Psychiatric Times January 2011 Vol XXVIII, No 1 by UBM Medica

Molecules of the Mind

The Neurobiology of Conscious Intent

A UBM Medica Publication®

Special Report Suicide, Part 1

Category 1 CME Atypical Depression

January 2011 • Vol. XXVIII, No. 1

www.PsychiatricTimes.com

NIMH Shifts Focus to Molecular Origins of Mental Illness by Arline Kaplan

and director of research at the Western Psychiatric Institute and Clinic, Pittsburgh, and John March, MD, MPH, director of the Division of Neurosciences Medicine at Duke Clinical Research Institute, Durham, NC. Recently, the workgroup published a report, From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illness.1 March describes it as a “policy infrastructure document” that builds on an earlier council report on transformative neurodevelopmental research in mental illness.2 In the new report, the workgroup makes several observations—that mental illnesses are brain disorders and that virtually all of them are developmental disorders; that nearly all drugs approved for mental illness have been incremental changes of compounds available 4 decades ago; that the NIMH’s practical trials, such as Clinical Antipsychotic Trials of Interventions Effectiveness (CATIE), have documented the limited effectiveness of current medications; that the NIMH receives relatively few applications proposing to translate basic findings into the development of novel interventions; and that several major phar-

o accelerate the development of personalized and preemptive treatments for those living with mental illness, the NIMH is shifting away from current-generation treatments and toward preclinical drug development and early-phase clinical pharmacology, according to the institute’s director and a workgroup co-chair. In a recent blog, Thomas Insel, MD, NIMH director, explained: “For existing treatments, we want to shift from trials studying group differences or adapting these treatments to yet another subpopulation to support trials that identify reliable predictors (eg, biomarkers) of individual response, including who may benefit from and who may experience adverse effects of a particular treatment. We are also searching for preemptive treatments—interventions that can be used early in the course of a disorder to prevent disability.” As the NIMH changes direction, Insel has relied on guidance from the National Mental Health Advisory Council’s Interventions Workgroup, made up of 20 experts from academia, private industry, nonprofit foundations and the NIH. It is co-chaired by David Lewis, MD, medical director

(Please see NIMH, page 2)

Diagnostic Criteria for PIISD: Private Insurance–Induced Stress Disorder by Carol A. Paris, MD he essential feature of private insurance–induced stress disorder (PIISD) is the development of characteristic symptoms following exposure to an insurance-induced traumatic stressor involving direct personal experience of an event or witnessing an event that threatens another person. Traumatic events include, but are not limited to, recission of health insurance after developing a costly illness; denial of health insurance because of a preexisting condition, such as being female and fertile; or delay of needed treatment or medication secondary to requirements for pre-authorization. In the case of physicians, traumatic events include witness-

ing the deterioration of patients from financial ruin resulting from uncovered costs of care. Similar to some forms of PTSD, this disorder is prone to be severe because the stressor is of human/ corporate design. Note: this diagnosis is not currently reimbursed by the health insurance companies. Diagnostic criteria for PIISD include a history of exposure to a traumatic insurance-induced event meeting the following criteria and symptoms: Criterion A. The person has been exposed to a traumatic insuranceinduced event in which both of the following have been present: • The person has experienced a health insurance traumatic event, due ei(Please see PIISD, page 6)

Issue Highlights ECT: The Second Most Controversial Medical Procedure Charles H. Kellner, MD

Psychiatric Assessments and Treatment in Preschool Children Joan L. Luby, MD

Understanding and Overcoming the Myths of Suicide Thomas Joiner, PhD

The Link Between Substance Abuse, Violence, and Suicide Mark Ilgen, PhD and Felicia Kleinberg, MSW COMPLETE CONTENTS, PAGE 8

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

NIMH Continued from page 1

maceutical companies have announced plans to “de-prioritize” psychiatric drug development. The NIMH’s challenge, says Insel, is to develop “far more effective strategies for prevention and treatment in a rational way and to do so with a limited budget.” Financial constraints are a major barrier, according to the workgroup’s report. The cost of bringing 1 neuroscience-specific drug to market has been estimated at $1.8 billion— nearly the entire yearly extramural NIMH budget. So the focus is on how to best use and leverage the funds the NIMH does have.

Target identification The NIMH spends the majority of its resources on discovery and translational neuroscience, but most of this work has yet to produce new novel druggable targets. According to March, however, epigenetic changes, brain circuit activation, intracellular signaling pathways modifications, structural brain changes, neuroplasticity, changes in RNA expression, and proteomic and metabolomic markers all hold great promise for understanding early disease processes and, by extension, may reveal novel treatment targets. For that reason, the report recommends that more money be spent both on the preclinical side and on the early-phase clinical pharmacology side. The hope is that this investment in translational neuroscience can be moved rapidly into interventions that are better for patients, said March, a professor of psychiatry and behavioral sciences at Duke. The NIH has already established a full continuum infrastructure for drug development, according to March. It includes target identification, assays, large-scale screening capacity, medicinal chemistry, animal testing, genetic toxicology, and reproductive toxicology. In addition, phase 1 unit capabilities for pharmacokinetic and pharmacodynamic studies are available through the NIH Rapid Access to Interventional Development (NIH-RAID) Program mechanism. Through its report, the workgroup sought to highlight such NIH resources for researchers as the Molecular Libraries Probe Production Centers Network (MLPCN) and the National Cooperative Drug Discovery and Development Group (NCDDDG) Program. The workgroup also called for increased sharing of resources and data.

J AN UARY 2011

“NIMH could leverage its investment in clinical trials by requiring standard collection of clinical, cognitive and laboratory data that can be integrated across diagnostic groups, across sites and across trials,” the workgroup said. According to March, “NIH is moving as fast as possible toward a model, already in place in physics, in which everything is shared as it happens, including raw data. So for

NIH-funded research, the goal will be to have all of the data up on the Web in these large shared databases.” As an example, March cited the National Database for Autism Research (NDAR), a biomedical informatics system and research data repository developed by the NIH to support and accelerate the advancement of research on autism spectrum disorders (ASD). Recently, NDAR made available the data from more

than 10,000 participants enrolled in ASD studies. The NDAR research portal provides tools to define and standardize data as well as to ensure a collaborative approach and open data access to the whole ASD research community.

Pharma’s involvement Asked about the report’s warnings of decreasing industry investments (Please see NIMH, page 4)

INTUNIV™ (guanfacine) Extended-Release Tablets

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relationship to INTUNIV™ could not be determined because these events may also occur as symptoms in pediatric patients with ADHD: agitation, anxiety, depression, emotional lability, nightmares or interrupted sleep. Twelve percent (12%) of patients receiving INTUNIV™ discontinued from the clinical studies due to adverse events, compared to 4% in the placebo group. The most common adverse reactions leading to discontinuation of INTUNIV™-treated patients from the studies were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: hypotension/decreased blood pressure, headache, and dizziness. In the controlled long term studies (mean duration of approximately 10 months) with a dose range of 1 to 4 mg/day of INTUNIV™, the most common adverse reactions (≥5%) reported during open label treatment were somnolence, headache, fatigue, upper abdominal pain, hypotension/decreased blood pressure, vomiting, dizziness, nausea, weight increased, and irritability. The most frequent adverse reactions leading to discontinuation (≥2%) were somnolence (3%), syncopal events (2%), increased weight (2%), depression (2%), and fatigue (2%). Other adverse reactions leading to discontinuation in the long-term studies (occurring in approximately 1% of patients) included: hypotension/decreased blood pressure, sedation, headache, and lethargy. In long-term open label studies, serious adverse reactions occurring in more than one patient were syncope (2%) and convulsion (0.4%). Adverse reactions that occurred in <5% of patients but ≥2% in open-label, longterm studies that are considered possibly related to INTUNIV™ include: syncopal events, constipation, stomach discomfort, hypertension/ increased blood pressure, decreased appetite, diarrhea, dry mouth, lethargy, and insomnia. Effects on Height, Weight, and Body Mass Index (BMI) Patients taking INTUNIV™ demonstrated similar growth compared to normative data. Patients taking INTUNIV™ had a mean increase in weight of 1 kg (2 lbs) compared to those receiving placebo over a comparative treatment period. Patients receiving INTUNIV™ for at least 12 months in open-label studies gained an average of 8 kg (17 lbs) in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV™. Laboratory Tests In short and long-term studies, no clinically important effects were identified on any laboratory parameters. Effects on Heart Rate and QT Interval The effect of two dose levels of immediaterelease guanfacine (4 mg and 8 mg) on the QT interval was evaluated in a doubleblind, randomized, placebo- and active-controlled, cross-over study in healthy adults. A dose-dependent decrease in heart rate was observed during the first 12 hours, at time of maximal concentrations. The mean change in heart rate was -13 bpm at 4 mg and -22 bpm at 8 mg. An apparent increase in mean QTc was observed for both doses. However, guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs. This finding has no known clinical relevance.

BRIEF SUMMARY: Consult the Full Prescribing Information for complete product information. INDICATIONS AND USAGE INTUNIV™ is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The efficacy of INTUNIV™ was studied for the treatment of ADHD in two controlled clinical trials (8 and 9 weeks in duration) in children and adolescents ages 6-17 who met DSM-IV® criteria for ADHD (see Clinical Studies in Full Prescribing Information). The effectiveness of INTUNIV™ for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials. Maintenance Treatment The effectiveness of INTUNIV™ for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials. Therefore the physician electing to use INTUNIV™ for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS Patients with a history of hypersensitivity to INTUNIV™, its inactive ingredients (see Description in Full Prescribing Information), or other products containing guanfacine (e.g. TENEX®) should not take INTUNIV™. WARNINGS AND PRECAUTIONS Hypotension, Bradycardia, and Syncope Treatment with INTUNIV™ can cause decreases in blood pressure and heart rate. In the pediatric, short-term (8-9 weeks), controlled trials, the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse were –5 mm Hg, –3 mm Hg, and –6 bpm, respectively, for all dose groups combined (generally one week after reaching target doses of 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day). These changes were dose dependent. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse event for 6% of the INTUNIV™ group and 4% of the placebo group. Orthostatic hypotension was reported for 1% of the INTUNIV™ group and none in the placebo group. In long-term, open label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric subjects in the clinical program. The majority of these cases occurred in the longterm, open-label studies. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use INTUNIV™ with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use INTUNIV™ with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated. Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies (38% for INTUNIV™ vs. 12% for placebo) in children and adolescents with ADHD, especially during initial use (see Adverse Reactions in Full Prescribing Information). Before using INTUNIV™ with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV™. Advise patients to avoid use with alcohol. Other Guanfacine-Containing Products Guanfacine, the active ingredient in INTUNIV™, is also approved as an antihypertensive. Do not use INTUNIV™ in patients concomitantly taking other guanfacine-containing products (e.g., Tenex). ADVERSE REACTIONS Clinical Trial Experience Two short-term, placebo-controlled, double-blind pivotal studies (Studies 1 and 2) were conducted in children and adolescents with ADHD with a dose range of 1 to 4 mg/day of INTUNIV™. The most commonly reported adverse reactions (occurring in ≥2% of patients) that were considered drug-related and reported in a greater percentage of patients taking INTUNIV™ compared to patients taking placebo were: somnolence, headache, fatigue, upper abdominal pain, nausea, lethargy, dizziness, irritability, hypotension/decreased blood pressure, decreased appetite, dry mouth, and constipation. Less common adverse reactions (<2%) reported in pivotal Studies 1 and 2 that occurred in more than one patient taking INTUNIV™ and were more common than in the placebo group are atrioventricular block, bradycardia, sinus arrhythmia, dyspepsia, asthenia, chest pain, increased alanine aminotransferase, increased blood pressure, increased weight, postural dizziness, increased urinary frequency, enuresis, asthma, orthostatic hypotension, and pallor. In addition, the following less common (<2%) psychiatric disorders occurred in more than one patient receiving INTUNIV™ and were more common than in the placebo group. The

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. There are no adequate and well-controlled studies of guanfacine in pregnant women. This drug should be used during pregnancy only if clearly needed. Nursing Mothers: It is not known whether guanfacine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when INTUNIV™ is administered to a nursing woman. Pediatric Use: The safety and efficacy of INTUNIV™ in pediatric patients less than 6 years of age have not been established. Geriatric Use: The safety and efficacy of INTUNIV™ in geriatric patients have not been established. DRUG ABUSE AND DEPENDENCE INTUNIV™ is not a controlled substance and has no known potential for abuse or dependence. OVERDOSAGE Two cases of accidental overdose of INTUNIV™ were reported in clinical trials in pediatric ADHD patients. These reports included adverse reactions of sedation and bradycardia in one patient and somnolence and dizziness in the other patient. Consult with a Certified Poison Control Center for up to date guidance and advice. Manufactured for Shire US Inc., Wayne, PA 19087. INTUNIV™ is a trademark of Shire LLC. © 2009 Shire Pharmaceuticals Inc. August 2009 513 0207 001 INT-00640 11/09

FOR CHILDREN AND ADOLESCENTS1

ADHD symptoms can manifest at school and at home.1,2

INTUNIV, a nonstimulant treatment for ADHD, may help1

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Indication INTUNIV is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents ages 6 to 17. Efficacy was established in two controlled clinical trials (8 and 9 weeks in duration). The physician electing to use INTUNIV for extended periods should periodically reevaluate its long-term usefulness for the individual patient. INTUNIV 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 INTUNIV should not be used in patients with a history of hypersensitivity to guanfacine or any of its inactive ingredients or by patients taking other products containing guanfacine. Hypotension, bradycardia, and syncope were observed in clinical trials. Use INTUNIV with caution in treating patients who have experienced hypotension, bradycardia, heart block, or syncope, or who may have a condition that predisposes them to syncope; are treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Heart rate and blood pressure should be measured prior to initiation of therapy, following dose increases, and periodically while on therapy. Patients should be advised to avoid becoming dehydrated or overheated. Sedation and somnolence were commonly observed in clinical trials. The potential for additive sedative effects with CNS depressant drugs should be considered. Patients should be cautioned against operating heavy equipment or driving until they know how they respond to INTUNIV. Advise patients to avoid use with alcohol. Common adverse reactions in patients taking INTUNIV that may be dose related over the range of 1 to 4 mg/day include somnolence, sedation, abdominal pain, dizziness, hypotension/decreased blood pressure, dry mouth, and constipation. Please see Brief Summary of Full Prescribing Information on adjacent page. References: 1. INTUNIV [package insert]. Wayne, PA: Shire US Inc; 08/2009. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision. Washington, DC: American Psychiatric Association; 2000.

INTUNIV is a trademark of Shire LLC. 1-800-828-2088 www.intunivpro.com ÂŠ2010 Shire US Inc., Wayne, PA 19087 INT-01102 07/10

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J AN UARY 2011

NIMH

Continued from page 2

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in psychiatric drug discovery and development, March said, “It is not a universal phenomenon, but in general, large pharma has backed away from psychiatry until the probability of success goes up—new mechanisms, new targets, new compounds, biologics that have real promise—then companies will come back in.” So who is doing that work? March responded that it is small pharma and biotech companies, often spin-offs of academic laboratories frequently funded by disease-specific foundations, venture capital, venture philanthropy, and government grants. “It is not as though industry is not involved; it is just restructuring where the effort lies. . . . Like the NIMH, industry is increasingly focused on phase 1 and 2 trials that should identify the next generation of compounds that are going to change lives of mentally ill patients,” he said. March said that industry is being forced by revenue declines from patent expirations, increased regulatory scrutiny, and strained health care budgets to devise new strategies for improving research and development productivity. Those strategies have been outlined in an article by psychiatrist Steven Paul, MD, former president of the Lilly Research Laboratories, who now leads the Helen & Robert Appel Institute for Alzheimer’s Research at Weill Cornell Medical College, New York.3 And despite rhetoric in the press suggesting that industry-academic collaborations by definition are unethical, March said there is clear movement toward what some have called the “new biotech,” a conjunction of academia, industry, and the NIH, dedicated to bringing forth novel drugs or devices to help patients. At Duke, for example, March said his institute is collaborating with industry on phase 1 and 2 trials of innovative treatments for both neurological and psychiatric diseases.

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Bright spots While the challenges ahead are many, March and the workgroup cited some bright spots. Trials are under way with metabotropic glutamate receptor 5 antagonists, which hold promise for those with fragile X syndrome who have intellectual deficits. Also, a new focus on glutamate receptors as a target for antidepressant action has yielded early evidence for rapidly acting anti-

depressants with effects evident in hours rather than weeks. The NIMH will shortly issue a request for proposals entitled “Rapidly Acting Treatments for Treatment-Resistant Depression (RAPID)” with a response date of January 12, 2011. In the area of nonpharmacological treatments, studies of cognitive remediation promise a new approach to the prodrome of schizophrenia based on principles of neuroplasticity. March describes the NIMH’s new direction as “incredibly exciting.” “I have reached a point in my life where I realize that science is like an organism made up of ideas, and those ideas morph and change,” he said. “Those of us who do research are custodians of the organism; we get to feed it, pet it, take care of it, and watch it grow and develop. These Council workgroup reports are part of the care and feeding of the organism that we call the science of mental illness. The workgroup report on transformative developmental neuroscience points the field toward the molecular origins of mental illness in early development; From Discovery to Cure pivots the field toward early-phase clinical pharmacology. Put the 2 together, and it becomes possible for the first time to envision preemptive treatments, a world without mental illness. How wonderful is that?” References 1. From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses. Report of the National Advisory Mental Health Council’s Workgroup. August 2010. http://www.nimh.nih.gov/about/advisory-boardsand-groups/namhc/reports/fromdiscoverytocure. pdf. Accessed December 2, 2010. 2. Transformative Neurodevelopmental Research in Mental Illness: Report of the National Advisory Mental Health Council’s Workgroup. 2008. http://www. nimh.nih.gov/about/advisory-boards-and-groups/ namhc/neurodevelopment_workgroup_report.pdf. Accessed December 2, 2010. 3. Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9:203-214. ❒

Erratum In the December 2010 issue of Psychiatric Times, we listed the wrong chairperson for the Special Report on collaborating with other medical professionals. Hoyle Leigh, MD, was the chairperson. Dr Leigh is professor of psychiatry at the University of California, San Francisco, and director of the Psychosomatic Medicine Program UCSF in Fresno. We apologize to Dr Leigh for the error. ❒

FOR MAJOR DEPRESSIVE DISORDER

Help your patients

on a path forward with proven SNRI therapy It’s not just about starting your adult patients with MDD on therapy; it’s about helping them toward their treatment goals. Patients should be periodically reassessed to determine the need for continued treatment.1

PRISTIQ 50 mg: • SNRI therapy with efficacy proven in 8-week clinical studies • Discontinuation rate due to adverse events comparable to placebo in 8-week clinical studies • One recommended therapeutic dose from the start 1

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

• SSRIs and SNRIs, including PRISTIQ, may increase the risk of bleeding events. Concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants may add to this risk. • Mydriasis has been reported in association with PRISTIQ; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored. • PRISTIQ is not approved for use in bipolar depression. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine the risk of bipolar disorder. • As with all antidepressants, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania, or with a history of seizure disorder. • Caution is advised in administering PRISTIQ to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders. Increases in blood pressure and small increases in heart rate were observed in clinical studies with PRISTIQ. PRISTIQ has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. • Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) cholesterol, and triglycerides were observed in clinical studies. Measurement of serum lipids should be considered during PRISTIQ treatment. • On discontinuation, adverse events, some of which may be serious, have been reported with PRISTIQ and other SSRIs and SNRIs. Abrupt discontinuation of PRISTIQ has been associated with the appearance of new symptoms. Patients should be monitored for symptoms when discontinuing treatment. A gradual reduction in dose rather than abrupt cessation is recommended whenever possible. • The recommended dose in patients with severe renal impairment or end-stage renal disease (ESRD) is 50 mg every other day. The dose should not be escalated in patients with moderate or severe renal impairment or ESRD. • Products containing desvenlafaxine and products containing venlafaxine should not be used concomitantly with PRISTIQ. • Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including PRISTIQ. Discontinuation of PRISTIQ should be considered in patients with symptomatic hyponatremia. • Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of PRISTIQ) therapy have been rarely reported. Adverse Reactions • The most commonly observed adverse reactions in patients taking PRISTIQ vs placebo for MDD in short-term fixed-dose premarketing studies (incidence ≥5% and ≥2x the rate of placebo in the 50-mg dose group) were nausea (22% vs 10%), dizziness (13% vs 5%), hyperhidrosis (10% vs 4%), constipation (9% vs 4%), and decreased appetite (5% vs 2%). Reference: 1. Pristiq® (desvenlafaxine) Prescribing Information, Wyeth Pharmaceuticals Inc.

Please see brief summary of Prescribing Information on adjacent page. For more information on PRISTIQ, please visit www.PristiqHCP.com.

Extended-Release Tablets BRIEF SUMMARY. See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. WARNING: Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Pristiq or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Pristiq is not approved for use in pediatric patients [see Warnings and Precautions (5.1), Use in Specific Populations (8.4), and Patient Counseling Information (17.1 in the full prescribing information)]. INDICATIONS AND USAGE: Pristiq, a selective serotonin and norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder (MDD). CONTRAINDICATIONS: Hypersensitivity-Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the Pristiq formulation. Monoamine Oxidase Inhibitors-Pristiq must not be used concomitantly in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with SNRI or SSRI treatment or with other serotonergic drugs. Based on the half-life of desvenlafaxine, at least 7 days should be allowed after stopping Pristiq before starting an MAOI [see Dosage and Administration (2.5) in the full prescribing information]. WARNINGS AND PRECAUTIONS: Clinical Worsening and Suicide Risk-Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 of the full prescribing information. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.9) and Dosage and Administration (2.3) in the full prescribing information for a description of the risks of discontinuation of Pristiq]. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Pristiq should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening patients for bipolar disorderA major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Pristiq is not approved for use in treating bipolar depression. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions- The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Pristiq treatment, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs that impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Serotonin syndrome in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Pristiq with MAOIs intended to treat depression is contraindicated [see Contraindications (4.2)]. If concomitant treatment of Pristiq with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Pristiq with serotonin precursors (such as tryptophan) is not recommended. Treatment with Pristiq and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated. Elevated Blood Pressure- Patients receiving Pristiq should have regular monitoring of blood pressure since dose-dependent increases were observed in clinical studies. Pre-existing hypertension should be controlled before initiating treatment with Pristiq. Caution should be exercised in treating patients with pre-existing hypertension or other underlying conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with Pristiq. Sustained hypertension- Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving Pristiq, either dose reduction or discontinuation should be considered [see Adverse Reactions (6.1)]. Treatment with Pristiq in controlled studies was associated with sustained hypertension, defined as treatmentemergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for

3 consecutive on-therapy visits. In clinical studies, regarding the proportion of patients with sustained hypertension, the following rates were observed: placebo (0.5%), Pristiq 50 mg (1.3%), Pristiq 100 mg (0.7%), Pristiq 200 mg (1.1%), and Pristiq 400 mg (2.3%). Analyses of patients in Pristiq controlled studies who met criteria for sustained hypertension revealed a dose-dependent increase in the proportion of patients who developed sustained hypertension. Abnormal Bleeding-SSRIs and SNRIs can increase the risk of bleeding events. Concomitant use of aspirin, other drugs that affect platelet function, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants can add to this risk. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Pristiq and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Narrowangle Glaucoma-Mydriasis has been reported in association with Pristiq; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored. Activation of Mania/Hypomania-During all MDD and VMS (vasomotor symptoms) phase 2 and phase 3 studies, mania was reported for approximately 0.1% of patients treated with Pristiq. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Pristiq should be used cautiously in patients with a history or family history of mania or hypomania. Cardiovascular/Cerebrovascular Disease-Caution is advised in administering Pristiq to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders [see Adverse Reactions (6.1)]. Increases in blood pressure and heart rate were observed in clinical studies with Pristiq. Pristiq has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were excluded from clinical studies. Serum Cholesterol and Triglyceride Elevation-Dose-related elevations in fasting serum total cholesterol, LDL (low-density lipoprotein) cholesterol, and triglycerides were observed in the controlled studies. Measurement of serum lipids should be considered during treatment with Pristiq [see Adverse Reactions (6.1)]. Discontinuation of Treatment with Pristiq- Discontinuation symptoms have been systematically and prospectively evaluated in patients treated with Pristiq during clinical studies in major depressive disorder. Abrupt discontinuation or dose reduction has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy. During marketing of SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors) and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (eg, paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Pristiq. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate [see Dosage and Administration (2.4) and Adverse Reactions (6.1) in full prescribing information]. Renal Impairment-In patients with moderate or severe renal impairment or end-stage renal disease (ESRD) the clearance of Pristiq was decreased, thus prolonging the elimination half-life of the drug. As a result, there were potentially clinically significant increases in exposures to Pristiq [see Clinical Pharmacology (12.6) in full prescribing information]. Dosage adjustment (50 mg every other day) is necessary in patients with severe renal impairment or ESRD. The doses should not be escalated in patients with moderate or severe renal impairment or ESRD [see Dosage and Administration (2.2) in full prescribing information]. SeizureCases of seizure have been reported in premarketing clinical studies with Pristiq. Pristiq should be prescribed with caution in patients with a seizure disorder. Hyponatremia- Hyponatremia can occur as a result of treatment with SSRIs and SNRIs, including Pristiq. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients can be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.6) in full prescribing information]. Discontinuation of Pristiq should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Coadministration of Drugs Containing Desvenlafaxine and Venlafaxine- Desvenlafaxine is the major active metabolite of venlafaxine. Products containing desvenlafaxine and products containing venlafaxine should not be used concomitantly with Pristiq. Interstitial Lung Disease and Eosinophilic PneumoniaInterstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of Pristiq) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with Pristiq who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of Pristiq should be considered. ADVERSE REACTIONS: Clinical Studies Experience: The most commonly observed adverse reactions in Pristiq-treated MDD patients in short-term fixed-dose studies (incidence ≥5% and at least twice the rate of placebo in the 50- or 100-mg dose groups) were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders. Adverse reactions reported as reasons for discontinuation of treatment- The most common adverse reactions leading to discontinuation in at least 2% of the Pristiq-treated patients in the short-term studies, up to 8 weeks, were nausea (4%); dizziness, headache and vomiting (2% each); in the long-term study, up to 9 months, the most common was vomiting (2%). Common adverse reactions in placebo-controlled MDD studies- Table 3 in full PI shows the incidence of common adverse reactions that occurred in ≥2% of Pristiq-treated MDD patients at any dose in the 8-week, placebo-controlled, fixed-dose, premarketing clinical studies. In general, the adverse reactions were most frequent in the first week of treatment. Cardiac disorders: Palpitations, Tachycardia, Blood pressure increased; Gastrointestinal disorders: Nausea, Dry mouth, Diarrhea, Constipation, Vomiting; General disorders and administration site conditions: Fatigue, Chills, Feeling jittery, Asthenia; Metabolism and nutrition disorders: Decreased appetite, weight decreased; Nervous system disorders: Dizziness, Somnolence, Headache, Tremor, Paraesthesia, Disturbance in attention; Psychiatric Disorders: Insomnia, Anxiety, Nervousness, Irritability, Abnormal dreams; Renal and urinary disorders: Urinary hesitation; Respiratory, thoracic, and mediastinal disorders: Yawning; Skin and subcutaneous tissue disorders: Hyperhidrosis, Rash; Special Senses: Vision blurred; Mydriasis, Tinnitus, Dysgeusia; Vascular Disorders: Hot flush. Sexual function adverse reactions-Table 4 shows the incidence of sexual function adverse reactions that occurred in ≥2% of Pristiq-treated MDD patients in any fixeddose group (8-week, placebo-controlled, fixed and flexible-dose, premarketing clinical studies). Men Only: Anorgasmia, Libido decreased, Orgasm abnormal, Ejaculation delayed, Erectile dysfunction, Ejaculation disorder, Ejaculation failure, Sexual dysfunction; Women Only: Anorgasmia; Other adverse reactions observed in premarketing clinical studies: Other infrequent adverse reactions occurring at an incidence of <2% in MDD patients treated with Pristiq were: Immune system disorders – Hypersensitivity. Investigations – Weight increased, liver function test abnormal, blood prolactin increased. Nervous system disorders – Convulsion, syncope, extrapyramidal disorder. Musculoskeletal and connective tissue disorders – Musculoskeletal stiffness. Psychiatric disorders – Depersonalization, hypomania. Respiratory, thoracic and mediastinal disorders – Epistaxis. Vascular disorders – Orthostatic hypotension. In clinical studies, there were uncommon reports of ischemic cardiac adverse events, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during Pristiq treatment as compared to placebo [see Warnings and Precautions (5.7)]. Discontinuation events-Adverse events reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical studies at a rate of ≥5% include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy [see Dosage and Administration (2.4) and Warnings and Precautions (5.9) in full prescribing information]. Laboratory, ECG and vital sign changes observed in MDD clinical studies-The following changes were observed in placebo-controlled, short-term, premarketing MDD studies with Pristiq. Lipids-Elevations in fasting serum total cholesterol, LDL (low-density lipoprotein) cholesterol, and triglycerides occurred in the controlled studies. Some of these abnormalities were considered potentially clinically significant [see Warnings and Precautions (5.8)]. Proteinuria-Proteinuria, greater than or equal to trace, was observed in the fixed-dose controlled studies (see Table 6 in full prescribing information). This proteinuria was not associated with increases in BUN or creatinine and was generally transient. ECG changes-Electrocardiograms were obtained from 1,492 Pristiq-treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between Pristiq-treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval. Vital sign changes-Table 7 summarizes the changes that were observed in placebo-controlled, short-term, premarketing studies with Pristiq in patients with MDD (doses 50 to 400 mg). Relative to placebo, Pristiq was associated with mean increase of up to 2.1 mm Hg in systolic blood pressure, 2.3 mm Hg in diastolic blood pressure, and 4.1 bpm with supine pulse. At the final on-therapy assessment in the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Pristiq during the initial 12-week, open-label phase, there was no statistical difference in mean weight gain between Pristiq- and placebo-treated patients. Orthostatic hypotension- In the short-term, placebo-

controlled clinical studies with doses of 50-400 mg, systolic orthostatic hypotension (decrease ≥30 mm Hg from supine to standing position) occurred more frequently in patients ≥65 years of age receiving Pristiq (8.0%, 7/87) versus placebo (2.5%, 1/40), compared to patients <65 years of age receiving Pristiq (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218). Adverse Reactions Identified During Post-Approval UseThe following adverse reaction has been identified during post-approval use of Pristiq. Because postapproval reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Skin and subcutaneous tissue disorders – Angioedema. DRUG INTERACTIONS: Central Nervous System (CNS)Active Agents-The risk of using Pristiq in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when Pristiq is taken in combination with other CNS-active drugs [see Warnings and Precautions (5.13)]. Monoamine Oxidase Inhibitors (MAOIs)Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on antidepressants with pharmacological properties similar to Pristiq (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI [see Contraindications (4.2)]. Serotonergic Drugs- Based on the mechanism of action of Pristiq and the potential for serotonin syndrome, caution is advised when Pristiq is coadministered with other drugs that may affect the serotonergic neurotransmitter systems [see Warnings and Precautions (5.2)]. Drugs that Interfere with Hemostasis (eg, NSAIDs, Aspirin, and Warfarin)- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Pristiq is initiated or discontinued. Ethanol- A clinical study has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking Pristiq. Potential for Other Drugs to Affect Desvenlafaxine-Inhibitors of CYP3A4 (ketoconazole)- CYP3A4 is a minor pathway for the metabolism of Pristiq. Concomitant use of Pristiq with potent inhibitors of CYP3A4 may result in higher concentrations of Pristiq. Inhibitors of other CYP enzymes- Based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of Pristiq. Potential for Desvenlafaxine to Affect Other Drugs- Drugs metabolized by CYP2D6 (desipramine)- In vitro studies showed minimal inhibitory effect of desvenlafaxine on CYP2D6. Clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. Concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 can result in higher concentrations of that drug. Drugs metabolized by CYP3A4 (midazolam)- In vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isozyme. Concomitant use of Pristiq with a drug metabolized by CYP3A4 can result in lower exposures to that drug. Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19- In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes. P-glycoprotein Transporter- In vitro, desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter. The pharmacokinetics of Pristiq are unlikely to be affected by drugs that inhibit the Pglycoprotein transporter, and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter. Electroconvulsive Therapy- There are no clinical data establishing the risks and/or benefits of electroconvulsive therapy combined with Pristiq treatment. USE IN SPECIFIC POPULATIONS: Pregnancy- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Teratogenic effects– Pregnancy Category C- There are no adequate and well-controlled studies of Pristiq in pregnant women. Therefore, Pristiq should be used during pregnancy only if the potential benefits justify the potential risks. Non-teratogenic effects- Neonates exposed to SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. When treating a pregnant woman with Pristiq during the third trimester, the physician should carefully consider the potential risks and benefits of treatment [see Dosage and Administration (2.2)]. Labor and Delivery- The effect of Pristiq on labor and delivery in humans is unknown. Pristiq should be used during labor and delivery only if the potential benefits justify the potential risks. Nursing Mothers- Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Pristiq, a decision should be made whether or not to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Only administer Pristiq to breastfeeding women if the expected benefits outweigh any possible risk. Pediatric Use- Safety and effectiveness in the pediatric population have not been established [see Box Warning and Warnings and Precautions (5.1)]. Anyone considering the use of Pristiq in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use- Of the 3,292 patients in clinical studies with Pristiq, 5% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term, placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with Pristiq [see Adverse Reactions (6)]. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose [see Dosage and Administration (2.2) and Clinical Pharmacology (12.6)]. If Pristiq is poorly tolerated, every other day dosing can be considered. SSRIs and SNRIs, including Pristiq, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.12)]. Greater sensitivity of some older individuals cannot be ruled out. Renal Impairment- In subjects with renal impairment the clearance of Pristiq was decreased. In subjects with severe renal impairment (24-hr CrCl < 30 mL/min) and end-stage renal disease, elimination half-lives were significantly prolonged, increasing exposures to Pristiq; therefore, dosage adjustment is recommended in these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.6) in the full prescribing information]. Hepatic Impairment- The mean t1/2 changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with hepatic impairment is 50 mg/day. Dose escalation above 100 mg/day is not recommended [see Clinical Pharmacology (12.6)]. OVERDOSAGE: Human Experience with Overdosage- There is limited clinical experience with desvenlafaxine succinate overdosage in humans. In premarketing clinical studies, no cases of fatal acute overdose of desvenlafaxine were reported. The adverse reactions reported within 5 days of an overdose >600 mg that were possibly related to Pristiq included headache, vomiting, agitation, dizziness, nausea, constipation, diarrhea, dry mouth, paresthesia, and tachycardia. Desvenlafaxine (Pristiq) is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of Pristiq) is presented below; the identical information can be found in the Overdosage section of the venlafaxine package insert. In postmarketing experience, overdose with venlafaxine (the parent drug of Pristiq) has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. Prescriptions for Pristiq should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Management of OverdosageTreatment should consist of those general measures employed in the management of overdosage with any SSRI/SNRI. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Induction of emesis is not recommended. Because of the moderate volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for desvenlafaxine are known. In managing an overdose, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians Desk Reference (PDR®). This brief summary is based on Pristiq Prescribing Information W10529C009, revised September 2009.

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ther to lack of access to health insurance or to failure of their health insurance to meet their health care needs. (NOTE: in the case of physicians/providers, the trauma is based on the inability to provide needed care to one’s patients, or doing so at one’s

December 2009

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personal expense, [ie, free care and/or oppressive paperwork burdens].) • The person’s traumatic response involved intense fear, helplessness, anger, and confusion and was caused by financial considerations that seriously complicate their (or their patient’s) medical treatment and recovery. Criterion B. The traumatic event is

persistently reexperienced in one (or more) of the following ways: • Feelings of anger, frustration, and shame at the thought of one’s inability to access (or provide) needed care. • Feelings of alienation from and abandonment by one’s countrymen and elected officials, precipitated by exposure to any form of corporate-controlled news media

coverage of the health care crisis. • Feelings of inadequacy, as an individual, as a family member, or as a physician/provider, due to the repeated inability to obtain needed care for oneself, one’s family member, or one’s patient. • Avoidance of seeking, or providing, needed care due to fear of serious financial strain or even bankruptcy.

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Poetry of the Times

by Richard M. Berlin, MD

New Year’s Eve

PIISD Continued from page 6

• Fear of an acute confusional state or other cognitive disorder following attempts to understand one’s EOBs (explanation of benefits). Criterion C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness, as indicated by 3 or more of the following:

often results in sanctions, possible loss of hospital privileges, and being labeled a “disruptive physician.” In the case of patients, it often results in suspiciousness directed at one’s physician, often being labeled a “difficult patient.” • Difficulty in concentrating, resulting in functional impairment and further jeopardizing career, health, and sense of well-being. • Hypervigilance, (eg, won’t let

At dawn, gray clouds hold the promise of snow, and by dusk, all the world’s flaws lay buried and concealed. One more patient stomps up my narrow stairs and shakes off his white mantle like an old workhorse, relieved to be back in the barn, our session ending with Happy New Year! And I turn down the heat, lock my files, and enter the drifts, knee-deep and alone, a string of blue bulbs framing the bistro’s bay window, streetlamps still dressed in red Christmas ribbons, ice devils dancing down rooftops, their crystals stinging my cheeks and melting into tears. I’m making a house call before the world breaks into party, my best friend alone and waiting, his year filled with blood tests and bone mets, a bottle of champagne resting outside his door, absorbing the cold, waiting to burst open. Dr Berlin is associate professor of psychiatry at the University of Massachusetts Medical School. He is the author of The Prophecy, published by Pudding House Press. ❒

Psychiatric Times serves as an impartial forum for information affecting mental health care professionals and their practices. The content of articles (including letters and book reviews) and the opinions expressed in Psychiatric Times are not necessarily endorsed by its editors, editorial board, or UBM Medica LLC. To protect patient confidentiality, dialogues and patient description represent a composite of patients, not a particular person. Copyright © 2011 UBM Medica LLC. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. Postmaster: Please send address changes to Psychiatric Times, UBM Medica LLC, 535 Connecticut Avenue, Suite 300, Norwalk, CT 06854 or visit www.surveymonkey.com/s/subscriptions. Psychiatric Times (ISSN 0893-2905) is published monthly by UBM Medica LLC, 535 Connecticut Avenue, Suite 300, Norwalk, CT 06854. Periodicals postage paid at Norwalk, CT, and additional offices.

• Efforts to avoid thoughts, feelings, or conversations about anything related to health insurance or health care. • Efforts to avoid interactions with physicians, hospitals, or health care centers that arouse recollection of the trauma. In the case of physicians, this includes efforts to avoid patients who are experiencing health insurance trauma. • Markedly diminished interest or participation in any significant activities. • Feelings of detachment or estrangement from others. • Restricted range of affect (eg, unable to experience feelings of well-being). • Sense of foreshortened future (eg, does not expect to have a career, marriage, children, or a normal life span). In the case of physicians, does not expect to remain in practice, anticipates early retirement or disability due to consequences of health insurance trauma. Criterion D. Persistent symptoms of increased arousal, as indicated by 2 or more of the following: • Difficulty in falling or staying asleep, due to intrusive thoughts about the health insurance trauma. • Irritability or outbursts of anger. In the case of physicians, this

children play on playground equipment for fear of minor injury resulting in possible retraumatizing need to interact with one’s health insurance company). Criterion E. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. Specify if: With bankruptcy With home foreclosure Dr Paris is a member of the Maryland Chapter of Physicians for a National Health Program and a board-certified adult psychiatrist in private practice in Leonardtown, Md. ❒

Visit Our Web Site Psychiatric Times’ Web site features free access to most of our current articles as well as archived articles from previous issues. In addition to breaking news from MedPage, Category 1 CME articles, and clinically useful psychiatric scales, the site is also home to SearchMedica.com, a search engine specifically designed for psychiatrists and mental health professionals. Please visit our Web site at www.psychiatrictimes. com. ❒

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JANUARY 2011

Top Papers of the Year: A Podcast Series

In This Issue CATEGORY 1 CME ARTICLE Atypical Depression in the 21st Century: Diagnostic and Treatment Issues Mario A. Cristancho, MD, John P. O’Reardon, MD, Michael E. Thase, MD. . . . . . . . . . . . . . . . . . . .

DEPARTMENTS COVER STORIES NIMH Shifts Focus to Molecular Origins of Mental Illness Arline Kaplan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Members of the editorial board of Psychiatric Times and columnists have chosen a single article that each believes has particularly important clinical implications for psychiatrists. We invite you to listen to succinct discussions of those papers on www.psychiatrictimes.com.

Diagnostic Criteria for PIISD: Private Insurance–Induced Stress Disorder Carol A. Paris, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 COMMENTARY Is Major Depression “Adaptive”?

Second-Generation Antipsychotics and Schizophrenia Ronald W. Pies, MD . . . . . . . . . . . . . . . . . . .

CLINICAL Psychiatric Assessment and Treatment in Preschool Children Joan L. Luby, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Antidepressants for Acute Treatment of Bipolar Disorder

SPECIAL REPORT SUICIDE: PART 1 Understanding and Overcoming the Myths of Suicide Thomas Joiner, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 The Link Between Substance Abuse, Violence, and Suicide Mark Ilgen, PhD and Felicia Kleinberg, MSW

..........

COLUMNS POETRY OF THE TIMES New Year’s Eve

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.

Richard M. Berlin, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

MOLECULES OF THE MIND The Neurobiology of Conscious Intent

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.

When a Patient Asks You for a Neuroenhancer What’s an appropriate response when one of your patients without a cognitive impairment asks for a prescription in the hopes of improving his or her memory, cognitive function, or attention span? Dr Cynthia Geppert explores a recent study of the ethical issues.

John J. Medina, PhD . . . . . . . . . . . . . . . .

What’s the Connection Between Cholesterol and Mental Health?

BOOK REVIEWS The Little Psychotherapy Book: Object Relations in Practice

There are growing concerns that chronic cholesterol depletion with statins may actually increase noncardiovascular deaths by suicide and violence-related deaths. Dr James Lake focuses on 2 studies of a topic that is under the radar of many mental health practitioners—but that has very real clinical implications.

BALANCE and Bipolar I Disorder

Is combination therapy with lithium and valproate more effective in preventing relapses in patients with bipolar I disorder than monotherapy with either drug alone? Listen to Dr S. Nassir Ghaemi discuss a key study.

Reviewed by Deborah Pollack, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Developmental Disabilities From Childhood to Adulthood: What Works for Psychiatrists in Community and Institutional Settings Reviewed by Kevin M. Antshel, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

RESIDENT’S CORNER Asking the Right Question

Howard Forman, MD . . . . . . . . . . . . . . . . . . . . . . . .

ELECTROCONVULSIVE THERAPY The Second Most Controversial Medical Procedure Charles H. Kellner, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ERRATUM

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Cover Image © David Plunkert/theispot.com

www.PsychiatricTimes.com/podcasts

JANUARY 2011

COMMENTARY

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Is Major Depression “Adaptive”? The Clinical Data Say No by Ronald W. Pies, MD he poet Denise Levertov was no stranger to sorrow and loss. In her poem, “Stepping Westward,”1 she writes of the aging process, as both a burden and a gift. The poem begins,

DSM-IV MDD criteria) are adduced as evidence. (Let’s leave aside the simplistic notion that depression arises from unresolved “social problems”—of course, this is sometimes so, but in many cases, interpersonal problems are the consequence of preexisting depression.8)

common with the seriously depressed patients we treat, who have often been ill for weeks, months, or even years. To be clear: I have many problems with the DSM-IV construct of MDD, such as its almost risible elasticity— MDD is a diagnosis that can be stretched around almost anyone with

1. Is there credible evidence showing that MDD (or clinically significant depression) enhances any specific types of cognitive skills or mental processes? 2. Is there credible evidence showing that rumination in MDD enhances any type of “problemsolving” skills? 3. Is there credible evidence showing that depressed individuals possess enhanced social or interpersonal skills, such that they might be at some kind of adaptive advantage?

What is green in me/darkens, muscadine . . . Muscadine is a woody vine that produces a musk-scented purple grape, used to make wine. Levertov’s image is one of growing darkness, but also of emotional growth and maturation. With old age comes “the fruit of the vine”—wisdom and awareness. Levertov’s poem goes on to observe, If I bear burdens/they begin to be remembered/as gifts . . . We all know that sorrow can bring insight, if it is properly and deeply understood. This “gift” may also emerge from the pensive reflection of ordinary grief and bereavement. I begin with Levertov’s poetic images because I want to distinguish what Thomas à Kempis called “the proper sorrows of the soul” from what psychiatrists know as major depression. I would never argue against the claim that on some level, ordinary grief may be adaptive—in fact, in a series of articles, Dr Sidney Zisook and I have stated as much.2,3 But when the same claim is made with regard to major depressive disorder (MDD), as in the so-called analytical (or adaptive) rumination hypothesis (ARH),4-6 I am left shaking my head. In its simplest formulation, the ARH asserts that “. . . depression is nature’s way of telling you that you’ve got complex social problems that the mind is intent on solving” and that “depression is in fact an adaptation, a state of mind which brings real costs, but also brings real benefits.”4 In effect, the ARH asserts that the “analytical” and ruminative cognitive processes of the depressed person facilitate complex, social problem solving. A number of experimental manipulations are cited to support the ARH (eg, see Hertel and colleagues7), but few psychometric studies of clinically depressed patients (eg, meeting

deeply skeptical of some recent claims regarding the benefits of “analytical rumination.”6 My intention here, however, is to examine the published studies of cognitive function in patients with major depression and to pose the following questions:

Illustration, courtesy of Wikipedia

The basic claims of the ARH do not square with anything in my experience as a specialist in mood disorders for over 25 years, nor with the overwhelming majority of clinical studies of cognitive function in MDD, to be reviewed presently. But first, it is critical that we distinguish studies of clinical populations from experimental manipulations involving non-clinical test subjects—usually described as being “sad” or in a “depressed mood state”—who are asked to solve various artificial “problems” (eg, see Hertel and colleagues7). These test subjects—eg, college student volunteers4—are usually “induced” to have very brief periods of depressed mood, using some experimental intervention. They have virtually nothing in

2 weeks, or 2 years, of depressive symptoms.9 But when carefully applied to someone with a month or more of severe depression, 1 or more melancholic features, pronounced suffering, and substantial socialvocational incapacity, “MDD” describes a very real disease entity, with a suicide rate of about 4 in 100.10 The notion that such a condition is in any sense “adaptive” flies in the face of clinical experience, the reports of most severely depressed patients and, as I hope to show, most studies of cognitive and social function in depressed individuals. As to “evolutionary” arguments for and against the ARH, I will leave those to authorities in the field of evolutionary biology,11 although I am

These questions, of course, cannot address whether those who have endured an episode of severe MDD are or are not “wiser” for the experience, or whether they were able to find lifeenhancing “meaning” or valuable perspectives in the course of their suffering. These are fundamentally philosophical and spiritual—not scientific—determinations. Finally, I will not address the controversial matter of antidepressant treatment, other than to note this: the claim that MDD is not “adaptive”—indeed, that it is pervasively maladaptive—is surely not to claim that all persons with MDD require, or benefit from, antidepressant treatment. Simply put, some do, and some probably do not.12 In any case, the issue of pharmacotherapy would take us far afield.

Clinical studies of cognition in depression Dr Charles DeBattista,13 in a recent review, concluded that “the types of executive deficits seen in depression include problems with planning, [as well as] initiating and completing goal-directed activities” and that such “executive dysfunction” tends to worsen in direct proportion to the severity of depression. Similarly, a review by French investigators concluded that “. . . executive deficits (Please see Major Depression, page 10)

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associated with frontal lobe dysfunction may be prominent in depression” and that “. . . unipolar depressed patients mainly exhibit cognitive inhibition deficits, problem-solving impairments, and planning deficits.”14 Furthermore, unipolar depressed patients tend to show “. . . difficulties in hypothesis testing with a loss of spontaneous and reactive cognitive flexibility,” attributable to dysfunction in the dorsolateral prefrontal cortex. (Ironically, proponents of the ARH suggest that prefrontal brain regions show enhanced activity in major depression, thus facilitating “analytical rumination”; in fact, the brain imaging evidence in MDD is complex and often conflicting, perhaps reflecting slightly differing subregions of the prefrontal cortex.15) Cognitive problems may be especially pronounced in older depressed individuals, as Alexopoulos and colleagues16 have shown. They note that “depressed patients often have disturbances in attention, speed of processing, and executive function even in the absence of dementing disorders.” Moreover, “. . . executive dysfunction and related cognitive abnormalities confer significant disability and add to adversity experienced by the depressed elderly person [italics added].”16 Collectively, these findings do not suggest any salient adaptive advantages in the cognitive state of most clinically depressed patients. Quite the contrary: as Alexopoulos and colleagues note, citing the work of Nezu and Ronan, problem-solving therapy for geriatric depression actually “. . . originated from the observation that depressed patients use inadequate or inappropriate approaches in addressing their problems. . . . [italics added].”

Rumination: friend or foe? There is little disagreement with the observation that clinically depressed patients tend to ruminate; ie, to focus repetitively on the same issue, problem, or thought (the term comes from the Latin ruminari , “to chew cud”). In general, the research literature points to the deleterious effects of depressive rumination. As Rimes and Watkins17 observe, citing the work of Nolen-Hoeksema18 and others, Increasing evidence suggests that rumination plays a role in the maintenance of depression. . . . Experimental studies have found that in dysphoric partici-

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COMMENTARY pants, compared to [use of] distraction, rumination increases depressed mood, cognitive distortions and . . . impairs problem-solving skills . . . These findings are consistent with those of Donaldson and Lam,19 who found that patients with major depression who were made to ruminate experienced a deterioration in their mood and gave poorer problem solutions. Similarly, Park and associates20 found that experimentally induced rumination, as compared with distraction, increases both depressed mood and negative memories in adolescents who have a first episode of MDD. Taken in total, these findings flatly contradict the central claim of the ARH, ie, that rumination is helpful and adaptive in addressing one’s problems, social or otherwise. But there is a complication we need to consider: rumination appears to be subdivided into analytical self-focus

focused rumination may be particularly maladaptive in depression.”17 Once again, no support for the ARH is provided. Indeed, in direct contradiction of the ARH, Watkins and colleagues21 have shown that treating depressive rumination with cognitive-behavioral therapy “. . . appears to yield generalized improvement in depression and comorbidity.” If rumination were indeed adaptive and productive, we would expect the opposite result.

Social and interpersonal skills in depression Does being clinically depressed somehow make one more empathic, or improve one’s ability to “read” the social cues of others? Might depression enhance social bonding in a way that could be “adaptive”—if not on an “evolutionary” time scale, at least in the here and now? Some preliminary answers have emerged from studies of the ability to recognize facial expression. What

. . . brief periods of mild depression may . . . permit useful reflection. . . . In my experience, it is usually despite—not because of—serious depression that solutions to life’s problems are found.

[namely] poor social skills as a cause of depression, depression as a cause of poor social skills, and poor social skills as a vulnerability factor in the development of depression. Currently, there is some evidence to support each of these conceptualizations. Despite this ambiguity, there is little doubt that clinically depressed individuals show a variety of social and interpersonal deficits, including, according to Segrin,8 . . . inhibition in initiating new relationships and interactions with others; problems in expressing themselves clearly to others; inappropriately and excessively self-disclosing information, especially if it is negatively toned, to others; and sometimes being overly negative and perhaps even hostile around other people. Once again, it is hard to imagine any short-term, adaptive advantage emerging from these widespread interpersonal difficulties in depression, much less an enhanced “evolutionary” advantage that would favor attracting a mate, engaging in sexual activity, reproducing, etc. But these are matters of debate for the evolutionary biologists.

Conclusion (ASF) and experiential self-focus (ESF). In essence, ASF involves thinking analytically ‘‘about’’ oneself and one’s symptoms, eg, “How did I get so depressed? Why do I feel so guilty?” In contrast, ESF involves a “here and now” focus on the direct experience of one’s thoughts, feelings, and sensations in the present, eg, “Right now, I’m feeling hurt and angry that John left me for someone else.” Rimes and Watkins17 studied these 2 types of rumination in 30 depressed participants (MDD by DSM-IV criteria) and 30 never-depressed volunteers. Participants were randomly allocated to “analytical” (high analysis) or “experiential” (low analysis) selffocused manipulations. The study found that in depressed participants, ASF increased ratings of feeling “worthless” and “incompetent.” The ESF condition resulted in no significant change in such judgments. (Neither mode of rumination had a significant effect in the nondepressed controls.) The authors concluded that “. . . an analytical mode of self-

does facial expression have to do with social and interpersonal skills? A good deal, according to Yoon and colleagues.22 They note that “biases in the processing of subtle facial expressions of positive affect may . . . contribute to the interpersonal difficulties that maintain [depression].”22 Put in more colloquial terms: if you can’t tell that someone is smiling at you, the two of you are not likely to hit it off. Indeed, in their study of subjects with MDD, Yoon and coworkers found that major depression interferes with “reading” subtle expressions of positive affect, such as the famous “Mona Lisa smile.” It is hard to see any adaptive advantage in this perceptual bias. A core argument of the ARH is that unresolved “social problems” precede clinical depression, which is said to be an adaptive response to these problems. But as Segrin8 observes in his review, Three different theoretical relationships between disrupted social skills and depression [have been] described . . .

I would wager that the great Renaissance artist Albrecht Dürer understood clinical depression far better than some modern-day proponents of the ARH. In his 1514 depiction of “Melencolia I” (“Melancholy”—see Figure), Dürer shows the pensive goddess sitting amidst an array of unused analytical tools and instruments, staring somberly into space. As one commentator observes, . . . her fixed state is one of intent though fruitless searching. She is inactive not because she is too lazy to work but because work has become meaningless to her; her energy is paralyzed not by sleep but by thought.”23 A psychiatrist could hardly have described severe depression more accurately, or refuted the ARH more succinctly. I do not doubt that for some patients with MDD, there are indeed “remembered gifts” that are appreciated on recovery from their depression. But this is not to say that MDD itself is “adaptive” during the course

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of the patient’s illness. Virtually all the evidence I have reviewed leads to precisely the opposite conclusion. Nonetheless, the final word has not been written on this controversy. It would be instructive to do a carefully designed, empirical study that examined the question of depression’s “upside” from the patient’s point of view—controlling for possible confounds, such as the type of depression; whether or not the patient is hospitalized; how much support the patient is receiving from significant others; when in the course of illness the patient is asked the question, etc. I’m not aware of such studies, whereas I have countless experiences hearing about the hellish suffering brought on by major depression. I remain open to the possibility that brief periods of mild depression may sometimes permit useful reflection on one’s problems, and perhaps even lead to some solutions. But in my experience, it is usually despite—not because of—serious depression that solutions to life’s problems are found. We owe our patients more than specious theories regarding the “upside” of their depression; we owe them safe, effective, and readily available treatment.12

COMMENTARY Dr Pies is professor of psychiatry and lecturer on bioethics and humanities at SUNY Upstate Medical University in Syracuse, NY, and clinical professor of psychiatry at Tufts University School of Medicine in Boston. Acknowledgments: I would like to express my appreciation to Drs Katharine Rimes and Rebecca Park for their helpful comments and references; and to Drs George Alexopoulos and Emily Becker-Weidman for providing their papers. I also want to acknowledge the seminal research of Dr Helen Mayberg in studying regional brain imaging in MDD. However, this commentary represents solely my own analysis and conclusions. References 1. Levertov D. Stepping Westward. http://www. chriscorrigan.com/parkinglot/levertov.htm#_ Toc23572766. Accessed October 20, 2010. 2. Zisook S, Simon NM, Reynolds CF 3rd, et al. Bereavement, complicated grief, and DSM, part 2: complicated grief. J Clin Psychiatry. 2010;71:10971098. 3. Pies R, Zisook S. Grief and depression redux: response to Dr Frances’s “compromise.” Psychiatr Times. http://www.psychiatrictimes.com/dsm-5/ content/article/10168/1679026. Accessed October 20, 2010. 4. Andrews PW, Thomson JA Jr. Depression’s evolutionary roots. Sci Am. August 25, 2009.

5. Andrews PW, Thomson JA Jr. The bright side of being blue: depression as an adaptation for analyzing complex problems. Psychol Rev. 2009;116: 620654. 6. Andrews PW, Thomson JA Jr. Coyne battles Darwin, many other evolutionary biologists—and himself. Psychiatr Times. http://www.psychiatrictimes. com/depressive-disorders/content/article/10168/ 1676033. Accessed October 22, 2010. 7. Hertel G, Neuhof J, Theuer T, Kerr NL. Mood effects on cooperation in small groups: does positive mood simply lead to more cooperation? Cogn Emotion. 2000;14:441-472. 8. Segrin C. Social skills deficits associated with depression. Clin Psychol Rev. 2000;20:379-403. 9. Ghaemi SN. Why antidepressants are not antidepressants: STEP-BD, STAR*D, and the return of neurotic depression. Bipolar Disord. 2008;10:957-968. 10. Ruter TJ, Davis M. Suicide prevention efforts for individuals with serious mental illness: roles for the State Mental Health Authority. In: Litts DA, Radke AQ, Silverman, MM, eds. March 2008. http://www. oregon.gov/DHS/mentalhealth/docs/nasmhpd.pdf. Accessed October 22, 2010. 11. Coyne JA. The evolutionary calculus of depression. Psychiatr Times. August 5, 2010. http://www. psychiatrictimes.com/depression/content/article/ 10168/1633704. Accessed October 22, 2010. 12. Pies R. Antidepressants work, sort of—our system of care does not. J Clin Psychopharmacol. 2010;30:101-104. 13. DeBattista C. Executive dysfunction in major depressive disorder. Expert Rev Neurother. 2005;5:7983. 14. Fossati P, Ergis AM, Allilaire JF. Executive functioning in unipolar depression: a review [in French].

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Encephale. 2002;28:97-107. 15. Hosokawa T, Momose T, Kasai K. Brain glucose metabolism difference between bipolar and unipolar mood disorders in depressed and euthymic states. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33:243-250. 16. Alexopoulos GS, Raue PJ, Kanellopoulos D, et al: Problem solving therapy for the depression-executive dysfunction syndrome of late life. Int J Geriatr Psychiatry. 2008;23:782-788. 17. Rimes KA, Watkins E. The effects of self-focused rumination on global negative self-judgements in depression. Behav Res Ther. 2005;43:1673-1681. 18. Nolen-Hoeksema S. The role of rumination in depressive disorders and mixed anxiety/depressive symptoms. J Abnorm Psychol. 2000;109:504-511. 19. Donaldson C, Lam D. Rumination, mood and social problem-solving in major depression. Psychol Med. 2004;34:1309-1318. 20. Park RJ, Goodyer IM, Teasdale JD. Effects of induced rumination and distraction on mood and overgeneral autobiographical memory in adolescent major depressive disorder and controls. J Child Psychol Psychiatry. 2004;45:996-1006. 21. Watkins E, Scott J, Wingrove J, et al. Ruminationfocused cognitive behaviour therapy for residual depression: a case series. Behav Res Ther. 2007; 45:2144-2154. 22. Yoon KL, Joormann J, Gotlib IH. Judging the intensity of facial expressions of emotion: depressionrelated biases in the processing of positive affect. J Abnorm Psychol. 2009;118:223-228. 23. Melencolia by Albrecht Dürer, 1514. Back to Classics.com. Virtual art gallery. http://www. backtoclassics.com/gallery/albrechtdurer/ melencolia. Accessed October 17, 2010. ❒

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JANUARY 2011

MOLECULES OF THE MIND

The Neurobiology of Conscious Intent by John J. Medina, PhD

erhaps the seminal component of any clinician’s behavioral repertoire is the ability to understand the conscious motivations and intentions of their clients. This article addresses the work of conscious motivations at the neuroanatomical level.

I seldom address the notion of consciousness—let alone motivations— in this column for a very good reason. Nobody really knows what they are or even if there is a “they.” The literature is confusing, but it hasn’t stopped researchers from speculating on possible neuroanatomical and biochemical substrates that undergird the phenomena. Without a broad consensus about what is being studied, there can be no neurons, let alone molecules, for active experimental consideration. After all these years, researchers have yet to isolate an area of the brain solely devoted to the experience of consciousness. There may be none. Given the importance of these issues to the mental health professions, I revisit the concept of motivations from time to time—but only when the data are conservatively presented, with sober, modest conclusions. The findings described here originate from experiments that have attempted to determine how we voluntarily choose to perform a motor task (action planning). This work requires reviewing background information on association cortices and the neural substrates behind a decision to initiate voluntary action.

Association cortices Functionally, the cortical regions of the brain and their myriad interlocking circuits can be divided into 3 modules. These consist of front-, back-, and middle-end domains. • Front-end functional domains are sensory information processing centers. The brain receives input from the eyes, ears, and other sensory systems. It sends the input off to various places for further processing. • Back-end functional domains involve motor control systems. These systems essentially respond to whatever command the sensory cortices give to it (eg, execute a decision to move). • The middle-end suite involves nearly everything other than front-end and back-end functional

domains. These association cortices generally entail higher processing features and are some of the least understood and the most mysterious parts of the brain. One such cortex, located in the inferior posterior parietal cortex, is a sensorimotor association region that links sensory stimuli to motor movement. It may even be involved in sensory prediction, which calculates the consequences of a given action through the simultaneous evaluation of input from both sensory (frontend) and motor (back-end) functional domains.

mentioned above, but they do not originate from responses to an external source. The movement instead arises spontaneously; a thought is internally generated through intentional actions. There is an observed rapid rise in electrical signals that build up just before the brain executes these actions. This has led to the notion that the presupplementary motor area harbors some kind of readiness potential, a useful function in generating movement (Figure). In terms of human behavior, complex human brains have many more research issues to solve than standard laboratory animal research can address. One potential confounder is conceptual. With research of this type, scientists often tell subjects to choose (or not to choose) from a variety of options. Is that voluntary? Hardly. This is like saying, “Okay, it’s time to have some voluntary vo-

Volitional motor movement Many of the actions humans initiate on a day-to-day basis seem to depend on a kind of internal free will. This sequence of events (also known as volitional motor movement) gives humans a sense of control: we act because we want to act. That is why researchers use volitional motor movements in their research designs. Researchers interested in volitional behavior study neural prime movers behind decision making. Exactly what does it mean to want to do something? We do not really know. The events that initiate movement occur in a fairly straightforward sequence (although it depends on the source of the signal). For example, a central processing area with directives for voluntary motor movements pass through a final staging area before the execution of an action. This region is the primary motor cortex. Research on laboratory animals demonstrates that this cortex decides on a course of action that depends on the source of signals it receives before the execution of that action. One source originates in the premotor cortex. Signals in this area initiate movements in response to a specific external trigger, such as a visual cue. The second source arises in the presupplementary motor area, which is stimulated when laboratory animals make the same movements

litional behavior now,” or like runners at a race who respond to the starting gun. Do volitional actions disappear in these experiments with human subjects? Are these subjects simply reacting to commands to respond, not to respond, or to respond however they want? To test volition, researchers should not control the input. Nevertheless the experimenter must, almost by definition.

Wilder Penfield revisited Another complexity involves engineering. How does conscious intent to move an arm relate to the actual movement of the arm? This could be partially resolved with electrical (Please see Conscious Intent, page 14)

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JANUARY 2011

MOLECULES OF THE MIND

Conscious Intent Continued from page 12

stimulation mapping in which surgeons create a map of the brain on conscious patients to understand what tissues need to be avoided during certain manipulations (such as resection). No pain neurons exist in the brain. The patient, immobilized in a stereotactic frame, can be consciously interrogated while the surgery takes place. The surgeon applies a gentle electrical current to the open tissue, talks to the patient about what he or she is experiencing, and makes a map that discerns what areas to avoid during cutting. Working primarily with epileptic patients, the legendary Canadian physician Wilder Penfield first performed these techniques.1 This technique has proved to be of great value in understanding volitional components of motor movement. It was discovered almost 2 decades ago that if one stimulates a specific area of the human presupplemental area, the patient will experience a conscious urge to move.2

This gets around the runner’s starting gun problem mentioned previously. An external electrical stimulator supplies a specific quantity of electricity—and a desire to do something is suddenly generated! As important and well-characterized as these data are, they hardly explain what causes the presupplemental area to generate the signal in subjects not undergoing surgery. Some research findings answer this question and have led to some intriguing results.3,4 When the inferior posterior parietal cortex was stimulated, the patient experienced an urge to move specific body parts. Stimulating one area caused patients to want to move their arms. Another region, the lips. Another region, the chest. This is similar to what one observes in frontal lobes, except that you are nowhere near the frontal lobes. Recall that this is the associative cortex region (a sensorimotor associative area at that), quite distinct from anything observed in the well-characterized general motor areas of the frontal lobes. Was this simply a remote stimulation?

This result showed that the answer would be no. The parietal cortex urges were qualitatively different from those obtained by stimulating parts of the presupplementary cortex. It is well known that if the presupplementary cortex is stimulated at a low current, the urge to act is acquired. However, if the same region is stimulated at high current, actual movement occurs. That’s not what happened in the parietal cortex. The urge was stimulated at low intensities, but movement was never generated at higher ones. Instead, subjects felt that they had already performed some movement. This is important. The desire to move did not result from subtle motor contractions that may have been generated by motor regions (an alternative idea that has been put forth as a rational explanation for the results in previous experiments). Parietal stimulation never produces muscle activity, regardless of the intensity. The stimulation of the premotor cortex itself produces large-limb movements in subjects, but never the desire to move the limbs. They usually remain unaware that movement has

Figure

The neurobiology of the conscious experience of intention? Shown below are some of the regions thought to be involved in the control of voluntary action. The premotor cortex (PC) is thought to prepare for the primary motor cortex (PMC) executable instructions for voluntary movement triggered by the outside world. Presupplementary motor areas (PMAs) are thought to prepare for the PMC instructions for internally generated “intentional” commands. These instructions are then executed by the PMC. Recent data suggest that intention-based motor commands also involve the inferior parietal cortex. These may allow the user to predict the sensory consequences of motion to be executed.

PMA

PMC ? Inferior posterior parietal cortex

PC ?

occurred when these regions are stimulated. These results suggest the presence of 2 specific aspects of conscious intention (however one defines it). One might be the conscious correlation of preparatory motor commands in the presupplemental cortex region, as is clearly observed in laboratory studies of animals. The other might involve sensory prediction of the consequences of those commands, under the domain of the association cortex region. A portion of conscious intent seems to be a specific class of experiences housed within the parietal lobe.

Conclusions It appears that the parietal lobe contributes to the conscious experience of intention, at least in regard to motor movement. These results cement 1 more brick onto the great construction project that seeks to define intention. But they hardly hint at the overall building. Pushing the edge of our understanding into the murky world of association cortex only means that future experiments will be trickier to interpret. Electrical stimulation mapping, as good as it is, is necessarily a blunt instrument that stimulates thousands of neurons simultaneously. Not isolated modules, these regions connect to each other in complex, little-understood ways. That the regions produce different behaviors is an important finding but not a defining one. How do the frontal and motor aspects of volitional experience differ from the parietal, sensory versions? What factors stimulate the parietal lobes in the first place? What about remote effects? Questions such as these remain to be answered and are just a few of the many that researchers will face as they attempt to define intentional and conscious experiences. 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. References

To muscles (voluntary movement)

1. Penfield W, Erickson TC. Epilepsy and cerebral localization: a study of the mechanism, treatment and prevention of epileptic seizures (Review). South Med J. 1942;35:222. 2. Fried I, Katz A, McCarthy G, et al. Functional organization of human supplementary motor cortex studied by electrical stimulation. J Neurosci. 1991;11: 3656-3666. 3. Haggard P. Human volition: towards a neuroscience of will. Nat Rev Neurosci. 2008;9:934-946. 4. Custers R, Aarts H. The unconscious will: how the pursuit of goals operates outside of conscious awareness. Science. 2010;329:47-50. ❒

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.

Visit the LEXAPRO website at www.lexapro.com

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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Visit the LEXAPRO website at www.lexapro.com

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

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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

JANUARY 2011

SUICIDE: PART 1 Understanding and Overcoming the Myths of Suicide What Goes On in the Minds of Those Who Attempt Suicide by Thomas Joiner, PhD yths about suicide abound in the therapeutic setting. They often inhibit the ability of clinicians (and families) to assess the severity and magnitude of a patient’s suicide risk. This special report discusses some of those myths. In Why People Die by Suicide,1 I argued that a kind of fearlessness is required to face voluntarily the daunting prospect of one’s death, and that doing so necessarily involves a fight against ancient, ingrained, and powerful selfpreservation instincts. In Myths About Suicide,2 I used the framework developed in the previous book to contend that death by suicide is neither impulsive, cowardly, vengeful, controlling, nor selfish.

Impulsivity myths The tragic death of a Florida television news reporter in 1974 illustrates the fallacy that suicide is an impulsive, spur-ofthe-moment whim, much like casting off peanut shells at the ballpark. In July of that year, the reporter was covering the story of a shooting that had happened the day before. When the reporter called for the news station’s video footage of the scene, the tape jammed. She shrugged and stated, “In keeping with Channel 40’s policy of bringing you the latest in blood and guts, and in living color, you are going to see another first—an attempted suicide.” She extracted a gun from beneath her desk and shot herself behind the right ear. She was rushed to a local hospital, but died 14 hours later. The usual reaction to this tragic tale beyond shock and horror was to dwell on the seemingly impulsive nature of the act and ask, “How could the reporter have known that the tape would jam?” However, the reporter’s behavior leading up to her suicide dispels the idea that she acted impulsively: • For years, she openly told her family that she felt depressed and suicidal • Four years before her death, she attempted suicide by overdose and frequently discussed the incident subsequently

• Weeks before she died, the news station granted her request to cover a story on suicide; and during one interview, she asked a police officer for details on self-inflicted gunshot wounds • One week before, she told a colleague that she had bought a gun and joked with him about killing herself on the air • On the day of her suicide (or possibly even before), she had put the gun in a bag that she brought to the set daily • Finally, she had prepared news copy for a fellow reporter to read about her suicide after the fact The news reporter’s death illustrates that her suicide was premeditated. Death by suicide is extremely fearsome and daunting, and thus requires considerable thought, planning, and resolve. To consider her death impulsive is to assign primacy to that spur-of-the-moment decision as to precisely when to pull out the gun, instead of focusing on the many factors that led up to that planned moment. In the book An Unquiet Mind,3 Kay Redfield Jamison discusses her own experience with suicidal behavior and describes how it actually works: “. . . for many months I went to the 8th floor of the stairwell of the UCLA hospital and, repeatedly, only just resisted throwing myself off the ledge. . . .” Contemplating © Phil Bliss/theispot.com suicide is a signature of serious suicidal be havior. Jamison’s months-long thought process and behaviors counter the notion of spontaneous death by suicide. The suicide of President Bill Clinton’s childhood friend and White House adviser Vince Foster was of this sort. Despite wildly irresponsible speculation to the contrary, Foster died of a self-inflicted gunshot wound. Foster snuck a gun out to his car in an oven mitt; he drove to a secluded area of a park, and he shot himself. To imagine that Foster’s death was impulsive is to (Please see Myths, page 24)

Special Report Chairperson: Eric D. Caine, MD

ALSO IN THIS SPECIAL REPORT:

25 The Link Between Substance Abuse, Violence, and Suicide Mark Ilgen, PhD and Felicia Kleinberg, MSW

See additional articles in the February 2011 Special Report, Suicide: Part 2

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

fifi fifififififififififififififififififififififififififififififi fifififififififififi fififififififififififififififififififififi fifififififififififififififi fifififififififi fififififififififififififififififififififififififi fifififififififififififififififififififififififififi fifififififififififififififififififififififififi fififififififififififififififififififififififififififififififififififififififififififififififi fififififififi fififififififi fififififififififififififififififififififififififi fififififififififififififififififififi fifififififififififififififififififififififififififi fifififififififififififififififififififififififififififififififififi fififififififififififififififififififififififi fifififi fififififi BRIEF SUMMARY:fififififififififififififififififififififi fifififififififififififififififififififififififififififififififififififi fififififififififififififififififi fifififififififififififififififififififififififififififififififififififififi fififififififififififififififi fifi fififififififififififififififififififififififififififififififififififififififififififififififififififififififififi fififififififififififififififififififififififififififififififififififififififi INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS—Elderly fififififi fififififififififififififififififififififififififififififi fififififififififififi fififififififififififififififififififififififififififififififififi fifififififififififififififififififififififififi fififififififififififififi fi patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk fififififififififififififi fifififififififififififififififififififififififififififififififi fiQT Prolongation and Torsade De Pointesfififififififififififififififififi of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in fififififififi fififififififififififififififififififififi fifififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififi fififififififififififififififififi patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of fififififififififififififififi fififi fi fifififififififi fi fifififififififififififififififififififififi fifififififififififififififififififififififififififififififififififififififififi fifififififififififififififififififififi between 1.6 to 1.7 times the risk of death in placebo-treated patients. 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fifififififififififififififififi fififififififififififififififififififi fififififififififififi dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. fifififififififififififififififififififififififififififififififififififififififififififififififi fififififififififififififififififi fififififififififififififififififififififififififififififififififififi fififififififififififififi GEODON is not approved for the treatment of dementia-related psychosis (see BOXED WARNING). fifififififififififififififififififififififififi fififififififififififififififififififififififififififi fifififififififififififififififififififififififififififififififififififi fifififififififififififi fifififififififififififi fifififififi fififififififififififi fifififififififififififififififififififififififififi fifififififififififififififififififififififififififififififififi fifififififififififi QT Prolongation and Risk of Sudden Death 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GEODON® (ziprasidone HCl) Capsules

GEODON® (ziprasidone mesylate) injection for intramuscular useﬁ

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fifififififififififififififififififififififififififififi fifififififififififififififififififififififififififi fififififififififififififififififififififififi fifififififififififififififififififififififififififi fififififififi fifififififififififififififififi Disorders:fifififififififififi Vascular Disorders:fifififififififififififififififififififififi fifififififififififi fififififififififififififififififififififififififififififififififififififififi fifififififififififififi PRECAUTIONSfififiBipolar Mania: fififififififififififififififififififi fifififififififififififififififififififififififififififi fififififififififififififififififififififififififififififififififififififififififififififi fifififififififififi DRUG ABUSE AND DEPENDENCE fififififififififififififififififififififififififififi fi fififififififififififififififififififififififi fifififififififififififififififi fififififififififififififififififififififififififififififi 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fifififififififi fifififififififififififififififififififififififififififififififi fi fifififififififififififififififififififififififififi fififififififi fifififififififififi fififififififififififififififififififififififi fifififififififififi tient taking the largest confirmed Adverse Events at an Incidence of ≥5% and at Least Twice the Rate of Placebo fifififififififififififififififififi fififififififififififififififififififififififififi fififififififififififififififififififififififififififififififififififififi fififififi fifififififififififififififififififififi fifififififififififififififi fifi fififififififififififififififififififififififififififififififi fifififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififififi fififififififi fifififififififififififififififififififififififififi fififififififififififififififififi fififififififififififififififififififififififififififififififififi fifififififififififififififififififififi © 2011 Pfizer Inc. All rights reserved. Revised January 2011 fififififififififififififififififififififififififififififififififififififififififififififififififififififi fifififififi fififififififififififififififififififififififififi fififififififififififififififififi fi GZU00989E

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

Myths Continued from page 20

ignore all of the facts in what was by far the most investigated suicide in history (multiple Congressional inquiries and forensic investigations were conducted). It is also to ignore the character of Vince Foster; he was a well-organized, thoughtful, and deliberate person. No one who knew him would have described him as impulsive. Foster’s friends and family were stunned by his death; it seemed “outof-the-blue.” However, death by suicide can both shock loved ones and be planned for weeks, months, or even years. This is because of the human capacity, quite spectacular in some cases, for privacy and secrecy. Except in works of fiction, I have never encountered a death by suicide that was truly impulsive. Many clinicians have mistakenly deemed suicidal deaths impulsive merely because they seemed to be “out-ofthe-blue.”

Suicide note myths Foster did not leave a suicide note, a factor that spurred conspiracy theories on cause of death. To my knowledge, no study has reported a rate of note leaving among suicide decedents to exceed 50%. Moreover, most studies find rates between 0% and 40%4; a reasonable average rate would be approximately 25%. Why are suicide notes so rare? Some have reasoned that because impulsivity is involved in suicidal behavior, suicidal persons often kill themselves before they have a chance to write a note. There are problems with this viewpoint, however. A major problem is that it draws on the distinct myth that dying on a whim is common. Another problem is the lack of empirical support that compares those who leave notes with those who do not. If it were true that note leavers are much less impulsive than those who do not leave notes, then this distinction should be easy to demonstrate in forensic studies that examine the lives, characteristics, and personalities of decedents. This difference has not been clearly demonstrated. The relative rarity of suicide notes reveals the state of mind of those about to die by suicide. To say that persons who die by suicide are lonely at the time of their deaths is a massive understatement. Loneliness, combined with alienation, isolation, rejection, and ostracism, is a better approximation. Still, it does not fully

JANUARY 2011

SUICIDE capture the suicidal person’s state of mind. In fact, I believe it is impossible to articulate the phenomenon, because it is so beyond ordinary experience. Notes are rare because most decedents feel alienated to the point that communication through a note seems pointless or does not occur to them at all.

Diagnostic myths Friends and family who have been surprised by a suicide often consider it to be deeply selfish. This is understandable because the bereaved are often convinced that the decedent did not consider the impact of his or her death on those left behind. However, those who die by suicide certainly do consider the impact of their deaths on others; but to them, death is a positive rather than a negative outcome. This is wrong, but nevertheless, it is the view of the person who attempts suicide. Still another reason to question whether selfishness is involved in suicidal behavior involves the associations of various aspects of psychopathy to suicidal behavior. In its description of psychopathy, DSM-IV includes aggressive behavior and reckless, out-of-control disregard for others and for rules and norms. Another aspect of psychopathy—evidently to be emphasized more in DSM-5 and included in Hervey Cleckley’s classic 1941 book, The Mask of Sanity5—describes psychopaths as controlled, callous, sometimes charming con men. They also demonstrate marked emotional detachment (ie, low anxiety; fake or shallow emotions; immunity to guilt and shame; and incapacity for love, intimacy, and loyalty). In the current DSM, psychopaths are considered out of control but not necessarily unfeeling. Cleckley psychopaths are very much in control and very much unfeeling, except, that is, when it comes to themselves. One cannot be a Cleckley psychopath and not be selfish—it is part of the core of the syndrome; but on the basis of DSM, one can be a psychopath and not be selfish. In short, one group is selfish to the core; the other, less so. If selfishness is key to suicidal behavior, it stands to reason that the group more prone to suicidal behavior should be the Cleckley psychopaths, but it is not. Genuine suicidal behavior is quite rare in this group.

Seasonal myths Another common myth that even some professionals harbor is that

death by suicide peaks around the winter holidays. In fact, far from peaking, the winter holidays represents a low point in suicide rates,6 possibly because it is a time of togetherness. My research group hypothesized that seasonality and suicidality are associated at least partly because of seasonal fluctuations in togetherness.6 Consider a large college campus in this regard. Campuses provide numerous activities for belonging; anyone who doubts this should check out a nearby university’s online master calendar. Universities offer many social, cultural, academic, athletic, and other events—many of them free of charge. Perhaps partly as a function of this high level of belonging inherent in these events, suicide rates of college students are relatively low compared with their same-aged peers not at college.6 Opportunities for togetherness are thus high on college campuses, but they are not uniform throughout the calendar year. During a standard academic year (the fall and spring semesters, roughly from September to May), most schools are clearly in session, and chances for social engagement abound through classes, dormitory and apartment life, sports, and so on. However, summer activities continue but they ebb considerably. Therefore, it is conceivable that students’ sense of belonging may be lower during the summer than during active semesters. We found that suicidal ideation was higher in the summer months than during the regular academic year, and we reasoned that this association might be partly explained by fluctuations in opportunities for socializing.6

Slow suicide myths A final collection of myths involves the notion of slow suicide, by which a person engages in unhealthy behaviors despite knowing that these behaviors may ultimately lead to death. Genuine suicidal behavior involves a rather clear intent to die, not to do something else like smoking or taking drugs because they like it. Consider, for example, smoking. By the logic of smoking as slow suicide, we should have witnessed a most remarkable decrease in the suicide rate in the past half century, as smoking rates plummeted; alas, we have not. People know smoking puts them at risk, but they smoke anyway—not because they intend to die—but because they like it. They are willing to take the risks because of how much they enjoy smoking. Addicts contin-

ue to use drugs even though they have been told and understand that continued use might kill them; but because they like “doing” drugs, the risks do not matter.

Therapeutic implications I articulated these perspectives in Why People Die by Suicide1 and Myths About Suicide,2 which encompass risk assessment, therapeutics, and suicide prevention. In addition to marked warning signs, such as talking about suicide and planning for it, the books discuss clinically severe agitation, insomnia, and nightmares (these latter 3 are themselves not considered acute risk factors in some clinical settings). Noting a patient’s fearlessness of death, perceived burdensomeness, and accelerating alienation may improve risk assessment. Myths About Suicide concludes with the following excerpt: We need to get it in our heads that suicide is not easy, painless, cowardly, selfish, vengeful, self-masterful, nor rash; that it is not caused by breast augmentation, medicines, “slow” methods like smoking or anorexia, or as some psychoanalysts thought, things like masturbation; that it is partly genetic and influenced by mental disorders, themselves often agonizing; and that it is preventable (eg, through means restriction like bridge barriers) and treatable (talk about suicide is not cheap and should occasion treatment referral). And once we get all that in our heads, at last, we need to let it lead our hearts. Therapeutic regimens and prevention protocols that target and acknowledge these factors should be given serious consideration. Dr Joiner is the Robert O. Lawton Distinguished Professor in the department of psychology at Florida State University in Tallahassee. He reports no conflicts of interest concerning the subject matter of this article. References 1. Joiner T. Why People Die by Suicide. Cambridge, MA: Harvard University Press; 2005. 2. Joiner T. Myths About Suicide. Cambridge, MA: Harvard University Press; 2010. 3. Jamison KR. An Unquiet Mind. New York: Alfred A. Knopf; 1995. 4. Joiner TE, Pettit JW, Walker RL, et al. Perceived burdensomeness and suicidality: two studies on the suicide notes of those attempting and those completing suicide. J Soc Clin Psychol. 2002;21:531545. 5. Cleckley H. The Mask of Sanity. St Louis: CV Mosby Co; 1941. 6. Van Orden KA, Witte TK, James LM, et al. Suicidal ideation in college students varies across semesters: the mediating role of belongingness. Suicide Life Threat Behav. 2008;38:427-435. ❒

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The Link Between Substance Abuse, Violence, and Suicide Implications and Interventions by Mark Ilgen, PhD and Felicia Kleinberg, MSW uicide is the 11th leading cause of death in the United States; it accounts for more than 34,000 deaths per year.1 And an even greater number of people attempt suicide. Based on data from community surveys, approximately 5% of adults have made a serious suicide attempt.2 Mental health problems are some of the best-known and well-studied risk factors linked to suicidal ideation, suicide attempts, and suicide mortality. Approximately 90% of all individuals who completed suicide met criteria for 1 or more diagnosable psychiatric conditions. Mental health conditions most strongly associated with fatal and nonfatal suicide attempts include depression, bipolar disorder, schizophrenia, posttraumatic stress disorder, and alcohol and/or drug use disorders.2-4 Because mental health treatment providers are in regular contact with patients at risk for suicide, they are an important resource for early detection and prevention of suicidal behavior.

Substance use and suicide risk Although it is difficult to compare the relative impact among different mental health problems with the risk of suicide, alcohol and drug use disorders have been found to be strongly

related to suicide risk.3,5 Individuals with a substance use disorder (ie, either a diagnosis of abuse or dependence on alcohol or drugs) are almost 6 times more likely to report a lifetime suicide attempt than those without a substance use disorder.2 Numerous studies of individuals in drug and alcohol treatment show that past suicide attempts and current suicidal thoughts are common.6-8 Recent evidence from veterans indicates that men with a substance use disorder are approximately 2.3 times more likely to die by suicide than those who are not substance abusers. Among women, a substance use disorder increases the risk of suicide 6.5-fold.9

Identifying substance abusers at greatest risk for suicide Although a consistent association exists between substance use disorders and suicidal behaviors, the vast majority of those with substancerelated problems will never die by suicide. Therefore, it is important to identify those individuals with substance use disorders who might be at particularly high risk for suicide. Many risk factors for suicide in the general population also apply to those with substance use disorders. Older men with substance use disorders are at greater risk for nonfatal attempts and for death by suicide than are younger persons.10,11 Past suicide attempts are a strong risk fac-

What is already known on this topic? A growing body of literature has identified the link between substance use disorders, interpersonal violence, and risk of suicide.

What new information does this article offer? This article reviews this literature and provides suggestions for how to identify substance use disorder patients who may be at elevated risk for suicide.

What are the clinical implications? Mental health providers should be aware that individuals with substance use disorders are at elevated risk for suicide and should include questions about prior violence toward others as part of a comprehensive suicide risk assessment.

tor for subsequent suicidal behaviors in those with substance use disorders.12 Depressed mood is a risk factor for suicidal behaviors in the general population and also predicts a greater likelihood of suicide in those with alcohol or drug use disorders.3,6,10 The link between depression and suicidal behaviors in those with substance use disorders may be particularly strong given the high comorbidity between mood and substance use disorders.13 Although it has not been examined thoroughly, independent mood disorders and substance-induced mood disorders are likely to confer risk for suicide. Emerging research suggests that some individuals with particular types of substance use and abuse may be more likely to engage in suicidal behaviors. For example, individuals who use opiates, cocaine, and sedatives may have a noticeably higher risk of suicide than those who use other drugs.12,14-16 Among those with an alcohol use disorder, a greater severity of recent drinking is associated with the greater likelihood of suicide attempt and suicide mortality.17,18 Co-occurring alcohol and drug use disorders may be particularly strong indicators of increased risk of suicide.19 Thus, the severity of substance use disorders (ie, a greater number of substances or misuse of more than 1 substance) may predict a greater likelihood of suicide.

Violent behavior toward others The tendency to engage in violent behavior is a potentially important risk factor for suicide in substance abusers. Up to 75% of those who begin addiction treatment report having engaged in violent behavior (eg, physical assault, mugging, attacking others with a weapon).20,21 Emerging research also indicates that violence may partially account for the connection between substance abuse and suicide risk. For example, in those seeking treatment for substance use disorders, the perception that they have difficulty in controlling their own violent behavior was associated with a greater likelihood of a prior suicide attempt.22 Tiet and colleagues22 hypothesized that individuals who have difficulty in con-

trolling their anger may be more likely to act impulsively, thus turning the violence on themselves rather than on others. Individuals with alcohol use disorders and prior aggressive behavior are more likely to report suicidal thoughts or past suicide attempts.6,23 In one recent study of more than 6000 adults who began addictions treatment, those who had committed serious violent acts (eg, rape, murder, assault resulting in serious injury) were more than twice as likely to report multiple suicide attempts. This finding held true even after statistically controlling for demographic characteristics, depression, and past victimization.6 Another study compared accident victims with individuals who completed suicide. Violent behavior in an individualâ&#x20AC;&#x2122;s last year of life was linked to a higher likelihood of suicide, even when controlling for alcohol use disorders and other potential suicide risk factors.24

Partner violence Violence toward a romantic partner may be a particularly important predictor of suicidal thoughts and behaviors in individuals with substance use disorders. In a study that examined data from a sample of 488 individuals who began substance and alcohol treatment, physical aggression toward a partner was associated with higher levels of suicidal ideation than was aggression toward a nonpartner.25 In addition, a history of domestic violence is common in men with alcohol use disorders who complete suicide.26 Individuals who perpetrated domestic violence were more likely to be separated from their partners; they therefore lacked social support (a key protective factor of suicide risk).

Understanding the link between violence and suicide risk Several factors can explain why engaging in interpersonal violence is associated with increased risk of suicidal behaviors in those with substance use disorders. Violence correlates with greater severity of sub(Please see Substance Abuse, page 26)

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

Substance Abuse Continued from page 25

stance abuse; thus, violent behavior may be a proxy indicator for the relationship between severity of substance abuse and suicide risk.17-19,27 Moreover, violence may be an indicator of increased impulsivity, which has been found to increase the risk of suicide.28 The relationship between impulsivity as an independent entity (distinct from aggression) and suicide risk has been rarely studied. One study that examined impulsive aggression (ie, reactive aggression) found that it did not increase the likelihood of suicide attempt in comparison with premeditated aggression (ie, proactive aggression).29 Self-report measures of impulsivity appear less closely associated with suicidal behaviors than laboratory measures of impulsivity.30 The literature does not provide a clear indicator of whether impulsivity fully or partially explains the link between violence and suicidal behaviors. Another possible explanation for the link between violence and suicide is that violence, particularly partner violence, can create significant social isolation, which increases the risk of suicide.26 Also, Joiner31 proposed that individuals who harm themselves have acquired the capacity to engage in self-injury through repeated exposure to violence and painful stimuli. Inflicting an injury on someone else may be a form of behavioral rehearsal for suicidal behaviors.

Clinical implications Causal mechanisms that explain the links between substance misuse, violence, and suicidal behaviors are not fully understood. Nevertheless, the literature provides several important clinical implications for mental health treatment providers. In all settings, it is important to incorporate questions about violent behavior and substance abuse into broader assessments of suicide risk. Clearly, patients who report a combination of past suicide attempts and/or serious plans of suicide, depression, significant substance misuse, and episodes of interpersonal violence are at significantly elevated risk for future suicidal behaviors. For such patients, treatment that focuses on only 1 of these domains (eg, depression) may not be optimally effective. • Treatment providers should develop a strategy that directly addresses each of these problems

JANUARY 2011

SUICIDE and contains specific steps for managing an acute suicidal crisis. • Treatment providers should consider prescribing medications that directly address the addictive disorder and/or make referrals to specialty addiction treatment facilities. • Treatment providers should consider referring violent patients to anger management therapy or to couple’s behavioral therapy designed to address aggressive behaviors and improve interpersonal problem solving and communication. Research is needed to determine whether such integrated treatment effectively reduces suicidal behaviors in high-risk individuals with substance use disorders and/or violent behavior. Cognitive-behavioral therapy (CBT) focuses directly on suicidal thoughts and behaviors. A large, randomized, controlled trial found that CBT significantly decreased the likelihood of suicidal behaviors over 18 months of follow-up.32 Recently, we have developed a modified version of CBT that focuses specifically on suicidal behaviors in those with substance use disorders. Although the evaluation of this intervention is ongoing, patients appear to appreciate the opportunity to discuss the links between their substance abuse, prior impulsive behaviors, and suicide attempts. Even without a specific CBT approach, the therapeutic relationship can benefit from a direct discussion of the patient’s perception of the connections between his or her substance abuse, tendency to become violent with others, and prior suicide attempts.

CASE VIGNETTE Frank is 45 years old, unemployed, and undergoing court-ordered residential treatment for cocaine dependence following his arrest for drug possession. He reports that he began drinking heavily and using cocaine and marijuana on a regular basis during his late teens. He also reports experiencing frequent “up and down” moods that coincide with his drug use. He has been in numerous romantic relationships, many of which involved physical and verbal altercations. Frank has received inpatient treatment for his addictions in the past. On one occasion, he left treatment early; he completed treatment twice, only to relapse within a week. Frank has made 2 suicide attempts. In previous treatment,

he mentioned his suicide attempts, but the response was either focused on his safety (eg, assigning him a “buddy” to accompany him to the restroom) or an antidepressant or mood stabilizer was prescribed. We added 8 sessions of CBT (2 sessions a week for 4 weeks) for suicidal thoughts and behaviors to standard residential drug treatment. We took a detailed history of Frank’s earlier suicide attempts and identified his perception of the link between his substance abuse, his feelings of frustration or anger, and his suicidal thoughts and behaviors. Much of this work was focused on helping him conceptualize suicidal thoughts as something that he could manage and that does not require him to take action. With our help, Frank was able to develop a detailed list of steps that he could take to keep himself safe when he is feeling suicidal. Frank and the therapist also discussed reasons to be hopeful and ways that he could remember these reasons posttreatment. The final CBT sessions involved an imaginary exposure exercise during which Frank was asked to recall his most recent suicide attempt and then envision himself seeking help before making the attempt. Overall, Frank seemed to appreciate the intervention, and he described the focus on his suicidal behavior as unique and helpful. The relative safety and stability of a residential addictions treatment facility allowed us to focus directly on content related to Frank’s suicidal thoughts, plans, and suicide attempts. Frank stayed for the full 60 days and plans to stay with his brother after discharge. He is part of an ongoing pilot CBT trial and will be followed up 3 months after leaving treatment.

Michigan Medical School in Ann Arbor. Ms Kleinberg is a research associate with the Ann Arbor VA hospital and the department of psychiatry at the University of Michigan Medical School. The authors report no conflicts of interest concerning the subject matter of this article.

References 1. Centers for Disease Control and Prevention. National Center for Injury Prevention & Control: Data & Statistics (WISQARSTM); 2009. http://www.cdc.gov/ injury. Accessed November 16, 2010. 2. Kessler RC, Borges G, Walters EE. Prevalence of and risk factors for lifetime suicide attempts in the National Comorbidity Survey. Arch Gen Psychiatry. 1999;56:617-626. 3. Harris EC, Barraclough B. Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry. 1997;170:205-228. 4. Cavanagh JT, Carson AJ, Sharpe M, Lawrie SM. Psychological autopsy studies of suicide: a systematic review [published correction appears in Psychol Med. 2003;33:947]. Psychol Med. 2003;33:395405. 5. Wilcox HC, Conner KR, Caine ED. Association of alcohol and drug use disorders and completed suicide: an empirical review of cohort studies. Drug Alcohol Depend. 2004;76(suppl):S11-S19. 6. Ilgen MA, Burnette ML, Conner KR, et al. The association between violence and lifetime suicidal thoughts and behaviors in individuals treated for substance use disorders. Addict Behav. 2010;35: 111-115. 7. Roy A. Characteristics of cocaine-dependent patients who attempt suicide. Am J Psychiatry. 2001; 158:1215-1219. 8. Roy A. Characteristics of cocaine dependent patients who attempt suicide. Arch Suicide Res. 2009; 13:46-51. 9. Ilgen MA, Bohnert AS, Ignacio RV, et al. Psychiatric

Summary

diagnoses and risk of suicide in veterans. Arch Gen

Research indicates that substance misuse is consistently associated with suicidal thoughts, suicide attempts, and suicide mortality. The risk of suicide is likely to be greater in persons with more severe levels of substance abuse as well as in those with depression. In addition, a propensity to engage in interpersonal violence is an important suiciderelated risk factor. These findings reinforce the need for increased suicide assessment and intervention efforts to address co-occurring problems in individuals with substance use disorders and/or interpersonal violence.

Psychiatry. 2010;67:1152-1158. 10. Conner KR, Beautrais AL, Conwell Y. Risk factors for suicide and medically serious suicide attempts among alcoholics: analyses of Canterbury Suicide Project data. J Stud Alcohol. 2003;64:551-554. 11. Darke S, Ross J. Suicide among heroin users: rates, risk factors and methods. Addiction. 2002; 97:1383-1394. 12. Ilgen MA, Harris AH, Moos RH, Tiet QQ. Predictors of a suicide attempt one year after entry into substance use disorder treatment. Alcohol Clin Exp Res. 2007;31:635-642. 13. Conner KR, Pinquart M, Gamble SA. Meta-analysis of depression and substance use among individuals with alcohol use disorders. J Subst Abuse Treat. 2009;37:127-137. 14. Maloney E, Degenhardt L, Darke S, et al. Suicidal behaviour and associated risk factors among opioiddependent individuals: a case-control study. Addic-

Dr Ilgen is a psychologist at the Ann Arbor VA

tion. 2007;102:1933-1941. 15. Darke S, Ross J, Lynskey M, Teesson M. Attempt-

hospital and assistant professor in the de-

ed suicide among entrants to three treatment mo-

partment of psychiatry at the University of

dalities for heroin dependence in the Australian

JANUARY 2011

PSYCHIATRIC TIMES

SUICIDE

w w w. psychi atr i cti mes. com

Treatment Outcome Study (ATOS): prevalence and

Am J Psychiatry. 2001;158:1701-1705.

expressed partner and non-partner violence among

30. Wojnar M, Ilgen MA, Czyz E, et al. Impulsive and

risk factors [published correction appears in Drug

25. Ilgen MA, Chermack ST, Murray R, et al. The as-

patients in substance abuse treatment. Drug Alcohol

non-impulsive suicide attempts in patients treated

Alcohol Depend. 2004;73:315]. Drug Alcohol De-

sociation between partner and non-partner aggres-

Depend. 2000;58:43-54.

for alcohol dependence. J Affect Disord. 2009;115:

pend. 2004;73:1-10.

sion and suicidal ideation in patients seeking sub-

28. Conner KR, Ilgen MA. Substance use and sui-

131-139.

16. Wines JD Jr, Saitz R, Horton NJ, et al. Suicidal

stance use disorder treatment. Addict Behav.

cidal behaviour. In: O’Connor R, Platt S, Gordon J,

behavior, drug use and depressive symptoms after

2009;34:180-186.

eds. International Handbook of Suicide Prevention.

detoxification: a 2-year prospective study. Drug Alco-

26. Conner KR, Duberstein PR, Conwell Y. Domestic

Chichester, UK: Wiley-Blackwell. In press.

hol Depend. 2004;76(suppl):S21-S29.

violence, separation, and suicide in young men with

29. Conner KR, Swogger MT, Houston RJ. A test of

17. Cornelius JR, Salloum IM, Day NL, et al. Patterns

early onset alcoholism: reanalyses of Murphy’s data.

the reactive aggression-suicidal behavior hypothe-

nitive therapy for the prevention of suicide attempts:

of suicidality and alcohol use in alcoholics with major

Suicide Life Threat Behav. 2000;30:354-359.

sis: is there a case for proactive aggression? J Ab-

a randomized controlled trial. JAMA. 2005;294:563-

depression. Alcohol Clin Exp Res. 1996;20:1451-

27. Chermack ST, Fuller BE, Blow FC. Predictors of

norm Psychol. 2009;118:235-240.

570. ❒

31. Joiner TE. Why People Die by Suicide. Cambridge, MA: Harvard University Press; 2005. 32. Brown GK, Ten Have T, Henriques GR, et al. Cog-

1455. 18. Murphy GE, Wetzel RD, Robins E, McEvoy L. Multiple risk factors predict suicide in alcoholism. Arch Gen Psychiatry. 1992;49:459-463. 19. Preuss UW, Schuckit MA, Smith TL, et al. Comparison of 3190 alcohol-dependent individuals with and without suicide attempts. Alcohol Clin Exp Res. 2002;26:471-477. 20. Burnette ML, Ilgen M, Frayne SM, et al. Violence perpetration and childhood abuse among men and women in substance abuse treatment. J Subst Abuse Treat. 2008;35:217-222. 21. Chermack ST, Murray RL, Walton MA, et al. Partner aggression among men and women in substance use disorder treatment: correlates of psychological and physical aggression and injury. Drug Alcohol Depend. 2008;98:35-44. 22. Tiet QQ, Ilgen MA, Byrnes HF, Moos RH. Suicide attempts among substance use disorder patients: an initial step toward a decision tree for suicide management. Alcohol Clin Exp Res. 2006;30:998-1005. 23. Koller G, Preuss UW, Bottlender M, et al. Impulsivity and aggression as predictors of suicide attempts in alcoholics. Eur Arch Psychiatry Clin Neurosci. 2002;252:155-160. 24. Conner KR, Cox C, Duberstein PR, et al. Violence, alcohol, and completed suicide: a case-control study.

Need to Contact Us? You can reach the Psychiatric Times editorial department at editor@psychiatrictimes.com. We encourage readers to send letters and comments about articles appearing in Psychiatric Times or topics of general interest to psychiatrists. Letters commenting on published articles may be referred to the authors, and all letters will be considered for publication on the basis of space availability and interest to readers. The editorial staff also extends a call for paper proposals. Topics should be timely and of interest to psychiatrists and other mental health care professionals. Please send proposals with a copy of your curriculum vitae by e-mail to editor@psychiatrictimes.com. Please note that submitted proposals and manuscripts may be sent for peer review. ❒

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Cymbalta is indicated in adults for1:

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

Reimbursement offered for up to 60 days of Cymbalta therapy to a maximum of $700. Prescriptions for more than 2 capsules per day are not eligible for reimbursement. Limit one reimbursement per person.

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

Offer void where prohibited by law. Valid only in the United States for US residents. Offer not valid for patients whose prescription claims for Cymbalta are reimbursed, in whole or in part, by (1) any governmental program, including, without limitation, Medicaid, Medicare, or any other federal or state program, such as Champus, the VA, TRICARE, or a state pharmaceutical assistance program, or (2) any thirdparty payer in the state of Massachusetts. By accepting this offer, patient agrees to notify his/her insurance carrier of reimbursement if required to do so by law or under the terms of coverage.

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

Additional exclusions may apply and this offer may be terminated, rescinded, revoked, or amended by Lilly USA, LLC, at any time without notice. Cymbalta® and the Cymbalta logo are registered trademarks of Eli Lilly and Company.

Reference: 1. Cymbalta full Prescribing Information.

Introducing the Cymbalta Promise program. The Cymbalta Promise program is designed to help get the right patients on the right treatment—whether it’s Cymbalta or not. If you and your patients who are new to Cymbalta are not satisfied, your patients may be reimbursed 100% of their out-ofpocket prescription costs for up to the first 60 days on Cymbalta. Ask your Cymbalta representative or visit cymbaltapromise.com to learn more. This program is not a guarantee of efficacy. It provides a trial period that may help patients and doctors assess the efficacy, safety, and tolerability of Cymbalta. Restrictions apply. See full Terms and Conditions below.

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 shortterm 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.

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. (cont.)

See Important Safety Information, including Boxed Warning, above and on next page, and Brief Summary of full Prescribing Information on following pages. DD68176 0111

Cymbalta is a registered trademark of Eli Lilly and Company.

Important Safety Information About Cymbalta (Cont.) Contraindications (Cont.) • 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. • 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 (cont.)

Important Safety Information About Cymbalta (Cont.) Warnings and Precautions (Cont.) and SNRIs. A gradual reduction in dose rather than abrupt cessation is recommended when possible. • Cymbalta should be used cautiously in patients with a history of mania or with a history of a seizure disorder. • 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. • 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 endstage renal disease (requiring dialysis) or severe renal impairment (creatinine clearance <30 mL/min). • 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 • Pregnancy and Nursing Mothers: Use only if the potential benefit justifies the potential risk to the fetus or child.

Most Common Adverse Events • 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%). * 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 full Prescribing Information, including Boxed Warning. DD HCP ISI 4NOV10

DD68176 0111

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

JANUARY 2011

CLINICAL

PSYCHIATRIC TIMES

w w w. psychi atr i cti mes. com

Psychiatric Assessment and Treatment in Preschool Children Early Disorder Detection and Diagnosis by Joan L. Luby, MD ignificant scientific progress has been made in the field of infant and preschool psychiatry over the past 2 decades. Although this is a field with a long and rich theoretical history, empirical investigations of psychiatric disorders in infants and preschoolers have significantly lagged behind other areas of psychiatry and medicine. Advances in the understanding of early normative social and emotional development over the past decade as well as the more recent availability of ageappropriate psychiatric interviews for the caregivers of young children have facilitated investigations of very early–onset mental disorders. Following these advances, empirical validation for several Axis I psychiatric disorders in children as young as 2 or 3 years has become available. These disorders include major depressive disorder (MDD), posttraumatic stress disorder (PTSD), oppositional defiant disorder (ODD), and attention-deficit/hyperactivity disorder (ADHD). Autism has been well described in young children for many decades, with more recent focus on even earlier detection in infancy. Investigations of the nosology of anxiety disorders and attachment disorders are under way. These advances are of obvious importance for ameliorating the impairments and relieving the suffering of young children. Beyond their importance to the field of child psychiatry, these advances may also have implications for intervention in mental disorders across the life span. This is based on the exciting possibility that earlier intervention during a period of rapid developmental change and brain neuroplasticity early in life may provide a window of opportunity for greater treatment effects. The robust efficacy of early intervention—while broadly accepted as key for many years in numerous general developmental domains, such as speech, language, and motor development—is also emerging in several specific mental disorders. The importance of identifying mental disorders at the earliest possible developmental point during infancy and the preschool period is underscored by relatively enhanced

treatment effects found in autistic spectrum and disruptive disorders.1-3

The social and emotional sentience of young children There has been a widespread and long-standing assumption that young children are not vulnerable to serious mental disorders. Related to this is the presumption that young children are emotionally unaware and unsophisticated and therefore are unreactive or relatively immune to emotional experiential events. The latter presumption has been refuted by empirical lit-

disorders, and autistic spectrum disorders are now known to arise in very early childhood.6,7 However, the detection and accurate diagnosis of these conditions in very young children can be complicated and challenging for the clinician. Psychiatric assessment of the infant and preschooler requires specialized techniques, observations over time whenever possible, and the need to distinguish clinically significant symptoms from the normative behavioral and emotional extremes known to characterize early childhood.

givers are also key to gaining a clear clinical picture. Semistructured interview formats that allow the clinician to observe the dyad under a variety of evocative circumstances, such as eating, structured play, free play, and brief separations and reunions, are often useful. Along this line, clinicians and parents should be wary of psychiatric diagnoses given to young children after only 1 brief observation of behavior. Articles outlining practice parameters and chapters describing these age-adjusted techniques in more detail are available.8,9

CHECK POINTS

Developmental adjustments to symptom manifestations

 Empirical validation for several Axis I psychiatric disorders in children as

One of the central issues in conducting an age-appropriate clinical or research assessment of the young child is the need to probe for developmentally adjusted symptom manifestations. Simply on the basis of life experiences of the young child compared with those of the older child or adult, some symptoms will be manifest and evidenced differently. One obvious example is decreased libido; this common manifestation of anhedonia in an adult is not a developmentally possible manifestation of anhedonia in a young child. However, age-adjusted manifestations of anhedonia, not a normative variation in a young child, includes the inability to enjoy play, which is commonly seen in depressed young children. Thus, anhedonia can occur throughout the age span, but its manifestations will be evident in a developmentally specific fashion. If clinicians probe for key symptoms of DSM disorders typically designed for adults and older children, they are likely to conclude that symptoms are not present and therefore may fail to detect a disorder. Several age-adjusted structured and semistructured interviews for research use have been developed for the caregivers of young children. Although they are not designed for clinical use, such tools may help guide clinical interviews.10,11

young as 2 or 3 years has become available. Basic developmental findings indicate that young children are vulnerable to traumatic life events and negative emotional experiences.

 Key features of the diagnostic assessment of young children are the

centrality of the child-caregiver relationship, or “dyad,” as the unit of observation. Multiple observations are needed because of the potentially powerful impact of fatigue or even mild illness on the behavior of a young child, which often gives rise to a nonrepresentative mental status examination.

 One of the central issues in conducting an age-appropriate clinical or research assessment of the young child is the need to probe for developmentally adjusted symptom manifestations.

erature on the social and emotional development of young children.4,5 As the early emotional competency of young children was elucidated—including their sensitivity to trauma, their very early ability to distinguish their caregivers from others, and their ability to experience complex emotions such as guilt and shame—so was detection and understanding of early-onset mental disorders. These findings highlight the vulnerability of young children to traumatic life events and negative emotional experiences and underscore the need for attention to these early developmental domains. A vast and diverse literature stresses the central importance of developing and maintaining nurturing psychosocial environments for young children.

The need for age-appropriate assessment techniques Numerous Axis I mental disorders, including MDD, PTSD, anxiety disorders, ADHD, ODD, attachment

Key features of the diagnostic assessment of the young child are the centrality of the child-caregiver relationship, or “dyad,” as the unit of observation. This is based on the wellestablished principle that the young child is inextricably dependent on the caregiver for emotional functioning and well-being. In addition, the context and relationship specificity of symptom expression and the use of play as the medium of observation are also key guiding principles of the infant and preschool mental health evaluation. The evaluation of the young child should always be done in the context of play within the child-caregiver dyad. Given the need for this, assessments are generally performed over several weeks. Multiple observations are needed because of the potentially powerful impact of fatigue or even mild illness on the behavior of a young child, which often gives rise to a nonrepresentative mental status examination. Play observations with different care-

Clinical presentation of Axis I disorders in preschoolers While a surprising level of continuity has been evident in the core symp(Please see Preschoolers, page 38)

W E N

F o r pat i e n t s s t r u g g l i n g TO STAY ASLEEP T H ROUG H T H E NIG H T. . .

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Silenor is indicated for the treatment of insomnia characterized by difficulty with sleep maintenance. IMPORTANT SAFETY INFORMATION Silenor is contraindicated in individuals who have shown hypersensitivity to doxepin HCl, any of its inactive ingredients, or other dibenzoxepines. Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors (MAOIs). Do not administer Silenor if patient is currently on MAOIs or has used MAOIs within the past two weeks. The exact length of time may vary depending on the particular MAOI dosage and duration of treatment. Silenor is contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a hypnotic, with amnesia for the event) have been reported with hypnotics. These

events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with hypnotics alone at therapeutic doses, the use of alcohol or other central nervous system depressants with hypnotics appears to increase the risk of such behaviors, as does the use of hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Silenor should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (i.e., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic. As with “sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably. Patients should not consume alcohol with Silenor. Patients should be cautioned about potential additive effects of Silenor used in combination with CNS depressants or sedating antihistamines.

A histamine antagonist with high affinity for the H1 receptor1

The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but is believed to be due to its antagonism of the H1 receptor

Demonstrated efficacy for the treatment of sleep maintenance insomnia in1:

dult and elderly patients A

Chronic and transient insomnia

Not a controlled substance1

No abuse potential or evidence of physical dependence/withdrawal symptoms

Low incidence of side effects and a discontinuation rate similar to placebo in clinical trials1

1 In clinical trials, the most common treatment-emergent adverse reaction was somnolence/sedation

Available in 3 mg and 6 mg tablets. Total daily dose should not exceed 6 mg. For samples, visit www.silenorsamples.com or for more information about Silenor, call 1-877-SILENOR or visit www.silenor.com.

In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of hypnotics. Doxepin, the active ingredient in Silenor, is an antidepressant at doses 10- to 100-fold higher than in Silenor. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Risk from the lower dose of doxepin in Silenor can not be excluded. Patients should not take Silenor unless they are prepared to get a full nightâ&#x20AC;&#x2122;s sleep. After taking Silenor, patients should confine their activities to those necessary to prepare for bed. Patients should avoid engaging in hazardous activities, such as operating a motor vehicle or heavy machinery, at night after taking Silenor, and should be cautioned about potential impairment in the performance of such activities that may occur the day following ingestion.

For faster onset and to minimize the potential for next day effects, Silenor should not be taken within 3 hours of a meal. In clinical trials, the most common treatment-emergent adverse reaction was somnolence/sedation. Silenor has not been studied in pregnant women. Silenor is excreted in human milk after oral administration. Silenor is not approved for use in children. Please see brief summary of Full Prescribing Information on adjacent page. Reference: 1. Silenor prescribing information, Somaxon Pharmaceuticals, Inc., March 2010.

Visit www.somaxon.com.

ÂŠ2010 Somaxon Pharmaceuticals, Inc.

SIL-0049.P2A

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

Preschoolers

nosology across this age span. MDD has been identified in preschoolers and shows continuity in the same core criteria when developmental adjustments of symptom manifestations are assessed. The question of whether the 2-week duration criterion should be modified for the preschooler has been raised; empirical data suggest that the same duration threshold may not apply at this younger age. Barring that adjustment, however, no

Continued from page 35

toms of several Axis I psychiatric disorders in children as young as preschool age, the need for some important developmental adjustments has also become clear. Two disorders well known in adults but also seen in preschoolers, for which there is a relatively large database, might serve as illustrative contrasting examples of continuities and discontinuities in

SilenorÂŽ (doxepin) tablets for oral administration Brief summary of Prescribing Information. For complete Prescribing Information, consult ofďŹ cial package insert. INDICATIONS AND USAGE Silenor is indicated for the treatment of insomnia characterized by difďŹ culty with sleep maintenance. The clinical trials performed in support of efďŹ cacy were up to 3 months in duration. CONTRAINDICATIONS Hypersensitivity: Silenor is contraindicated in individuals who have shown hypersensitivity to doxepin HCl, any of its inactive ingredients, or other dibenzoxepines. Co-administration With Monoamine Oxidase Inhibitors (MAOIs): Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Do not administer Silenor if patient is currently on MAOIs or has used MAOIs within the past two weeks. The exact length of time may vary depending on the particular MAOI dosage and duration of treatment. Glaucoma and Urinary Retention: Silenor is contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention. WARNINGS AND PRECAUTIONS Need to Evaluate for Comorbid Diagnoses: Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Exacerbation of insomnia or the emergence of new cognitive or behavioral abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such ďŹ ndings have emerged during the course of treatment with hypnotic drugs. Abnormal Thinking and Behavioral Changes: Complex behaviors such as â&#x20AC;&#x153;sleep-drivingâ&#x20AC;? (i.e., driving while not fully awake after ingestion of a hypnotic, with amnesia for the event) have been reported with hypnotics. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Although behaviors such as â&#x20AC;&#x153;sleep-drivingâ&#x20AC;? may occur with hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with hypnotics appears to increase the risk of such behaviors, as does the use of hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Silenor should be strongly considered for patients who report a â&#x20AC;&#x153;sleep-drivingâ&#x20AC;? episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic. As with â&#x20AC;&#x153;sleep-drivingâ&#x20AC;?, patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably. Suicide Risk and Worsening of Depression: In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of hypnotics. Doxepin, the active ingredient in Silenor, is an antidepressant at doses 10- to 100-fold higher than in Silenor. 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. Risk from the lower dose of doxepin in Silenor cannot be excluded. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

and 283 healthy subjects) participated in six randomized, placebo-controlled efďŹ cacy studies with Silenor doses of 1mg, 3 mg, and 6 mg for up to 3-months in duration. 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 reďŹ&#x201A;ect the rates observed in practice. However, data from the Silenor studies provide the physician with a basis for estimating the relative contributions of drug and non-drug factors to adverse reaction incidence rates in the populations studied. Associated with Discontinuation of Treatment: The percentage of subjects discontinuing Phase 1, 2, and 3 trials for an adverse reaction was 0.6% in the placebo group compared to 0.4%, 1.0%, and 0.7% in the Silenor 1 mg, 3 mg, and 6 mg groups, respectively. No reaction that resulted in discontinuation occurred at a rate greater than 0.5%. _ 2% in Adverse Reactions Observed at an Incidence of > Controlled Trials: Table 1 shows the incidence of treatment-emergent adverse reactions from three long-term (29 to 85 days) placebocontrolled studies of Silenor in adult (N=221) and elderly (N=494) subjects with chronic insomnia. Reactions reported by Investigators were classiďŹ ed using a modiďŹ ed MedDRA dictionary of preferred terms for the purposes of establishing incidence. The table includes only reactions that occurred in 2% or more of subjects who received Silenor 3 mg or 6 mg in which the incidence in subjects treated with Silenor was greater than the incidence in placebo-treated subjects. Incidence (%) of Treatment-Emergent Adverse Reactions in Long-term Placebo-Controlled Clinical Trials System Organ Class Preferred Terma

Placebo (N=278)

Silenor Silenor 3 mg 6 mg (N=157) (N=203)

Nervous System Disorders Somnolence/Sedation

Upper Respiratory Tract Infection/Nasopharyngitis

Gastroenteritis

Infections and Infestations

Gastrointestinal Disorders Nausea Vascular Disorders Hypertension a

_ 2% in any Includes reactions that occurred at a rate of > Silenor-treated group and at a higher rate than placebo.

The most common treatment-emergent adverse reaction in the placebo and each of the Silenor dose groups was somnolence/sedation. Studies Pertinent to Safety Concerns for Sleeppromoting Drugs: Residual Pharmacological Effect in Insomnia Trials: Five randomized, placebo-controlled studies in adults and the elderly assessed next-day psychomotor function within 1 hour of awakening utilizing the digit-symbol substitution test (DSST), symbol copying test (SCT), and visual analog scale (VAS) for sleepiness, following night time administration of Silenor. In a one-night, double-blind study conducted in 565 healthy adult subjects experiencing transient insomnia, Silenor 6 mg showed modest negative changes in SCT and VAS. In a 35-day, doubleblind, placebo-controlled, parallel group study of Silenor 3 and 6 mg in 221 adults with chronic insomnia, small decreases in the DSST and SCT occurred in the 6 mg group. In a 3-month, double-blind, placebo-controlled, parallel group study in 240 elderly subjects with chronic insomnia, Silenor 1 mg and 3 mg was comparable to placebo on DSST, SCT, and VAS.

CNS Depressant Effects: After taking Silenor, patients should conďŹ ne their activities to those necessary to prepare for bed. Patients should avoid engaging in hazardous activities, such as operating a motor vehicle or heavy machinery, at night after taking Silenor, and should be cautioned about potential impairment in the performance of such activities that may occur the day following ingestion. When taken with Silenor, the sedative effects of alcoholic beverages, sedating antihistamines, and other CNS depressants may be potentiated. Patients should not consume alcohol with Silenor. Patients should be cautioned about potential additive effects of Silenor used in combination with CNS depressants or sedating antihistamines.

DRUG INTERACTIONS Cytochrome P450 Isozymes: Silenor is primarily metabolized by hepatic cytochrome P450 isozymes CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Inhibitors of these isozymes may increase the exposure of doxepin. Silenor is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations. The ability of Silenor to induce CYP isozymes is not known.

ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of labeling:

Alcohol: When taken with Silenor, the sedative effects of alcohol may be potentiated.

s !BNORMAL THINKING AND BEHAVIORAL CHANGES

CNS Depressants and Sedating Antihistamines: When taken with Silenor, the sedative effects of sedating antihistamines and CNS depressants may be potentiated.

s 3UICIDE RISK AND WORSENING OF DEPRESSION s #.3 $EPRESSANT EFFECTS Clinical Trials Experience: The pre-marketing development program for Silenor included doxepin HCl exposures in 1017 subjects (580 insomnia patients and 437 healthy subjects) from 12 studies conducted in the United States. 863 of these subjects (580 insomnia patients

Cimetidine: Silenor exposure is doubled with concomitant administration of cimetidine, a nonspeciďŹ c inhibitor of CYP isozymes. A maximum dose of 3 mg is recommended in adults and elderly when cimetidine is co-administered with Silenor.

Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 g/day) 11 days after the addition of oral doxepin (75 mg/day).

modifications of the basic nosology appear to be indicated, which suggests that the nosology of MDD shows continuity across the age span. In contrast, PTSD has also been detected and validated in children as young as 3 years. However, to cross the clinical threshold, the empirical data suggest that fewer avoidance and numbing (criterion C) symptoms be required.12 Adjustments are also needed reUSE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate and well-controlled studies of Silenor in pregnant women. Silenor should be used during pregnancy only if the potential beneďŹ t justiďŹ es the potential risk to the fetus. Administration of doxepin to pregnant animals resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 6 mg/day. When doxepin (30, 100, and 150 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, developmental toxicity (increased incidences of fetal structural abnormalities and decreased fetal body weights) was noted _ 100 mg/kg/day. The plasma exposures (AUC) at the at > no-effect dose for embryo-fetal developmental toxicity in rats (30 mg/kg/day) are approximately 6 and 3 times the plasma AUCs for doxepin and nordoxepin (the primary metabolite in humans), respectively, at the MRHD. When administered orally to pregnant rabbits (10, 30, and 60 mg/kg/day) during the period of organogenesis, fetal body weights were reduced at the highest dose in the absence of maternal toxicity. The plasma exposures (AUC) at the no-effect dose for developmental effects (30 mg/kg/day) are approximately 6 and 18 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD. Oral administration of doxepin (10, 30, and 100 mg/kg/day) to rats throughout the pregnancy and lactation periods resulted in decreased pup survival and transient growth delay at the highest dose. The plasma exposures (AUC) at the no-effect dose for adverse effects on pre- and postnatal development in rats (30 mg/kg/day) are approximately 3 and 2 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD. Labor and Delivery: The effects of Silenor on labor and delivery in pregnant women are unknown. Nursing Mothers: Doxepin is excreted in human milk after oral administration. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking the higher dose of doxepin used to treat depression. Caution should be exercised when Silenor is administered to nursing women. Pediatric Use: The safety and effectiveness of Silenor in pediatric patients have not been evaluated. Geriatric Use: _ 65 years and 86 subjects A total of 362 subjects who were > _ 75 years received Silenor in controlled clinical who were > studies. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects. Greater sensitivity of some older individuals cannot be ruled out. Sleep-promoting drugs may cause confusion and over-sedation in the elderly. A starting dose of 3 mg is recommended in this population and evaluation prior to considering dose escalation is recommended. Use in Patients With Hepatic Impairment: Patients with hepatic impairment may display higher doxepin concentrations than healthy individuals. Initiate Silenor treatment with 3 mg in patients with hepatic impairment and monitor closely for adverse daytime effects. Use in Patients With Sleep Apnea: Silenor has not been studied in patients with obstructive sleep apnea. Since hypnotics have the capacity to depress respiratory drive, precautions should be taken if Silenor is prescribed to patients with compromised respiratory function. In patients with severe sleep apnea, Silenor is ordinarily not recommended for use. OVERDOSAGE Doxepin is routinely administered for indications other than insomnia at doses 10- to 50-fold higher than the highest recommended dose of Silenor. The signs and symptoms associated with doxepin use at doses several-fold higher than the maximum recommended dose (Excessive dose) of Silenor for the treatment of insomnia are described, as are signs and symptoms associated with higher multiples of the maximum recommended dose in the full prescribing information. PATIENT COUNSELING INFORMATION Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the beneďŹ ts and risks associated with treatment with hypnotics, should counsel them in appropriate use, and should instruct them to read the Medication Guide. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

JANUARY 2011

garding the manner in which multiple symptoms may manifest (a developmental adjustment as above). Therefore, PTSD is a disorder in which developmental adjustments to the basic nosology appear to be indicated. Empirical studies of several other Axis I disorders in preschoolers have been done or are ongoing and will clarify the continuity and discontinuity of nosology across the age span.

Prevalence rates and referral patterns As is well established in older children with mental health disorders, young children with disruptive behavior are more frequently referred for evaluation and treatment than those with primary symptoms of mood or anxiety disorders. Autistic spectrum disorders are increasingly being detected earlier, and young children often present to infant and preschool mental health settings with symptoms of these disorders. It is less common for children with mood or anxiety disorders to be referred unless symptoms become severe or unless families are particularly familiar with or sensitive to these symptoms. More subtle manifestations that do not produce obvious impairment in the home or school setting are likely to go undetected. To date, large-scale epidemiological studies of mental disorders in young children that use updated DSM criteria and assessment techniques have not been conducted and are needed. However, smaller epidemiological studies have demonstrated that the prevalence of Axis I major mental disorders is similar to that in older children, when age-adjusted criteria were used when indicated.13,14

Treatment of early-onset mental disorders Because the recognition of earlyonset mental disorders has only recently become more widely accepted, the testing and development of age-specific treatments has also been slow to emerge. Some empirically supported early interventions are available, such as Parent-Child Interaction Therapy (PCIT) and the Incredible Years, for disruptive behavioral disorders, and Applied Behavior Analysis and its variants, for autistic spectrum disorders. Other psychotherapeutic treatments, in particular, various forms of play therapy, have been widely used clinically but have not for the most part been

sufficient-ly tested in empirical studies. Early dyadic psychotherapeutic interventions for MDD (an adapted version of PCIT) and PTSD (an adaptation of cognitive-behavioral therapy) are undergoing testing, and preliminary findings appear to be promising.12,15 Despite increasing rates of pharmacological treatment being prescribed for preschool-age children, in general, psychopharmacology should be avoided in this age-group. The exceptions to this are for use to target dangerous self-destructive or aggressive symptoms in autism and the cautious use of stimulants for ADHD in preschoolers; both indications are supported by double-blind placebo-controlled studies. With these exceptions, psychopharmacological options are insufficiently tested and not indicated as first- or second-line treatment of psychiatric disorders in preschoolers.

The gap between scientific data, clinical practice, and public policy Advances in our understanding of early emotional development and early-onset mental disorders have yet to be incorporated into clinical practice and public policy. Despite a significant body of emerging data that demonstrate that children as young as 2 or 3 years can manifest Axis I psychiatric disorders, it is still uncommon for such young children to be referred for mental health services. Unfortunately, primary care physicians still commonly assume that these children are too young to be vulnerable to mental disorders. At the same time, psychotropic medications are being prescribed for very young children at an exponentially increasing rate for unclear indications and presumably without age-appropriate mental health evaluations.16 A likely contributor to this trend is the lack of mental health clinicians with expertise in the assessment and treatment of young children. There is also a lack of access to age-appropriate psychotherapies, which are not widely available despite several psychotherapeutic and developmental treatments with very solid empirical data to support their efficacy.1,3 In this context, primary care physicians may be inclined to prescribe psychotropic medications to provide more immediate, and unfortunately more feasible, assistance to distressed families. Problems with access to treatment notwithstanding, significant efforts must now be made to educate general psychiatrists and primary care physicians about advances in infant and

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preschool mental health. This should include knowledge of how to screen for and refer children with early-onset symptoms as well as of the availability of age-appropriate psychotherapeutic treatments. Expansion of ageappropriate developmental psychotherapeutic services must become a top public health priority to make these treatments more widely available to young children and to capture the potential greater benefit of the earliest possible intervention for mental disorders.

Book Review The Little Psychotherapy Book: Object Relations in Practice by Allan Frankland, MD; New York: Oxford University Press, 2010 200 pages • $29.95 (paperback)

Reviewed by Deborah Pollack, PhD

Dr Luby is professor of child psychiatry and director of the Early Development Program at Washington University School of Medicine in St Louis. She has received grant support from the NIMH, National Alliance for Research on Schizophrenia and Depression, and Communities Healing Adolescent Depression and Suicide. References 1. Brinkmeyer M, Eyberg SM. Parent-child interaction therapy for oppositional children. In: Kazdin AE, Weisz JR, eds. Evidence-Based Psychotherapies for Children and Adolescents. New York: Guilford Press; 2003:204-223. 2. Dawson G. Early behavioral intervention, brain plasticity, and the prevention of autism spectrum disorder. Dev Psychopathol. 2008;20:775-803. 3. Rogers SJ, Vismara LA. Evidence-based comprehensive treatments for early autism. J Clin Child Adolesc Psychol. 2008;37:8-38. 4. Saarni C. Emotional competence: a developmental perspective. In: Bar-On R, Parker JDA, eds. The Handbook of Emotional Intelligence. San Francisco: Jossey-Bass; 2000:68-91. 5. Denham SA. Emotional Development in Young Children. New York: Guilford Press; 1998. 6. Luby JL, Belden A. Mood disorders. In: Luby JL, ed. Handbook of Preschool Mental Health: Development, Disorders and Treatment. New York: Guilford Press; 2006. 7. Luby JL. Depression. In: Zeanah CH Jr, ed. Handbook of Infant Mental Health. 2nd ed. New York: Guilford Press; 2000:382-396. 8. Luby JL, Tandon M. Assessing the preschool-age child (4-5). In: Dulcan MK, ed. Dulcan’s Textbook of Child and Adolescent Psychiatry. Washington, DC: American Psychiatric Publishing; 2009:15-25. 9. Thomas JM, Benham AL, Gean M, et al. Practice parameters for the psychiatric assessment of infants and toddlers (0-36 months). American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry. 1997;36(10 suppl):21S-36S. 10. Egger HL, Ascher B, Angold A. The Preschool Age Psychiatric Assessment: Version 1.4. Durham, NC: Center for Developmental Epidemiology, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center; 2003. 11. Fisher P, Lucas C. Diagnostic Interview Schedule for Children (DISC-IV): Young Child. New York; Columbia University; 2006. 12. Scheeringa MS, Weems CF, Cohen JA, et al. Trauma-focused cognitive-behavioral therapy for posttraumatic stress disorder in three through six year-old children: a randomized clinical trial. J Child Psychol Psychiatry. In press. 13. Egger HL, Angold A. Common emotional and behavioral disorders in preschool children: presentation, nosology, and epidemiology. J Child Psychol Psychiatry. 2006;47:313-337. 14. Lavigne JV, Lebailly SA, Hopkins J, et al. The prevalence of ADHD, ODD, depression, and anxiety in a community sample of 4-year-olds. J Clin Child Adolesc Psychol. 2009;38:315-328. 15. Lenz SN, Pautsch J, Luby JL. Parent-child interaction therapy emotion development: a novel treatment for depression in preschool children. Depression Anxiety. In press. 16. Olfson M, Crystal S, Huang C, Gerhard T. Trends in antipsychotic drug use by very young, privately insured children. J Am Acad Child Adolesc Psychiatry. 2010;49:13-23. ❒

w w w. psychi atr i cti mes. com

In The Little Psychotherapy Book: Object Relations in Practice, Dr Allan Frankland simplifies objectrelational theory and offers concrete advice for the beginning clinician. Throughout the text, Dr Frankland successfully demystifies technical terms, such as “projective identification” and “object constancy,” in a way that is easily digestible for the new therapist— all without losing their depth and complexity. Particularly impressive are explanations of Klein’s paranoidschizoid and depressive positions and his application of these abstract concepts to a realistic case example. His use of the same case throughout the book provides simplicity and continuity, and transcripts that illustrate the progression of the case over time are annotated with descriptions of the therapist’s use of techniques such as confrontation, clarification, and interpretation. The book offers a nice balance of structure and flexibility in its didactic approach. For example, Dr Frankland developed 2 mnemonic acronyms to help guide the novice clinician (eg, psychiatric residents and doctoral students in clinical psychology) through their sessions with patients. The first concerns the therapist’s interventions: Hear, Observe, React, Synthesize, Execute (H.O.R.S.E.). The second focuses on the content of the client’s communication: Concrete, Others, Self, Therapist (C.O.S.T.). In so doing, the author simplifies what can often seem a like a mystifying process. At the same time, Dr Frankland

encourages his readers to develop their own style and clinical intuition and discourages dogmatism and rigidity. The second half of the book reads like a trusted supervisor offering advice on basic clinical quandaries. For example, Dr Frankland makes recommendations on how to begin an initial session (including whether or not to speak before the patient does); self-disclosure; and how to handle gift giving and requests for advice from patients. His discussion of these topics is likely to be appreciated, since trainees often hesitate to ask their supervisors such questions, fearing they should already know how to handle difficult situations. On the other hand, more often than not, supervisors take for granted that their trainees must have learned about these issues “somewhere along the way” and rarely explicitly address them. At times, Dr Frankland’s suggestions are drawn directly from object-relational theory; but more often, he seems to rely on his own clinical experience, ie, what has worked for him. Of course, the danger of offering such idiosyncratic solutions is that trainees may merely mimic Dr Frankland without a full understanding of the theoretical and clinical rationale underlying the intervention. For example, he could have spent more time discussing the “healing factors” in object-relational psychotherapy so that trainees could go beyond learning what to say and when to say it and develop a deeper appreciation for why these techniques work. Nonetheless, this book is recommended for therapy trainees who are interested in relational psychodynamic approaches and concerned with putting these seemingly abstract concepts into “real world” practice. Dr Pollack is clinical assistant professor in the department of psychiatry and behavioral sciences at the SUNY Upstate Medical University in Syracuse, NY, and a psychologist in private practice. ❒

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JANUARY 2011

RESIDENT’S CORNER

Asking the Right Question by Howard Forman, MD

eflecting on my internship year evokes anxious feelings, despite the fact that I am separated from it by time, distance, and hundreds of positive experiences.

After my initial anxious reflex, I am calmed when my thoughts about the year turn not toward a favorite lecture by an attending physician or a particularly rewarding patient interaction, but rather to a question posed by a senior psychiatrist with whom I had only a tangential relationship. Working as an intern at a major urban hospital center, I often admitted patients who received their outpatient psychiatric care at one of the numerous other training clinics in the city. One evening, I admitted a man with paranoid schizophrenia whose outpatient psychiatrist was the chief resident of a program just down the street from my hospital. The chief resident and I talked several times to ensure that the patient’s hospital care would be compatible with the outpatient treatment setting to which he would be discharged. When the patient was ultimately discharged, I got a call from the chief resident’s program director, Dr M, who thanked me for the care I had

given the patient. Dr M and I knew each other because I had interviewed with him when I applied to his residency program. That interview had been quite memorable. We hit it off, and I found Dr M’s passion for the science and art of training future psychiatrists electrifying. The 2-hour interview had felt like 15 minutes. Our phone call on that October day would be much shorter but would seem much longer than our initial conversation. Although Dr M’s voice had the same enthusiasm I remembered, he must have had insight into the muting of mine. I recall the disappointment I felt on the phone with Dr M because the last time we met, we had spoken about my plans and goals for the future. Now I was thinking about how to trudge through each day of work. When Dr M simply asked, “Are you happy?” I was silent and could not answer right away. To answer untruthfully did not seem right, and to answer honestly meant admitting

something of which I was greatly ashamed. Dr M ended the silence by telling me, “If you ever want to come to my office for guidance, please feel free to give me a call.” A month later, I took Dr M up on his offer and was sitting in the same office in which I had interviewed about a year earlier. After we exchanged pleasantries, he asked if psychiatry was still the right career choice for me. After I said yes, he asked me what had changed in the months since our first meeting. He listened and inquired, “Have you thought about moving to a new program that may be a better fit?” Although I had not previously thought about it and did not even know if it would be possible, Dr M encouraged me to consider switching programs. He made it clear that if there was anything he could do to help me, he would be available. He said it seemed like I had changed a great deal and that it was sad to see me without the eagerness he remembered from our first meeting. Eventually, through a string of good fortune, I was able to find a second-year spot at my current program. Although it is premature to declare a victorious ending to this

story (I am at just about the midway point of my residency training), I can say with a great deal of gratitude that I am at a “happy middle.” From my perspective, there is one thing that makes this more than a purely feel-good story of a senior doctor who owed a neophyte nothing and gave him so much. It is the impact that Dr M’s guidance continues to have on me. Dr M did not set me on a better course with a brilliant interpretation; he helped me see things differently with the shortest, most succinct question: “Are you happy?” Possibly most important, he communicated sincere concern and a desire to help. Dr M’s elegance was in his simplicity. Thanks to him, when I feel those anxious pangs thinking about intern year, they are quickly relieved by consideration of one of the most important lessons I learned that year. Simple words and basic kindness are necessary therapeutic components that can help me direct my patients to the places in life that are the right fit for them. Dr Forman is a third-year resident in the department of psychiatry and behavioral sciences at Montefiore Medical Center in the Bronx, NY. ❒

Book Review Developmental Disabilities From Childhood to Adulthood: What Works for Psychiatrists in Community and Institutional Settings Edited by Roxanne C. Dryden-Edwards and Lee Combrinck-Graham; Baltimore: Johns Hopkins University Press, 2010 • 376 pages • $65 (hardcover)

Reviewed by Kevin M. Antshel, PhD This book is a welcome addition to the library of any mental health professional working in the field of developmental disabilities. An increasing number of developmentally disabled individuals are living in the community in independent or semi-independent settings. Relatively fewer persons who are generally more functionally impaired reside in institutional settings. Psychiatrists and other mental health professionals are increasingly involved in the multimodal treatments provided in both settings. Thus, a book that provides relevant information regarding assessment and treatment of persons with developmental disabilities, especially one that approaches this issue from a life span perspective, is

greatly appreciated. The editors have assembled relevant reviews of the broad topics important to any practicing mental health clinician. While the title clearly states that the book is written with psychiatrists in mind, any clinician can readily use information provided in the book. Except for the chapter on psychopharmacology, the others broadly apply to anyone working in the field. All are well written and contain relevant information. Several stand out in both novelty and practicality. The chapter on geropsychiatry, written by John de Figueiredo, covers a topic not often found in other texts. As correctly noted by de Figueiredo, the aging population of individuals with developmental disabilities is an underserved cohort. He also covers the topic of diagnostic overshadowing (attributing psychiatric symptoms to the developmental disorder rather than to an independent psychiatric disorder). Diagnostic overshadowing is a very real challenge to mental health clinicians who work with this population regardless of age, yet it can be especially salient to those who work in geropsychiatry. (Diagnostic overshadowing is also covered in the assessment chapter written by Stephanie Hamarman.) The chapter on acquired brain injury is especially helpful. Gregory O’Shanick and Ronald

Savage outline many strategies and interventions for teachers who work with students with acquired brain injuries. In a chapter on special education laws, Robin Church and Derek Glaaser address issues relevant to the Americans with Disabilities Act as well as the Individuals with Disabilities Education Act. Church and Glaaser use case examples that highlight the inherent complexities of these laws. The ethical and legal issues chapter, written by Judith Levy and Maureen van Stone, also has case examples to discuss decision-making capacities of individuals in this population and ethical and legal issues that may arise. In sum, Dryden-Edwards and CombrinckGraham have edited a wonderful text relevant to those mental health professionals who work in the developmental disabilities field. While there is some redundancy between chapters, and it would have been nice to see more charts, tables, and graphs, my overall impression of this book is quite positive. In fact, my largest issue with the book is its title; this book is a great reference for all who work with this population, not just psychiatrists. Dr Antshel is associate professor of psychiatry, department of psychiatry and behavioral sciences at SUNY Upstate Medical University, Syracuse, NY. ❒

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PSYCHIATRIC TIMES

CONVULSIVE THERAPY

w w w. psychi atr i cti mes. com

Electroconvulsive Therapy: The Second Most Controversial Medical Procedure by Charles H. Kellner, MD any articles about electroconvulsive therapy (ECT) begin with a statement about ECT’s stature as the most effective treatment for serious depression1; the statement is a reminder to the reader that, yes, ECT is still used and is still a part of mainstream psychiatry.

Such a reminder is necessary because, for the most part, ECT remains in the shadows; most laypersons are surprised to find it is still widely practiced, and many psychiatrists are unaware of, or even oppose, its widespread use. A recent cover story of The New York Times Magazine about abortion2 brought to mind several similarities between the position of abortion in American medicine and that of ECT. The Times article describes the efforts of several ob-gyn physicians to make modern, safe abortion available in the United States and to make abortion training a standard part of the medical school curriculum.2 It came as a surprise to me that abortion training is not universally part of what is taught in medical school. Much of the article centered on the commitment, patient advocacy, and courage of the physicians involved— courage, because of the threats to which they are exposed. Antiabortion activists have used all manner of methods to assert their views, including bombing clinics and murdering abortion doctors. In subsequent letters about the article, a reader worried that the article itself would increase the risks to the abortion providers who were chronicled. While no ECT practitioners have been murdered and the rhetoric about ECT may be one notch below that about abortion, the parallels are quite striking. ECT is controversial, like abortion; a vocal minority of people expend substantial effort to discredit ECT and its practitioners, promulgating a view that ECT is somehow morally wrong and should be banned.3 Education about ECT, although listed among the Psychiatry Residency Review Committee requirements, is mostly given short shrift in residencies, not to mention in medical school curricula.4 That education, such as it is, is meant only to familiarize physicians with ECT, not provide them with a level of skill needed to perform the procedure.

Moreover, there is no official certification or training path to become an ECT provider.5 Almost all of the controversy about ECT is anecdotal opinion, unsupported by evidence. In fact, there is a remarkably wide gap between what anti-ECT activists claim and the very substantial body of clinical and scientific evidence supporting its efficacy and safety. The negative opinions are largely driven by organizations that are antipsychiatry in general, not just anti-ECT; they in-

Why such animosity toward a medical procedure that is solely intended to provide relief to people who have severe depression? Much of the answer lies in a checkered remote history that remains alive today, largely because of the film One Flew Over the Cuckoo’s Nest. Made in 1975, it depicts a form of ECT that was already nearly 20 years obsolete in 1975. It was fiction taken literally as medical fact.7 When ECT was invented in 1938, modern anesthesia had not yet been developed; thus, ECT had to be given in unmodified form. Furthermore, because it was so effective for severe psychiatric illness, at a time when there were few other viable treatments, it was tried on patients with many different disorders. It was clearly overused— even abused. The fact that memory loss is an adverse effect of ECT is also impor-

clude the Committee for Truth in Psychiatry and the Citizens Commission on Human Rights of the Church of Scientology. Anti-ECT books have been written (eg, Doctors of Deception: What They Don’t Want You to Know About Shock Treatment by Linda Andre6) that are full of inaccuracies. The Internet is also host to many anti-ECT Web sites, including www.ECT.org, which features the ECT “Hall of Shame.” While the Hall of Shame may not put ECT practitioners at risk for bodily harm, it certainly might be considered libelous.

tant to the high level of emotion accompanying the animosity.8 Memory is special, even sacred to some people, because it defines one’s sense of self and identity. That ECT can interfere with one’s personal memories— even if only temporarily and to a minor degree in most instances—puts it in a special class among medical procedures. The scientific and clinical evidence base for the efficacy and safety of ECT is large; more than 9000 citations are catalogued on PubMed. Modern ECT is a standard treatment option at many major medical cen-

ters worldwide. Informed consent is always sought; indeed, much more attention is paid to the informed consent process with ECT than with many other surgical procedures.9 Full general anesthesia is a feature of modern ECT, and the procedure is frequently administered on an outpatient basis.10 Modern ECT technique has been refined to produce much less cognitive impairment than in the past. Patients often participate in the choice of type of ECT (unilateral versus bilateral electrode placement) they receive. As noted above, the antidepressant effectiveness of ECT remains very high, unequaled by antidepressant medications or other depression treatments, even in patients whose depression has proved to be resistant to antidepressant medications.11 ECT may be lifesaving for patients who are severely suicidal, malnourished from depression, or catatonic.12 That much of the psychiatric community is ambivalent and relatively ill-informed about ECT is largely a function of inadequate education in medical schools and residencies. Surveys have shown that medical personnel at all levels, from students to board-certified psychiatrists, are woefully deficient in their knowledge of ECT.13 It should be standard practice for all medical students to learn the basics of ECT and for all psychiatric residents to know enough about it to refer patients for whom ECT is an appropriate treatment consideration. Only a small minority of psychiatrists need to be fully trained to perform ECT; this requires the acquisition of a discrete body of knowledge as well as supervised practical in-hospital training. Privileging to perform ECT is handled locally by hospital administrations; there is neither national certification of practitioners nor accreditation of ECT services in the United States. Great Britain has recently developed such an accreditation service, and while it is voluntary, it has gained wide acceptance in the few years since its inception.14 Some of the professional and pop(Please see ECT, page 47)

CATEGORY SPONSORED BY CME LLC • PSYCHIATRIC TIMES • JANUARY 2011

Atypical Depression in the 21st Century: Diagnostic and Treatment Issues by Mario A. Cristancho, MD, John P. O’Reardon, MD, and Michael E. Thase, MD he existence of different subtypes of depressive episodes (ie, endogenous and nonendogenous) was initially postulated at least 80 years ago.1,2 In the early formulations, the term “endogenous depression” was used to describe a more severe biologically mediated illness, whereas “nonendogenous depression” or “exogenous depression” referred to a less

severe and environmentally mediated condition characterized by mood reactivity.3 It was not until the introduction of the first monoamine oxidase inhibitor (MAOI)—iproniazid—that the term “atypical depression” began to emerge to describe a particular variant of nonendogenous depression. Originally, endogenous, or melancholic, depression was thought to be the prototypical form of depression.4 Endogenous depression manifested with neurovegetative symptoms and nonreactive mood and regularly responded to the

tricyclic antidepressant (TCA) imipramine and/ or electroconvulsive therapy (ECT). A different subgroup of patients was found to be responsive to iproniazid (the first commercially available MAOI, but currently off the market because of significant toxicity) and nonresponsive to wellestablished treatments for depression (ie, imipramine and ECT).5 Furthermore, those patients presented an unusual constellation of symptoms characterized by the absence of endogenoustype neurovegetative symptoms and the pres-

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This continuing medical education activity is intended for

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Mario A. Cristancho, MD

psychiatrists, psychologists, primary care physicians,

Research Associate–Psychiatry Resident

nurse practitioners, and other health care professionals

John P. O’Reardon, MD, Associate Professor of Psychiatry

who seek to improve their care for patients with mental

Michael E. Thase, MD, Professor of Psychiatry Department of Psychiatry, University of Pennsylvania Philadelphia

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depression

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