD1 gene with a healthier version in affected children would be the gold standard treatment option. Since you have a brain delivery system already available with HSCs, what if you could put a corrected ABCD1 gene into those stem cells, then allow the cells to migrate via those normal pathways into the brain? What would be the first step? Anyone contemplating gene therapy manipulations begins with the choice of molecular transport vehicles. These are normally genetically re-engineered viruses fashioned into benign vectors, each capable of delivering corrected genes to the patient. Many laboratories have used mouse gammaretroviruses as the vectors of choice. The big problem is that they will only transduce (supply the foreign gene) dividing cells. Since Jesse’s death, researchers have genetically engineered HIV-1 viruses to do the shuttling (Figure). Although they have been made replicatively defective, these viruses readily transduce nondividing cells. This property makes them the vector of first resort for many laboratories interested in gene replacement studies. Modified HIV-1 viruses are remarkably efficient at infecting HSCs. Once inside these cells, a certain per-

RISPERDAL® CONSTA® provides ConstaCoverage *— assurance that antipsychotic medication is on board when administered every 2 weeks. *

Based on pharmacokinetic properties/plasma concentrations.

IMPORTANT SAFETY INFORMATION FOR RISPERDAL® CONSTA® (risperidone) WARNING: Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drugtreated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis. t Contraindications: RISPERDAL® CONSTA® is contraindicated in patients with a known hypersensitivity to the product. t Cerebrovascular Adverse Events (CAEs): CAEs (e.g., stroke, transient ischemia attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone. The incidence of CAEs was significantly higher than with placebo. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis. t Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications. Clinical manifestations include muscle rigidity, fever, altered mental status,

and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems. t Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly women patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. t Hyperglycemia and Diabetes: Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death has been reported in patients treated with atypical antipsychotics (APS), including RISPERDAL® CONSTA®. Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug. t Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.

MAY 2011

MOLECULES OF THE MIND

the next 2 to 3 years. The researchers were looking not only to see whether the stem cells “took” but also to determine how many of them were expressing the corrected protein. To their excitement, the researchers found healthy ABCD1 proteins expressed in a wide variety of HSCs, including monocytes, T and B cells, granulocytes, and bone marrow progenitors. It wasn’t a great percent-

age, hovering between 9% and 14%. Would it be enough to produce a positive therapeutic outcome? The answer was yes! More than a year later, progressive cerebral demyelination in both boys stopped. This was quite an achievement. Despite its relatively low level of correction, the boys’ brains were getting better—or at least stopped getting worse. The results are similar to

those in ALD patients who have had the good fortune to find a donor source and subsequent transplantation. In a single stroke, a positive effect had been produced in patients with no such advantage. It had been done with a technology previously under a cloud, with a disease whose research efforts had been couched as negative high drama. Perhaps we have come a long

In a 52-week adjunctive therapy trial

RISPERDAL® CONSTA®, when added to lithium or valproate, signiﬁcantly delayed time to relapse vs placebo plus lithium or valproate (P=0.01)1,2

Percentage of patients who relapsed

Demonstrated in a 52-week, multicenter, randomized, double-blind, placebo-controlled study in 124 patients with Bipolar I Disorder. Doses of 25, 37.5, or 50 mg were given by intramuscular injection every 2 weeks, in addition to their individually deﬁned adjunctive treatment, which consisted of mood stabilizers (primarily lithium and/or valproate), antidepressants, and/or anxiolytics. All other antipsychotics were discontinued after the ﬁrst 3 weeks of the initial injection. Patients who were judged to be stable for at least the last 4 weeks of a 16-week, open-label phase were randomized in the double-blind phase. The primary endpoint was time to relapse to any new mood episode.1

45.8%

Percentage

23.1%

RISPERDAL® CONSTA® + lithium or valproate (N=65)

Placebo + lithium or valproate (N=59)

References: 1. RISPERDAL ® CONSTA ® [Prescribing Information]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2. Macfadden W, Alphs L, Haskins JT, et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord. 2009;11:827-839.

t Orthostatic Hypotension and Syncope: RISPERDAL® CONSTA® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period. RISPERDAL® CONSTA® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of MI or ischemia, conduction abnormalities), cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia) and additionally elderly patients with renal or hepatic impairment. Monitoring should be considered in patients for whom this may be of concern. t Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including RISPERDAL® CONSTA®. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of RISPERDAL® CONSTA® should be considered. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue RISPERDAL® CONSTA® and have their WBC followed until recovery. t Potential for Cognitive and Motor Impairment: Somnolence was reported in multiple trials in subjects treated with RISPERDAL® CONSTA®. Since RISPERDAL® CONSTA® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that RISPERDAL® CONSTA® does not adversely affect them. t Seizures: RISPERDAL ® CONSTA ® should be used cautiously in patients with a history of seizures.

Text CONSTA4 to 30333 or scan this code with your smartphone, using a 2D code reader app, to visit the RISPERDAL® CONSTA® mobile Web site. Standard text and data rates may apply.

t Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Use cautiously in patients at risk for aspiration pneumonia. t Priapism has been reported. Severe priapism may require surgical intervention. t Thrombotic Thrombocytopenic Purpura (TTP) has been reported. t Administration: For intramuscular injection only. Care should be taken to avoid inadvertent injection into a blood vessel. t Suicide: The possibility of suicide attempt is inherent in bipolar disorder. Close supervision of high-risk patients should accompany drug therapy. t Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies has been reported. Manifestations and features are consistent with NMS. t Use RISPERDAL® CONSTA® with caution in patients with conditions and medical conditions that could affect metabolism or hemodynamic responses (e.g., recent myocardial infarction or unstable cardiac disease). t Commonly Observed Adverse Reactions for RISPERDAL® CONSTA®: The most common adverse reactions in clinical trials in patients with bipolar disorder were weight increased (5% in monotherapy trial) and tremor and Parkinsonism (≥10% in adjunctive therapy trial).

Please see accompanying brief summary of full Prescribing Information for RISPERDAL® CONSTA®. Visit our Web site at www.JanssenCNS.com/risperdal

PSYCHIATRIC TIMES

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way after all, I thought. After hearing about the breakthrough—and recalling Lorenzo—it turned out to be a remarkably good day to be a scientist. Dr Medina is a developmental molecular biologist and private consultant, with research interests in the genetics of psychiatric disorders. For more about Dr Medina, visit http:// brainrules.net. ❒

RISPERDAL® CONSTA® (risperidone) LONG-ACTING INJECTION

Brief Summary BEFORE PRESCRIBING RISPERDAL® CONSTA®, PLEASE SEE FULL PRESCRIBING INFORMATION, INCLUDING BOXED WARNING. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. RISPERDAL® CONSTA® (risperidone) is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions] RISPERDAL® CONSTA® is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder [see Clinical Studies (14.2, 14.3) in full PI]. CONTRAINDICATIONS: RISPERDAL® CONSTA® (risperidone) is contraindicated in patients with a known hypersensitivity to the product. WARNINGS AND PRECAUTIONS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL® CONSTA® (risperidone) is not approved for the treatment of dementia-related psychosis (see Boxed Warning). Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with oral risperidone compared to patients treated with placebo. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis. [See also Boxed Warning and Warnings and Precautions] Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, RISPERDAL® CONSTA® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL® CONSTA®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL® CONSTA® despite the presence of the syndrome. Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including RISPERDAL®, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL®, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL®, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including RISPERDAL®, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL®, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of RISPERDAL®. Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving

prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. Orthostatic Hypotension: RISPERDAL® CONSTA® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period with oral risperidone, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated with RISPERDAL® CONSTA® in multiple-dose studies. Patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). RISPERDAL® CONSTA® should be used with particular caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral RISPERDAL® and antihypertensive medication. Leukopenia, Neutropenia, and Agranulocytosis: Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including RISPERDAL® CONSTA®. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of RISPERDAL® CONSTA® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue RISPERDAL® CONSTA® and have their WBC followed until recovery. Potential for Cognitive and Motor Impairment: Somnolence was reported by 5% of patients treated with RISPERDAL® CONSTA® in multiple-dose trials. Since risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that treatment with RISPERDAL® CONSTA® does not affect them adversely. Seizures: During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated with RISPERDAL® CONSTA®. Therefore, RISPERDAL® CONSTA® should be used cautiously in patients with a history of seizures. Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. RISPERDAL® CONSTA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and Precautions] Priapism: Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9) in full PI]. Severe priapism may require surgical intervention. Thrombotic Thrombocytopenic Purpura (TTP): A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to RISPERDAL® therapy is unknown. Body Temperature Regulation: Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral RISPERDAL® or RISPERDAL® CONSTA® use. Caution is advised when prescribing RISPERDAL® CONSTA® for patients who will be exposed to temperature extremes. Administration: RISPERDAL® CONSTA® should be injected into the deltoid or gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel. [See Dosage and Administration (2) and Adverse Reactions (6.8) in full PI] Antiemetic Effect: Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumor. Suicide: There is an increased risk of suicide attempt in patients with schizophrenia or bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. RISPERDAL® CONSTA® is to be administered by a health care professional [see Dosage and Administration (2) in full PI]; therefore, suicide due to an overdose is unlikely. Use in Patients with Concomitant Illness: Clinical experience with RISPERDAL® CONSTA® in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL® CONSTA®, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome. Caution is advisable when using RISPERDAL® CONSTA® in patients with diseases or conditions that could affect metabolism or hemodynamic responses. RISPERDAL® CONSTA® has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2) treated with oral RISPERDAL®; an increase in the free fraction of risperidone is also seen in patients with severe hepatic impairment. Patients with renal or hepatic impairment should be carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with renal or hepatic impairment [see Dosage and Administration]. Osteodystrophy and Tumors in Animals: RISPERDAL® CONSTA® produced osteodystrophy in male and female rats in a 1-year toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks. RISPERDAL® CONSTA® produced renal tubular tumors (adenoma, adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition, RISPERDAL® CONSTA® produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. (Cellular proliferation was not measured at the low dose or in females in either study.) The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum recommended human dose (MRHD) (50 mg) on a mg/m2 basis and is associated with a plasma exposure (AUC) 2 times the expected plasma exposure (AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal to the IM MRHD on a mg/m2 basis). Plasma exposure (AUC) at the no-effect dose was one third the expected plasma exposure (AUC) at the IM MRHD. Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally administered risperidone. Osteodystrophy was not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study. The renal tubular and adrenomedullary tumors in male rats and other tumor findings are described in more detail in Section 13.1 in full PI (Carcinogenicity, Mutagenesis, Impairment of Fertility). The relevance of these findings to human risk is unknown. Monitoring: Laboratory Tests: No specific laboratory tests are recommended. ADVERSE REACTIONS: The following are discussed in more detail in other sections of the labeling: • Increased mortality in elderly patients with dementia-related psychosis • Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis • euroleptic malignant syndrome • Tardive dyskinesia • Hyperglycemia and diabetes mellitus • Hyperprolactinemia • Orthostatic hypotension • Leukopenia/Neutropenia and Agranulocytosis • Potential for cognitive and motor impairment • Seizures • Dysphagia • Priapism • Thrombotic Thrombocytopenic Purpura (TTP) • Disruption of body temperature regulation • Avoidance of inadvertent injection into a blood vessel • Antiemetic effect • Suicide • Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy

bodies • Diseases or conditions that could affect metabolism or hemodynamic responses • Osteodystrophy and tumors in animals. The most common adverse reactions in the double-blind, placebo-controlled periods of the bipolar disorder trials were weight increased (5% in the monotherapy trial) and tremor and parkinsonism (≥ 10% in the adjunctive treatment trial). Adverse reactions that were associated with discontinuation from the double-blind, placebo-controlled periods of the bipolar disorder trials were hyperglycemia (one patient in the monotherapy trial) and hypokinesia and tardive dyskinesia (one patient each in the adjunctive treatment trial). The data described in this section are derived from a clinical trial database consisting of 2392 patients exposed to one or more doses of RISPERDAL® CONSTA® for the treatment of schizophrenia. Of these 2392 patients, 332 were patients who received RISPERDAL® CONSTA® while participating in a 12-week double-blind, placebo-controlled trial. Two hundred two (202) of the 332 were schizophrenia patients who received 25 mg or 50 mg RISPERDAL® CONSTA®. The conditions and duration of treatment with RISPERDAL® CONSTA® in the other clinical trials varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 4 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs. In addition to the studies in patients with schizophrenia, safety data are presented from a trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapy for maintenance treatment in patients with bipolar I disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who were stable on risperidone (oral or long-acting injection), were stable on other antipsychotics or mood stabilizers, or were experiencing an acute episode. After a 3-week period of treatment with open-label oral risperidone (n=440), subjects who demonstrated an initial response to oral risperidone in this period and those who were stable on risperidone (oral or long-acting injection) at study entry entered into a 26-week stabilization period of open-label RISPERDAL® CONSTA® (n=501). Subjects who demonstrated a maintained response during this period were then randomized into a 24-month double-blind, placebo-controlled period in which they received RISPERDAL® CONSTA® (n=154) or placebo (n=149) as monotherapy. Subjects who relapsed or who completed the double-blind period could choose to enter an 8-week open-label RISPERDAL® CONSTA® extension period (n=160). Safety data are also presented from a trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as adjunctive maintenance treatment in patients with bipolar disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I or Type II and who experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study. At the start of this study, all patients (n = 275) entered into a 16-week open-label treatment phase in which they received RISPERDAL® CONSTA® in addition to continuing their treatment as usual, which consisted of various mood stabilizers (primarily lithium and valproate), antidepressants, and/or anxiolytics. Patients who reached remission at the end of this 16-week open-label treatment phase (n = 139) were then randomized into a 52-week double-blind, placebo-controlled phase in which they received RISPERDAL® CONSTA® (n = 72) or placebo (n = 67) as adjunctive treatment in addition to continuing their treatment as usual. Patients who did not reach remission at the end of the 16-week open-label treatment phase could choose to continue to receive RISPERDAL® CONSTA® as adjunctive therapy in an open-label manner, in addition to continuing their treatment as usual, for up to an additional 36 weeks as clinically indicated for a total period of up to 52 weeks; these patients (n = 70) were also included in the evaluation of safety. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of RISPERDAL® CONSTA® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for RISPERDAL® CONSTA® often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of all adverse reactions were mild to moderate in severity. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Disorder: Table 2 lists the treatment-emergent adverse reactions reported in 2% or more of RISPERDAL® CONSTA®-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapy for maintenance treatment in patients with Bipolar I Disorder. Table 2. Adverse Reactions in ≥2% of Patients with Bipolar I Disorder Treated with RISPERDAL® CONSTA® as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial, System/Organ Class, Percentage of Patients Reporting Event, RISPERDAL® CONSTA® (N=154) first, Placebo (N=149) second, Adverse Reaction, Investigations: Weight increased 5, 1; Nervous system disorders: Dizziness 3, 1; Vascular disorders: Hypertension 3, 1. Table 2 lists the treatment-emergent adverse reactions reported in 4% or more of patients in the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as adjunctive maintenance treatment in patients with bipolar disorder. Table 2. Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated with RISPERDAL® CONSTA® as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial, System/Organ Class, Percentage of Patients Reporting Event, RISPERDAL® CONSTA® + Treatment as Usuala (N=72) first, Placebo + Treatment as Usuala (N=67) second, Adverse Reaction, General disorders and administration site conditions: Gait abnormal 4, 0; Infections and infestations: Upper respiratory tract infection 6, 3; Investigations: Weight increased 7, 1; Metabolism and nutrition disorders: Decreased appetite 6, 1; Increased appetite 4, 0; Musculoskeletal and connective tissue disorders: Arthralgia 4, 3; Nervous system disorders: Tremor 24, 16; Parkinsonismb 15, 6; Dyskinesiab 6, 3; Sedationc 7, 1; Disturbance in attention 4, 0; Reproductive system and breast disorders: Amenorrhea 4, 1; Respiratory, thoracic and mediastinal disorders: Cough 4, 1. a Patients received double-blind RISPERDAL® CONSTA® or placebo in addition to continuing their treatment as usual, which included mood stabilizers, antidepressants, and/or anxiolytics. b Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia includes muscle twitching and dyskinesia. c Sedation includes sedation and somnolence. Other Adverse Reactions Observed During the Premarketing Evaluation of RISPERDAL® CONSTA®: The following additional adverse reactions occurred in < 2% of the RISPERDAL® CONSTA®-treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in < 2% of the RISPERDAL® CONSTA®-treated patients in the above double-blind, placebo-controlled period of the monotherapy bipolar disorder trial dataset, or in < 4% of the RISPERDAL® CONSTA®-treated patients in the above double-blind, placebo-controlled period of the adjunctive treatment bipolar disorder trial dataset. The following also includes additional adverse reactions reported at any frequency in RISPERDAL® CONSTA®-treated patients who participated in the open-label phases of the above bipolar disorder studies and in other studies, including double-blind, active controlled and open-label studies in schizophrenia and bipolar disorder. Blood and lymphatic system disorders: anemia, neutropenia Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block right Ear and labyrinth disorders: ear pain, vertigo Endocrine disorders: hyperprolactinemia Eye disorders: conjunctivitis, visual acuity reduced Gastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort, gastritis General disorders and administration site conditions: injection site pain, chest discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, injection site induration, injection site swelling, injection site reaction, face edema Immune system disorders: hypersensitivity Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory tract infection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection, infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess Injury and poisoning: fall, procedural pain Investigations: blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased, hepatic enzyme increased, aspartate aminotransferase increased, electrocardiogram QT prolonged, glucose urine present Metabolism and nutritional disorders: anorexia, hyperglycemia Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, back pain, buttock pain, muscular

weakness, neck pain, musculoskeletal chest pain Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia, libido decreased, nervousness Renal and urinary disorders: urinary incontinence Reproductive system and breast disorders: galactorrhea, oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed, menstrual disorder, ejaculation delayed Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea Skin and subcutaneous tissue disorders: rash, eczema, pruritus generalized, pruritus Vascular disorders: hypotension, orthostatic hypotension Additional Adverse Reactions Reported with Oral RISPERDAL®: The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of oral RISPERDAL®, regardless of frequency of occurrence: Blood and Lymphatic Disorders: granulocytopenia Cardiac Disorders: atrioventricular block Ear and Labyrinth Disorders: tinnitus Eye Disorders: ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma Gastrointestinal Disorders: abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecal incontinence, lip swelling, cheilitis, aptyalism General Disorders: thirst, feeling abnormal, gait disturbance, pitting edema, edema, chills, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness Immune System Disorders: drug hypersensitivity Infections and Infestations: tonsillitis, eye infection, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, heart rate increased, eosinophil count increased, white blood cell count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, joint stiffness, rhabdomyolysis, torticollis Nervous System Disorders: hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack, cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractions involuntary, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma Psychiatric Disorders: blunted affect, confusional state, middle insomnia, listless, anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and Breast Disorders: vaginal discharge, retrograde ejaculation, ejaculation disorder, ejaculation failure, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders: epistaxis, wheezing, pneumonia aspiration, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, skin disorder, rash erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalised, rash maculopapular Vascular Disorders: flushing Discontinuations Due to Adverse Reactions: Bipolar Disorder In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 RISPERDAL® CONSTA®-treated patients discontinued due to an adverse reaction (hyperglycemia). In the 52-week double-blind phase of the placebo-controlled trial in which RISPERDAL® CONSTA® was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their treatment as usual, approximately 4% (3/72) of RISPERDAL® CONSTA®-treated patients discontinued treatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in RISPERDAL® CONSTA®-treated patients were: hypokinesia (one patient) and tardive dyskinesia (one patient). Dose Dependency of Adverse Reactions in Clinical Trials: Extrapyramidal Symptoms: Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week double-blind, placebo-controlled trial comparing three doses of RISPERDAL® CONSTA® (25 mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia, including: (1) the incidence of spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS). The overall incidence of EPS-related adverse reactions (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL® CONSTA® was comparable to that of patients treated with placebo; the incidence of EPS-related adverse reactions was higher in patients treated with 50 mg RISPERDAL® CONSTA®. The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with RISPERDAL® CONSTA® compared with patients treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg group). Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Changes in Body Weight: In the 24-month double-blind, placebo-controlled treatment period of a trial assessing the efficacy and safety of RISPERDAL® CONSTA® when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 11.6% of patients treated with RISPERDAL® CONSTA® compared with 2.8% of patients treated with placebo experienced a weight gain of >7% of body weight at endpoint. In the 52-week double-blind, placebo-controlled trial in patients with bipolar disorder, 26.8% of patients treated with RISPERDAL® CONSTA® as adjunctive treatment in addition to continuing their treatment as usual, compared with 27.3% of patients treated with placebo in addition to continuing their treatment as usual, experienced a weight gain of >7% of body weight at endpoint. Changes in ECG: The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the 24-month double-blind, placebo-controlled period. There were no clinically relevant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL® CONSTA® compared to placebo. The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 52-week double-blind, placebo-controlled trial. There were no statistically significant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL® CONSTA® 25 mg, 37.5 mg, or 50 mg when administered as adjunctive treatment in addition to continuing treatment as usual compared to placebo. Pain Assessment and Local Injection Site Reactions: The mean intensity of injection pain reported by patients with schizophrenia using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL® CONSTA® experienced redness, swelling, or induration at the injection site. In a separate study to observe local-site tolerability in which RISPERDAL® CONSTA® was administered into the deltoid muscle every 2 weeks over a period of 8 weeks, no patient discontinued treatment due to local injection site pain or reaction. Clinician ratings indicated that only mild redness, swelling, or induration at the injection site was observed in subjects treated with 37.5 mg or 50 mg RISPERDAL® CONSTA® at 2 hours after deltoid injection. All ratings returned to baseline at the predose assessment of the next injection 2 weeks later. No moderate or severe reactions were observed in any subject. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention, and water intoxication. In addition, the following adverse reactions have been observed during postapproval use of RISPERDAL® CONSTA®: cerebrovascular disorders, including cerebrovascular accidents, and diabetes mellitus aggravated. DRUG INTERACTIONS: The interactions of RISPERDAL® CONSTA® with coadministration of other drugs have not been systematically evaluated. The drug interaction data provided in this section is based on studies with oral RISPERDAL®. Centrally-Acting Drugs and Alcohol: Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® CONSTA® is administered in combination with other centrally-acting drugs or alcohol. Drugs with Hypotensive Effects: Because of its potential for inducing hypotension, RISPERDAL® CONSTA® may enhance the hypotensive effects of other therapeutic

agents with this potential. Levodopa and Dopamine Agonists: RISPERDAL® CONSTA® may antagonize the effects of levodopa and dopamine agonists. Amitriptyline: Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral RISPERDAL®. Cimetidine and Ranitidine: Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%. Clozapine: Chronic administration of clozapine with risperidone may decrease the clearance of risperidone. Lithium: Repeated doses of oral RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13). Valproate: Repeated doses of oral RISPERDAL® (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of oral RISPERDAL®. Digoxin: Oral RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Topiramate: Oral RISPERDAL® administered at doses from 1-6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone Cmax and a 33% decrease in risperidone AUC0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral RISPERDAL® on the pharmacokinetics of topiramate. Drugs That Inhibit CYP 2D6 and Other CYP Isozymes: Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs [see Clinical Pharmacology (12.3) in full PI]. Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n=˜70 patients) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made. In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Fluoxetine and Paroxetine: Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. When RISPERDAL® CONSTA® is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. [See also DOSAGE AND ADMINISTRATION (2.5) in full PI]. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. Erythromycin: There were no significant interactions between oral RISPERDAL® and erythromycin. Carbamazepine and Other CYP 3A4 Enzyme Inducers: Carbamazepine co-administration with oral RISPERDAL® decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL® CONSTA® treatment. At the initiation of therapy with carbamazepine or other known hepatic enzyme inducers, patients should be closely monitored during the first 4–8 weeks, since the dose of RISPERDAL® CONSTA® may need to be adjusted. A dose increase, or additional oral RISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL® CONSTA® should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL® CONSTA® and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. [See also DOSAGE AND ADMINSTRATION (2.5) in full PI] Drugs Metabolized by CYP 2D6: In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL® CONSTA® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral RISPERDAL® did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category C.: The teratogenic potential of oral risperidone was studied in three embryofetal development studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the oral maximum recommended human dose [MRHD] on a mg/m2 basis) and in one embryofetal development study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the oral MRHD on a mg/m2 basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the oral MRHD on a mg/m2 basis. In three reproductive studies in rats (two peri/post-natal development studies and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times the oral MRHD on a mg/m2 basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. In one peri/post-natal development study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the oral MRHD on a mg/m2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Days 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the oral MRHD on a mg/m2 basis. No studies were conducted with RISPERDAL® CONSTA®. Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to oral RISPERDAL® therapy is unknown. Non-Teratogenic Effects: Neonates exposed to antipsychotic drugs (including RISPERDAL®) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. RISPERDAL® CONSTA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: The effect of RISPERDAL® CONSTA® on labor and delivery in humans is unknown. Nursing Mothers: Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women should not breast-feed during treatment with RISPERDAL® CONSTA® and for at least 12 weeks after the last injection. Pediatric Use: RISPERDAL® CONSTA® has not been studied in children younger than 18 years old. Geriatric Use: In an open-label study, 57 clinically stable, elderly patients (≥ 65 years old) with schizophrenia or schizoaffective disorder received RISPERDAL® CONSTA® every 2 weeks for up to 12 months. In general, no differences in the tolerability of RISPERDAL® CONSTA® were observed between otherwise healthy elderly and nonelderly patients. Therefore, dosing recommendations for otherwise

healthy elderly patients are the same as for nonelderly patients. Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly patients, elderly patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). In addition, monitoring of orthostatic vital signs should be considered in elderly patients for whom orthostatic hypotension is of concern [see Warnings and Precautions (5.7) in full PI]. Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated with oral risperidone alone or with oral placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of oral risperidone regardless of concomitant use with furosemide. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions] DRUG ABUSE AND DEPENDENCE: Controlled Substance: RISPERDAL® CONSTA® (risperidone) is not a controlled substance. Abuse: RISPERDAL® CONSTA® has not been systematically studied in animals or humans for its potential for abuse. Because RISPERDAL® CONSTA® is to be administered by health care professionals, the potential for misuse or abuse by patients is low. Dependence: RISPERDAL® CONSTA® has not been systematically studied in animals or humans for its potential for tolerance or physical dependence. OVERDOSAGE: Human Experience: No cases of overdose were reported in premarketing studies with RISPERDAL® CONSTA®. Because RISPERDAL® CONSTA® is to be administered by health care professionals, the potential for overdosage by patients is low. In premarketing experience with oral RISPERDAL®, there were eight reports of acute RISPERDAL® overdosage, with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience with oral RISPERDAL® includes reports of acute overdose, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to oral RISPERDAL® overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of oral RISPERDAL® and paroxetine. Management of Overdosage: In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers. 10130507B Revised December 2010 © Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007

Risperidone is manufactured by: Microspheres are manufactured by: Janssen Pharmaceutical Ltd. Alkermes, Inc. Wallingstown, Little Island, Wilmington, Ohio County Cork, Ireland Diluent is manufactured by: Vetter Pharma Fertigung GmbH & Co. KG Ravensburg or Langenargen, Germany or Cilag AG Schaffhausen, Switzerland or Ortho Biotech Products, L.P. Raritan, NJ RISPERDAL® CONSTA® is manufactured for: Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

MAY 2011

PAIN MANAGEMENT

PSYCHIATRIC TIMES

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Analgesic Medications: Balancing Efficacy, Adverse Effects, and Convenience by Steven A. King, MD, MS hen deciding what medication to prescribe for any specific problem, physicians are faced with the ongoing challenge of balancing the efficacies of the various choices with the relative risk of adverse events. An additional factor to consider is convenience of use, usually reflected in how frequently the medication must be taken and how many pills are involved. For some problems, medication choices are limited and choices are constrained. When it comes to analgesics, however, there are usually many options and various factors must be weighed to make the best choice for each patient.

Opioid/acetaminophen combinations In January 2011, the FDA announced that over a 3-year period it will phase in an order that limits the amount of acetaminophen that can be included in combination medications with opioids to 325 mg per pill (ie, with codeine [Tylenol with codeine], with hydrocodone [Vicodin], and with oxycodone [Percocet]).1 The lowest-dose Vicodin compounds contain 500 mg of acetaminophen and 5 mg of hydrocodone; Vicodin ES has 750 mg of acetaminophen with 7.5 mg of hydrocodone. There is also a hydrocodone/acetaminophen compound (Zydone) that contains 400 mg of acetaminophen. Percocet contains up to 650 mg of acetaminophen per pill. In the real world, it is very easy for patients taking these medications to exceed the maximum recommended daily dose of 4 g of acetaminophen. Thus, the dose limitation is an improvement. However, I would have preferred that the FDA follow the recommendation of its advisory panel to ban these combination medications altogether. Acetaminophen is readily available and inexpensive; as such, there does not appear to be any clear reason to continue to have combinations with this agent available, except for dosing convenience. Furthermore, patients who take products such as Vicodin and Percocet may be unaware that these medications contain acetaminophen and they may take additional doses of acetaminophen separately. The FDA limitation also fails to address the issue of tolerance adequately. Because there is no ceiling on the dosing of μ-opioid receptor agonists that include hydrocodone, oxycodone, and codeine, the dosage can be increased safely when the opi-

oid is taken alone. However, the maximum recommended daily dose of acetaminophen never changes and patients do not become tolerant to its potential hepatotoxicity. Fortunately, there is no reason to wait for the FDA restriction to be fully implemented to eliminate the risk of acetaminophen toxicity associated with the use of these combination medications. While hydrocodone is only available in compounds with other medications, oxycodone and codeine can be given alone.

acetaminophen overdose. In a recent editorial, MacDonald and MacLeod2 noted ongoing concerns about codeine. Although they focused on its use in children, their concerns would also appear to apply to adults. Codeine is metabolized to its analgesic form—morphine—by the CYP2D6 system. Because of variability in this system, some patients metabolize codeine rapidly. The authors report that it might be safer to prescribe morphine for patients instead of codeine, thereby eliminating the risk of morphine toxicity resulting from this faster metabolism. This is a good recommendation. However, I have not been a supporter of the use of oral formulations of these medications. For moderate pain that requires an oral opioid, I prefer oxycodone instead of codeine or, for that matter, hydrocodone. For more severe pain, I believe hydromorphone (Dilaudid) is much more effective than oral morphine. An extended-release form of hydromorphone (Exalgo) is now avail-

The FDA will limit the amount of acetaminophen in combination drugs . . . Oxymorphone—the analgesic metabolite of oxycodone—is also available in both immediate- and extended-release formulations (Opana). There is no evidence, however, that oxymorphone provides any more analgesia than oxycodone, and because it is not yet available in a generic formulation, it is more expensive than generic oxycodone. Oxymorphone is a useful alternative for patients taking medications that inhibit the cytochrome P-450 2D6 (CYP2D6) isoenzyme system, such as some of the SSRIs: oxycodone is metabolized to oxymorphone through this system. Furthermore, if patients require around-the-clock opioids for more than a few days, extended-release forms of opioids—none of which contain acetaminophen—would make more sense. These formulations are taken once or twice a day and appear to provide more stable pain relief than do their immediaterelease counterparts. Moreover, they eliminate the risk of inadvertent

able. My lack of support for hydrocodone stems not only from its unavailability in a non-combination formulation but also from similar concerns regarding toxicity that might be raised about hydrocodone because it, too, is metabolized by the CYP2D6 system to its analgesic form, hydromorphone. As a result, I rarely prescribe hydrocodone.

Cardiovascular toxicity and NSAIDs When one thinks of adverse events related to NSAIDs, GI problems are usually at the top of the list. However, following the discovery of cardiovascular (CV) problems with rofecoxib (Vioxx) and its subsequent removal from the market, there has been increasing awareness that other selective cyclooxygenase-2 (COX2) inhibitors and the nonselective NSAIDs may also cause similar problems. A recent meta-analysis sought to determine whether there is any other difference between the various

NSAIDs with regard to CV toxicity. 3 Trelle and colleagues 3 examined 31 studies that looked at 7 different NSAIDs. Three were nonselective (ibuprofen, diclofenac, and naproxen). Four were selective COX-2 inhibitors (celecoxib, the only one of this class now available in this country; rofecoxib; and 2 agents that have never been approved in this country—etoricoxib and lumiracoxib). Compared with placebo, all these drugs were associated with an increased risk of stroke. Ibuprofen and diclofenac were most strongly associated; naproxen was least strongly associated. Rofecoxib and lumiracoxib were most strongly associated with myocardial infarction (MI); there was no apparent increased risk of MI with the other medications. Finally, all the drugs except naproxen were associated with an increased risk of CV death relative to placebo. Trelle and colleagues3 thus concluded that with regard to CV adverse events, naproxen appears to be the safest of the NSAIDs. Celecoxib is an alternative, especially for patients who have difficulty with tolerating naproxen secondary to GI distress. Obviously, this recommendation is limited by the relatively few NSAIDs for which the CV risks have been studied. Of special interest would be how the nonacetylated salicylates, such as choline magnesium trisalicylate (Trilisate), compare with the others. Medications in this class appear to be associated with less GI toxicity than the other nonselective NSAIDs, and their use avoids the concerns associated with selective COX-2 inhibitors. Dr King is in the private practice of pain medicine in New York, and he is clinical professor of psychiatry at the New York University School of Medicine, New York. References 1. FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm239894.htm. Accessed March 14, 2011. 2. MacDonald N, MacLeod SM. Has the time come to phase out codeine? Can Med Assoc J. 2010;182: 1825. 3. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342: c7086. doi:10.1136/bmj.c7086. ❒

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MAY 2011

COGNITIVE DIFFICULTIES

Cognitive Symptoms in Schizophrenia Recognizing and Treating Cognitive Deficits in Schizophrenia by Lewis A. Opler, MD, PhD ognition has more than one meaning. Cognitive-behavioral therapy (CBT) refers to therapies that work on changing automatic thoughts and resulting schemas. When it is effective, CBT helps patients: • Become aware of automatic thoughts • Appreciate how these lead to schemas that distort global perception and limit one’s repertoire of responses • Question and alter thoughts and schemas and thus achieve cognitive restructuring A common metaphor for successful CBT is that a patient comes in seeing the glass as “half empty” and leaves able to see that even “halfempty” glasses are simultaneously “half full.” In contrast, cognitive remediation, developed by neuropsychologists who initially used techniques for helping persons with traumatic brain injury, uses exercises—many computer-based—and other techniques to help patients with deficits in underlying processes that lead to disruptions in thinking. Cognitive remediation is focused not on distortions in global schemas but on neurocognitive processes that need to be either strengthened or bypassed by auxiliary pathways. Pharmacotherapy for cognitive symptoms uses medications to correct dysfunctions in the processes that underlie thinking. Eventually, we will

Table

find ways to combine cognitive remediation with pharmacological interventions in treating cognitive symptoms in schizophrenia and other neuropsychiatric disorders. An excellent operational definition for cognition as conceptualized in this article is that of Medalia and Revheim,1 2 leaders in the field of cognitive remediation. “Cognition refers to thinking skills, the intellectual skills that allow you to per-

pirical work led researchers to propose that schizophrenia be seen as a disorder comprising more than 1 underlying process.2-4 In the 1990s, as pharmaceutical companies began marketing atypical antipsychotics as agents that improved negative as well as positive symptoms in addition to having fewer motor adverse effects, the concept of schizophrenia as a multidimensional disorder became widely accepted.5

CHECK POINTS

 During the 1970s and 1980s, empirical work led researchers to propose

that schizophrenia is a disorder comprising more than one underlying process. In the 1990s, the concept of schizophrenia as a multidimensional disorder became widely accepted.

 The NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative has developed a consensus battery to evaluate the efficacy of new medications for the management of cognitive symptoms in schizophrenia.

 Three neurochemical systems have emerged as potential targets for pharmacological agents: the cholinergic, the D1 dopamine, and the N-methyl D-aspartate (NMDA) subtype of glutamate receptors.

 Although smoking itself should cease, nicotine replacement therapy may need to be continued indefinitely to prevent a worsening of cognition.

ceive, acquire, understand and respond to information. This includes the abilities to pay attention, remember, process information, solve problems, organize and reorganize information, communicate and act on information.”1(p5) During the 1970s and 1980s, em-

The 7 cognitive domains assessed by the MATRICS Consensus Cognitive Battery13

• Speed of processing • Attention/vigilance • Working memory • Verbal learning • Visual learning • Reasoning and problem solving • Social cognition MATRICS, Measurement and Treatment Research to Improve Cognition in Schizophrenia.

Assessing cognition Large-scale pharmaceutical company studies, along with investigatorinitiated studies they inspired, frequently used 1 or more of the following symptom severity rating scales: • The Scale for the Assessment of Negative Symptoms (SANS)6 • The Scale for the Assessment of Positive Symptoms (SAPS)7 • The Positive and Negative Syndrome Scale (PANSS)8 Large-scale studies provided data for the SANS/SAPS- and the PANSS-rated symptoms, which led to the approval of risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole and allowed for factor analysis. Factor analysis of the SANS/ SAPS ratings revealed 3 factors: positive, negative, and disorganized symptoms. Factor analysis of the PANSS-rated symptoms revealed 5 factors: positive, negative, dysphoric mood, excitement/hostility (some-

times called activation), and cognitive (sometimes called autistic preoccupation) symptoms. For both SANS and SAPS, poor performance on neuropsychological tests was found to correlate with the negative and disorganized factors. Negative symptoms were related to poor performance on tests of verbal learning and memory, verbal fluency, visual memory, and visual-motor sequencing, while disorganized symptoms were correlated with lower verbal IQ and poor concept attainment.9 For the PANSS, poor performance on neuropsychological tests was found to correlate with the negative and the cognitive/autistic preoccupation factors, but not with severity of positive symptoms. In a study by Opler and colleagues,10 PANSS negative symptoms were found to be associated with difficulties in performing the Wisconsin Card Sorting Test (WCST), a measure of executive functioning and prefrontal integrity. Bell and colleagues11 found that the PANSS cognitive factor significantly correlated with poorer performance on all neuropsychological tests in a comprehensive battery that included the WCST. Clearly, important questions remain to be answered about whether neurocognitive deficits are best conceptualized as correlates of negative and disorganized symptoms or whether they are a distinct independent feature. To the extent that neurocognitive deficits correlate with negative and disorganized symptoms, we also need to better understand how they are underlying contributors to these symptom dimensions. The NIMH’s initiative Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) has jump-started the process for treating cognitive deficits in patients with schizophrenia. It has brought together experts and developed a consensus battery to be used by the FDA, and presumably other regulatory agencies, to evaluate the efficacy of new medications for the treatment of cognitive symptoms in schizophrenia.12 As shown in the Table, the resulting MATRICS Consensus Cognitive Battery consists of 10 tests that assess 7 cognitive domains.13

MAY 2011

The role of neurochemical systems Three neurochemical systems have emerged as potential targets for pharmacological agents: the cholinergic, D1 dopamine, and N-methyl d-aspartate (NMDA) glutamate systems. While not the only systems suggested and worthy of investigation, the consensus appears to be that these 3 offer the most promise. In discussing these systems, rather than cataloging ongoing or recently completed clinical trials, I focus on ways that practicing clinicians can begin to target these systems. Since there are no FDA-approved medications for the treatment of cognitive symptoms in schizophrenia, any suggested use of a presently available medication for treating cognitive symptoms in schizophrenia is by definition an off-label use. The off-label use of medications approved for other purposes is appropriate but needs to be evidence-based, discussed with the patient, and the best alternative. Pharmacotherapy should be used with other psychosocial interventions. In the case of cognitive symptoms, combining pharmacotherapy with cognitive remediation, in addition to more traditional approaches, may lead to better quality of life and more rapid recovery.

The cholinergic system In the 1970s, it was found that Alzheimer disease was caused primarily by the degeneration of acetylcholine or cholinergic neurons that emanate from the nucleus basalis of Meynert. This landmark finding was on the one hand startling, since it had been thought that more widespread neurochemical deficits would be found. On the other hand, it was consistent with decades of work that showed that anticholinergic medications disrupted cognitive functions and, in particular, memory in nonpatient populations. Regarding schizophrenia, a small but compelling literature indicates that anticholinergics counter the therapeutic action of neuroleptics.14 Findings from recent clinical trials indicate that both muscarinic and nicotinic agonists hold promise in the treatment of cognitive symptoms of schizophrenia.15,16 While awaiting new cholinergic agonists, we can begin to address the cholinergic deficit in schizophrenia. First is to “do no harm” by avoiding the use of highly anticholinergic regimens that can exacerbate cognitive deficits. For example, if the use of anticholinergics to treat extrapyramidal syndrome (EPS) appears to be exacerbating cognitive symptoms, con-

COGNITIVE DIFFICULTIES sider amantadine, which treats EPS but is not an anticholinergic. In a double-blind, crossover study, Silver and Geraisy17 showed that biperiden (an anticholinergic), but not amantadine, interferes with memory and, in particular, visual memory. It is extremely important to help those with schizophrenia to stop smoking; bear in mind, however, that they may smoke because nicotine improves their cognitive symptoms.

site is simultaneously occupied by either glycine or d-serine, both of which are released into the synapse by astrocytes. Glycine’s action is terminated when it binds to a glycine transporter protein and is brought back to the astrocytes where it is oxidized. High doses of dietary glycine added to antipsychotic regimens can lead to clinical improvement, but in clinical practice, glycine-induced nausea limits its utility.23

Three neurochemical systems have emerged as potential targets for pharmacological agents: the cholinergic, D1 dopamine, and NMDA glutamate . . . While the smoking itself should cease, nicotine replacement therapy may need to be continued indefinitely to prevent a worsening of cognition.

D1 dopamine–mediated processes A link has been shown between prefrontal dysfunction and the cognitive deficits observed in schizophrenia.18,19 Goldman-Rakic20 has suggested that disruption of D1 dopamine receptor activity can contribute to the cognitive symptoms of schizophrenia, while stimulation of the D1 dopamine receptor improves cognition.21 Modafinil has been found to improve short-term verbal memory span, visual memory, and spatial planning in patients with chronic schizophrenia. It is reasonable to hypothesize that it does this, at least in part, by stimulating D1 dopamine receptors.22

Hypofunction of the NMDA glutamate system In the 1980s, phencyclidine (PCP), “angel dust,” was a widely used recreational drug of abuse. Some people were brought to psychiatric emergency departments with schizophrenialike symptoms, including positive, negative, and cognitive symptoms. The hypothesis that schizophrenia may be a result of hypofunction of the NMDA glutamate system emerged when it was found that PCP blocked calcium efflux through channels controlled by NMDA glutamate receptors. In the NMDA glutamate system, glutamate binding to a subset of receptors leads to the opening of the calcium channel, but only if a second

Recently, another promising strategy has emerged. Glycine levels in the synapses can be raised by glycine transport inhibitors that prevent glycine from entering the surrounding astrocytes. Consequently, more glycine remains in the synapse. Several glycine transport inhibitors are presently in or are entering clinical trials. One promising candidate is N-methylglycine, or sarcosine.24 Preliminary studies indicate that added to antipsychotics, 1 to 2 g of sarcosine per day can lead to significant improvement in positive, negative, and cognitive symptoms.

Conclusion The next decade should bring new drugs that will treat cognitive symptoms in schizophrenia. While practicing clinicians wait for these new agents, this article suggests pharmacological agents and strategies that may improve cognitive symptoms in persons with schizophrenia. Dr Opler is professor of clinical psychiatry at Columbia University College of Physicians and Surgeons, New York, and adjunct professor of psychiatry at New York University School of Medicine, New York. He reports that as a coauthor of The Positive and Negative Syndrome Scale (PANSS), he receives royalties from the publisher, Multi-Health Systems, Inc, for sale of the PANSS Manual, the Structured Clinical Interview for the PANSS, and the Informant Questionnaire for the PANSS. Dr Opler is also on the speakers panel of Eli Lilly and Merck. References 1. Medalia A, Revheim N. Dealing With Cognitive Dysfunction Associated With Psychiatric Disabilities: A Handbook for Families and Friends of Individuals

PSYCHIATRIC TIMES

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With Psychiatric Disorders. Albany, NY: New York State Office of Mental Health; 2002. 2. Strauss JS, Carpenter WT, Bartko JJ. The diagnosis and understanding of schizophrenia, III: speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull. 1974;11:6169. 3. Crow TJ. Molecular pathology of schizophrenia: more than one disease process? Br Med J. 1980; 280:66-68. 4. Andreasen NC, Olsen S. Negative v positive schizophrenia. Definition and validation. Arch Gen Psychiatry. 1982;39:789-794. 5. Opler LA, Hwang MY. Schizophrenia: a multidimensional disorder. Psychiatr Ann. 1994;24:491495. 6. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS). Iowa City: The University of Iowa; 1983. 7. Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City: The University of Iowa; 1984. 8. Kay SR, Opler LA, Fiszbein A. The Positive and Negative Syndrome Scale (PANSS) Manual. Toronto: Multi-Health Systems Inc; 2006. 9. O’Leary DS, Flaum M, Kesler ML, et al. Cognitive correlates of the negative, disorganized, and psychotic symptom dimensions of schizophrenia. J Neuropsychiatry Clin Neurosci. 2000;12:4-15. 10. Opler LA, Ramirez PM, Rosenkilde CE, Fiszbein A. Neurocognitive features of chronic schizophrenic inpatients. J Nerv Ment Dis. 1991;179:638-640. 11. Bell MD, Lysaker PH, Milstein RM, Beam-Goulet JL. Concurrent validity of the cognitive component of schizophrenia: relationship of PANSS scores to neuropsychological assessments. Psychiatry Res. 1994; 54:51-58. 12. Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull. 2005;31:5-19. 13. Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;165:203-213. 14. Singh MM, Kay SR. A comparative study of haloperidol and chlorpromazine in terms of clinical effects and therapeutic reversal with benztropine in schizophrenia. Theoretical implications for potency differences among neuroleptics. Psychopharmacologia. 1975;43:103-113. 15. Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165:1033-1039. 16. Freedman R, Olincy A, Buchanan RW, et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry. 2008;165:1040-1047. 17. Silver H, Geraisy N. Effects of biperiden and amantadine on memory in medicated chronic schizophrenic patients. A double-blind cross-over study. Br J Psychiatry. 1995;166:241-243. 18. Merriam AE, Kay SR, Opler LA, et al. Neurological signs and the positive-negative dimension in schizophrenia. Biol Psychiatry. 1990;28:181-192. 19. Wolkin A, Angrist B, Wolf A, et al. Low frontal glucose utilization in chronic schizophrenia: a replication study. Am J Psychiatry. 1998;145:251-253. 20. Goldman-Rakic PS. The relevance of dopamineD1 receptor in the cognitive symptoms of schizophrenia. Neuropsychopharmacology. 1999;21:S170S180. 21. Goldman-Rakic PS, Castner SA, Svensson TH, et al. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl). 2004;174:3-16. 22. Turner DC, Clark L, Pomarol-Clotet E, et al. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology. 2004;29:1363-1373. 23. Javitt DC, Zylberman I, Zukin SR, et al. Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry. 1994;151:1234-1236. 24. Tsai G, Lane HY, Yang P, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2004;55:452-456. ❒

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Board Certification: Two Perspectives Dr Sidney Weissman made some interesting observations in his December 2010 commentary regarding the American Board of Psychiatry and Neurology’s (ABPN) Maintenance of Certification (MOC) program.1 The MOC program is a work in progress and we welcome constructive feedback about how it might be improved. However, we would like to address several of Dr Weissman’s misperceptions regarding the goals and requirements of the ABPN MOC program. By way of background, the American Board of Medical Specialties (ABMS) comprises 24 Member Boards—one of which is the ABPN— that are committed to the ABMS MOC® program. Each Member Board develops its own program on the basis of the needs of its specialty and subspecialties while adhering to the standards established by consensus of all the Member Boards. In devising this program, the ABPN collaborates with its affiliated professional organizations, including the American Psychiatric Association (APA), to encourage the development of a variety of self-assessment, continuing medical education, and performance improvement modules that physicians can use to compare their clinical practices with standards of care (eg, practice guidelines). Dr Weissman states that “MOC is meant to ensure that diplomates maintain the competency they had when they graduated from residency.” In fact, a primary goal of the ABMS MOC program is lifelong learning, and the 4-part process was developed to encourage continuous improvement and expansion of competencies beyond what was required for graduation from residency. Diplomates are expected to not only possess the up-to-date competencies to provide quality patient care but also demonstrate that they do so with their own patients. Regarding the ABPN MOC Part IV requirements for patient and peer feedback, the program requires board-certified physicians to seek regular input from patients and peers about the manner in which they relate and how they might improve their clinical practice. This is entirely different from requiring that the practitioner’s work be reviewed, as Dr Weissman maintains. The ABPN Web site (www.abpn.com) contains straightforward model forms for patient and peer feedback that physi-

DEBATE cians might use to meet this requirement. Physicians are asked to obtain feedback from 30 patients and 30 peers over the course of 10 years. Furthermore, physicians themselves select the peers and patients to complete these surveys, collect and analyze the feedback, and decide what structural or process changes, if any, they might want to make to improve the quality of care they provide to their patients. Much of the experience to date suggests that psychiatric patients are very willing and able to provide their opinions about the care they receive. There is also growing sentiment about the importance of teamwork and collaboration to the delivery of quality patient care and that professional peers might actually be in the best position to provide physicians with constructive criticism and rec-

credit for their meaningful participation in quality improvement activities at the Clinic. In addition, the ABPN and other Member Boards are considering other ways in which they might recognize the current quality improvement activities of diplomates. When programs do not exist, however, it is incumbent on the Member Boards to make sure that resources are available to diplomates so that they can readily fulfill the requirements for the MOC program. The ABMS, the ABPN, and all the Member Boards have made great strides during the past decade to implement increasingly rigorous standards of care while also providing health care institutions, insurers, and consumers with the information they need to evaluate the commitment to quality of their physicians within a

The MOC program is a complex process . . . and a work in progress . . . ommendations for improvement, especially in the humanistic aspects of their performance. In our current era of patient advocacy, patient-centered care, and transparency, it seems likely that pressures will only increase on physicians to consider the perspectives of patients themselves when they deliver clinical services. It would indeed be unfortunate and ironic for the medical specialty that justly takes pride in its special emphasis on the importance of the physician-patient relationship to attempt to separate itself from the rest of medicine in this regard and to deny its patients the opportunity to provide input into their care. While Dr Weissman’s concerns about “issues of transference” are certainly relevant, it is also true that transference issues are part of all aspects of clinical practice. It remains to be seen whether patient surveys will provoke anything special in this regard. As Dr Weissman notes, quality improvement programs are hardly unique and already exist at many psychiatric facilities. The ABMS and its Member Boards—including the ABPN—are concerned about redundancy and wish to reduce the burden on physicians. Therefore, we are working toward synergies when these programs exist. For instance, several of the ABMS Member Boards are involved with a pilot project with the Mayo Clinic that provides physician MOC Part IV

given specialty. We concur that the various Member Boards’ MOC programs must continually evolve to provide tools for meaningful continuous professional development. The ABPN recognizes that its MOC program is a complex process and a work in progress and encourages debate about how the elements of its MOC program might be improved to make them more relevant and less burdensome. The ultimate challenge for the ABPN is to design its MOC program in a manner that is credible enough to the public and external organizations so as to be of value to its diplomates, yet convenient enough so that they will choose to participate in it. That is not an easy balance to achieve, and it will only be possible with the help and input of informed diplomates. Kevin B. Weiss, MD, President and CEO American Board of Medical Specialties Larry R. Faulkner, MD, President and CEO American Board of Psychiatry and Neurology Reference 1. Weissman S. Does maintenance of certification ensure maintenance of competency? Psychiatr Times. 2010;27(12):17.

Dr Weissman Responds I am delighted to have this opportunity to respond. Drs Weiss and Faulkner assert that I have misperceived or misinterpreted a number of the positions or policies of the ABMS

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MOC and the ABPN MOC. A careful reading of my comments will confirm that no misinterpretation occurred. Rather, Drs Weiss and Faulkner present an interesting interpretation of ABMS MOC policy and history. A brief review of the ABMS Mission Statement (Article II of the ABMS Bylaws) is helpful. The intent of the certification of physicians is to provide assurance to the public that a physician specialist certified by a Member Board of ABMS has successfully completed an approved education program and an evaluation process, which includes an examination designed to assess the knowledge, skills, and experience required to provide quality patient care in that specialty.

In the 1990s, the ABMS required all of its Member Boards to develop a recertification process for all new diplomates and to put an end to the process of lifetime certificates. It did so to meet the demands of society and to effectively enforce its mission statement. Board certification in this new model would last 10 years, and every 10 years diplomates would need to be recertified. Boards were required to develop processes to affirm the ongoing knowledge base of their diplomates. Boards opted to use either proctored paper and pencil type examinations or take-home examinations for this recertification purpose. Over time, take-home examinations were deemed inadequate and proctored examinations were required to assess the knowledge of the diplomates of all Boards who were taking recertification examinations. The recertification process evolved into MOC. We all understand that on graduation from residency and the initial successful passing of the Board Certification Examination, a new diplomate has the broadest, most up-todate knowledge of his or her field. The challenge for every clinician is to maintain that knowledge base throughout clinical practice and to ensure the continued evolution of clinical skills. It was thought that recertification every 10 years did not adequately assess the diplomate’s knowledge base, nor did it address the specific knowledge essential for a diplomate’s practice. Restated in terms of the ABMS mission, it did not adequately inform the public as to the ongoing competency of the practitioner and as such did not meet the requirements of the ABMS mission. The MOC program was designed

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to strengthen the earlier recertification process. It focused on lifelong learning as an essential professional requirement of every practicing physician. The 4-part process Drs Weiss and Faulkner allude to is designed to facilitate and inform the physician’s lifelong learning process. In theory, the process ensures that throughout the physician’s practice life, his knowledge base is as current and relevant as when he graduated from residency. The process includes an external review of the physician’s functioning by peers and patients. This aids the practitioner’s self-assessment. The required external review of physician activity by patients and peers in many ways parallels the process now in place in residency training. The clinical work of residents is observed and reported on by physician supervisors, patients, and others to the resident’s training director. The training director is responsible for both grading resident performance and providing relevant feedback to the trainee. An implicit question is whether Boards will someday use such feedback to grade the performance of a practitioner. This possibility raises further questions as to the reliability of such data. Drs Weiss and Faulkner assert that I err in conceptualizing the assessment of practitioner performance noted above as reviews of functioning. They contend that the ABMS requirement for feedback of a physician’s performance by 30 patients and 30 peers over 10 years is not a review of a practitioner’s work, it is rather “entirely different from requiring the practitioner’s work be reviewed.” The practitioner receives feedback from patients and peers. The feedback from these 2 groups is based on a review of their interactions with the practitioner, which are guided by the evaluation tools they use. The value of the feedback is determined by the skill of the evaluator and the instrument used. As we examine this process, we might ask why feedback from 30 patients and 30 peers over 10 years? Why not 40 or 100? The unique nature and structure of a practice determines how many patients or peers need to comment to obtain useful data. An arbitrary number is not adequate and will not provide useful information. Effective feedback to practitioners requires that statistically appropriate numbers of patients and peers are used. Furthermore, the feedback must be guided by effective evaluation tools. If both criteria are not in place, the feedback

process may not be reliable or valid and will not aid the practitioner’s self-assessment. Drs Weiss and Faulkner imply that I am opposed to gathering data from psychiatric patients because of transference issues and argue that I appear to support separating psychiatry from the rest of medicine. Nothing can be further from the truth. In many psychiatric practices, issues of transference may make obtaining meaningful data from patients difficult. This reality does not separate us from the rest of medicine but highlights how we must be clear on the strengths and limitations of collecting patientgenerated data in all medical practices. This reality further informs us of the need to develop effective tools for gathering this information. Psychiatrists can lead the development of these essential tools because understanding the physician-patient relationship is central to much of our work. Drs Weiss and Faulkner also imply that the APA has had a key role in the development of ABPN policies. The APA has worked with the ABPN in developing a number of educational programs to meet the ABPN’s new requirements. But it has not had a truly collaborative role in developing ABPN policy. During my 6 years of service as a trustee on the APA Board of Trustees, we did not affirm any actions of the ABPN. Maintaining the competency of our nation’s physicians is a critical element in the delivery of health care. We have made a number of significant strides in the development of educational models to meet these goals. But we do not have definitive answers as to what does and does not work. Lifetime certification of physician specialists lasted for 8 decades. Recertification as a model to accomplish this goal lasted but a decade. In 10 more years, MOC may also be replaced by a new, still undefined, construct. We must not allow the current model of MOC to either be or become a rigid set of requirements, but must use it as a guide to the future. Society has given the medical profession the critical role of monitoring and ensuring the competence of our nation’s physicians. The ABMS, in its mission statement, acknowledges this responsibility to the public. I hope that Drs Weiss and Faulkner share this view of the responsibilities of the ABMS. Sidney Weissman, MD Professor of Clinical Psychiatry Department of Psychiatry Feinberg School of Medicine Northwestern University, Chicago ❒