Psychiatric Times April 2011 Vol XXVIII, No 4 by UBM Medica

Practice Management How to Protect Patient Information

A UBM Medica Publication®

Special Report Clinical Pharmacology

Category 1 CME Cardiovascular Risks of Psychotropics

April 2011 • Vol. XXVIII, No. 4

www.PsychiatricTimes.com

Psychotherapy Is Alive and Talking in Psychiatry by Ronald W. Pies, MD he title of Gardiner Harris’s frontpage story in the March 6 New York Times was blunt: “Talk Doesn’t Pay, So Psychiatry Turns Instead to Drug Therapy.” For those of us who see our profession as a humanistic calling, this piece is likely to provoke a mixture of sadness and anger. After all, its depiction of psychiatric practice was one of grim, damage control, in which maintaining the financial bottom line and keeping patients functional seem to be the prime directives. The main character in this sorry tale appears to be a decent soul, overwhelmed by the demands of his practice, and ashamed of his own therapeutic apostasy. The besieged and beleaguered psychiatrist, trained in the “old style” of in-depth therapy, describes his office as resembling “a bus station” and concludes that psychotherapy is no longer “economically viable.”

The declining use of psychotherapy in psychiatric practice is unquestionably worrisome. Unfortunately, the New York Times article uses the anecdotal experience of one psychiatrist to

create, at best, a partial picture of psychiatric practice, and at worst, a caricature that perpetuates a number of myths and misconceptions. Among the most injurious of these myths is that

Ketamine: A Possible Role for Patients Who Are Running Out of Options? by Arline Kaplan ncouraged by recent studies showing that a single IV infusion of ketamine can have antidepressant effects within hours in patients with treatment-resistant major depression (TRD) or bipolar depression, a psychiatric team at the University of California, San Diego (UCSD) Medical Center has begun offering ketamine infusions to patients who “are running out of options.” “We are not studying ketamine per se,” said David Feifel, MD, PhD, asso-

ciate professor of psychiatry and neurosciences at UCSD and director of the Medical Center’s Neuropsychiatry and Behavioral Medicine Service. Rather, he and his team have developed a protocol of IV ketamine for severely depressed patients who have unsuccessfully run the gamut of medications and possibly ECT. It is one of several approaches offered in their Treatment Refractory Program. According to Feifel, patients are informed that ketamine is not approved for this use, that insurance does not (Please see Ketamine, page 10)

psychiatrists have essentially abandoned psychotherapy; that pharmacotherapy is something psychiatrists typically provide “instead of” psychotherapy; and that in the course of a 15-minute medication visit, there is little one can do for the patient’s emotional suffering, beyond referring him or her to a “real” psychotherapist. The article also perpetuates the popular but mistaken impression that pharmacotherapy is a rather crude and simple-minded intervention. Perhaps worst of all, this saga of an overworked psychiatrist may leave millions of readers with the fear that most psychiatrists are now “training” themselves not to get “too interested” in their patients’ problems. First of all, what is the reality of psychiatry’s use of psychotherapy in recent years? The Times cited a 2005 government survey showing that “just 11% of psychiatrists provide talk therapy to all patients. . . .” Presumably, (Please see Psychotherapy, page 9)

Issue Highlights Antipsychotics and the Shrinking Brain Donald C. Goff, MD

Severe Funding Shortfalls Likely for Mental Health Programs Stephen Barlas

Antidrug Vaccines: Fact or Science Fiction? Daryl Shorter, MD and Thomas R. Kosten, MD

Custom-Made Neural Stem Cells John J. Medina, PhD

COMPLETE CONTENTS, PAGE 10

Sarah

Senior Executive Sales Representative

(cuts to the chase)

Cymbalta is indicated in adults for: • The treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in 4 short-term trials and 1 maintenance trial.

• 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 general anxiety disorder (GAD). The efficacy of Cymbalta was established in 3 short-term trials and 1 maintenance trial.

• The management of diabetic peripheral neuropathic pain (DPNP).

DD68601 0311

Cymbalta is a registered trademark of Eli Lilly and Company.

• The management of fibromyalgia (FM).

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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 DD68601 0311

Cymbalta is a registered trademark of Eli Lilly and Company.

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

PS YC H I ATRI C TI M E S

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w w w. psychi atr i cti mes. com

Psychotherapy Continued from page 1

this was a reference to the study by Mojtabai and Olfson,1 based on data from the 1996 - 2005 cross-sectional National Ambulatory Medical Care Survey (NAMCS). Indeed, the study found a decline in the number of psychiatrists who provided psychotherapy to all of their patients, from 19.1% in 1996 - 1997 to 10.8% in 2004 - 2005. The study also found that the percentage of visits involving psychotherapy declined from 44.4% in 1996 - 1997 to 28.9% in 2004 2005, which “. . . coincided with changes in reimbursement, increases in managed care, and growth in the prescription of medications.” So far, all this is in line with the New York Times piece. But the article failed to mention that most psychiatrists (59.4%) continue to provide psychotherapy to at least some of their patients.1 Moreover, when we read the discussion section of the Mojtabai-Olfson study, we find an important caveat. Their study required that “psychotherapy visits” had to be longer than 30 minutes and had to be “explicitly designated as a psychotherapy visit by the psychiatrist or office staff.” The authors added this telling observation: Some visits likely involved use of psychotherapeutic techniques but were not classified as psychotherapy in the current analysis. Psychotherapeutic techniques can be effectively taught and used in brief medication management visits by psychiatrists and other health care providers.1(p968),2,3 Furthermore, the NAMCS survey did not examine the type of psychotherapy provided. As Mojtabai and Olfson1 note, “Examining the types of psychotherapy would be of special interest as there has been an expansion in the use of more structured short-term therapies in recent years.” Indeed, not all psychotherapy corresponds to, or necessarily requires, the classic “50-minute hour” associated with psychoanalytically oriented therapy. My colleague, James P. Gustafson, MD, has developed a form of “very brief psychotherapy” that sometimes involves 5- or 10-minute interventions. Surprisingly, these very brief encounters can be transformative on a very deep level, for carefully selected patients.3 Indeed, while I am no fan of the 15-minute “med check,” the critical issue is not so much the available minutes as it is the deftness and

sensitivity of the psychiatrist’s intervention. Faced with a patient who is experiencing a painful issue in her marriage or job, there is a good deal more we can do in 5 to 10 minutes besides saying, “Sorry, I’m not your therapist. That stuff is not in my bailiwick.” We can offer understanding, empathy, and clarification—and I believe most psychiatrists do just that, during a medication visit. Similarly, Dr Glen Gabbard has described how psychodynamic principles and an understanding of the patient’s urgent personal concerns are necessary parts of the muchmaligned “15-minute med check.” He notes the following: Psychiatry has probably made far too much of a distinction between psychotherapy and pharmacotherapy in training and in practice. Psychotherapeutic skills are needed in every context in psychiatry because the same phenomena that emerge in psychotherapy—transference, resistance, countertransference, schema, automatic thoughts—appear in other contexts. . . . Psychiatry residents need to be taught that psychotherapeutic principles apply in all settings where psychiatric treatment is delivered [italics added].4 The other unfortunate aspect of the Harris article is its implicit reinforcement of the “mind-body” split that has so bedeviled psychiatry for the past 50 years, as Tanya Luhrmann documented in her classic study, Of Two Minds: The Growing Disorder in American Psychiatry. Thus, pharmacotherapy is portrayed as something psychiatrists do “instead of” psychotherapy, rather than as part of an integrated and holistic form of treatment. But in my experience, many psychiatrists continue to provide such comprehensive medical-psychological care, although the Mojtabai-Olfson data do not tell us what percentage do so (M. Olfson, personal communication, March 8, 2011). In truth, there are often reasons—including cost-effectiveness—for preferring a “single provider” model of combined treatment. Dr Mantosh Dewan5 showed, for example, that when treatment requires both psychotherapy and medication, combined treatment by a psychiatrist costs about the same or less than split treatment with a social worker psychotherapist and is usually less expensive than split treatment with a psychologist

psychotherapist. Furthermore, with respect to the treatment of major depression, there is reasonably good evidence that the combination of psychotherapy and medication works better than either treatment alone, at least in chronically or severely depressed patients.6,7 Yet in the Times article, there is a not-too-subtle disparagement of pharmacotherapy. Our harried psychiatrist, estranged from his psychotherapeutic training, opines that “. . . there’s not a lot to master” in psychopharmacology, and that he often feels like “the ape with the bone.” It’s true that the kind of complexity involved in medication treatment is quite different from that of, say, psychoanalysis or objectrelations theory. But psychopharmacology has its own complexity, if—to borrow a phrase from Woody Allen—“you are doing it right.” Quite aside from the innumerable drug-drug interactions one needs to sort through, there are the issues of medicating patients with comorbid illnesses, such as diabetes or heart disease; understanding how psychiatric medications affect the very young and the very old; monitoring potential metabolic effects of medications; and mitigating adverse effects without undermining otherwise successful pharmacotherapy.8 Then there is the realm of medication’s “psychodynamics”—the hopes, fears, and fantasies the patient often attaches both to the physician’s prescribing a medication and to the particular drug prescribed. A failure to understand these often unconscious issues can spell disaster for pharmacotherapy. As Dewan has put it: Some patients derive a psychological benefit from being given medications, because they consider it a caring, nurturing act that feeds their dependency needs or validates their suffering as genuine. Other patients may see the prescription of medications as an imposition of external control, or as a statement by the therapist that they are not strong enough to solve their problems by themselves. These feelings may contribute to noncompliance with both medications and brief therapy.9(pp257-264) To be sure, given a 15-minute time slot, the harried psychiatrist focusing only on medication adverse effects is at a severe disadvantage—and so is the patient. Based on the principles

of beneficence and non-malfeasance, one might argue that it is frankly unethical to limit an emotionally distraught or suicidal patient to such a procrustean time slot, if her medical and psychological needs demand more thorough evaluation and management. (Our beleaguered New York Times psychiatrist nearly fails to detect suicidal ideation in a patient who initially complained of “ADD” and, to his credit, winds up extending the session to 55 minutes.) Speaking of ethics: we should remind ourselves that there are still over 45 million Americans who lack health insurance, and that most patients with major depression do not receive any professional treatment 10—never mind, psychotherapy. Finally, even the constraints of a 15-minute session are no excuses for putting off patients with comments such as “I’m not your therapist.” Like it or not, our patients often do not make a sharp distinction between “therapist” and “psychiatrist,” and we continue to be seen by them as sources of advice, comfort, and solace.4 As even our harried psychiatrist observed of his patients, “The sad thing is that I’m very important to them. . . .” But it really isn’t sad, Doctor—it is hopeful, and our patients should not be discouraged from seeing us as compassionate healers. After all, this is probably the image we had of ourselves when we entered this profession, our humanitarian ideals still intact. No, a brief medication check is hardly a substitute for the revered 50-minute therapy hour. But even in a 15-minute meeting, we can still engage in what Theodor Reik called “listening with the third ear.” Furthermore, we can and must convey to our patients that we are intensely interested in their problems. Dr Pies is editor in chief emeritus of Psychiatric Times and professor in the psychiatry departments of SUNY Upstate Medical University, Syracuse, NY, and Tufts University School of Medicine, Boston. He is the author, most recently, of Becoming a Mensch: Timeless Talmudic Ethics for Everyone; The Judaic Foundations of Cognitive-Behavioral Therapy; and a collection of short stories, Ziprin’s Ghost. Acknowledgments—I would like to thank Susan Kweskin, Dr Glen Gabbard, Dr James Knoll, and Dr Mark Olfson for their helpful comments on earlier drafts of this piece. References 1. Mojtabai R, Olfson M. National trends in psychotherapy by office-based psychiatrists. Arch Gen Psychiatry. 2008;65:962-970. (Please see Psychotherapy, page 10)

PSY 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

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2. Castelnuovo-Tedesco P. The twenty-minute “hour”: an experiment in medical education. N Engl J Med. 1962;266:283-289. 3. Gustafson JP. Very Brief Psychotherapy. New York: Routledge; 2005. 4. Gabbard GO. Deconstructing the “med check.” Psychiatric Times. September 3, 2009. http://www. psychiatrictimes.com/display/article/10168/ 1444238. Accessed March 8, 2011. 5. Dewan M. Are psychiatrists cost-effective? An analysis of integrated versus split treatment. Am J Psychiatry. 1999;156:324-326. 6. Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive behavioralanalysis system of psychotherapy, and their combination for the treatment of chronic depression [published correction appears in N Engl J Med. 2001; 345:232]. N Engl J Med. 2000;342:1462-1470. 7. Friedman MA, Detweiler-Bedell JB, Leventhal HE, et al. Combined psychotherapy and pharmacotherapy for the treatment of major depressive disorder. Clin Psychol Sci Pract. 2004;11:47-68. 8. Jacobson SA, Pies RW, Katz IR. Clinical Manual of Geriatric Psychopharmacology. Washington, DC: American Psychiatric Publishing, Inc; 2007. 9. Dewan MJ, Steenbarger BN, Greenberg RP, eds. In: Gabbard GO, series ed. The Art and Science of Brief Psychotherapies. Washington, DC: American Psychiatric Publishing, Inc; 2004. 10. Wang SS. Studies: mental ills are often overtreated, undertreated. Wall Street Journal. January 5, 2010. http://online.wsj.com/article/SB1000142405 2748703580904574638750777038042.html. Accessed March 9, 2011.

Further reading: Manring J. No, psychiatry has not lost its “mind”: here, psychotherapy training thrives. Psychiatric Times. June 2, 2010. http://www.psychiatrictimes. com/display/article/10168/1579811. Accessed March 9, 2010. ❒

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cover its use, and that optimal use of ketamine in depression is still being studied. Patients are also warned that if they do respond to ketamine, its effects are temporary, and that staff will work with them on how to maintain a treatment response.

What the research shows The impetus for ketamine research stems from the need for rapidresponse antidepressants. Many patients do not benefit from standard antidepressants; others may take weeks or months to respond, said Carlos Zarate Jr, MD, chief of the Experimental Therapeutics and Pathophysiology Branch of the Division of the Intramural Research Program at the NIMH and lead investigator on several ketamine studies. The Sequenced Treatment Alternatives to Relieve Depression Trial (STAR*D), for example, showed that only a third of patients with major depressive disorder achieved remission (ie, minimal/no residual symptoms) after 1 adequate treatment trial with a traditional antidepressant.1 We can rapidly control blood sugar or high blood pressure in a matter of minutes or hours, Zarate

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said. Similarly, we need interventions that can work rapidly in depressed patients, he added. Evidence indicates that the glutamatergic system is involved in the pathophysiology and treatment of mood disorders, Zarate said. Earlier studies found altered glutamate levels in serum and cerebrospinal fluid from patients with mood disorders.2 Postmortem studies found altered glutamate levels in diverse brain areas in individuals with mood disorders.3 Ketamine increases the firing rate of glutamatergic neurons and the presynaptic release of glutamate. Much is known about ketamine, a high-affinity N-methyl-d-aspartate (NMDA) receptor antagonist, according to Zarate. “It is an approved anesthetic that is used worldwide, particularly in ED settings as well as in children, so it has a good track record of safety,” he said. “Using ketamine as an experimental drug, we tested the hypothesis of whether directly going to the NMDA receptor complex target would bring about rapid antidepressant effects, and indeed we found it to be the case,” he said. The first small, preliminary investigation by Berman and colleagues4 found significant antidepressant effects within 72 hours after ketamine infusion in 7 individuals with TRD. Zarate and coworkers5 subsequently confirmed the rapid antidepressant response with ketamine. Zarate’s team conducted a doubleblind, crossover, placebo-controlled study involving 18 patients; those with TRD experienced symptom relief in as little as 2 hours with a single IV dose of ketamine (0.5 mg/kg over 40 minutes). Of the 17 patients treated with ketamine (1 patient dropped out), 71% met response criteria (50% improvement on 21-item Hamilton Depression Rating Scale) and 29% met remission criteria the day following the infusion. The response was sustained for at least 1 week in 35% of patients. “We have conducted a series of other studies,” Zarate told Psychiatric Times. Some looked at bipolar depression, suicidal ideation, and predictors of response. His team recently completed a placebo-controlled study in treatment-resistant bipolar depression with 18 subjects.6 “After a single IV infusion, we found very rapid antidepressant effects starting within 1 hour, which lasted most of the week,” Zarate said. In the randomized, placebo-controlled, double-blind, crossover, add-on study, 12 of 17 (Please see Ketamine, page 12)

In This Issue CATEGORY 1 CME ARTICLE Proarrhythmic 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 Psychotherapy Is Alive and Talking in Psychiatry Ronald W. Pies, MD

Ketamine: A Possible Role for Patients Who Are Running Out of Options? Arline Kaplan NEWS Antipsychotics and the Shrinking Brain

Donald C. Goff, MD

Excavation in Austria Uncovers Mass Grave Thought to Hold Nazi Psychiatric Victims Susan Kweskin PRACTICE MANAGEMENT How to Protect Patient Information—and What to Do if It Gets Lost or Stolen Rick Kam, CIPP Managing Risks When Practicing in Three-Party Care Settings Robindra K. Paul, MD, DPH, MBA, Christopher Lockey, MD, Ryan C. W. Hall, MD, and Harold J. Bursztajn, MD

SPECIAL REPORT CLINICAL PSYCHOPHARMACOLOGY, PART 1 Introduction: Looking to the Future of Psychopharmacology Thomas L. Schwartz, MD

Antidrug Vaccines: Fact or Science Fiction? Daryl Shorter, MD and Thomas R. Kosten, MD

Novel Treatment Avenues for Bipolar Depression Roger S. McIntyre, MD and Danielle S. Cha

COLUMNS MOLECULES OF THE MIND Custom-Made Neural Stem Cells

John J. Medina, PhD

POETRY OF THE TIMES Expert Witness Richard M. Berlin, MD BOOK REVIEWS The Judaic Foundations of Cognitive-Behavioral Therapy: Rabbinical and Talmudic Underpinnings of CBT and REBT Reviewed by H. Steven Moffic, MD and Rabbi Evan Moffic

We’ve Got Issues: Children and Parents in the Age of Medication Reviewed by Gabrielle A. Carlson, MD

WASHINGTON REPORT Severe State and Federal Funding Shortfalls Likely for Local Mental Health Programs Stephen Barlas Cover Image © iStockphoto.com

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

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

Ketamine Continued from page 10

(71%) patients responded to ketamine; 3 patients had a response that lasted 2 weeks or more. Ketamine also has an anti-suicidal effect, which is critically important given that individuals with mood disorders are often at risk for suicide within the first month of starting a medication, Zarate said. Adding to the challenge, he said, is that in the

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past decade there has been a significant increase in ED visits for suicidal ideation or attempts. Suicides have occurred even in inpatient psychiatric units and have become an urgent issue for the US military. At the Mount Sinai School of Medicine in New York, researchers found that a single subanesthetic dose of IV ketamine had rapid effects (1 day after infusion) on suicidal ideation in patients with TRD and

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

that acute improvements in suicidality could be sustained through repeated ketamine infusions.7 DiazGranados and others,8 part of Zarateâ&#x20AC;&#x2122;s team, showed that in patients with major depressive disorder who had significant suicidal ideation, improvement occurred within 40 minutes of a ketamine infusion. Predictors of response to IV ketamine, Zarate said, include a family history of alcohol depen-

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% Daytrananutrition disorders treated children or adolescents with ADHD 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

dence, 9,10 increased pretreatment rostral anterior cingulate cortex activity,11 and anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task.12 In the next few months, Zarate said his team will start a ketamine mechanism of action study (http:// patientinfo.nimh.nih.gov). â&#x20AC;&#x153;We will be looking at people who have failed only one adequate antidepressant trial in their lifetime, so it will be a much less treatment refractory group,â&#x20AC;? he said. â&#x20AC;&#x153;We will be studying several hundred people with unipolar depression or bipolar depression and using novel technologies, including multimodal brain imaging, polysomnography, genetics, and cognitive measures.â&#x20AC;? The reason for this extensive battery, according to Zarate, is to better understand how ketamine works and to tease out who might respond and what might be the markers for predicting response. â&#x20AC;&#x153;We hope to be able to identify signatures of rapid response which then could be utilized to develop other similar types of compounds,â&#x20AC;? Zarate said. The teamâ&#x20AC;&#x2122;s research has also prompted investigation of ketamine for other mental disorders. â&#x20AC;&#x153;We have not published these data yet, but ketamine has significant anti-anxiety effects,â&#x20AC;? said Zarate. People with certain symptoms of anxiety or trauma and those with obsessive symptom profiles appear to benefit from the ketamine infusion, he noted. The NIHâ&#x20AC;&#x2122;s Web site (www. clinicaltrials.gov) indicates that some studies of ketamine in obsessive-compulsive disorder and PTSD, and as augmentation of ECT for severe major depression, are under way. Other researchers are looking at the feasibility of repeated-dose IV ketamine for acute management of TRD. In one recent study, symptoms relapsed, on average, 19 days after the sixth ketamine infusion; however, 1 patient remained antidepressant-free with minimal symptoms for more than 3 months.13 Asked about the notoriety ketamine gained as the abusable club drug known as â&#x20AC;&#x153;K,â&#x20AC;? Zarate said that during its infusion, ketamine can cause dissociative side effects. He noted that his team has safely administered ketamine to more than 100 patients in a controlled setting. We are trying to determine â&#x20AC;&#x153;which subunit of the NMDA receptor is responsible for side effects and which is responsible for improvement,â&#x20AC;? he said, explaining that there are ma-

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jor efforts in academia and the pharmaceutical industry to find safer ketamine-like drugs. Zarate added that his NIMH program is “geared to looking at rapid treatments.” He hopes that having ketamine and scopolamine, which temporarily block the muscarinic cholinergic receptor, “will serve as a great model to better understand what mechanism is involved in the beginning of an antidepressant response. We hope this will lead to the development of treatments with a rapid onset of action.”

Clinical practice As regards his clinical work with ketamine at UCSD, Dr Feifel had this to say: You have patients who have been severely depressed for years and nothing has helped. Both patients and their providers wonder whether there is any possibility that patients will ever be free of their depression. Part of our goal is to see whether their nervous system is amenable to turning off depression through some sort of biological intervention, such as ketamine. So if ketamine is able to turn off a patient’s depression, even for one day, you have accomplished something important, whether or not you can maintain it. This is because you have at least given the patient hope . . . that in itself is very significant from a therapeutic perspective.

Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol Psychiatry. 2009;65:289-295. 12. Salvadore G, Cornwell BR, Sambataro F, et al. Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine. Neuropsychopharmacology. 2010;35:1415-1422. 13. aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139-145. ❒

Dear Readers On behalf of the editors and editorial board of Psychiatric Times, let me extend thanks to over 1200 of you who took time from your busy schedule to respond to an array of difﬁcult questions about ethical issues that arise in clinical practice. Our ethics survey is now closed, and we are mining the data. A quick perusal shows that: • Most of you—78% in fact—encounter ethical dilemmas at least once or twice a week or once or twice a month. • A large minority of you—44%— think that the ethical issues you now encounter are more difﬁcult than those you confronted in the past decade. • Just under 70% of you said you occasionally need help in analyzing and resolving ethical issues. We are eager to dive deeper into the trove of comments you contributed. To that end, editorial board member and psychiatric ethicist Cynthia Geppert, MD, PhD, MPH—who helped us develop our survey—will be presenting her analysis of the results in our May issue. We hope you’ll stay tuned.

References

Thanks again,

1. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40. 2. Machado-Vieira R, Salvadore G, Ibrahim LA, et al. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des. 2009;15:1595-1611. 3. Hashimoto K, Sawa A, Iyo M. Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry. 2007;62:1310-1316. 4. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354. 5. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864. 6. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793-802. 7. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522-526. 8. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71:1605-1611. 9. Machado-Vieira R, Zarate CA Jr. Proof of concept trials in bipolar disorder and major depressive disorder: a translational perspective in the search for improved treatments. Depression Anxiety. In press. 10. Phelps LE, Brutsche N, Moral JR, et al. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. 2009;65:181-184. 11. Salvadore G, Cornwell BR, Colon-Rosario V, et al.

Susan Kweskin, Editor

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APRIL 2011

PSYCHIATRIC TIMES

NEWS

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Antipsychotics and the Shrinking Brain by Donald C. Goff, MD n the February 2011 issue of the Archives of General Psychiatry, Ho and colleagues1 published an article that examined the relationship between long-term antipsychotic treatment and brain volume in firstepisode schizophrenia patients. That paper triggered considerable media attention. Because it was widely interpreted as showing that antipsychotics damage the brain, it may have caused many people—both patients and family members—to reconsider whether to take their prescribed medication. As is so often the case, the picture is far from clear. Ho and colleagues performed structural brain imaging every 3 years for up to 14 years in 211 first-episode patients who had been treated naturalistically. In the beginning, 15% were medication-naive and the majority were treated with first-generation antipsychotics; by the third scan, this had changed to most receiving second-generation antipsychotics and 23% receiving clozapine. On average, each subject was scanned 3 times and had already been treated for 5 months before the first scan. The investigators found that gray matter volumes of all brain regions except for the cerebellum decreased over time; white matter volume on average was unchanged. Subjects who had received higher average lifetime doses of an antipsychotic had less gray matter at baseline and at all future time points. Neither antipsychotic dose nor type of antipsychotic (first-generation, second-generation, or clozapine) appeared to influence the rate at which gray matter loss progressed over time. In contrast, patients who received a low-dose antipsychotic tended to have modest increases in white matter volume over time compared with modest white matter loss in patients whose lifetime average dose was higher. The only advantage for second-generation antipsychotics over typical antipsychotics was a reduction in parietal white matter loss over time. If we were to draw conclusions from this study alone, it would appear that gray matter loss can’t be altered by reducing antipsychotic exposure or by switching antipsychotic class— it just happens. The one possible benefit of a low-dose antipsychotic,

the preservation of white matter, is of unclear clinical significance, as is the possible increase in parietal white matter with second-generation agents. However, the story gets more complicated as we look earlier in the course of treatment. Back in 2007, Ho and colleagues2 published a report based on roughly half their current sample. In this analysis, they discovered that antipsychotic dose was related to the rate of loss of frontal gray matter, but only in medication-naive patients. Frontal gray matter loss, in turn, corresponded with cognitive decline. These relationships disappeared if subjects had been treated with medication before baseline scanning—in these subjects, brain-derived neurotrophic factor (BDNF) genotype predicted the rate of gray matter loss and the pattern of cognitive deficits. This suggests that gray matter loss associated with antipsychotic dose may have been missed entirely in the recent publication by Ho and colleagues because it may occur very early in treatment— before the baseline scan in the great majority of subjects. Many additional potential confounds complicate these findings. First, it’s not possible to determine whether higher antipsychotic doses are contributing to the progression of brain loss or are merely a response to it. In the absence of an untreated control group, it’s also not possible to detect neurotoxic effects of drugs that are not related to dose and, without a healthy control group, it is not clear which changes in brain volume are pathological. Animal studies can begin to address these issues. A study in monkeys conducted by David Lewis’ group prompted concern about antipsychotic neurotoxicity several years ago. Monkeys treated with haloperidol and olanzapine for 17 to 27 months lost roughly 10% of their total brain volume, both gray and white matter, compared with sham-treated controls, with greatest volume loss in frontal and parietal cortex.3 Further examination revealed a reduction in the number of glial cells4; a similar postmortem finding in schizophrenia brains previously had been attributed to the illness. However, this study included only 6 monkeys per treatment group and did not provide information on the time course of neurotoxic changes.

Other studies suggest that antipsychotic effects on brain volume may occur rapidly. For example, Vernon and colleagues5 found a significant loss of frontal cortical volume after only 8 weeks in rats given haloperidol or olanzapine. Evidence of the rapidity at which antipsychotics can affect brain volume in humans was recently provided by Tost and associates.6 These investigators found a significant, reversible decrease in striatal volume in healthy subjects within 2 hours after they were treated intravenously with haloperidol. Loss of striatal volume powerfully predicted neurological adverse effects. Taken together, these studies suggest that antipsychotics may contribute to early gray matter loss and, later in the course of treatment, to white matter loss. These effects may be dose-related and probably are not prevented by the use of second-generation agents. This argues for minimizing antipsychotic exposure both

acutely and long-term. However, we are left with the additional dilemma that a longer duration of untreated psychosis (DUP) may also be neurotoxic. Longer DUP has been associated with poorer symptomatic and functional outcomes7 as well as brain volume loss.8 Studies of DUP have their own methodological limitations and controversies, but they should serve to warn us that the rapid control of psychosis may also be important. Psychosis at any phase of the illness can be extremely distressing, disruptive, and potentially dangerous for patient and family. New approaches for early intervention are needed and, with existing drugs, the potential for neurotoxicity must be weighed against short-term and long-term clinical gains. In the meantime, clinicians should avoid using antipsychotics unnecessarily and, when needed, use the lowest effective dose.

(Please see Antipsychotics, page 16)

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Antipsychotics Continued from page 15

Dr Goff is director of the Schizophrenia Program at Massachusetts General Hospital and

How to Protect Patient Information— and What to Do if It Gets Lost or Stolen

professor of psychiatry at Harvard Medical

by Rick Kam, CIPP

School in Boston. References 1. Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68:128-137. 2. Ho BC, Andreasen NC, Dawson JD, Wassink TH. Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatry. 2007;164:1890-1899. 3. Dorph-Petersen KA, Pierri JN, Perel JM, et al. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005; 30:1649-1661. 4. Konopaske GT, Dorph-Petersen KA, Pierri JN, et al. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology. 2007; 32:1216-1223. 5. Vernon AC, Natesan S, Modo M, Kapur S. Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex vivo and postmortem confirmation. Biol Psychiatry. 2010 Dec 30; [Epub ahead of print]. 6. Tost H, Braus DF, Hakimi S, et al. Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nat Neurosci. 2010; 13:920-922. 7. Marshall M, Lewis S, Lockwood A, et al. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry. 2005;62:975983. 8. Malla AK, Bodnar M, Joober R, Lepage M. Duration of untreated psychosis is associated with orbitalfrontal grey matter volume reductions in first episode psychosis. Schizophr Res. 2011;125:13-20. ❒

s a practicing psychiatrist, your day is spent with your patients; you listen to them describe their health histories and you administer mental health tests, prescribe medication, engage in therapy, and review patients’ records. When do you have time to think about the best way to protect all of the patient information you gather daily? And in the event your laptop computer, personal digital assistant (PDA), or smart phone is lost or stolen, what do you need to do if any of these devices contained patient information? My objective is to give the practicing psychiatrist a short primer on how to address these 2 questions: • How do you protect the patient information you have on your laptop computer, PDA, or smart phone? • What should you do if any of

these devices get lost or stolen and have patient information stored on them? You are well aware that the psychiatric patient information you hold is some of the most sensitive and personal health information that exists. At a recent conference where I spoke, many of your colleagues told me they refuse to store patient information on a laptop, PDA, or smart phone, and instead maintain confidential and secure paper-based records. While this may reduce the risk of this information being stolen by electronic means (ie, a hacker breaking into your server or identity thief stealing your laptop), in several states, the unauthorized disclosure due to loss or theft of paperbased patient records requires legal notification to the affected patients. In California, notification needs to be made within 5 business days from the day a breach is discovered. What changed on February 17,

Risk Analysis

receive, maintain, or share the personal information of your patients? Have you implemented third-party agreements re-

by Eric Nelson, CIPP, Director, Breach Prevention Any health care practitioner who collects, manages, and stores patient information faces the risk that his or her data may be viduals. While technology (eg, encryption) may provide some level of protection, it is only one component of an effective security program.

In “Demystifying Health Reform Legislation” in our March 2011 issue (page 26), James C. Pyles, JD, presents an update on the status of implementation of health care reform legislation. An error appears in the section entitled “The need for health reform.” Mr Pyles notes that a December 2010 report from the Bipartisan Deficit Reduction Committee concludes (among other things) that federal health spending represents our single largest fiscal challenge and goes on to say that “The legislation includes specific recommendations to reduce health care spending between now and 2020.” That sentence should have read, “The report includes specific recommendations to reduce health care spending between now and 2020.” We regret the error. ❒

2009? Federal legislation called the Health Information Technology for Economic and Clinical Health (HITECH) Act was enacted as part of the American Recovery and Reinvestment Act. It promotes the adoption and meaningful use of health information technology. It also addresses privacy and security concerns with the electronic transmission of health information by strengthening civil and criminal enforcement of the Health Insurance Portability and Accountability Act (HIPAA). In short, this act requires that all covered entities or business associates protect patient information and promptly notify individuals if their information is disclosed in an unauthorized way (ie, lost or stolen with the potential to create reputational, medical, financial, or other harm, such as identity theft or health care fraud). Within the context of this legislation, you, the psychiatrist, are considered the “covered en-

SIDEBAR

lost, misused, or accessed by or disclosed to unauthorized indi-

Erratum

APRIL 2011

PRACTICE MANAGEMENT

The Health Insurance Portability and Accountability Act (HIPAA) Security and Privacy Rules apply to all covered entities, regardless of size, and require the implementation of administrative, technical, and physical safeguards. The first step, and required under the Security Rule–Administrative Safeguards, is to perform a risk analysis. The HIPAA risk analysis requirement specifically states:

quiring information safeguards and HIPAA compliance? 3. Identify and document potential threats and vulnerabilities. How do employees access personal information? How do you restrict unauthorized access to information? Have your employees been trained to access and protect PHI appropriately? Do you currently encrypt the information that you store or transmit? 4. Assess security measures, policies, and procedures. Do you have the appropriate policies and procedures in place to reduce risks and vulnerabilities? Have you assigned security responsibility? Do you have policies and procedures in place regarding access and storage of PHI? Do you share information with third parties and have agreements in place that require them to safeguard your information? 5. Determine the level of risk and potential impact of threats.

Conduct an accurate and thorough assessment of the

A smaller organization (eg, a solo practice) may have more

potential risks and vulnerabilities to the confidentiality,

control. However, such organizations are still required to deter-

integrity, and availability of electronic protected health

mine their level of risk and the impact of all threats and vulner-

information held by the organization.

abilities that may affect the “confidentiality, integrity, and availability of electronic protected health information held by the

Although the Security Rule applies only to electronic health

organization.”

information, the Privacy Rule requires safeguarding any type

HIPAA security compliance requirements provide some flex-

or medium of protected health information (PHI). Steps to per-

ibility, which is based on an organization’s size and complexi-

form a risk analysis are:

ty. However, performing a risk analysis and documenting risks

1. Identify the information that your practice collects, man-

and steps taken to mitigate those risks is a requirement of the

ages, and shares. How can you protect something when you

Security Rule. Finally, risk analysis is not a one-time exercise.

don’t know what you have to protect? Many health care orga-

Rather, it is an ongoing process that should provide an organi-

nizations perform some type of security assessment and de-

zation with a detailed understanding of its risks and informa-

velop privacy and security policies, but many don’t take the

tion necessary to address those risks in a timely manner, and

crucial first step and actually perform an inventory of their or-

the means to reduce associated risks to reasonable and appro-

ganization’s personal information and understand the internal

priate levels.

and external flow of that information.

Additional information can be found at the US Department of

2. Identify third-party risks. What are the external sources of PHI? Do you work with vendors or consultants who create,

Health and Human Services Web site (http://www.hhs.gov/ocr/ privacy/hipaa/understanding/srsummary.html). ■

APRIL 2011

tity.” An example of a business associate would be the company where you host and manage your e-mail and practice management systems. Protecting patient information is an essential part of maintaining patient trust. Yet you might ask, does the HITECH Act apply to me and my practice or small clinic? The answer is more than likely “yes”—especially if you use an electronic health record system to bill your patients or for insurance claims. And, remember: the state data breach notification laws also apply to your practice. So where do you start with regard to protecting your patient information? The suggestions I outline here are for solo practitioners.

Protecting patient information Data encryption. Implement data encryption on your laptop, PDA, or smart phone. Data encryption makes information unreadable on these devices by unauthorized persons (ie, someone who stole your laptop). It also provides safe harbor under the HITECH Act and state breach notification laws. This means that the data are considered secure; as such, the requirement to notify individuals is eliminated. You can buy data encryption software at your local computer store. Use secure e-mail. E-mail services are available that provide encrypted transmission and other protections to ensure security and regulatory compliance. Free e-mail tools are available that provide adequate privacy and security controls and protect your

PRACTICE MANAGEMENT e-mail from being intercepted and read without your or your patient’s authorization. Privacy policy. Implement a privacy policy not to accept patient information over the Web or by unsecured e-mail. Have a written policy that you and your staff adhere to specific electronic transmission of patient information. While this may not stop all of your patients from sending you information in this way, it makes it clear that you do not want to receive it in this form. Security assessment. Perform a security assessment and determine where your patient information is. The HITECH Act requires an annual security assessment to determine vulnerabilities in your security of patient information. This assessment should also help you understand where your office stores patient information today and how it is shared or transmitted to other providers, payers, and your patients. Many breaches occur because doctors do not know where these data are kept and how the information flows to others in dayto-day practice. There are experts who can help with this assessment (see Sidebar, “Risk Analysis,” by Eric Nelson). Buy data breach insurance. A new insurance product has emerged over the past few years to mitigate the financial cost of a breach of patient information. It covers the majority of costs associated with responding to a breach—including computer forensics investigation, consumer notification, legal advice, identity

SIDEBAR Data Breach Insurance by Mark Camillo, Vice President—Professional Liability, Chartis Insurance The demand for security/privacy insurance is growing rapidly as health care practitioners realize that traditional insurance does not address privacy exposures. The cost to notify affected individuals adds up quickly, particularly if the clinician must provide some form of credit monitoring, hire legal and public relations firms to mitigate reputational damage, and pay for a computer forensic investigation. Lawsuits that may arise from a breach are costly to defend, even if groundless, and class action lawsuits are on the rise. Regulatory actions are becoming more common and can impose a significant financial burden on even a well-capitalized practice. Applying for coverage has been simplified, and the cost has come down dramatically over the past few years. As such, security/privacy insurance has become a good value for most organizations. Specialty risk protection insurance is sold by coverage part, so you can buy what you need and have access to the latest enhancements, including: • Express coverage for claims arising from breaches of confidential information considered “electronic-protected health information” • Coverage for regulatory actions and fines/penalties (where insurable by law) • Flexible event management options (eg, covering forensic investigation expenses, costs to notify and provide identity monitoring for individuals whose personal information is compromised) For additional information, go to http://www.chartisinsurance.com or e-mail Mark.Camillo@chartisinsurance.com. ■

theft monitoring, and victim restoration services. Talk to your insurance professional to understand your options and obtain a policy that is right for your practice (see Sidebar, “Data Breach Insurance,” by Mark Camillo).

What to do if you discover a data breach Now that you have taken reasonable steps to protect patient information, let’s talk about what you do if you discover a data breach. Let me start by highlighting a few examples that might alert you that a data breach has occurred. • You walk into your office in the morning and your office assistant tells you that someone has stolen all the computers and backup disk drives • You are sitting on an airplane getting ready to fly home from a conference and suddenly realize you forgot your smart phone in the taxi . . . or was it the restaurant • You return to your car after attending to several patients at your clinic and realize your car has been broken into and your backpack containing paper-based patient files is missing • Your home computer with patient records is displaying a flashing message telling you it has been taken over by a virus and all of the files have been forwarded to everyone in your electronic address book If you find yourself facing any of these scenarios, this doesn’t necessarily mean you have a data breach situation. If your patient information was encrypted and you implemented the suggestions outlined in this article, your patient information is secure and would not trigger federal or state data breach notification laws. However, read on for suggestions if this was not the case. Determine what the laws are. Call your attorney to determine whether there are federal or state data breach notification laws that apply to the situation. The circumstances of each data breach are unique and the laws that apply are evolving. Your attorney can determine the specific laws that apply and provide legal advice on how to comply. Determine what data were lost. Engage a computer forensics expert to determine what data were lost or stolen and whether there is a potential for misuse. It is important to first understand whether there was patient information on the affected device. This is easier said than done, because in many cases, you may not know

PSYCHIATRIC TIMES

w w w. psychi atr i cti mes. com

what information was on your device. Patient information may have been in a spreadsheet or document or an insurance claim file. A forensics expert can also determine whether any of the information was accessed and who accessed the information. You may be able to confirm that there was no patient data on the device or that no one accessed it, which reduces the risk of it being misused. Deploy the breach response team. This is the group of professionals who you designate to manage the response to the data breach. It includes your attorney, forensics expert, office manager, and others who can provide an effective response so you can remain productive in your practice. The response team provides crisis management and manages all of the vendors who help with consumer notification; call center services; and identity protection services that mitigate the regulatory, reputational, legal, and other risks of a data breach. You can engage an organization that manages this process if the available resources are not available to you or your practice. It is best to engage such an organization before a breach and to get an agreement for services. Notify affected patients and the appropriate regulatory agencies. This step is the foundation for both federal and state compliance with the breach notification provisions of the various laws. It helps the patients affected by a breach take action to protect themselves from identity theft and other forms of health care fraud. If the breach involved 500 or more records, you will be required to notify Health and Human Services and in some cases local media concurrently. Many organizations also notify the state attorneys general and insurance commissioners where affected individuals live. Expect the Office of Civil Rights to initiate an investigation of a breach of more than 500 records and be prepared to show the steps your practice had taken to protect patient information and to close security gaps that caused the breach. Mr Kam is president and co-founder of ID Experts, which is a leader in comprehensive data breach solutions. The company contributes to relevant legislation and rules, including HITECH, and is a corporate member of Healthcare Information and Management Systems Society (HIMSS). ID Experts is active with privacy organizations, including ANSI/Identity Theft Prevention, Identity Management Standards Panel, and the International Association of Privacy Professionals. For more information, visit http://www. idexpertscorp.com. ❒

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

PRACTICE MANAGEMENT

APRIL 2011

Managing Risks When Practicing in Three-Party Care Settings Helping Your Patients While Minimizing Your Risks by Robindra K. Paul, MD, DPH, MBA, Christopher Lockey, MD, Ryan C. W. Hall, MD, and Harold J. Bursztajn, MD ollowing trends in medicine, psychiatry is faced with limited resources and third-party administration of resource allocation. This has affected psychiatric practice in many ways and altered the doctor-patient relationship. Trends toward resource-sensitive, third-party– related psychiatric practice may be accelerated by the current social concerns regarding the economy. Thus, an awareness of social context and the growing recognition that autonomyenhancing alternatives to paternalistic care are fundamental to improve both the effectiveness and accessibility of care in limited-resource environments are each becoming vital for an informed clinical and riskmanagement practice perspective.1 To increase the likelihood of effective help for patients, psychiatrists need to know how third-party administration and limited resources influence their practice. It is also important to ask whether an individual who presents for help is actually willing to assume sufficient responsibility for his or her care to benefit from what help is available. Psychiatrists must also understand how to follow up if treatments are not covered or claims are denied. In addition, when a psychiatrist leaves a preferred provider network, he also needs to know what steps can be taken to ensure continuity of care for patients.

Practicing within the standard of care Psychiatric practice is affected by limited resources administered by third parties such as managed care organizations.2 The persistence of irrational beliefs—such as the conviction that medical care (including psychiatric care) occurs in a vacuum of unlimited resources—is among the biggest impediments to adequate care and risk management for clinicians and patients.3 As Voltaire recognized, “the better [perfect] is the enemy of the good.”4 The limited resources that face psychiatrists include relatively short face-to-face time with patients, a fi-

nite number of sessions budgeted to treat insured patients on an inpatient and outpatient basis, and the ongoing struggle to provide care for the uninsured. One way to cope is to practice in a more cost-effective manner. This may include using screening instruments such as patient questionnaires, using limited time more effectively, and prescribing generic equivalents instead of brand-name medications whenever possible. Used critically, evidence-based practice guidelines may offer direction for more costeffective treatment.5 Other mental health providers, such as physician assistants or psychiatric nurses, can see patients for routine visits at a lower overall cost.

malpractice was described in the 1976 California Supreme Court case of Landeros v Flood.6 The case standard states: “A physician is required to exercise, in both diagnosis and treatment, that reasonable degree of knowledge and skill which is ordinarily possessed and exercised by other members of his profession in similar circumstances.” A key phrase here is “in similar circumstances.”6 A psychiatrist’s care may fall below the standard of care if, for example, he fails to conduct an adequate risk assessment of a suicidal patient, or if he prescribes a medication—eg, a neuroleptic—without informing the competent patient about the potential for tardive dyskinesia or metabolic

CHECK POINTS

 The persistence of irrational beliefs—such as the conviction that medical care, including psychiatric care, occurs in a vacuum of unlimited resources—is among the biggest impediments to adequate care and risk management.

 Practicing in a more cost-effective manner may include use of screening instruments, using limited time more effectively, and using generic equivalents instead of brand-name medications whenever possible.

 In light of third-party administration and the need for more efficiency amid limited resources, respecting patient autonomy has become increasingly important in clinical practice.

Screening instruments help separate persons who may benefit from psychiatric care from those for whom it may not be helpful or may even be counterproductive. For example, individuals who are actively abusing substances need to commit to being substance-free before they will benefit from psychiatric care. Similarly, the autonomy of long-standing paranoid patients with schizoid or avoidant traits who drop in and out of treatment needs to be respected. Even in an environment of limited resources, psychiatrists can make treatment recommendations that fit the patient’s problems. This means being informed about laws, professional ethics, and standards of care that can be learned through training, continuing education, and consultation with colleagues. Malpractice standards vary state by state. In California, for example, a representative standard for medical

syndrome. It is important to distinguish optimal care from care that is sufficient to meet the standard of care. The standard of care can be met in a variety of ways. What a physician can do may be limited by considerations that range from respect for a patient’s autonomy to resources that are available when a problem arises. It helps for the clinician to be flexible in coordination and communication and to consider the limits of doctor-patient confidentiality. For example, in the outpatient setting, enlisting help from other office members in dealing with a patient in crisis can bring about efficient transfer to the hospital. Coordinating the management of a patient’s acute psychosocial stressors with social workers may allow more time for a treatment session. Physicians should avoid unrealistic expectations about available resources and the utility of those re-

sources. This includes refraining from expressing unrealistic hope that certain treatments will be successful when research data indicate otherwise or from practicing defensive medicine by considering hospitalization inevitably to be the best treatment. For some, hospitalization can be counterproductive insofar as it undermines a patient’s ability or motivation to be responsible for his own treatment. Similarly, any short-term benefit of a forced hospitalization must be weighed against the potential risk of undermining the potential for a therapeutic alliance with a careavoiding patient. When working with limited resources, it is important to use approaches that respect patient autonomy and are cost-effective. Approaches that respect patient autonomy promote good clinical practice and, with proper documentation and consultation, good risk management. Critical consideration of evidencebased guidelines and being open to the use of decision aids and systems approaches to patient care can also be of help.5,7

Understanding health plans to provide care and anticipate risks Psychiatrists should be knowledgeable about the benefits provided under their patients’ health care plans. There are significant differences among plans, whether they are private or government-sponsored organizations. Most health care plans, including HMOs and PPOs, use evidence-based guidelines as a road map to decide what treatments are approved and in their review of physicians’ recommendations. Understanding the basics of each plan, such as the recommended formularies and approved treatment, will allow you and your patients to make more informed decisions. Plans list certain mental illnesses as “coverable.” For each illness, plans specify approved treatments and the contexts in which those treatments can be prescribed. Although medication may be covered, many brandname medications will not be approved until there have been trials of generic alternatives. A patient may not be able to continue to take certain

APRIL 2011

brand-name medications started as an inpatient when outpatient use of those medications is not covered by his plan. In this situation, switching to a generic or other alternative treatment may lead to the loss of any shortterm gain as the patient transitions to outpatient care. That is, such transitions may involve hidden transaction costs, such as when the patient is uninformed of the potential consequences of switching from a brandname to a generic medication. For example, patients may be left without medications for a while, until they can see their outpatient provider. Also, alternative treatments may not be as effective as the inpatient treatment. In both of these cases, the transaction cost is the increased risk of decompensation of the patient. Thus, a lack of planning, information, and communication increases the risk of an eventual negative outcome, including possible rehospitalization. In light of third-party administration and the need for more efficiency amid limited resources, respect for patient autonomy has become increasingly important in clinical practice. Encouraging patients to learn about their illness, to reduce stress, to take responsibility for avoidance of substance use, and to understand their plan promotes thoughtful patient decisions about where to access care.8 This also allows patients to make more informed decisions about treatment, including when they may be required, or may even elect, to pay for services out-of-pocket. If benefits are denied by a health care plan, psychiatrists may appeal on behalf of patients or, alternatively, educate patients about their rights so that patients can pursue their own appeals. This is especially important in cases where there is no adequate alternative to care. However, the likelihood of a successful appeal must be considered in light of information such as that from the New York Insurance Department, which indicates that of 11,179 appealed decisions to 15 HMOs, only 38% were successful.9 Even in cases where an insurance company acts egregiously, such as by denying standard care, patients who sue their health care plan providers may be limited to recovering only the benefit itself or a monetary equivalent under the Employee Retirement Income Security Act of 1974 (ERISA).10 Recovery cannot be gained from plans covered under ERISA for expenses lost and personal injury, including pain and suffering, because of an inappropriate denial of benefits.10 Administrative guidelines may

PSYCHIATRIC TIMES

PRACTICE MANAGEMENT protect the managed care organization when benefits are denied but may not protect the clinician. In sum, understanding covered conditions and treatment allows both psychiatrists and patients to better understand the most cost-effective ways to proceed with treatment. This also allows psychiatrists and patients to anticipate any potential denial of benefits and, therefore, prospectively plan for potential alternatives to care.

How to provide for continuity of care when leaving an insurance panel Psychiatrists occasionally choose to leave a third-party insurance panel. When this occurs, the psychiatrist must continue to address issues such as limited resources available to provide continued mental health treatment; obligations to patients, including guarding against actual and perceived abandonment; and following

contractual specifications and ethical guidelines in providing a smooth transition to another mental health provider. When psychiatrists leave insurance panels, patients must receive adequate notification and continuity of care to reduce the risk that a patient will decompensate or “be lost to follow-up.” More planning and assis(Please see Three-Party Care Settings, page 20)

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*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.

w w w. psychi atr i cti mes. com

Atlanta, Georgia.

KAP10-PAD-002-00

PSYCHIATRIC TIMES www.psych i a t r i c t i me s. c o m

Three-Party Care Settings Continued from page 19

tance during transitions of care may be required for patients in crisis. Some insurance panels require that treating psychiatrists continue to care for a patient in crisis even if the psychiatrist leaves the panel. Therefore, if a psychiatrist leaves a panel while

APRIL 2011

PRACTICE MANAGEMENT a patient is in crisis, he may need to refer to the initial insurance panel contract or review the contract with a lawyer to determine his obligation to the patient and the steps required for the patient’s transition. The following recommendations assume a “stable” patient population. Many of the notification steps that a medical practitioner should take when leaving a panel are similar to

those that psychiatrists take when retiring from practice. For example, when psychiatrists retire, they need to notify their patients of the closure of their practice, help patients find a new psychiatrist, offer to forward records to the new treating psychiatrist and, if possible, be available for emergencies for a reasonable period while the patient is transitioning to a new therapist.11 The difference be-

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.

tween retiring from practice and leaving a panel is that in the latter case a patient may choose to continue to be treated by the psychiatrist, but the patient needs to be notified of the change and how it may affect the doctor-patient relationship.12,13 Patients can be notified that a physician has retired or has left an insurance panel via letter, by informing patients during a session, or by post-

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.

APRIL 2011

PRACTICE MANAGEMENT

ing an announcement in the office. The last 2 methods can be problematic. In terms of risk management, it may be helpful to inform patients in writing with a letter to ensure that the patient has been notified. It is advisable to send patients at high risk for adverse transition-of-care events a certified letter at least 30 days be-fore leaving the panel to ensure its receipt. The letter should in-

form the patient that: • The psychiatrist is leaving the panel. • The patient may continue to be seen at the office but may be subject to a different fee schedule. • If the patient does not express an intention to continue at the office, then his file will be closed. • The patient can contact the insurance company for a list of avail-

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)].

able psychiatrists still in the panel. • Records will be sent to the patient’s new doctor on request. The earlier the notification before the actual termination the better, because it allows the patient more time to decide whether he wishes to continue with the psychiatrist or find a new one. It can be a lengthy process to find a new therapist (depending on the availability of psychiatrists in the

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. 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

PSYCHIATRIC TIMES

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community). While it may be therapeutic to inform a patient during a session, oral communication does not provide sufficient documentation to prevent a malpractice suit (since it may become a “he said, she said” issue). It is not enough to inform patients merely with an announcement in the office because patients can legitimately claim not to have noticed the announcement. Electronic means such as e-mails, instant messaging, blogs, or Web sites may soon become an acceptable way to notify patients. However, from a risk management stance, electronic communication is not currently the best means of communication because of potential confidentiality issues and Health Insurance Portability and Accountability Act (HIPAA) concerns.14-17 Also, if a psychiatrist corresponds electronically, he needs to respond as quickly to an e-mail as to a telephone call. For some psychiatrists, this means of communication is less practical or less efficient.16,17 If a patient “chooses” to terminate his relationship with a psychiatrist when the psychiatrist leaves the panel, the patient may be asked to sign a “voluntary termination of treatment” form during the final visit. This form should clearly indicate that the patient: • Is choosing to leave treatment. • Has been given a list of referrals or has been referred to the insurance provider to obtain a list. • Understands that the psychiatrist with whom he is terminating will be available for emergencies for at least 30 days or until he finds a new psychiatrist. This practice encourages sound documentation for rebuttal for any subsequent allegation of abandonment made by the patient. It is not a psychiatrist’s obligation to find a new psychiatrist for the patient but rather to “assist” the patient in doing so. This is usually accomplished by providing names and numbers of other practitioners or contact information for the local mental health department. It is important to provide patients with as much forewarning as possible because in some locations it may take 6 to 8 weeks to obtain an appointment with a new therapist.

Summary In third-party, resource-administered, time-limited environments, it is vital to be mindful of fundamental principles, particularly in the midst of the stress of decision making under conditions of uncertainty.7 This in(Please see Three-Party Care Setting, page 22)

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

Three-Party Care Setting Continued from page 21

cludes recognizing that clinical decision making in real time contains elements of uncertainty, and thus shared responsibility expressed as a

APRIL 2011

PRACTICE MANAGEMENT respect for patients’ autonomy is crucial. When clinical time or resources are limited, it is vital to distinguish between patients who want to take responsibility and pseudopatients who are not interested in treatment by reason of character or motive. The

psychiatrist who respects a patient’s autonomy is in the best position to provide wise, effective, nondefensive clinical care while also being able to manage the risks for the practice in resource-constrained third-party treatment environments.

New York Consumer Guide to Health Insurers. http:// www.ins.state.ny.us/hgintro.htm. Accessed January 21, 2009. 10. ERISA. 29 USC §1132(a)(1)(A)-(B) (2003). 11. American Medical Association. Principles of Medical Ethics. June 17, 2001. http://www.amaassn.org/ama/pub/category/2512.html. Accessed January 21, 2009. 12. Health and Ethics Policies of the AMA House of

Excavation in Austria Uncovers Mass Grave Thought to Hold Nazi Psychiatric Victims

Dr Paul is board-certified in psychiatry and

Delegates. H-285.952 Amendments to Managed

is a forensic psychiatrist in practice in San

Care Contracts. http://www.ama-assn.org/ad-com/

Diego. He completed a fellowship in forensic psychiatry at Case Western Reserve Uni-

by Susan Kweskin United Press International recently reported that construction workers in Hall, Austria, have exhumed what may turn out to be grim remains of the Third Reich’s Action T4 program

Delegates. E-9.06 Free Choice. http://www.amaassn.org/ad-com/polfind/Hlth-Ethics.pdf. Accessed

Kline and Rappeport Fellow. Dr Lockey is

January 22, 2009.

assistant professor of psychiatry at Oregon

14. Houston TK, Sands DZ, Jenckes MW, Ford DE.

Health and Science University in Portland.

Experiences of patients who were early adopters of

He completed a fellowship in forensic psy-

electronic communication with their physician: sat-

Dr Hall is an affiliate instructor of psychiatry

cally disabled men, women, and children.1

13. Health and Ethics Policies of the AMA House of

versity in Cleveland and is a past GlaxoSmith-

chiatry at Case Western Reserve University.

that sought to exterminate mentally and physi-

polfind/Hlth-Ethics.pdf. Accessed January 22, 2009.

isfaction, benefits, and concerns. Am J Manag Care. 2004;10:601-608. 15. Don’t e-mail your way into treacherous waters.

During recent excavations near a psychiatric

at the University of South Florida and a past

hospital, workers uncovered a mass grave of

Rappeport Fellow of the American Academy

220 bodies that had been buried between 1942

of Psychiatry and the Law. Dr Bursztajn is

legal, and ethical implications of e-mail for the pa-

and 1945. Those buried may have been victims

cofounder of the Program in Psychiatry and

tient-physician relationship. JAMA. 1998;280:1353-

the Law at Beth Israel Deaconess Medical

1359.

Center, department of psychiatry, Harvard

17. Recupero PR, Rainey SE. Websites and e-mail in

Medical School, Boston. He has an active

medical practice: suggestions for risk management.

of the Nazi’s infamous “euthanasia” program. They are to be exhumed and efforts will be made to identify each person and the cause of death. This process may take up to 2 years. Under the direction of Philip Bouhler and Dr Karl Brandt, Hitler’s personal physician, the secret Action T4 program was launched in 1939 to kill disabled children. Later that year, the pro-

The poster shown here (from around 1938) reads: “60,000 Reichsmarks is what this person suffering from a hereditary disease costs the People’s community during his lifetime. Comrade, that is your money too. Read ‘[A] New People,’ the monthly magazine of the Bureau for Race Politics of the NSDAP.” Courtesy of Wikipedia.

clinical and forensic neuropsychiatric prac-

patients, and third-party organizations and is a consultant for independent peer-review or-

Between 70,000 and 200,000 physically or mentally ill men, women, and chil-

Barger Excellence in Mentoring Award from

dren judged to be “undeserving of life” are believed to have been murdered.

Harvard Medical School.

A public outcry led the program to be halted in 1941; nevertheless, evidence

References

cians continued to exterminate patients after 1941.2,3 At the psychiatric hospiduring the last years of the war. Between 1940 and 1944, an estimated 30,000 disabled people were killed in Hartheim castle—the most notorious euthanasia facility in Austria during the

1. Perlin ML, Bursztajn H, Gledhill K, Szeli E. UNESCO Chair in Bioethics. Psychiatric ethics and the rights of persons with mental disabilities in institutions and the community. 2008. http://medlaw.haifa.ac.il/ index/main/4/psychethicsperlin.pdf. Accessed Janu-

war. The physically and mentally disabled who died there succumbed to gas-

ary 22, 2009.

sing or lethal injection. Dr Brandt, then professor of psychiatry at Würzburg

2. Hamm RM, Reiss DM, Paul RK, Bursztajn HJ.

University, made regular visits to the castle.2,3

Knocking at the wrong door: insured workers’ inad-

Action T4 had its roots in Nazi “racial hygienist” policies, which the party

equate psychiatric care and workers’ compensation

began to implement as early as 1933. During that year, the “Law for the Pre-

claims. Int J Law Psychiatry. 2007;30:416-426.

vention of Hereditarily Diseased Offspring” mandated compulsory steriliza-

3. Hamm RM. Irrational persistence in belief. In:

tion for people with a range of conditions believed to be hereditary; these

Kattan MW, ed. Encyclopedia of Medical Decision

included schizophrenia, “manic depressive insanity,” “congenital mental deficiency,” epilepsy, Huntington chorea, blindness, deafness, and severe deformity. References 1. Scally D. Mass grave in Austria believed to contain Nazi euthanasia victims. The Irish Times. January 5, 2011. http://www.irishtimes.com/newspaper/world/2011/0105/1224286779725.html. Accessed March 8, 2011. 2. Action T4. Wikipedia. http://en.wikipedia.org/wiki/Action_T4. Accessed March 8, 2011. 3. Law for the prevention of hereditarily diseased offspring. http://en.wikipedia.org/wiki/Law_for_ the_Prevention_of_Hereditarily_Diseased_Offspring. Accessed March 14, 2011.

Med Health R I. 2007;90:173-177. ❒

expert for attorneys representing physicians,

ganizations. He is a recipient of the Clifford A.

tal at Hall, for example, there was a marked increase in the number of deaths

16. Spielberg AR. On call and online: sociohistorical,

tice. He has been a consulting and testifying

gram was expanded to include disabled adults.

presented at the Nuremberg trials showed that German and Austrian physi-

Hosp Case Manag. 2000;8:166, 175.

Making. Vol 2. Thousand Oaks, CA: Sage Publications, Inc; 2009:640-644. 4. Voltaire. “La Bégueule” [poem]. 1772. 5. Salzman C. The limited role of expert guidelines in teaching psychopharmacology. Acad Psychiatry. 2005;29:176-179. 6. Landeros v Flood, 17 Cal 3d 399, 551 P.2d 389, 131 Cal Rptr 69 (Cal 1976). 7. Hammond KR. Beyond Rationality: The Search for Wisdom in a Troubled Time. New York: Oxford University Press; 2007. 8. Bursztajn HJ, Feinbloom RI, Hamm RM, Brodsky A.

For more information

Medical Choices, Medical Chances: How Patients,

Lifton RJ. The Nazi Doctors: Medical Killing and the Psychology of Genocide. New York: Basic Books; 2000. ■

Families, and Physicians Can Cope With Uncertainty. New York: Delacorte; 1981. 9. State of New York Department of Insurance. 2008

Residents, Do You Like to Write? Do you have an experience you have learned from during your residency that you would like to share with your colleagues? Is there a patient interaction that has helped you to become a better doctor? A meaningful lesson you learned from a patient, nurse, or supervisor? A difficulty you encountered that raised questions about your career path or your approach to patients? Is there an aspect of your career development you have been thinking about that may interest other residents as well as practicing psychiatrists? Psychiatric Times invites contributions from residents concerning their experiences, challenges, frustrations, and triumphs. Residents are encouraged to send a brief description of the topic they would like to write about, a sample of their writing, and their curriculum vitae to Editor, Psychiatric Times, 535 Connecticut Avenue, Suite 300, Norwalk, CT 06854, or by e-mail to editor@ 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  -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

APRIL 2011

CLINICAL PSYCHOPHARMACOLOGY Introduction: Looking to the Future of Psychopharmacology by Thomas L. Schwartz, MD he focus of this Special Report is on some futureoriented aspects of psychopharmacology. First, it is an eclectic set of articles that cover treating resistant depression, using currently illegal drugs to treat psychiatric problems, and finally the potential of using vaccines to treat substance use disorders. Frankly, each of these topics can fill its own Special Report. One of the considerations in a discussion of the ethics of psychopharmacology is the use of brand-name, expensive drugs versus generics. Sometimes the generics are not equal; there may be a 30% sway in bioavailability between the brandname drug and available generics. The slow-release technology also differs from brand name to generics and allows for differential adverseeffect issues in practice. This must be weighed against the clear cost difference. Monotherapy approaches are the FDA norm and are specified as first-line treatments in most guidelines. However, monotherapy

does not often yield true remission of symptoms. Polypharmacy certainly drives up cost and adverse effects, but it appears to be more of the norm in clinical practice despite a relative lack of empirical evidence that polypharmacy is inherently more effective. One could discuss off-label prescribing and the use of this rational polypharmacy approach. Does the FDA approval process that ultimately allows advertising provide enough evidence to move more risky drugs into early treatment phases in guidelines instead of using less risky agents that have less empirical data? Should unipolar antidepressants be used in bipolar, depressed patients? There is an increased risk of manic escalation with formal antidepressants; however, they seem to be devoid of the risk of movement disorders and severe metabolic disorders that are possible adverse effects of the current bipolar depressionâ&#x20AC;&#x201C; approved atypical antipsychotics. Perhaps we will find nonmonoamine, nonmania-escalating bipolar depres-

ÂŠ Jean Francois Podevin/theispot.com

Special Report Chairperson: Thomas L. Schwartz, MD

ALSO IN THIS SPECIAL REPORT:

Antidrug Vaccines

Novel Treatment Avenues for Bipolar Depression

Daryl Shorter, MD Thomas R. Kosten, MD

Roger S. McIntyre, MD Danielle S. Cha

We'd like to thank David A. Osser, MD, associate professor of psychiatry, Harvard Medical School, and one of our Editorial Board members for his contributions to this Special Report.

APRIL 2011

sion drugs in the research pipeline. In their article, Roger S. McIntyre, MD, and Danielle S. Cha review some novel approaches to the treatment of bipolar depression that include insulin sensitizers, anti-inflammatory agents, and glutamate-modulating drugs such as ketamine. Ketamine is a legally prescribed drug, but it also has street value and abuse potential. Investigators are looking into this product, and other glutamate modulators, for the treatment of resistant unipolar and bipolar depression. The article by Daryl Shorter, MD, and Thomas R. Kosten, MD, deals with one of the most interesting advances in psychopharmacological approaches: a vaccine to treat substance use disorders. Simplistically, when we ingest or inject drugs, they enter our bloodstream and make their way across the blood-brain barrier where they cause addiction pathways to fire, allowing for reward pathways and behaviors to occur. A vaccine would allow antibodies in the patient’s system to bind to the addictive drug and mitigate the drug’s ability to cross the blood-brain barrier and, thus, reduce the addiction/ reward pathway response in the CNS. This might promote less illicit drug use and help promote sobriety.

CLINICAL PSYCHOPHARMACOLOGY sues associated with the greater reliance and application of psychotropic medications and the risks associated with their use, such as the reverse effects of some antidepressants on the pediatric population and the serious metabolic effects associated with atypical antipsychotics, as well as what some see as overprescription of psychotropic medications.

Dr Schwartz is associate professor in the department of psychiatry at SUNY Upstate Medical University in Syracuse, NY. He reports that he is on the Speaker’s Bureau for AstraZeneca and Merck; he has received research grants from Forest, Cephalon, and Cyberonics; and he is a consultant for PamLab. ❒

PSYCHIATRIC TIMES

Looking for Residents Residents are encouraged to send their CVs along with topic proposals and writing samples to Editor, Psychiatric Times, 535 Connecticut Avenue, Suite 300, Norwalk, CT 06854, or e-mail to editor@psychiatrictimes.com. ❒

Upcoming in Part 2 In Part 2 of the Special Report coming in the May 2011 issue of Psychiatric Times, Michael C. Mithoefer, MD, reviews the evidence for another controlled substance that is not legally prescribed—MDMA (3,4-methylenedioxy-methamphetamine), or ecstasy. This Class I Drug Enforcement Administration drug was once considered for lower category III status. It promotes serotonergic facilitation, and phase 1 and 2 regulatory data are being collected. Findings from these studies on anxiety disorders indicate that MDMA may facilitate psychotherapeutic response. A whole special issue could be dedicated to illegal drugs or drugs of abuse that are used in psychopharmacology practice, ie, ketamine for depression, MDMA for anxiety, sodium oxybate (a GHB derivative) for anxiety and, of course, our currently widespread use of sedatives, hypnotics, and stimulants. The availability of psychotropic medications has improved the lives of millions of patients with severe mental illness. However, the increased use of these medications has created ethical and societal concerns. Laura Roberts, MD, explores the is-

Complex puzzles. Comprehensive solutions. At Western Psychiatric Institute and Clinic of UPMC, we take on complex disorders that others won’t even attempt to treat. Whether a patient has a difficult-to-treat disorder or one more easily treated, teams of specialists in psychiatry, psychopharmacology, clinical psychology, and medicine craft complete, individualized treatment plans that draw upon the latest clinical research, much of it conducted by our own investigators. Our work to advance the understanding and treatment of bipolar disorder, eating disorders, autism, and geriatric behavioral health issues is world-class. In fact,

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we have one of the most comprehensive programs for mood disorders, with research-based treatments for patients at every level of need, at every stage of life. With nearly 400 inpatient psychiatric beds and 50 ambulatory programs, we care for people when they’re feeling their worst and support them when they’re at their best, back with their families in their communities. Each year, Western Psychiatric helps people of all ages — at all stages of recovery, from all over the world — live healthier and more productive lives. To learn more, visit UPMCPhysicianResources.com.

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APRIL 2011

Antidrug Vaccines Fact or Science Fiction? by Daryl Shorter, MD and Thomas R. Kosten, MD ubstance use disorders (SUD) are recognized worldwide as causes of negative medical, psychological, and social outcomes, and they result in significant personal consequences for affected persons, their families, and society at large. Treatment of SUD has focused on a combination of pharmacotherapy and behavioral therapies in an effort to improve patients’ chances of successfully entering and maintaining recovery.

activate target neurotransmitter systems. One factor of particular importance in addiction pharmacology relates to the size of the molecule, because substances of abuse must be small enough to traverse the bloodbrain barrier. Once in the brain, the initial common pathway of the addictive process is through stimulation of dopamine release from the ventral tegmental area to the nucleus accumbens; this, in part, determines the addictive liability of a substance. Although the use of a vaccine to treat chemical dependency—an illness characterized by its multifacto-

Poetry of the Times

by Richard M. Berlin, MD

Expert Witness I’m driving the MassPike west just before sunset, blacktop cleared of snow, the only car for miles

What is already known about antidrug vaccines? They are medically safe and effective in reducing abuse of cocaine and nicotine in humans through a mechanism of competitive antagonism.

after a late April storm. The distant silhouettes of bare trees line up along the Berkshire hills like the stubble

What new information does this article add?

of my three-day beard, and wild clouds

It provides a brief summary of the studies done with these vaccines over the past 15 years when they were first tested in humans and updates the status of their development in ongoing multisite randomized clinical trials.

spin arcs of steel-bar-blue, Creedence

What are the implications for psychiatric practice? Addictions, particularly nicotine dependence in psychotic patients, are the most common disorders in psychiatric practice. Nicotine has a few pharmacotherapies, but no blocking therapies, and the efficacy of existing treatments is relatively limited. Medical safety issues have also arisen with varenicline, the most effective agent, which is a partial blocker. Cocaine addiction has no FDA-approved therapies. For both these disorders, vaccines are significant additions to the treatment options and should be available commercially within a few years.

on the radio singing “Fortunate Son,” me remembering my father like I always do at dusk on the highway, 1954, riding shotgun in our new Oldsmobile sedan on Route 1, traffic streaming toward us from the glow of New York City, my father warning me that twilight and dawn are the most

Antidrug vaccines are a potentially important class of medications currently under investigation. They represent yet another frontier in the ongoing quest for novel pharmacological strategies that could be easily integrated into treatment plans to reduce substance use and establish abstinence. Ultimately, these vaccines reflect an important shift in our conceptualization of drugs of abuse, ie, that these substances are “foreign” and that the body’s own defenses can be used against them.

Mechanisms of action Drugs of abuse act centrally on the reward and reinforcement pathways of the brain. After introduction into the body, via oral, intranasal, inhalation, or intravenous route, these substances rapidly enter the brain to

rial etiology and biopsychosocial underpinnings—sounds like a concept from the pages of a science fiction novel, the field of addictions treatment is much closer than many may realize. Interestingly, the idea of treating SUD using immunological means was introduced almost 40 years ago. In 1972, based on an animal study, Berkowitz and Spector1 published their findings on the creation of a morphine vaccine. In rats, administration of a morphine hapten–bovine serum albumin (a carrier protein) was found to result in the creation of antimorphine antibodies. These antibodies were observed to reduce the plasma concentration of the drug in rats and to decrease self-administration of heroin in rhesus monkeys.2 (Please see Vaccines, page 30)

dangerous times to drive. In a few days I will listen for his voice again when I turn around and drive east at sunrise, rehearsing my testimony for the trial of a drug dealer accused of murder. “Crazy or sane?” they will ask me, “Life in a hospital ward or slow death in a prison yard?” The defendant’s father will be speeding down the MassPike, too, the sun’s glare filling our eyes with tears, both of us driving blind. 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. ❒

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CLINICAL PSYCHOPHARMACOLOGY

Vaccines Continued from page 28

In 1986, Owens and Mayersohn3 highlighted the ability of antibodies to sequester substances of abuse within the circulatory system. The researchers first characterized the pharmacokinetics and clearance of phencyclidine (PCP) in dogs.4 They

followed this study by creating antigen-binding fragments through a process of passive immunization. Goats were immunized with PCP, which generated high-affinity antibody proteins that were then collected from the animal serum and purified. In their final experiment, they administered PCP to dogs and used the PCP-specific antigen-binding

fragments to bind the drug, confining it to the plasma and limiting its distribution into tissue.3 Since that time, additional studies of passive immunization for treatment of SUD have been conducted. Antibodies specific for methamphetamine, heroin, and morphine were shown to bind these drugs in the circulation, to reduce euphoric effects

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and symptoms of toxicity, and to protect against overdose. These agents are akin to other immunoglobulin treatments for a wide array of illnesses, including malignancies and infectious diseases. Antidrug vaccines work via active immunization, where administration of the vaccine triggers an immunological response against the agent.5 Immunological memory is created, whereby re-exposure to the agent (ie, through booster injection) results in amplification of the initial response. Because the immune system has been primed by vaccination, later introduction of the agent produces an antigen-specific, IgG-mediated antibody response. These antibodies bind the substance of abuse and create immune complexes too large to cross the blood-brain barrier; as such, they trap the drug in the circulation and allow it to be cleared from the system. The individual’s subjective experience (ie, euphoria) and reward are reduced, which also affects the reinforcing nature of the drug. Drugs of abuse do not typically cause the user to mount an immunological response with the creation of antibodies capable of binding and clearing the substance. Thus, in creating antidrug vaccines, the targeted substance of abuse (ie, drug hapten) must be conjugated to a molecule that carries immunogenicity—such as a foreign carrier protein (eg, inactivated cholera toxin, bovine serum albumin). The effectiveness of the vaccine is then measured by its ability to create antibodies with specificity and high binding affinity for the drug of abuse and the robustness of the antibody response, ie, the concentration of antibody produced.6 Clinical trials of substance abuse vaccines that target both cocaine and nicotine dependence are ongoing. Phase 1 and 2 clinical trials of these new medications are discussed below.

Cocaine vaccine The cocaine vaccine, TA-CD, is a cocaine hapten conjugated to inactivated cholera toxin B (Table 1). The vaccine induces a cocaine-specific antibody response. Antibody-bound cocaine molecules are then broken down by cholinesterases in the circulation, which convert cocaine into inactive metabolites that are subsequently excreted.7 In the phase 1 trial (N = 34), TACD demonstrated an ability to induce the creation of cocaine-specific antibodies in all vaccinated subjects.8

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Participants reported attenuation in their subjective experience and euphoria from smoked cocaine.7,9 The antibody levels did not persist beyond 1 year; the immunological effect appeared to last approximately 2 to 4 months following the final vaccination, as evidenced by a decline in the level of circulating antibody within that time span. Overall, the safety profile for the vaccine was quite favorable. Almost all recipients (33 of 34) reported lo-

cal pain and/or tenderness at the injection site, with no difference between active-treatment and placebo groups. Treatment-related systemic adverse effects that occurred in both groups included tachycardia, elevated temperature, and hypertension.8 It is important to note that there were no serious adverse effects during the 12 months of follow-up.7 In the phase 2a trial (N = 18), TACD was administered at 2 dose levels (100 μg ⫻ 4 injections, or 400 μg ⫻

of the high-dose group). Sixteen of 18 participants (89%) successfully completed the study; there were no hospitalizations, deaths, or serious adverse effects.7 The 2 participants who did not complete the study received only 1 vaccination and did not report any adverse effects before discontinuing treatment. In the initial phase 2b trial (N = 115), either TA-CD, at a single dose

5 injections). The vaccine demonstrated an ability to elicit an immunological response in participants from both the low- and high-dose groups. 7 Participants from both groups developed cocaine-specific antibodies that persisted for at least 6 months.10 Mean antibody levels were higher in the high-dose group. Persons in this group were also more likely to remain abstinent at 6-month follow-up (89% of the low-dose group experienced a relapse vs 43%

(Please see Vaccines, page 32)

Phase

Participants

Completion rate

Dosage(s)

Results

N = 34, former cocaine abusers

27/34 received all 3 injections

• 6 received placebo • 8 received 13 µg • 10 received 82 µg • 10 received 709 µg

Cocaine-specific antibody (Ab) production in all vaccinated subjects; significantly higher Ab response in highest-dose group

N = 18, treatment-seeking, cocaine-dependent subjects

16/18

• 9 received 100 µg ⫻ 4 injections • 7 received 400 µg ⫻ 5 injectionsa

Subjects in the higher-dose group produced a more robust Ab response and had a better treatment outcome as measured by proportion of cocainepositive urine samples submitted throughout treatment; reduction in cocaine use and euphoric effects were reported in both groups

N = 115, cocaine-dependent, methadone-maintained subjects

94/115

• 47 received placebo • 47 received 360 µg ⫻ 5 injections

Vaccinated subjects stratified into highand low-Ab responders; high-Ab responders with more cocaine-negative urine samples had longer period of abstinence

Large-scale multicenter

To be completed in 2011

• 400-µg injections at weeks 1, 3, 5, 9, and 13

Ongoing

8 subjects received booster vaccines (2 subjects received 400 mg and 6 subjects received 2000 µg) between 9 and 12 months.

Nicotine vaccine trials

Table 2 Vaccine

Carrier

Completion rate

Dosage

Results

NicVAXa

Pseudomonas aeruginosa

56/68

• Placebo ⫻ 4 injections

All vaccinated subjects mounted antibody

exoprotein A

• 45 vaccine group

• 50 µg ⫻ 4 injections

(Ab) response; Ab titer increased as dose

• 23 placebo group

• 100 µg ⫻ 4 injections

increased; reduced smoking behavior and

• 200 µg ⫻ 4 injections

higher rates of abstinence in high-dose group

NicQba

Virus-like particle

239/340

• Placebo ⫻ 5 injections

High-Ab responders’ rate of continuous

• 159/229 vaccine group

• 100 µg ⫻ 5 injections

abstinence found to be statistically

• 80/111 placebo group

significant (P > .05) and clinically relevant in comparison with placebo group

TA-NICb

Cholera toxin B

50 smokers, 10 nonsmokers

• Placebo ⫻ 4 - 6 injections

Higher quit rates were observed in the

• 10 g ⫻ 4 - 6 injections

high-dose vaccine group in comparison

• 50 g ⫻ 4 - 6 injections

with the control group (38% vs 8%); however, statistical analysis not reported because of small cohort size

a b

w w w. psychi atr i cti mes. com

Summary of cocaine vaccine trials

Table 1

PSYCHIATRIC TIMES

CLINICAL PSYCHOPHARMACOLOGY

Only phase 2 clinical trial information included. Participants were randomized to 1 of 4 dosing regimens, ranging from a total of 6 to 20 weeks in trial duration and an additional booster injection at week 32.

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

Vaccines Continued from page 31

level (360 μg ⫻ 5 injections), or placebo was administered to cocainedependent, methadone-maintained participants. Those who received the vaccine were analyzed according to response and stratified into high- and low-antibody–producing groups. The high-antibody group showed a greater percentage of cocaine-free urine samples.11 The safety profile of the vaccine was favorable: all severe adverse effects were deemed unrelated to the vaccine. At present, TACD is undergoing large-scale, multicenter, phase 2b clinical testing.

CLINICAL PSYCHOPHARMACOLOGY The safety of NicQb was found to be favorable overall, although there was a significantly higher rate of reported “flu-like symptoms” among recipients of the vaccine than among recipients of placebo (70% vs 12.5%). Other commonly reported adverse effects in the vaccine group included pyrexia (42% vs 8% in the control group), headache (40% vs

demonstrated the ability to mount an immunological response, with serum antibody levels that increased significantly (P > .05) after each subsequent dose. Higher quit rates were observed in the high-dose vaccine group than in the control group (38% vs 8%). Note, however, that because of the small cohort size, statistical analysis was not reported.15.17

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

Nicotine vaccine There are 3 nicotine conjugate vaccines, NicVAX, NicQb, and TA-NIC (Table 2). NicVAX is composed of a nicotine hapten linked to Pseudomonas aeruginosa exoprotein A. NicVAX is currently in the second of 2 phase 3 clinical trials; in previous studies, it has been found to produce antibody titers in a linear dose-response fashion.12,13 The nicotine-specific IgG antibodies produced resulted in a reduction of smoking among vaccinated persons, rather than compensatory smoking behavior.13 NicVAX was well tolerated from a safety standpoint. Local reactivity at the site of vaccination was seen in both placebo and treatment groups, which suggests that these events were related to the adjuvant, rather than vaccine, components. There were no significant differences between groups in terms of commonly reported systemic adverse effects (ie, malaise, headache, myalgia).13 A nicotine hapten structurally similar to that used in NicVAX makes up the core of NicQb. With the NicQb vaccine, however, the nicotine hapten is conjugated to a virus-like particle formed by recombinant expression of the protein coat of bacteriophage Qb.14 Moreover, this vaccine is not mixed with an aluminum adjuvant, as is the case with most vaccines.15 In a phase 2 trial, there was no statistically significant difference in rates of continuous abstinence between vaccinated persons and controls (P > .05).14 However, when stratified according to antibody response, those with high antibody production had higher continuous abstinence rates than those who received placebo (56.6% vs 31.3%); the difference between the groups was statistically significant.

27%), nasopharyngitis (32% vs 26%), rigors (13.5% vs 0%), and myalgia (13.5% vs 5%).16 NicQb is in phase 2b/3 clinical trials.16 Similar to the cocaine vaccine, TA-NIC is composed of a nicotine hapten conjugated with inactivated cholera toxin B. During the clinical trial to assess safety and immunogenicity of the vaccine, participants

APRIL 2011

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.

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CLINICAL PSYCHOPHARMACOLOGY

Conclusion Antidrug vaccines represent an exciting area of development in the pharmacological treatment of chemical dependency. In addition to the clinical trials being conducted on vaccines for cocaine and nicotine dependence, preclinical development of vaccines for methamphetamine and heroin is ongoing. Future direc-

tions for vaccine trials will likely focus on the use of booster injections to prolong antibody effects and methods for combining immunotherapy with current behavioral approaches. As we think about the implications of this treatment, alleviating the suffering of those struggling with active addiction might only be the first step. Although years away, there

may be a day when those persons at increased risk for chemical dependency (because of factors such as family history) may elect to prophylactically receive antidrug vaccines in an effort to reduce their likelihood of progression to addiction. Therefore, it is important that our ongoing conversation about this pharmacotherapeutic option strike a balance

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

w w w. psychi atr i cti mes. com

between the practical implications of vaccines, ethical considerations of treatment, and financial realities within society. Dr Shorter is assistant professor in the Menninger Department of Psychiatry and Behavioral Science at the Baylor College of Med(Please see Vaccines, page 37)

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

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Vaccines Continued from page 33

icine and staff psychiatrist at the Michael E. DeBakey Veterans Administration Medical Center (MEDVAMC) in Houston. Dr Kosten is JH Waggoner Chair and professor of psychi-

CLINICAL PSYCHOPHARMACOLOGY

PSYCHIATRIC TIMES

w w w. psychi atr i cti mes. com

Novel Treatment Avenues for Bipolar Depression Going Beyond Lithium

atry, pharmacology, and neuroscience in the Menninger Department of Psychiatry and Behavioral Science at the Baylor College of Medicine and research director of the National VA Substance Use Disorders, Quality Enhancement Research Initiative (QUERI) in Houston. The authors report no conflicts of interest concerning the subject matter of this article. Acknowledgments—Research support was provided by VA SUD-QUERI, DOD, NIH grants K05-DA0454, P50-DA18197. References 1. Berkowitz B, Spector S. Evidence for active immunity to morphine in mice. Science. 1972;178: 1290-1292. 2. Bonese KF, Wainer BH, Fitch FW, et al. Changes in heroin self-administration by a rhesus monkey after morphine immunisation. Nature. 1974;252:708-710. 3. Owens SM, Mayersohn M. Phencyclidine-specific Fab fragments alter phencyclidine disposition in dogs. Drug Metab Dispos. 1986;14:52-58. 4. Woodworth JR, Owens SM, Mayersohn M. Phencyclidine (PCP) disposition kinetics in dogs as a function of dose and route of administration. J Pharmacol Exp Ther. 1985;234:654-661. 5. Kosten T, Owens SM. Immunotherapy for the treatment of drug abuse. Pharmacol Ther. 2005;108:7685. 6. Orson FM, Kinsey BM, Singh RA, et al. Substance abuse vaccines. Ann N Y Acad Sci. 2008;1141:257269. 7. Martell BA, Mitchell E, Poling J, et al. Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol Psychiatry. 2005;58:158-164. 8. Kosten TR, Rosen M, Bond J, et al. Human therapeutic cocaine vaccine: safety and immunogenicity. Vaccine. 2002;20:1196-1204. 9. Haney M, Kosten TR. Therapeutic vaccines for substance dependence. Expert Rev Vaccines. 2004;3:11-18. 10. Orson FM, Kinsey BM, Singh RA, et al. Vaccines for cocaine abuse. Hum Vaccin. 2009;5:194-199. 11. Martell BA, Orson FM, Poling J, et al. Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double blind, placebo-controlled efficacy trial. Arch Gen Psychiatry. 2009;66:1116-1123. 12. Riedmann EM. NicVAX: pivotal phase III study initiated. Hum Vaccin. 2010;6:430-435. 13. Hatsukami DK, Rennard S, Jorenby D, et al. Safety and immunogenicity of a nicotine conjugate vaccine in current smokers [published correction appears in Clin Pharmacol Ther. 2006;79:396]. Clin Pharmacol Ther. 2005;78:456-467. 14. Cornuz J, Zwahlen S, Jungi WF, et al. A vaccine against nicotine for smoking cessation: a randomized controlled trial. PLoS One. 2008;3:e2547. 15. LeSage MG, Keyler DE, Pentel PR. Current status of immunologic approaches to treating tobacco dependence: vaccines and nicotine-specific antibodies. AAPS J. 2006;8:E65-E75. 16. Heading CE. Drug evaluation: CYT-002-NicQb, a therapeutic vaccine for the treatment of nicotine addiction. Curr Opin Investig Drugs. 2007;8:71-77. 17. St Clair Roberts J, Dobson J, Wood D, Settles M. Safety and immunogenicity of a human nicotine conjugate vaccine. Drug Alcohol Depend. 2002;66: S148. ❒

by Roger S. McIntyre , MD and Danielle S. Cha ipolar disorders are heterogeneous in phenomenology, pathoetiology, comorbidity, and treatment. These disorders are highly prevalent and often misdiagnosed and underrecognized. For bipolar patients who are correctly identified, the time from onset of symptoms to correct identification is often 10 to 15 years. It is disquieting that mortality studies indicate that bipolar disorder is associated with approximately 15 to 25 years of life lost largely because of associated cardiometabolic disorders.1 Despite the development and widespread use of several novel pharmacological, psychosocial, and neuromodulatory approaches for bipolar disorder during the past decade, outcomes remain rather disappointing. For example, results from efficacy as well as effectiveness studies indicate that the majority of individuals with bipolar disorder who receive guideline-concordant measurement-based care fail to achieve symptomatic, syndromal, or functional recovery. Moreover, phenomenological studies indicate that the longitudinal course in bipolar disorder largely consists of depressive symptoms and episodes. Research into bipolar depression symptoms is particularly important because bipolar depression symptoms carry a much higher illness burden—these symptoms are by far more prevalent than manic symptoms.2-4 This latter observation provides the impetus for developing genuinely novel disease-modifying treatment strategies. Except for lithium, most treatments for bipolar disorder symptoms were not primarily developed as “antibipolar therapies” (eg, anticonvulsants, conventional unimodal antidepressants). Most were initially used off-label and only later were evaluated in bipolar disorder (eg, atypical antipsychotics). Still others continue to be frequently prescribed off-label (eg, antidepressants). A major limitation to genuinely novel drug discovery in bipolar disorder is the absence of a consensually agreed-on neuro-

pathology as well the unavailability of a sufficient animal model with appropriate face, construct, and pathological and pharmacological validity.5 Although the field continues to be preoccupied with the monoamine hypothesis, it is abundantly clear that monoamine dysregulation has never been established as a central disturbance in bipolar disorder and that targeting monoamines is not sine qua non for symptom relief. Other models that have been proposed to exist alongside the monoamine hypothesis include the excitotoxicity, neurotrophic/neuroplasticity, neuroinflammatory, metabolic, and cellular redox (ie, oxidative stress to the cell) models. Novel treatments for bipolar disorder that are a focus of clinical research attempt to target one or more of the effector systems within these pathophysiological models. Currently, only quetiapine, quetiapine XR, and an olanzapine/fluoxetine combination are FDAapproved for the acute treatment of bipolar depression. Although these agents are highly beneficial for some individuals, most fail to sufficiently benefit and/or are intolerant of these agents, which underscores the need for novel alternatives. This article aims to provide a succinct summary of novel pharmacological treatment avenues that are under investigation as treatment for bipolar depression. We present some of these novel treatments according to the overarching disease model that they derive from.

Excitotoxicity Several lines of evidence suggest that glutamatergic system dysfunction (eg, N-methyl d-aspartate [NMDA] receptor complex) may play a critical role in the pathophysiology of bipolar disorder. In keeping with this view, the use of glutamatergic modulators may be predicted to alleviate symptoms and modify the disease process. Postmortem studies indicate that altered NMDA receptor complexes are observed in the brain tissue of patients with bipolar disorder. Moreover, genetic polymorphisms for genes implicated in the glutamate receptor complex have been associated with this disorder.6

Riluzole, an inhibitor of glutamate release, is approved by the FDA for the treatment of amyotrophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS). Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.7 Results from a double-blind, randomized, placebo-controlled, crossover study indicate that a single intravenous infusion of ketamine combined with lithium or valproate was capable of alleviating depressive symptoms within 40 minutes of administration when compared with placebo.7 The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was not associated with significant increases in hypomania or mania but was associated with dissociative symptoms.

Inflammatory network Abnormal activation in function of the inflammatory network has been implicated as causative and consequential in bipolar depression symptomatology. For example, elevated concentrations of proinflammatory cytokines (interleukin-6 and tumor necrosis factor [TNF]-␣) have been implicated in bipolar depression and mania.8,9 Conventional pharmacotherapy for bipolar disorder (eg, lithium) exerts a modulatory effect on the proinflammatory–anti-inflammatory network.8 Proinflammatory cytokines are known to induce behavioral symptoms (eg, anorexia, psychomotor retardation) in humans that are thought to mimic sickness behavior described in animals.8 Cyclooxygenase-2 (COX-2) in(Please see Novel Treatment, page 38)

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

Novel Treatment Continued from page 37

hibitors have been shown to protect against glutamate-induced neurotoxicity; to prevent normal aging-related increases of cytokines, prostaglandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis.10 The COX-2 inhibitor celecoxib was evaluated as a potential antidepressant in adults with bipolar I/II depression (N = 28).10 This drug was administered at a dosage of 400 mg daily in combination with a mood stabilizer or antipsychotic medication as part of a 6-week, randomized, double-blind, placebo-controlled study. Depressive symptoms in both the treatment group and the placebo group improved, with a statistically significant (P = .01) advantage at week 1 in patients treated with celecoxib compared with patients who received placebo. Although there was an advantage in favor of the treatment group at week 1, both the active-treatment and placebo groups had similar reductions for each of the remaining observation points. Taken together, the results suggest that an anti-inflammatory ap-

APRIL 2011

CLINICAL PSYCHOPHARMACOLOGY proach may offer a rapid onset of antidepression action in bipolar disorder. More work is needed to replicate/extend or refute these findings, however.

Metabolic action Neuronal insulin mediates multiple biological actions characterized as metabolic (eg, increases in glucose uptake), neuromodulatory (eg, inhibition of neuronal reuptake of noradrenaline), growth regulatory (eg, promotion of neurite outgrowth and synaptogenesis), and neuroendocrine. For example, insulin modulates the CNS concentration of neuropeptides, monoamines, and other neurotransmitters (eg, acetylcholine) implicated in the pathophysiology of mood disorders, schizophrenia, and Alzheimer disease. Insulin inhibits the firing of neurons in the hippocampus and hypothalamus, inhibits the reuptake of noradrenaline in rat brains, modulates catecholamine turnover in the hypothalamus, stimulates phosphoinositide turnover in the hippocampus, and regulates the noradrenaline and dopamine transporter messenger RNA concentration in neurons.

Insulin is transported into the CNS across the blood-brain barrier by a saturable insulin receptorâ&#x20AC;&#x201C;mediated transport process.11-13 Long-term potentiation, the neurobiological model of learning, is partially modulated by insulin. Insulin deficiency in diabetic rats triggers a retraction of dendrites and reduces NMDA transmission of hippocampal neurons, with associated decrements in memory performance. Taken together, cellular, molecular, and physiological data indicate that insulin is important for normal (and pathological) memory processes.12 Several case reports and case series suggest that insulin sensitizers (eg, rosiglitazone) may offer an antidepressant effect in persons with major depressive disorder. Studies are currently under way in bipolar disorder. For example, several studies are evaluating the antidepressant effects of intranasal insulin and insulin secretagogues (eg, incretins) in bipolar disorder. Moreover, there is ongoing research to determine whether weight loss, bariatric surgery, and dietary modification (eg, ketogenic diet) improve depressive symptoms in persons with bipolar disorder.

Antioxidant implications Available evidence implicates oxidative stress and abnormalities in cellular redox in the pathophysiology of bipolar disorder. Evidence also indicates that lithium and valproate may protect neurons from oxidative stress. Glutathione is an antioxidant distributed throughout multiple tissues; levels of this antioxidant have been reported to be abnormal in individuals with bipolar disorder. Glutathione production rate is limited by its precursor, cysteine.14 N-acetylcysteine is the acetylated derivative of cysteine and is more efficiently bioavailable. N-acetylcysteine has been reported to be neuroprotective in preclinical neurodegenerative disease models. Results from a randomized, double-blind, multicenter, placebo-controlled study of adults with bipolar disorder (N = 75) indicate that N-acetylcysteine (1 g bid) adjunctive to usual medications was capable of alleviating depressive symptoms as measured by the MADRS.14 The benefit on depressive symptoms was noted at week 20 as part of this 24-week study. Benefits were noted by week 8 on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale. N-acetylcysteine did not induce hypomania or mania and was

well tolerated. Adverse events reported in more than 15% of the N-acetylcysteine group included change in energy, headaches, heartburn, and increased joint pain.

Modafinil Modafinil is currently approved by the FDA for improving wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea-hypopnea syndrome and shift work sleep disorder. This drugâ&#x20AC;&#x2122;s mechanism of action is not fully characterized but is thought to involve multiple neurochemical systems that include dopamine signaling.15 Modafinil at a dosage of 100 to 200 mg/d has been shown to alleviate depressive symptoms when compared with placebo in adults with bipolar disorder across 6 weeks of treatment.16 Improvement in depressive symptoms was statistically significantly greater (P = .01) in the modafinil group by week 2, with greater response and remission rates. Modafinil was not associated with treatment-emergent hypomania or mania. Armodafinil is the longer-lasting isomer of modafinil, and its therapeutic indications are similar to those of the racemic agent modafinil. Armodafinil at a dosage of 150 mg/d was evaluated as an antidepressant in adults with bipolar disorder who received either olanzapine, lithium, or valproic acid as part of an 8-week double-blind placebo-controlled study.17 Patients who received armodafinil exhibited greater improvement of depressive symptoms as measured by the 30-item Inventory of Depressive Symptomatology, Clinician-Rated score. The rate of newonset hypomania or mania did not differ between groups. The most frequently reported adverse events among armodafinil recipients were headache, diarrhea, and insomnia.

Conclusions The treatment of adults with bipolar depression may begin with an FDAapproved agent such as quetiapine or an olanzapine/fluoxetine combination. The evidence-based approach to bipolar depression includes treatment with lithium, conventional unimodal antidepressants, lamotrigine, or divalproex. The evidence base does not provide sufficient guidance for next treatment steps in bipolar disorder and, as such, treatment decisions are made empirically. Pharmacological options that are commonly considered are pramipaxole, modafinil, and armodafinil.

APRIL 2011

CLINICAL PSYCHOPHARMACOLOGY

Although ketamine and riluzole are not considered standard treatments for bipolar depression, they are proof of concept of the role of glutamate systems. These proof of concept studies provide indirect pharmacodynamic support for safer

and easier to use treatments that also target glutamate (eg, lamotrigine) in bipolar depression. Results with Nacetylcysteine look promising and could be considered; however, replication in other studies is warranted. Results with omega-3 (not reviewed

in this article) are equivocal in bipolar depression but can be considered. The role of exercise, weight loss, and dietary modification are research vista for the future. (Please see Novel Treatment, page 40)

Book Review The Judaic Foundations of Cognitive-Behavioral Therapy: Rabbinical and Talmudic Underpinnings of CBT and REBT by Ronald W. Pies, MD; Bloomington, IN: iUniverse Books; 2010 • 208 pages • $17.95 (softcover)

Reviewed by H. Steven Moffic, MD and Rabbi Evan Moffic The upshot for consumers: medical wisdom that has stood the test of time—and large, randomized, controlled trials—is more likely to be right than the latest news flash about a single food or drug. —S. Begley1 The above is not a quote by Ronald Pies, author of The Judaic Foundations of Cognitive-Behavioral Therapy: Rabbinical and Talmudic Underpinnings of CBT and REBT. Rather, it is by well-known journalist, Sharon Begley, as she concluded her recent Newsweek article, “Why Almost Everything You Hear About Medicine Is Wrong.” She focuses on the work of Dr John P. A. Ioannidis, who questions the very framework of medical investigation. Recent examples of questionable findings include hormone replacement therapy, prostate-specific antigen testing for prostate cancer, and even antidepressant medication for mild to moderate depression. Pies must have known the flawed nature of scientific studies. Cognitive-behavioral therapy (CBT) has been extensively tested, and the author’s timely new book creatively places CBT in the context of time-tested religious wisdom. By doing so, Pies even goes beyond this important psychiatric confirmation to expand the implications to morality, ethics, and character. Of course, the title itself would imply its relevance. It should be of interest to any clinician practicing today’s most popular form of psychotherapy. Even here, the potential interest is broader. Rather than focus on Aaron Beck’s legacy (as so many other

writers do), Pies concentrates on the relatively neglected work of Albert Ellis, founder of Rational Emotive Behavioral Therapy. It may also be of interest to psychoanalytic therapists, given that Freud was known to have studied and incorporated other Jewish teachings, especially on mysticism, into his theories. From the religious side, pastoral counselors of almost any religious denomination may find the underlying principles of CBT to be applicable. Although his main focus is Judaic foundations, Pies also touches on Christian, Islamic, Hindu, and Zen Buddhist beliefs. He quotes the Maharishi Mahesh Yogi: “For the forest to be green, each tree must be green.” In other words, society won’t change for the better unless we as individuals change our selfdefeating habits. As Pies himself concludes, both rabbinical Judaism and CBT share “the conviction that human beings can exercise their reason in the service of self-improvement, self-control, and selfdiscipline.” For CBT to work, there needs to be a positive therapeutic alliance in which the clinician conveys empathy, warmth, and a positive regard toward the patient. It would have been helpful if Pies had added this information to this relatively brief book. Along with a faith in shared positive expectations and beliefs, this relationship will contribute to a baseline placebo benefit. There is no evidence that the founders of CBT used rabbinical and Talmudic insights to develop their treatments, but the overlap is striking. See if you can tell if the following quote comes from religious wisdom or a CBT therapist: “To defeat depression, you must introduce a fresh perspective to your thinking. You must begin to replace troubling, destructive thoughts with positive, constructive ones.” To this, we say, “Amen.” 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 blogger on www.psychiatrictimes.com. Rabbi Moffic is the Senior Rabbi at Congregation Solel, Highland Park, Chicago. Dr and Rabbi Moffic are father and son. Reference 1. Begley S. Why Almost Everything You Hear About Medicine Is Wrong. http://www.newsweek.com/2011/01/23/why-almost-everything-youhear-about-medicine-is-wrong.html. Accessed February 14, 2011. ❒

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Remember that electroconvulsive therapy is a highly effective treatment in bipolar depression and is probably underused in some centers. Results with transcranial magnetic stimulation look promising in bipolar depression; several academic centers are evaluating the role of deep brain stimulation. As for all patients with bipolar disorder, the pharmacological treatment of bipolar depression is part of a multicomponent chronic disease management approach. A critical component of this model includes psychoeducation and in many cases the provision of manual-based psychotherapy, such as cognitive-behavioral therapy, interpersonal therapy, social rhythm therapy, or familyfocused therapy.

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try and pharmacology, University of Toronto, macology Unit, University Health Network, Mood Disorders Psychopharmacology Unit, University Health Network. Dr McIntyre re-

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new insight into the biology of depression. Am J Psychiatry. 2010;167:1305-1320. 6. Zarate CA Jr, Quiroz JA, Singh JB, et al. An openlabel trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57:430-432. 7. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793-802. 8. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry. 2009;70:1078-1090. 9. Soczynska JK, Kennedy SH, Goldstein BI, et al. The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: novel hypothesis-driven treatments for bipolar depression? Neurotoxicology. 2009;30:497-521. 10. Nery FG, Monkul ES, Hatch JP, et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol. 2008;23:87-94. 11. McIntyre RS, Kenna HA, Nguyen HT, et al. Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: points of pathophysiological commonality with mood disorders? Adv Ther. 2010;27: 63-80. 12. McIntyre RS, Soczynska JK, Konarski JZ, et al. Should depressive syndromes be reclassified as “metabolic syndrome type II”? Ann Clin Psychiatry. 2007;19:257-264. 13. McIntyre RS, Soczynska JK, Lewis GF, et al. Managing psychiatric disorders with antidiabetic agents: translational research and treatment opportunities. Expert Opin Pharmacother. 2006;7:1305-1321. 14. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder— a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468-475. 15. Andersen ML, Kessler E, Murnane KS, et al. Dopamine transporter-related effects of modafinil in rhesus monkeys. Psychopharmacology (Berl). 2010;210:439-448. 16. Frye MA, Grunze H, Suppes T, et al. A placebocontrolled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164:1242-1249. 17. Calabrese JR, Ketter TA, Youakim JM, et al. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proofof-concept study. J Clin Psychiatry. 2010;71:13631370. ❒

grants from Eli Lilly, Janssen-Ortho, Shire, and from Bristol-Myers Squibb. Ms Cha reports

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ing the subject matter of this article. References 1. McIntyre RS, Konarski JZ. Bipolar disorder: a national health concern. CNS Spectr. 2004;9(11 suppl 12):6-15. 2. Judd LL, Schettler PJ, Solomon DA, et al. Psychosocial disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders. J Affect Disord. 2008;108:49-58. 3. Judd LL, Akiskal HS, Schettler PJ, et al. Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch Gen Psychiatry. 2005;62:1322-1330. 4. Judd LL, Schettler PJ, Akiskal HS, et al. Long-term symptomatic status of bipolar I vs. bipolar II disorders. Int J Neuropsychopharmacol. 2003;6:127-137. 5. Krishnan V, Nestler EJ. Linking molecules to mood:

Opinionated Psychiatrists Wanted Psychiatric Times invites readers to suggest Commentaries and Point/Counterpoint articles. Topics should be relevant to practicing psychiatrists and mental health care professionals. Point/Counterpoint issues should have 2 distinct viewpoints with a corresponding author for each. Proposals and articles should be grounded in scientific literature and include ref erences. Send proposals to editor@psychiatrictimes.com. Please note that manuscripts may be sent for peer review. ❒

APRIL 2011

MOLECULES OF THE MIND

PSYCHIATRIC TIMES

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Custom-Made Neural Stem Cells by John J. Medina, PhD

t is ironic that an attempt to do a molecular end-run around a politically hot topic could result in an important breakthrough in the treatment of neurological disease with potentially strong implications for the psychiatric community. Ironic maybe, but true.

In this column, we explore how the judicious use of neural stem cells (NSCs) has led to a research Holy Grail: the creation of research-ready, patient-specific neurons. This technology did not use the famously controversial embryonic stem cells. These custom-made NSCs were created from politically neutral adult tissues (fibroblasts), which were originally isolated from an affected patient. With no embryo in sight, scientists genetically reprogrammed fibroblasts into stem cells, which were then induced to develop into NSCs. This is an extraordinary finding with many topics to be discussed here: • The potential research utility for patient-specific neurons • An explanation of how stem cells can be made from adult tissues • A striking set of results that involve one of the most commonly inherited and lethal childhood neurological disorders: spinal muscular atrophy (SMA)

Research utility for NSCs Of what possible utility could molecular investigations of a motor disorder have for the mental health community? Before getting into the specifics of the breakthrough, it might be useful to address a realworld psychiatric need, using depression and SSRIs as an example, to see where these data fit. When we consider the molecular mechanisms of SSRI interactions, it is easy to resort to commonly taught ideas about interactions that involve a single synapse. Nothing could be further from the truth. The most comprehensive neurological view of SSRI interactions must take into account the participation of thousands of individual neurons strung together in coordinated, complex neural networks. And not just serotonergic neurons. These cells are in contact with many other central nervous denizens, from adjacent glial cells to the extracellular matrix into which the cells are embedded. What do these

circuits actually look like in patients who are vulnerable to depression? Is their architecture all that different from patients who do not exhibit this vulnerability? If there are differences, could they eventually predict drug efficacy? Could these differences only be detected by constructing parts of the circuit from scratch, or could they be observed at the level of a single cell? The first step in answering these questions involves growing a custom-made batch of serotonergic neurons derived only from the affected patients, and then asking relevant structure/function questions. From attempting to understand molecular mechanisms of disease to testing the efficacy of potential medications, such patient-specific test beds would have a powerful research utility. Until recently, the creation of such tailor-made neural substrates had been an impossible goal. While it will certainly be quite some time before we can grow entire parkinsonian dopaminergic pathways in a dish, it is now possible to create individual patient-specific neurons in culture. The technology comes from that end-run I mentioned earlier, through the use of a certain type of stem cell. It is to these interesting cellular substrates that we now turn.

Inducible stem cells To say that embryonic stem cell research has been subject to heated political debate is an understatement. The bugaboo has been the source materials from which the stem cells would be isolated—human embryos—many left over from embryos generated in in vitro fertilization laboratories. In 2006, researchers found a way to create stem cells that bypassed the need for human embryos. The original technique involved the introduction of 4 specific gene products into mature mouse fibroblasts. Surprisingly, this cocktail was found to reprogram adult stem cells and reverse-engineer them into pluripotent

stem cells. Like embryonic stem cells, the altered stem cells had the ability to differentiate into any cell type. Eventually, a protocol was developed that did the same thing in human tissues. The cells were called iPSCs, short for induced pluripotent stem cells. This was quite a breakthrough. No longer would researchers need to harvest cells from extant human embryos to do stem cell research. Skin cells would do. Scientists were soon able to regenerate—and then correct—molecular dysfunction in a mouse model of sickle cell anemia using this technology. Could any of this work apply to humans, specifically to human neural tissue? Another successful round of experiments (with amyotrophic lateral sclerosis neurons) prompted researchers to study motor disease, ie, SMA. Of those hereditary neurological disorders capable of causing death in pediatric populations, SMA is easily the most common. The disease is unique to humans and associated with 2 genes, SMN1 and SMN2. For reasons that are not well understood, the absence of the survival motor neuron (SMN) protein results in an alteration of the function of spinal motor neurons. The primary feature is muscle weakness and atrophy. Death occurs at infancy in the most severe forms of the disease, with symptoms generally presenting several weeks after birth. There are many other, nonlethal forms of the disorder, however, with a wide spectrum of symptoms that range from trivial motor effects to catastrophic impairment. Why this variation? Both genes express in unaffected individuals, but the biological heavy lifting belongs to the SMN1 gene. Because of structural constraints, the expression pattern of the SMN2 gene normally results in only 10% of its protein being processed as a full-length (and functional) polypeptide; 90% of its protein output is truncated (and nonfunctional). That is okay, as long as the SMN1 gene is intact. But when SMN1 is mutated and silent, the disease condition results. Assuming there is a damaged SMN1, the severity of SMA varies according to the number of other SMN2 copies the infant may carry. The more copies of SMN2 gene, the greater the pop-

ulation of functional protein. This interaction explains in part why there can be so much variation in the clinical presentation. The great mystery is why SMN protein loss results in motor cell alterations that lead to the disease state in the first place. The protein is known to be essential for normal messenger RNA processing and is expressed throughout the body. Yet its absence most severely affects spinal motor neurons. The most exacting way to attack this “black box” would be to isolate the motor neuron populations from the patient, then compare these populations with unaffected controls and look for differences, of which there are many. These include responses to various medications. It is well known that the application of valproic acid (an anticonvulsant and/or mood stabilizer) or tobramycin (an aminoglycoside) to cultured cells, for example, leads to changes in the expression patterns of both fulllength SMN protein and truncated forms. What is the molecular basis of this unusual interaction? And could such differences be used as a “molecular flashlight” to ferret out other secrets regarding the SMN protein? Creating custom-made neurons—one population from an affected individual, another from an unaffected control—would certainly give a test bed capable of answering this question.

The data Studying these 2 populations is precisely what a group of investigators did. The researchers isolated fibroblasts from an affected child and also from the child’s healthy unaffected mother. The next step was to generate custom-made neurons. Several steps would be required (Figure). First, using the iPSC protocols I mentioned, the researchers would attempt to create stem cells from both child and parent sources. If that worked, the researchers would then try to induce these patient-derived stem cells into motor neurons—ones that would carry the same biological mechanisms observed in both the (Please see Neural Stem Cells, page 42)

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Neural Stem Cells Continued from page 41

diseased and the healthy populations. If successful, the researchers would have their custom-made test beds. They could begin characterization studies; reactions to valproic acid and tobramycin would make obvious first choices to try. The first step worked. The researchers were able to generate custom-made stem cells from both child and parent. The researchers then tackled the hard part: manufacturing spinal motor neurons from these stem cell populations. They certainly generated promising cellular populations. But the iPSC technologies are new enough that a visual inspection of the generated cells might be necessary—but certainly not sufficient—to show the presence

Figure

APRIL 2011

MOLECULES OF THE MIND of motor neurons. There are ways to gain greater reassurance. One way to assay the success of the protocol is to look for bona fide molecular markers of developing spinal neurons. It is known, for example, that extant motor neurons express the protein SMI032 and choline acetyltransferase. Did these induced cells express such proteins? The answer turned out to be yes, both for the affected child and for the unaffected parent. Developing cells in these populations possess transcription factors such as HOXB4, ISLET1, HB9, and OLIG2 as well. Did the induced populations express these markers? They did indeed. While not completely conclusive, it appeared that the researchers had generated patient-specific motor neurons from known affected and

unaffected sources. The next characterization experiments also yielded fruit. They were able to find that the child and parent neurons reacted very differently to the normally stimulating effects of valproic acid and tobramycin. The child’s cells showed elevated levels of SMN protein, both of the truncated form and full-length version. In addition, SMN-containing nuclear structures were altered. No such elevation occurred in the unaffected maternal line of cells. These differences were significant for 2 reasons. First, it gave the investigators a toehold in their attempts to characterize at a more intimate level the differences between affected and unaffected cells. Second, the differences were discovered as reactions to known medications. The hope is that similar approaches

Custom-made motor neurons

The ability to create patient-specific neurons from stem cells holds great promise in elucidating the molecular mechanisms behind many neurological disorders, including, as shown below, spinal muscular atrophy. (iPSCs, induced pluripotent stem cells; TF, transcription factor.)

Fibroblasts isolated From related unaffected adult (mother [M])

From affected infant (I)

1. With the introduction of specific gene transcription factors, iPSCs were generated from fibroblast substrates

M I

I I

2. These iPSCs were used to generate patient-specific spinal motor neurons

3. Putative spinal neurons were assayed for motorspecific neurons

M M

ISLET1

HOXB4

OLIG2

SM1-32

4. Cells were tested for reactions to medications; differences were observed VALPROIC ACID

VALPROIC ACID

TOBRAMYCIN

SM1-32

could be used to test the efficacy of various medications before committing to human trials.

Conclusions These data, full of promising implications as they are, need to be treated with some caution. First, the experimental cells are pure populations derived from stem cells. This hardly reflects the physical in vivo situation. The cells and matrix components that normally surround such cells in nature, including skeletal muscle tissues and even other neurons, are not present in these studies. Another objection concerns the fidelity of the conversion process itself. The differentiation pattern seen in various molecular markers hinted that the investigators generated real live spinal motor neurons; however, one cannot a priori say they have in every way created a motor neuron that precisely mimics the real-world situation. These cells may lack many subtle molecular processes—and a few extra, equally subtle interactions—that could easily escape detection, at least by current technologies. Because subtle differences can profoundly influence intracellular molecular interactions, especially when we think about reactions to medications, this is a true concern. The most exciting aspect of these studies comes from what the future holds. A great deal of speculation has gone into thinking about how to tailor medications to individual patients. That certainly is a psychiatric issue . . . I need not talk to this audience about the variable effects of, say, fluoxetine on clinical outcomes. We have visited this topic in past columns. The ability to create patientspecific cellular test beds may go a long way toward solving some of these problems. Indeed, clinics of the future might routinely screen to decide what medications their patients should receive—and in what concentrations. There is much work to do. To date, none has been applied to neurological systems relevant to mental health professionals. Even given the cautions mentioned above, there is no reason why it couldn’t. That’s not bad for having to do with an end-run around a hostile, politically charged issue such as stem cell debates. Would that all ethical issues could be decided so cleanly, or with so much fruit.

M 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. ❒

Treat your patients with the demonstrated efďŹ cacy 1-5 of LEXAPRO In adults with MDD and Generalized Anxiety Disorder (GAD)1 In adolescents aged 12 to 17 with Major Depressive Disorder (MDD)1

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 Lexapro 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. Lexapro is not approved for use in pediatric patients less than 12 years of age. Please see additional Important Safety Information on following pages.

See the effect of LEXAPRO

Proven efﬁcacy in MDD in adolescents aged 12 to 17,* 1-5 and in MDD and GAD in adults

There is no generic available for LEXAPRO

• Signiﬁcantly improved MDD symptoms in adolescents2

Lexapro (escitalopram oxalate) is indicated for the acute and maintenance treatment of major depressive disorder (MDD) in adults and adolescents aged 12-17 years. Lexapro is also indicated for the acute treatment of generalized anxiety disorder (GAD) in adults. *LEXAPRO is indicated as an integral part of a total treatment program for MDD. Drug treatment may not be indicated

IMPORTANT SAFETY INFORMATION (continued) Contraindications • Lexapro is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). There have been reports of serious, sometimes fatal, reactions with some cases resembling neuroleptic malignant syndrome (NMS) and serotonin syndrome. Features 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 SSRI treatment and have been started on an MAOI. Serotonin syndrome was reported for two patients who were concomitantly receiving linezolid, an antibiotic which has MAOI activity. Lexapro should not be used in combination with an MAOI or within 14 days of discontinuing an MAOI. MAOIs should not be initiated within 14 days of discontinuing Lexapro. • Lexapro is contraindicated in patients taking pimozide or with hypersensitivity to escitalopram or citalopram.

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 within the ﬁrst few months of treatment or when changing the dose. Consideration should be given to changing the therapeutic regimen, including discontinuing medication, in patients whose depression is persistently worse, 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. Families and caregivers of patients treated with antidepressants should be alerted about the need to monitor patients daily for the emergence of agitation, irritability, unusual changes in behavior, or the emergence of suicidality, and report such symptoms immediately. Prescriptions for Lexapro should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.

• Signiﬁcantly higher rates of response and remission vs placebo in MDD and GAD in adults4,5

• A major depressive episode may be the initial presentation of bipolar disorder. In patients at risk for bipolar disorder, treating such an episode with an antidepressant alone may increase the likelihood of precipitating a mixed/ manic episode. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder. Lexapro should be used cautiously in patients with a history of mania or seizure disorder. Lexapro is not approved for use in treating bipolar depression. • The concomitant use of Lexapro with other SSRIs, SNRIs, triptans, tryptophan, antipsychotics or other dopamine antagonists is not recommended due to potential development of life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions. Reactions have been reported with SNRIs and SSRIs alone, including Lexapro, but particularly with drugs that impair metabolism of serotonin (including MAOIs). Management of these events should include immediate discontinuation of Lexapro and the concomitant agent and continued monitoring. • Patients should be monitored for adverse reactions when discontinuing treatment with Lexapro. During marketing of Lexapro and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation, including dysphoric mood, irritability, agitation, dizziness, sensory

disturbances (e.g., paresthesias), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania. A gradual dose reduction rather than abrupt cessation is recommended whenever possible. • SSRIs and SNRIs have been associated with clinically signiﬁcant hyponatremia. Elderly patients and patients taking diuretics or who are otherwise volume-depleted appear to be at a greater risk. Discontinuation of Lexapro should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Please see Boxed Warning on ﬁrst page and additional Important Safety Information on next page.

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LEXAPRO: Proven efﬁcacy in MDD in adolescents aged 12 to 17, and in MDD and GAD in adults1-5

Warnings and Precautions (continued) • SSRIs (including Lexapro) and SNRIs may increase the risk of bleeding. Patients should be cautioned that concomitant use of aspirin, NSAIDs, warfarin or other anticoagulants may add to the risk. • Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Lexapro does not affect their ability to engage in such activities. • Lexapro should be used with caution in patients with severe renal impairment or with diseases or conditions that alter metabolism or hemodynamic responses. In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of Lexapro in hepatically impaired patients is 10 mg/day. • For pregnant or nursing mothers, Lexapro should be used only if the potential beneﬁt justiﬁes the potential risk to the fetus or child.

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LEXAPRO® (escitalopram oxalate) TABLETS/ORAL SOLUTION Brief Summary: For complete details, please see full Prescribing Information for Lexapro.

Rx Only

WARNINGS: 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 Lexapro 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. Lexapro is not approved for use in pediatric patients less than 12 years of age. [See Warnings and Precautions: Clinical Worsening and Suicide Risk, Patient Counseling Information: Information for Patients, and Used in Specific Populations: Pediatric Use]. INDICATIONS AND USAGE: Major Depressive Disorder-Lexapro (escitalopram) is indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age [see Clinical Studies]. A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. Generalized Anxiety Disorder-Lexapro is indicated for the acute treatment of Generalized Anxiety Disorder (GAD) in adults [see Clinical Studies]. Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance. CONTRAINDICATIONS: Monoamine oxidase inhibitors (MAOIs)-Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated [see Warnings and Precautions]. Pimozide-Concomitant use in patients taking pimozide is contraindicated [see Drug Interactions]. Hypersensitivity to escitalopram or citalopram-Lexapro is contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in Lexapro. 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. 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 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 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.

Age Range

<18 18-24 25-64 65

Adverse Reactions • In clinical trials of MDD, the most common adverse reactions in adults treated with Lexapro (approximately 5% or greater and at least twice the incidence of placebo) were nausea (15% vs 7%), insomnia (9% vs 4%), ejaculation disorder (9% vs <1%), fatigue (5% vs 2%), somnolence (6% vs 2%), and increased sweating (5% vs 2%). In pediatric patients, the overall proﬁle of adverse reactions was similar to that seen in adults; however, the following additional adverse reactions were reported at an incidence of at least 2% for Lexapro and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion. • In clinical trials of GAD, the most common adverse reactions in adults treated with Lexapro (approximately 5% or greater and at least twice the incidence of placebo) were nausea (18% vs 8%), ejaculation disorder (14% vs 2%), insomnia (12% vs 6%), fatigue (8% vs 2%), decreased libido (7% vs 2%) and anorgasmia (6% vs <1%). Please see accompanying brief summary of Prescribing Information for LEXAPRO, including Boxed Warning. References: 1. LEXAPRO [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2009. 2. Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S. Escitalopram in the treatment of adolescent depression: a randomized placebo-controlled multisite trial. J Am Acad Child Adolesc Psychiatry. 2009;48:721-729. 3. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry. 2002;63:331-336. 4. Davidson JRT, Bose A, Korotzer A, Zheng H. Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, ﬂexible dose study. Depress Anxiety. 2004;19:234-240. 5. Wade A, Lemming OM, Hedegaard KB. Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol. 2002;17:95-102.

TABLE 1 Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo 14 additional cases 5 additional cases Decreases Compared to Placebo 1 fewer case 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 anti-depressants can delay the recurrence of depression. All patients being treated with anti-depressants 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 Dosage and Administration]. 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 [see also Patient Counseling Information]. Prescriptions for Lexapro 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 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 Lexapro is not approved for use in treating bipolar depression. 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 Lexapro 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 Lexapro with MAOIs intended to treat depression is contraindicated. If concomitant treatment of Lexapro 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 Lexapro with

serotonin precursors (such as tryptophan) is not recommended. Treatment with Lexapro 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. Discontinuation of Treatment with Lexapro-During marketing of Lexapro and 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, and hypomania. 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 Lexapro. 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]. Seizures-Although anticonvulsant effects of racemic citalopram have been observed in animal studies, Lexapro has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product’s premarketing testing. In clinical trials of Lexapro, cases of convulsion have been reported in association with Lexapro treatment. Like other drugs effective in the treatment of major depressive disorder, Lexapro should be introduced with care in patients with a history of seizure disorder. Activation of Mania/Hypomania-In placebo-controlled trials of Lexapro in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with Lexapro and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with Lexapro treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Lexapro should be used cautiously in patients with a history of mania. Hyponatremia-Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Lexapro. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when Lexapro was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. 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 Geriatric Use]. Discontinuation of Lexapro 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. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding-SSRIs and SNRIs, including Lexapro, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the 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 SSRIs and SNRIs 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 Lexapro and NSAIDs, aspirin, or other drugs that affect coagulation. Interference with Cognitive and Motor Performance-In a study in normal volunteers, Lexapro 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Lexapro therapy does not affect their ability to engage in such activities. Use in Patients with Concomitant Illness-Clinical experience with Lexapro in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using Lexapro in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Lexapro has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing. In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of Lexapro in hepatically impaired patients is 10 mg/day [see Dosage and Administration]. Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Lexapro, however, it should be used with caution in such patients [see Dosage and Administration]. Potential for Interaction with Monoamine Oxidase InhibitorsIn patients receiving serotonin reuptake inhibitor drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including 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 SSRI treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of SSRIs and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that Lexapro should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping Lexapro before starting an MAOI. Serotonin syndrome has been reported in two patients who were concomitantly receiving linezolid, an antibiotic which is a reversible non-selective MAOI. ADVERSE REACTIONS: Clinical Trials Experience-Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Clinical Trial Data Sources; Pediatrics (6 -17 years)-Adverse events were collected in 576 pediatric patients (286 Lexapro, 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectiveness of Lexapro in pediatric patients less than 12 years of age has not been established. Adults-Adverse events information for Lexapro was collected from 715 patients with major depressive disorder who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to escitalopram in open-label trials. The adverse event information for Lexapro in patients with GAD was collected from 429 patients exposed to escitalopram and from 427 patients exposed to placebo in double-blind, placebo-controlled trials. Adverse events during exposure were obtained primarily by general inquiry and recorded by 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 events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Events Associated with Discontinuation of Treatment; Major Depressive Disorder; Pediatrics (6 -17 years)-Adverse events were associated with discontinuation of 3.5% of 286 patients receiving Lexapro and 1% of 290 patients receiving placebo. The most common adverse event (incidence at least 1% for Lexapro and greater than placebo) associated with discontinuation was insomnia (1% Lexapro, 0% placebo). Adults-Among the 715 depressed patients who received Lexapro in placebocontrolled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving 10 mg/day Lexapro was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day Lexapro was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day Lexapro (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with Lexapro, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients). Generalized Anxiety Disorder; Adults-Among the 429 GAD patients who received Lexapro 10-20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with Lexapro, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%). Incidence of Adverse Reactions in Placebo-Controlled Clinical Trials; Major Depressive Disorder; Pediatrics (6 -17 years)-The overall profile of adverse reactions in pediatric patients was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading) were reported at an incidence of at least 2% for Lexapro and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion. Adults-The most commonly observed adverse reactions in Lexapro patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence. Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received Lexapro at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with Lexapro and for which the incidence in patients treated with Lexapro was greater than the incidence in placebo-treated patients. TABLE 2 Treatment-Emergent Adverse Reactions Observed with a Frequency of ≥ 2% and Greater Than Placebo for Major Depressive Disorder Adverse Reaction Autonomic Nervous System Disorders Dry Mouth Sweating Increased Central & Peripheral Nervous System Disorders Dizziness Gastrointestinal Disorders Nausea Diarrhea Constipation Indigestion Abdominal Pain General Influenza-like Symptoms Fatigue Psychiatric Disorders Insomnia Somnolence Appetite Decreased Libido Decreased Respiratory System Disorders Rhinitis Sinusitis Urogenital Ejaculation Disorder1,2 Impotence2 Anorgasmia3

Lexapro (N=715)

Placebo (N=592)

6% 5%

5% 2%

15% 8% 3% 3% 2%

7% 5% 1% 1% 1%

5% 5%

4% 2%

9% 6% 3% 3%

4% 2% 1% 1%

5% 3%

4% 2%

9% 3% 2%

<1% <1% <1%

1Primarily ejaculatory delay. 2Denominator used was for males only (N=225 Lexapro; N=188 placebo). 3Denominator used was for females only (N=490 Lexapro; N=404 placebo).

Generalized Anxiety Disorder; Adults-The most commonly observed adverse reactions in Lexapro patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia. Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse events that occurred among 429 GAD patients who received Lexapro 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with Lexapro and for which the incidence in patients treated with Lexapro was greater than the incidence in placebo-treated patients. TABLE 3 Treatment-Emergent Adverse Reactions Observed with a Frequency of ≥ 2% and Greater Than Placebo for Generalized Anxiety Disorder Adverse Reactions Autonomic Nervous System Disorders Dry Mouth Sweating Increased Central & Peripheral Nervous System Disorders Headache Paresthesia Gastrointestinal Disorders Nausea Diarrhea Constipation Indigestion Vomiting Abdominal Pain Flatulence Toothache General Fatigue Influenza-like Symptoms Musculoskeletal System Disorder Neck/Shoulder Pain Psychiatric Disorders Somnolence Insomnia Libido Decreased Dreaming Abnormal Appetite Decreased Lethargy Respiratory System Disorders Yawning Urogenital Ejaculation Disorder1,2 Anorgasmia3 Menstrual Disorder

Lexapro (N=429)

Placebo (N=427)

9% 4%

5% 1%

24% 2%

17% 1%

18% 8% 5% 3% 3% 2% 2% 2%

8% 6% 4% 2% 1% 1% 1% 0%

8% 5%

2% 4%

13% 12% 7% 3% 3% 3%

7% 6% 2% 2% 1% 1%

14% 6% 2%

2% <1% 1%

1Primarily ejaculatory delay. 2Denominator used was for males only (N=182 Lexapro; N=195 placebo). 3Denominator used was for females only (N=247 Lexapro; N=232 placebo).

Dose Dependency of Adverse Reactions-The potential dose dependency of common adverse reactions (defined as an incidence rate of ≥5% in either the 10 mg or 20 mg Lexapro groups) was examined on the basis of the combined incidence of adverse events in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg Lexapro-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day Lexapro-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day Lexapro group with an incidence that was approximately twice that of the 10 mg/day Lexapro group and approximately twice that of the placebo group. TABLE 4 Incidence of Common Adverse Reactions in Patients with Major Depressive Disorder Adverse Reaction Placebo 10 mg/day 20 mg/day (N=311) Lexapro Lexapro (N=310) (N=125) Insomnia 4% 7% 14% Diarrhea 5% 6% 14% Dry Mouth 3% 4% 9% Somnolence 1% 4% 9% Dizziness 2% 4% 7% Sweating Increased <1% 3% 8% Constipation 1% 3% 6% Fatigue 2% 2% 6% Indigestion 1% 2% 6% Male and Female Sexual Dysfunction with SSRIs-Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. TABLE 5 Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials Adverse Event Lexapro Placebo In Males Only (N=407) (N=383) Ejaculation Disorder (primarily ejaculatory delay) 12% 1% Libido Decreased 6% 2% Impotence 2% <1% In Females Only (N=737) (N=636) Libido Decreased 3% 1% Anorgasmia 3% <1% There are no adequately designed studies examining sexual dysfunction with escitalopram treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Vital Sign ChangesLexapro and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with Lexapro treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving Lexapro indicated that Lexapro treatment is not associated with orthostatic changes. Weight Changes-Patients treated with Lexapro in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight. Laboratory Changes-Lexapro and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Lexapro treatment. ECG Changes-Electrocardiograms from Lexapro (N=625), racemic citalopram (N=351), and placebo (N=527) groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed (1) a decrease in heart rate of 2.2 bpm for Lexapro and 2.7 bpm for racemic citalopram, compared to an increase of 0.3 bpm for placebo and (2) an increase in QTc interval of 3.9 msec for Lexapro and 3.7 msec for racemic citalopram, compared to 0.5 msec for placebo. Neither Lexapro nor racemic citalopram were associated with the development of clinically significant ECG abnormalities. Other Reactions Observed During the Premarketing Evaluation of Lexapro-Following is a list of treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with Lexapro for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those events already listed in Tables 2 & 3, those events for which a drug cause was remote and at a rate less than 1% or lower than placebo, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Events are categorized by body system. Events of major clinical importance are described in the Warnings and Precautions section. Cardiovascular - hypertension, palpitation. Central and Peripheral Nervous System Disorders - light-headed feeling, migraine. Gastrointestinal Disorders - abdominal cramp, heartburn, gastroenteritis. General - allergy, chest pain, fever, hot flushes, pain in limb. Metabolic and Nutritional Disorders - increased weight. Musculoskeletal System Disorders - arthralgia, myalgia jaw stiffness. Psychiatric Disorders - appetite increased, concentration impaired, irritability. Reproductive Disorders/Female - menstrual cramps, menstrual disorder. Respiratory System Disorders - bronchitis, coughing, nasal congestion, sinus congestion, sinus headache. Skin and Appendages Disorders - rash. Special Senses - vision blurred, tinnitus. Urinary System Disorders - urinary frequency, urinary tract infection. Post-Marketing Experience; Adverse Reactions Reported Subsequent to the Marketing of Escitalopram-The following additional adverse reactions have been identified from spontaneous reports of escitalopram received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to escitalopram and have not been listed elsewhere in labeling. However, because these adverse reactions were 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. These events include: Blood and Lymphatic System Disorders: anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia. Cardiac Disorders: atrial fibrillation, bradycardia, cardiac failure, myocardial infarction, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular tachycardia. Ear and Labyrinth Disorders: vertigo Endocrine Disorders: diabetes mellitus, hyperprolactinemia, SIADH. Eye Disorders: diplopia, glaucoma, mydriasis, visual disturbance. Gastrointestinal Disorders: dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage. General Disorders and Administration Site Conditions: abnormal gait, asthenia, edema, fall, feeling abnormal, malaise. Hepatobiliary Disorders: fulminant hepatitis, hepatic failure, hepatic necrosis, hepatitis. Immune System Disorders: allergic reaction, anaphylaxis. Investigations: bilirubin increased, decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin decreased. Metabolism and Nutrition Disorders: hyperglycemia, hypoglycemia, hypokalemia, hyponatremia. Musculoskeletal and Connective Tissue Disorders: muscle cramp, muscle stiffness, muscle weakness, rhabdomyolysis. Nervous System Disorders: akathisia, amnesia, ataxia, choreoathetosis, cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions), hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardive dyskinesia, tremor. Pregnancy, Puerperium and Perinatal Conditions: spontaneous abortion. Psychiatric Disorders: acute psychosis, aggression, agitation, anger, anxiety, apathy, completed suicide, confusion, depersonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual and auditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughts of self-harm, suicide attempt, suicidal ideation, suicidal tendency. Renal and Urinary Disorders: acute renal failure, dysuria, urinary retention. Reproductive System and Breast Disorders: menorrhagia, priapism. Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, pulmonary embolism, pulmonary hypertension of the newborn. Skin and Subcutaneous Tissue Disorders: alopecia, angioedema, dermatitis, ecchymosis, erythema multiforme, photosensitivity reaction, Stevens Johnson Syndrome, toxic epidermal necrolysis, urticaria. Vascular Disorders: deep vein thrombosis, flushing, hypertensive crisis, hypotension, orthostatic hypotension, phlebitis, thrombosis. DRUG INTERACTIONS: Serotonergic Drugs-Based on the mechanism of action of SNRIs and SSRIs including Lexapro, and the potential for serotonin syndrome, caution is advised when Lexapro is coadministered 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 [see Warnings and Precautions]. The concomitant use of Lexapro with other SSRIs, SNRIs or tryptophan is not recommended. Triptans-There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Lexapro with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions]. CNS Drugs- Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs. Alcohol-Although Lexapro did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking Lexapro is not recommended. Monoamine Oxidase Inhibitors (MAOIs)-[see Contraindications and Warnings and Precautions]. Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)-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 the 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 Lexapro is initiated or discontinued. Cimetidine-In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown. Digoxin-In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin. Lithium-Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised when Lexapro and lithium are coadministered. Pimozide and Celexa-In a controlled study, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known. Sumatriptan-There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised. Theophylline-Combined administration of racemic citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not

evaluated. Warfarin-Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown. Carbamazepine-Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered. Triazolam-Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam. KetoconazoleCombined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. Ritonavir-Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram. CYP3A4 and -2C19 Inhibitors-In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram. Because escitalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance. Drugs Metabolized by Cytochrome P4502D6-In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6. Metoprolol-Administration of 20 mg/day Lexapro for 21 days in healthy volunteers resulted in a 50% increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of Lexapro and metoprolol had no clinically significant effects on blood pressure or heart rate. Electroconvulsive Therapy (ECT)-There are no clinical studies of the combined use of ECT and escitalopram. USE IN SPECIFIC POPULATIONS: Pregnancy; Pregnancy Category C-In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately ≥ 56 times the maximum recommended human dose [MRHD] of 20 mg/day on a body surface area [mg/m2] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 28 times the MRHD on a mg/m2 basis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/m2 basis). When female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/m2 basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was also seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD on a mg/m2 basis. In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. In two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit. When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose. The no-effect dose was 12.8 mg/kg/day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day. A no-effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy-Nonteratogenic Effects-Neonates exposed to Lexapro and other SSRIs or 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]. Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective, case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with Lexapro during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment [see Dosage and Administration]. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Labor and Delivery-The effect of Lexapro on labor and delivery in humans is unknown. Nursing Mothers-Escitalopram is excreted in human breast milk. Limited data from women taking 10-20 mg escitalopram showed that exclusively breast-fed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weightadjusted dose of desmethylcitalopram. There were two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a racemic citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of racemic citalopram by its mother and, in the second case, no follow-up information was available. Caution should be exercised and breastfeeding infants should be observed for adverse reactions when Lexapro is administered to a nursing woman. Pediatric Use-Safety and effectiveness of Lexapro has not been established in pediatric patients (less than 12 years of age) with Major Depressive Disorder. Safety and effectiveness of Lexapro has been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder [see Clinical Studies]. Although maintenance efficacy in adolescent patients with Major Depressive Disorder has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients. Safety and effectiveness of Lexapro has not been established in pediatric patients less than 18 years of age with Generalized Anxiety Disorder. Geriatric UseApproximately 6% of the 1144 patients receiving escitalopram in controlled trials of Lexapro in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of Lexapro between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of Lexapro cannot be ruled out. SSRIs and SNRIs, including Lexapro, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Hyponatremia]. In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and Cmax was unchanged [see Clinical Pharmacology]. 10 mg/day is the recommended dose for elderly patients [see Dosage and Administration]. Of 4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. 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 again, greater sensitivity of some elderly individuals cannot be ruled out. DRUG ABUSE AND DEPENDENCE: Abuse and Dependence; Physical and Psychological Dependence-Animal studies suggest that the abuse liability of racemic citalopram is low. Lexapro has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with Lexapro did not reveal any drug-seeking behavior. However, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate Lexapro patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior). OVERDOSAGE: Human Experience-In clinical trials of escitalopram, there were reports of escitalopram overdose, including overdoses of up to 600 mg, with no associated fatalities. During the postmarketing evaluation of escitalopram, Lexapro overdoses involving overdoses of over 1000 mg have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of escitalopram has been rarely reported. Symptoms most often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Management of Overdose-Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Lexapro. In managing overdosage, 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.

Rev. 05/09

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

Severe State and Federal Funding Shortfalls Likely for Local Mental Health Programs A political tsunami threatens access to mental health care for individuals who depend on community programs. States are axing Medicaid recipients and/or reducing Medicaid

APRIL 2011

WASHINGTON REPORT funding to community mental health centers. Meanwhile, Republicans in Congress are intent on budget cuts that would make major reductions to the federal mental health block grant that supplements state programs beyond state Medicaid funding. Chuck Ingoglia, MSW, vice president, public policy, National Council for Community Behavioral Healthcare, explained that Medicaid funds 50% of outpatient mental health care provided in total—in lo-

cal, state, federal, and private-pay programs—in the United States. In Arizona, for example, Governor Janice Brewer has announced that she will eliminate 280,000 Medicaid recipients from the program. Perhaps 140,000 of those adults and children are receiving some form of out-patient psychiatric care. Other Medicaid recipients around the country have been and will be losing access to psychiatrists and other mental health providers be-

by Stephen Barlas cause of state Medicaid funding cuts occasioned by the lingering results of the 2008-2009 recession. On February 16, 2011, Kevin Martone, deputy commissioner of the New Jersey division of mental health and addiction services, keynoted a congressional staff briefing in Washington. He noted that states have been forced to cut mental health agency budgets

Book Review We’ve Got Issues: Children and Parents in the Age of Medication We invite you to listen to succinct discussions on www.psychiatrictimes.com. Suicide Risk Assessment Since suicide is almost impossible to predict, why is it that a psychiatrist could be held liable for a bad outcome? Have any suicide assessment forms been validated in the prediction of suicide risk? Is it risky for a psychiatrist to accept a patient’s denial of suicidal ideas at face value? Forensic psychiatrist Phillip Resnick addresses these 3 questions in the first in his podcast series.

Special Report Chair Discusses Suicide Dr Eric Caine discusses the things physicians need to know about suicide, including the myths that surround it, who is at increased risk, and prevention strategies.

Second-Generation Antipsychotics and Schizophrenia Dr David Osser focuses on a meta-analysis of the relative magnitude and risk of QT prolongation posed by several agents in this class in patients with schizophrenia.

Antidepressants for Acute Treatment of Bipolar Disorder Dr Ronald Pies discusses a meta-analysis that sheds new light on the safety and efficacy of antidepressants in the acute treatment of bipolar disorder.

www.PsychiatricTimes.com/podcasts

by Judith Warner; New York: Penguin Group; 2010 336 pages • $25.95 (hardcover)

Reviewed by Gabrielle A. Carlson, MD For those of us who treat seriously emotionally disturbed children, We’ve Got Issues is a welcome change from the invectives of those who believe that the use psychotropic medication is virtually criminal. Ms Warner began with that supposition—and when she dug deeper into the matter, she found that most parents and doctors do the best they can for children whose psychological problems are anything but trivial. “Issues” is a clever word. I had first heard the term from the mother of a boy with high-functioning autism. She called his explosive meltdowns “issues.” I thought, “What kind of euphemism is that?” It is a nice disguise, though, for the many behavioral difficulties parents face with their children when they don’t want to use a more stigmatizing label. Ms Warner turns out to have other “issues” too. Her first was finding that much of the ambient information that depicts doctors as “drugging and pathologizing kids,” “profit-mad scientists” and parents who are looking for a quick fix comes from uninformed and oversimplified “public opinion and most media treatment.” Hunkering down with well-referenced research, she fills her chapters with “observation, scores of interviews with mental health experts, critical thinking and, above all, the compassion gained from talking to dozens and dozens of the parents who stare at the whole ‘issue’ of children’s mental health.”

Ms Warner then returns to a discussion of how public understanding of children’s mental health treatment has gone wrong. Among other things, the author recognizes that “kids with serious problems are no longer routinely institutionalized . . . they’re kept functioning with medication,” and there are real risks in not being properly treated. She debunks what she calls the MedScare—the “now common conviction that psychiatric drugs are being used to control and denature normal and healthy children and adults who don’t conform to society’s expectations.” Ms Warner says “Industry/BigPharma” has corrupted medicine and psychiatry. However, her understanding of how drugs are studied is naive, and her notion of “conflicts of interest” is limited only to financial ones. Like many in the public sector, she doesn’t recognize that more is broken than overzealous marketing. She fails to realize that if there were no connection between academic clinicians and pharmaceutical companies, drug development would be seriously compromised. Any practicing child psychiatrist can get behind the book’s most serious concern that “science has outpaced our capacity to use it well. Progress has been betrayed by commercial interests, political complaisance, and a lack of policy directed at making sure that new scientific advances are safely . . . made available to . . . the public.” While Ms Warner tends to be redundant and oversimplifies matters—and diehard opponents of the practice of mental health medicalization will not be persuaded—worried parents and caring doctors have an articulate champion in their corner. Dr Carlson is professor of psychiatry and pediatrics and director of child and adolescent psychiatry at Stony Brook University School of Medicine in New York. ❒

APRIL 2011

by a combined total of nearly $2.2 billion over the past 3 fiscal years. “Many states have been forced to reduce funding for a wide array of community-based interventions, including crisis services, targeted case management, prescription medications, and outpatient clinics,” he said. “These services are at the heart of every public mental health system in the country.” Martone was in Washington to help build congressional support for President Obama’s proposed fiscal 2012 budget for the Substance Abuse and Mental Health Services Administration (SAMHSA), which, next to Medicaid, is the second largest federal source of mental health funding. SAMHSA’s main contribution in that regard is its community mental health block grant program. That money is distributed to states on a formula basis, and the states then divvy their portion up among their cities and counties. In fiscal 2012, beginning October 1, 2011, an increase from $420.8 million in fiscal 2011 to $434.7 million is proposed. Congress, however, has not yet approved a fiscal 2011 budget. It has been passing a series of continuing resolutions that have kept all federal 2011 budgets at 2010 levels. For the mental health block grant program, that is $420.8 million—the same level Obama has proposed for 2011. Congress has delayed passing a 2011 budget because Republicans want to make reductions across the board in discretionary programs totaling $61 billion below 2010 levels. In the Continuing Resolution (H.R. 1) the House passed by a vote of 235 to 189 on February 19, 2011, the SAMHSA budget for fiscal 2011 was cut by $200 million below the 2010 budget of $3.43 billion. There was an additional cut of $2.9 million for mental health programs of regional and national significance, a catchall category that funds a variety of local mental health programs. H.R. 1 did not prescribe how SAMHSA should apportion that $200 million in cuts. But mental health lobbyists believe that most, if not all, of that $200 million would be cut from the mental health ($420 million) and substance abuse ($1.45 billion) block grants, probably proportionally. Two things seem certain at this point. When Congress finally passes a 2011 budget for SAMHSA, there will be a significant cut in mental health block grants below 2010 levels. James K. Finley, senior associate government relations, National Association of Social Workers, explained, “The cuts under discussion now would certainly impact

PSYCHIATRIC TIMES

WASHINGTON REPORT SAMHSA activities. If H.R. 1 is ultimately passed, SAMHSA would take a 7% overall cut since last year. There is no chance that Obama’s SAMHSA budget request for ’12 will be enacted.” So the $14 million increase to the $420 million Obama proposed for fiscal 2012 is dead. The only question is whether Congress will cut the mental health block grant again, in 2012—and by how much. Ingoglia explained that Sen Debbie Stabenow (D-Mich)

planned to lead an effort in the Senate to ward off severe cuts to the mental health block grant program. He noted, however, that given the political pressure to cut the federal budget deficit, the debate over SAMHSA spending and spending for other discretionary programs— whether those be food stamps or home heating subsidies for the poor—will “not be about if we cut, it will be about how much we cut, and both Republicans and Democrats

will support some level of reductions in these programs.” Very doubtful, too, is funding for the new $90 million program for state mental health prevention grants the President proposed for 2012. According to Ingoglia, that initiative is meant to run parallel to the Accountable Care Act’s (that was the controversial health care reform bill passed in 2010) programs dedicated to upgrading primary care prevention services. ❒

November 7-10, 2011 ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ/ iÊ6i iÌ > Ê >ÃÊ6i}>ÃÊ Ìi ÊUÊ >ÃÊ6i}>Ã]Ê 6

CME LLC Announces Charles Raison, MD as the Program Chair of 2011 Psych Congress “We plan to make this year’s program a collective process through community development in order to best teach each other using our shared knowledge and wisdom to establish better practices in this wonderful profession of ours.

CME LLC’s goal is to provide an optimal educational experience. One of the key aspects is focusing on the endeavor of how we can more involve providers who are going to come to the conference not just as a listener or a learner, but also as a participant.” Charles Raison, MD* 2011 Psych Congress Chair

“I’m very excited about this year’s Psych Congress and I really think we’re going to knock this one out of the park.” Charles Raison, MD* 2011 Psych Congress Chair

For more information about Dr. Raison, the Steering Committee, and to register with special Early Bird discounts, please visit:

PsychCongress.com or call (800) 447-4474. * Dr. Raison is paid by CME LLC to chair Psych Congress. The opinions expressed are those of Dr. Raison and do not necessarily reﬂect the views of Emory University or Emory Healthcare. Dr. Raison’s participation in this activity does not constitute or imply endorsement by Emory University or Emory Healthcare.

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CATEGORY SPONSORED BY CME LLC • PSYCHIATRIC TIMES • APRIL 2011

Cardiometabolic Risks of Antidepressant and Antipsychotic Drugs, Part 1

Proarrhythmic Risks of Antidepressant and Antipsychotic Drugs Understanding QTc Interval Prolongation, Polymorphic Ventricular Tachycardia, and Its Subtype Torsade de Pointes

by W. Victor R. Vieweg, MD, Mehrul Hasnain, MD, Mark A. Wood, MD, Antony Fernandez, MD, Edward J. Lesnefsky, MD, and Ananda K. Pandurangi, MD

epression will soon join coronary artery disease (CAD) to become 1 of the 2 leading causes of disability in developed countries.1 In the United States, morbidity and mortality from CAD is decreasing while the prevalence and burden of depression are increasing. In contrast, both the prevalence of and mortality associated with schizophrenia have remained stable over the past several decades.2 Thus, psychiatrists continue to face the daunting task of improving the mental health of the many persons suffering from depression or schizophrenia. Although the literature is somewhat mixed,

CREDITS: 1.5

they must do this in the face of emerging evidence that suggests that cardiometabolic toxicity is associated with the use of antidepressant and antipsychotic drugs. In this first of 2 articles on the cardiometabolic risks of antidepressant and antipsychotic drugs, we address their proarrhythmic adverse effects and focus on the role of the corrected QT interval (QTc) prolongation as a marker of such effects. In the next article, to be published in the May 2011 issue of Psychiatric Times, we will discuss the metabolic risks associated with these psychotropic agents.

ACCREDITATION STATEMENT

RELEASE DATE: April 20, 2011

This activity has been independently reviewed for balance.

EXPIRATION DATE: April 20, 2012

TARGET AUDIENCE

FACULTY

This continuing medical education activity is intended for

W. Victor R. Vieweg, MD

psychiatrists, psychologists, primary care physicians, nurse

Clinical Professor, Departments of Psychiatry and Internal

practitioners, and other health care professionals who seek

Medicine, Virginia Commonwealth University School of

to improve their care for patients requiring treatment with

Medicine, Richmond

antidepressant and antipsychotic drugs.

Mehrul Hasnain, MD

GOAL STATEMENT

Clinical Associate Professor, Department of Psychiatry,

This activity will provide participants with an understanding

Memorial University of Newfoundland, Wateford Hospital,

of the life-threatening proarrhythmic risks associated with

St John’s, Newfoundland

antidepressant and antipsychotic drug administration and how to monitor and protect patients from these risks.

Mark A. Wood, MD Professor, Department of Internal Medicine, Virginia

ESTIMATED TIME TO COMPLETE

Commonwealth University School of Medicine, Richmond

The activity in its entirety should take approximately 90 minutes to complete.

Antony Fernandez, MD

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of CME LLC and Psychiatric Times. CME LLC is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION CME LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLAIMER The opinions and recommendations expressed by faculty and other experts whose input is included in this activity are their own and do not necessarily reflect the views of the sponsors or supporter. Discussions concerning drugs,

Professor, Department of Psychiatry, Virginia

LEARNING OBJECTIVES

dosages, and procedures may reflect the clinical experience

Commonwealth University School of Medicine, Staff

After completing this activity, participants should be able to:

of the faculty or may be derived from the professional

Psychiatrist, Hunter Holmes McGuire Veterans Affairs

•

Identify the proarrhythmic risks associated with

literature or other sources and may suggest uses that are

antidepressant and antipsychotic medications

investigational in nature and not approved labeling or

Understand the underlying causes for these

indications. Activity participants are encouraged to refer to

proarrhythmic risks

primary references or full prescribing information resources.

Medical Center, Richmond •

Edward J. Lesnefsky, MD Professor, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Chief of Cardiology, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond

•

Monitor their patients for adverse proarrhythmic effects associated with antidepressant and antipsychotic drugs

METHOD OF PARTICIPATION Participants are required to read the entire article and to complete the posttest and evaluation to earn a certificate

Ananda K. Pandurangi, MD

COMPLIANCE STATEMENT

of completion. A passing score of 80% or better earns the

Professor, Department of Psychiatry, Virginia

This activity is an independent educational activity under

participant 1.5 AMA PRA Category 1 Credits™. A fee of

Commonwealth University School of Medicine, Richmond

the direction of CME LLC. The activity was planned and

$15 will be charged. Participants are allowed 2 attempts

implemented in accordance with the Essential Areas and

to successfully complete the activity.

FACULTY DISCLOSURES Drs Vieweg, Hasnain, Wood, Fernandez, and Lesnefsky have no relationships to disclose relating to the subject matter of this article. Dr Pandurangi reports that she is a consultant for Prophase Inc and principal investigator for Eli Lilly & Co.

policies of the ACCME, the Ethical Opinions/Guidelines of the AMA, the FDA, the OIG, and the PhRMA Code on