Are You Up to Date? Latest Guidance for Evidence-Based Treatment of Adults With Bipolar Depression

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1 Available at CurrentPsychiatry.com/BipolarDepression This promotional, non-cme program is intended only for health care professionals involved in the treatment of adult patients with bipolar disorder. THIRD IN A SERIES OF 3 NEWSLETTERS A SUPPLEMENT TO This newsletter series was developed and brought to you by Sunovion Pharmaceuticals Inc. It did not undergo peer review by Current Psychiatry. Newsletter content was developed in collaboration with the faculty. Faculty William Clay Jackson, MD, DipTh, FAAFP Assistant Professor of Clinical Psychiatry and Family Medicine Departments of Psychiatry and Family Medicine University of Tennessee College of Medicine Memphis, Tennessee Susan L. Kraus, MSN, MAgS, CRNP-A, CRNP-PMH Chief Executive Officer Kraus Behavioral Health LLC Baltimore, Maryland Henry A. Nasrallah, MD Professor and Chair The Sydney W. Souers Endowed Chair Department of Psychiatry and Behavioral Neuroscience Saint Louis University School of Medicine Psychiatrist-in-Chief Saint Louis University Hospital St. Louis, Missouri Diane M. Snow, PhD, APRN, PMHNP-BC, FAANP, FIAAN Psychiatric Mental Health Nurse Practitioner Private Practice Denton, Texas DISCLOSURES Drs. Jackson, Nasrallah, and Snow and Ms. Kraus serve or have served as consultants, speakers, or researchers for various pharmaceutical companies, including Sunovion. The clinical expert commentary reflects the view of an actual licensed clinician who has been engaged by Sunovion. The information contained herein is intended for general informational purposes only and is not a substitute for your professional medical advice and judgment. This supplement is sponsored by, SUNOVION, and are registered trademarks of Sumitomo Dainippon Pharma Co., Ltd. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Dainippon Pharma Co., Ltd Sunovion Pharmaceuticals Inc. All rights reserved. 08/18 LAT Are You Up to Date? Latest Guidance for Evidence-Based Treatment of With Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. INDICATIONS is indicated for monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) and adjunctive treatment with lithium or valproate in adult patients with bipolar depression. The effectiveness of for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. The efficacy of in the treatment of mania associated with bipolar disorder has not been established. IMPORTANT SAFETY INFORMATION AND INDICATIONS FOR Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. A multidisciplinary panel of clinical experts contributed to the development of this 3-part newsletter series. Each issue explores strategies for the management of patients with bipolar disorder and features expert commentary from the psychiatry, primary care, or nurse-practitioner/ physician-assistant perspective. A Need for Guidance Early and accurate diagnosis of the condition underlying depressive episodes is essential for appropriate treatment of patients. 1 Specifically, it is important to recognize the depressive episodes associated with bipolar I disorder which we also know as bipolar depression and differentiate it from other forms of depression, such as those associated with general medical conditions, substance use, or major depressive disorder (MDD), according to Henry A. Nasrallah, MD. 1 Although no antidepressant is approved by the United States (US) Food and Drug Administration (FDA) as monotherapy for the treatment of bipolar disorder and there is limited evidence of efficacy, antidepressants are S1

2 LATEST GUIDANCE FOR EVIDENCE-BASED TREATMENT FOR BIPOLAR DEPRESSION AN EXPERT S PERSPECTIVE Commentary by Henry A. Nasrallah, MD s we learn more about the management Aof depressive episodes associated with bipolar I disorder, which is referred to as bipolar depression, we should factor this updated knowledge into our clinical decision-making. However, with a plethora of published information to sift through, how do health care professionals (HCPs) know where to begin? Treatment guidelines can serve as a good foundation, as long as we take into account that they are living and breathing documents that continuously evolve as new evidence emerges. When HCPs seek to apply guidelines to their practices, they should consider several factors, including the up-to-dateness of the recommendations, the reliability of their sources, and any therapeutic advances that have occurred since the last guidelines were published. For example, the latest American Psychiatric Association (APA) guideline for the treatment of patients with bipolar disorder was published 15 years ago (2002) and updated 12 years ago (2005), but the update is not considered a formal policy of the APA. 1,2 In this newsletter, my colleagues and I provide a snapshot of the latest guidelines published between 2013 and 2016 for the management of bipolar depression, which is an important clinical distinction from unipolar depression (also known as major depressive disorder). Among other updates, additional atypical antipsychotics have been incorporated into these guidelines as treatment options for individuals with bipolar depression consistent with clinical trial data demonstrating the drugs efficacy and safety in this patient population. 3-5 Because practice guidelines should reflect the latest advances in the management of bipolar depression, I encourage my HCP colleagues to ask the question, Am I up to date? as they weigh the options available for the evidence-based treatment of bipolar depression. Henry A. Nasrallah, MD References 1. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(suppl 4): Hirschfeld RM. Guideline Watch: Practice Guideline for the Treatment of Patients With Bipolar Disorder, 2nd Edition. Arlington, VA: American Psychiatric Association; Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update Bipolar Disord. 2013;15(1): Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6): Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49(12): commonly used treatments for this serious mental illness. 2-4 Labeling any and all depressive symptoms as depression potentially perpetuates this longstanding practice trend, opines William Clay Jackson, MD, DipTh, FAAFP. He points to a study of 649 primary care patients receiving antidepressants for treatment of depression between April 2003 and March 2004 in which 21.3% of the patients screened positive for bipolar disorder. 5 Consistent with Dr. Nasrallah s statement above about differentiating the condition underlying a patient s depressive episodes, Dr. Jackson says that referring to depressive symptoms as simply depression rather than specifying which disorder is driving them may lead clinicians to incorrectly generalize all symptoms of depression as MDD. A 2013 study examining practice patterns of US psychiatrists suggests that, even when a diagnosis of bipolar disorder is considered, patients may still receive antidepressants. Glauser and colleagues reported that more than one-half of the 200 psychiatrists surveyed indicated that they would prescribe antidepressant monotherapy for patients with symptoms of depression and a family history of bipolar disorder. 6 The importance of a precise diagnosis cannot be overstated, especially when it comes to unipolar and bipolar depression, because an accurate diagnosis can guide the prescription of appropriate treatment, say Susan L. Kraus, MSN, MAgS, CRNP-A, CRNP-PMH, and Diane M. Snow, PhD, APRN, PMHNP-BC, FAANP, FIAAN. Treating bipolar depression with an antidepressant alone may result in rapid relapse, rapid cycling, or induction of hypomania, mania, or mixed states. 7 Adjunctive antidepressants can also be ineffective: A decade ago, the Systematic Treatment Enhancement Program for Bipolar Disorder, or STEP-BD, showed that antidepressants, when added to mood stabilizers, were no more effective than placebo in treating bipolar disorder. 8 In addition, findings of a study conducted from January 2008 to July 2011 that evaluated 377 patients with bipolar depression taking a mood stabilizer or an atypical antipsychotic demonstrated that adjunctive antidepressants did not reduce rehospitalization rates or delay the time to readmission compared with no adjunctive antidepressant therapy. 9 What Are the Latest Guidelines and Recommendations? As evidence-based treatments for bipolar disorder evolve, it is important that clinical practice guidelines and recommendations evolve as well. Within the past 5 years, 3 societies have released updated practice guidelines that include recommendations relevant to clinicians who treat patients with bipolar depression. 3,10,11 The British Association for Psychopharmacology (BAP), The Royal Australian and New Zealand College of Psychiatrists (RANZCP), and the Canadian Network for Mood and Anxiety Treatments (CANMAT) with the International Society for Bipolar Disorders (ISBD) guidelines acknowledge the efficacy of 2 groups of medications atypical antipsychotics and mood stabilizers (including anticonvulsants) for the treatment of bipolar depression. The guidelines support the use of select drugs from these classes either as monotherapy or as adjunctive therapy options for first- and second-line treatment. 3,10,11 While there is growing consensus that, if possible, antidepressant monotherapy should be avoided for the treatment of bipolar depression, the role of antidepressants in conjunction with atypical antipsychotics or mood stabilizers remains unclear. 11 To help shed some light on the issue, an ISBD task force released clinical recommendations specifically addressing antidepressant use in bipolar disorder, stating that antidepressant monotherapy in patients with bipolar I disorder should be avoided a position consistent with the aforementioned practice guidelines. 3,10-12 Specifically, antidepressant use should be avoided in patients with bipolar depression who have manic symptoms, psychomotor agitation, rapid cycling, or a history of antidepressantinduced mood elevation. 12 Adjunctive antidepressants may be considered in carefully selected patients, including those with bipolar depression who have a history of positive response to this class of drugs. 3,10-12 Overall, the treatment of patients with bipolar depression can be challenging, in part because the number of approved treatment options for the disorder is limited and management requires careful contemplation of complex issues. Drs. Jackson, Nasrallah, and Snow, and Ms. Kraus conclude that when selecting treatment for an individual with bipolar depression, it is essential for health care professionals to take into consideration the evidence, guidelines, and recommendations, as well as the patient s particular needs and preferences. Clinicians should refer to individual guidelines and recommendations for specific guidance. S2 Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5.

3 : A Treatment Option for in is indicated in adults for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate. The efficacy of was established in a 6-week monotherapy study and a 6-week adjunctive therapy study with lithium or valproate in adult patients with bipolar depression. The effectiveness of has not been established for longer-term use (more than 6 weeks) or for the treatment of mania associated with bipolar disorder. 13 Each adult, phase 3, multicenter, randomized, double-blind, placebocontrolled clinical trial enrolled patients with major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features. All psychotropic medications were tapered off, and patients were randomly assigned to a treatment group. 14,15 Patients in the monotherapy study were randomized to flexibly dosed mg/ (N=166), flexibly dosed mg/ (N=169), or placebo (N=170). 14 Patients in the adjunctive therapy study were randomized to flexibly dosed mg/ plus lithium or valproate (N=183) or placebo plus lithium or valproate (N=165). 15 dose adjustments within the assigned dosing range were permitted to optimize efficacy and tolerability. Study medication was taken once daily in the evening by mouth with a meal (eg, dinner) or within 30 minutes after eating. 14,15 Efficacy in Efficacy was measured by the change from baseline to Week 6 in the Montgomery- Åsberg Depression Rating Scale (MADRS) score, the primary efficacy endpoint of the 2 trials. monotherapy achieved a 44% greater reduction in MADRS score at Week 6 versus placebo (Figure 1). 14 The mean decrease in MADRS score between baseline and Week 6 was 15.4 points for patients randomized to mg/ or mg/ versus 10.7 points for patients randomized to placebo (P<.001). 14 The higher dose range ( mg/) did not provide additional efficacy, on average, compared with the lower dose range (20-60 mg/). 13 With as adjunctive therapy with lithium or valproate, the mean decrease in the MADRS score between baseline and Week 6 was 17.1 points for patients randomized to adjunctive mg/ versus 13.5 points for patients randomized to placebo (P<.01) (Figure 1). 15 Safety and Tolerability in Adverse reactions occurring in at least 2% of patients in either monotherapy group and at a greater incidence than placebo during acute therapy were nausea, akathisia, somnolence, dry mouth, extrapyramidal symptoms (EPS), diarrhea, anxiety, nasopharyngitis, back pain, vomiting, urinary tract infection, and influenza. Overall, in the combined treatment groups, 6.0% (20/331) of patients discontinued treatment due to adverse reactions compared with 5.4% (9/168) of patients in the placebo group. 13 The safety and tolerability of adjunctive with lithium or valproate compared with placebo were examined in 2 short-term, randomized clinical trials of patients with bipolar depression. The adverse reactions that occurred in at least 2% of -treated patients and at a greater incidence than placebo in the 2 studies combined were nausea, EPS, somnolence, akathisia, nasopharyngitis, vomiting, restlessness, fatigue, increased appetite, and increased weight. Overall, treatment was discontinued due to adverse reactions by 5.8% of patients (21/360) receiving as adjunctive therapy with lithium or valproate and by 4.8% of patients (16/334) in the placebo group. 13 Patients from both the and placebo groups of the 6-week monotherapy and adjunctive therapy trials were eligible to continue into a 6-month, uncontrolled, open-label, flexible-dose extension study. 13, The adverse reactions in at least 5% of patients who continued on monotherapy in the longer-term study were headache, nausea, nasopharyngitis, akathisia, insomnia, and anxiety. Of those who continued on adjunctive therapy plus lithium or valproate in the longer-term study, at least 5% experienced parkinsonism, somnolence, akathisia, insomnia, anxiety, headache, and nausea. 16 Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk. 13 Changes in weight and laboratory parameters during both the short-term and longer- The effectiveness of for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. FIGURE 1. PRIMARY EFFICACY ENDPOINT IN ADULT CLINICAL TRIALS: MADRS SCORE LS Mean Change From Baseline Baseline Baseline mean = mg (n=161) 14 * ** Time (Weeks) Effect size: mg: mg: 0.51 * ** mg (n=162) ** *** *** *** *** *** (n=162) LS Mean Change From Baseline Baseline Adjunctive Therapy 15 Time (Weeks) mg + Li/VPA (n=179) Effect size: 0.34 *** *** * ** + Li/VPA (n=161) Baseline mean = Reduction in severity of depression *P<.05; **P<.01; ***P<.001. Abbreviations: Li, lithium; LS, least squares; MADRS, Montgomery-Åsberg Depression Rating Scale; VPA, valproate. The higher dose range ( mg/) did not provide additional efficacy, on average, compared to the lower dose range (20-60 mg/). MADRS scale range, Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. S3

4 LATEST GUIDANCE FOR EVIDENCE-BASED TREATMENT FOR BIPOLAR DEPRESSION FIGURE 2. MONOTHERAPY AND ADJUNCTIVE THERAPY IN ADULTS: WEIGHT AND LABORATORY PARAMETERS Mean Change From Baseline* Weight 13 (lb) Total Cholesterol 13 (mg/dl) Glucose 13 (mg/dl) (n=143) (n=147)(n=151) (n=140)(n=144)(n=147) (n=140)(n=143)(n=148) mg mg Longer-term, Open-label Extension Study Change from open-label baseline 16, : 0.3 lb (n=153) -0.1 mg/dl (n=154) 1.5 mg/dl (n=153) Adjunctive Therapy Mean Change From Baseline* Weight 13 (lb) Total Cholesterol 13 (mg/dl) (n=327) (n=307) -1 (n=321) (n=303) mg + Li/VPA Glucose 13 (mg/dl) (n=319) (n=302) + Li/VPA Longer-term, Open-label Extension Study Change from open-label baseline 16, : 1.7 lb (n=173) 0.4 mg/dl (n=182) -0.5 mg/dl (n=181) Abbreviations: Li, lithium; VPA, valproate. *Last observation carried forward. Observed cases; patients who continued on. Safety population. Notes: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. term monotherapy and adjunctive therapy studies are presented in Figure 2. 13,16 Overall, the clinical trials demonstrated that at 6 weeks, metabolic changes were similar in the and placebo groups, 13 and at 24 weeks, no clinically significant changes in body weight or clinically relevant changes or shifts from open-label baseline in lipid parameters and glucose were observed. 16 For prolactin in the short-term monotherapy study, the median change in concentration was +1.7 ng/ml, +3.5 ng/ ml, and +0.3 ng/ml for the low-dose, high-dose, and placebo groups, respectively, and -1.1 ng/ml for those who continued on in the longer-term trial. In the short-term adjunctive therapy studies, the median change was +2.8 ng/ml in the group and ng/ml in the placebo group, and in the longer-term trial, it was -1.3 ng/ml in patients who continued on. 13,16 Changes from baseline to endpoint in EPS, akathisia, and tardive dyskinesia were also evaluated in the monotherapy and adjunctive therapy short-term and longer-term trials using the Simpson-Angus Scale (SAS), the Barnes Akathisia Scale (BAS), and the Abnormal Involuntary Movement Scale (AIMS), respectively. Categorical change was defined as a shift from normal at baseline to abnormal at study endpoint for the SAS, or as worsening from baseline to study endpoint for the BAS and AIMS. The mean change from baseline for -treated patients was comparable to placebo on all 3 movement scales. 13,16 References 1. Nasrallah HA. Consequences of misdiagnosis: inaccurate treatment and poor patient outcomes in bipolar disorder. J Clin Psychiatry. 2015;76(10): e1328. doi: /JCP.14016tx2c. 2. Valentí M, Pacchiarotti I, Bonnín CM, et al. Risk factors for antidepressant-related switch to mania. J Clin Psychiatry. 2012;73(2):e271-e276. doi: /JCP.11m Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update Bipolar Disord. 2013; 15(1): Baldessarini RJ, Leahy L, Arcona S, Gause D, Zhang W, Hennen J. Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv. 2007;58 (1): Hirschfeld RM, Cass AR, Holt DC, Carlson CA. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract. 2005;18(4): Glauser TA, Cerenzia W, Wiley S, Howson A, Thase M. Identifying psychiatrists practice patterns when managing depression in patients with bipolar I disorder: a descriptive study to inform education needs. Postgrad Med. 2013;125(1): Motovsky M, Pecenak J. Psychopathological characteristics of bipolar and unipolar depression potential indicators of bipolarity. Psychiatr Danub. 2013;25(1): Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17): Vardi K, Warner JL, Philip NS. Effects of antidepressant use and anxiety on psychiatric rehospitalization in bipolar depression. Ann Clin Psychiatry. 2014; 26(3): Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6): Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49(12): Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) Task Force Report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11): (lurasidone HCl) prescribing information. Marlborough, MA: Sunovion Pharmaceuticals Inc.; March Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebocontrolled study. Am J Psychiatry. 2014;171(2): Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2): Data on file. Sunovion Pharmaceuticals Inc. S4 Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5.

5 BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION* WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. is not approved for the treatment of patients with dementia-related psychosis. Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. INDICATIONS AND USAGE is indicated for: Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia. treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression). Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression). CONTRAINDICATIONS Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone. Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.). Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John s wort, phenytoin, carbamazepine, etc.). WARNINGS AND PRECAUTIONS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. is not approved for the treatment of patients with dementia-related psychosis. Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebotreated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. 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 antidepressant drug effect on suicide. Table 1: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled -Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug- Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to <18 14 additional patients additional patients Decreases Compared to fewer patient 65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression. *Note: Read the full Prescribing Information before prescribing. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue and provide intensive symptomatic treatment and monitoring. Tardive Dyskinesia Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on, drug discontinuation should be considered. However, some patients may require treatment with despite the presence of the syndrome. Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. S5

6 Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 7. Table 7: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies 20 to 120 mg/ Mean Change from Baseline (mg/dl) n=303 n=321 Total cholesterol Triglycerides Proportion of Patients with Shifts Total cholesterol ( 240 mg/dl) Triglycerides ( 200 mg/dl) 5.7% (15/263) 8.6% (21/243) 5.4% (15/276) 10.8% (28/260) Patients were randomized to flexibly dosed 20 to 120 mg/ or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dl at week 24, respectively. In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dl for 20 to 80 mg/ (n=144) and -1.4 mg/dl for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dl for 20 to 80 mg/ (n=144) and +5.9 mg/dl for placebo (n=145). Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 8. The mean weight gain was kg for -treated patients compared to -2 kg for placebo-treated patients. Change in weight from baseline for olanzapine was kg and for quetiapine extended-release was kg in Studies 3 and 5, respectively. The proportion of patients with a 7% increase in body weight (at Endpoint) was 4.8% for -treated patients and 3.3% for placebo-treated patients. Table 8: Mean Change in Weight (kg) from Baseline in Adult Studies (n=696) 20 mg/ (n=71) 40 mg/ (n=484) 80 mg/ (n=526) 120 mg/ (n=291) 160 mg/ (n=114) All Patients In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), was associated with a mean change in weight of kg at week 24 (n=755), kg at week 36 (n=443) and kg at week 52 (n=377). Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 9. The mean change in weight gain was +0.5 kg for -treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 3.3% for -treated patients and 4.5% for placebo-treated patients. Table 9: Mean Change in Weight (kg) from Baseline in the Adolescent Study (n=111) 40 mg/ (n=109) 80 mg/ (n=104) All Patients Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 10. The mean change in weight gain was kg for -treated patients compared to -4 kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 2.4% for -treated patients and 0.7% for placebo-treated patients. Table 10: Mean Change in Weight (kg) from Baseline in the Adult Study (n=151) 20 to 60 mg/ (n=143) 80 to 120 mg/ (n=147) All Patients Patients were randomized to flexibly dosed 20 to 60 mg/, 80 to 120 mg/, or placebo. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -2 kg at week 24 (n=130). Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 11. The mean change in weight gain was kg for -treated patients compared to kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 3.1% for -treated patients and 0.3% for placebo-treated patients. Table 11: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Studies (n=307) 20 to 120 mg/ (n=327) All Patients Patients were randomized to flexibly dosed 20 to 120 mg/ or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of kg at week 24 (n=86). Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 12. The mean change in weight gain was +0.7 kg for -treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 4.0% for -treated patients and 5.3% for placebo-treated patients. Table 12: Mean Change in Weight (kg) from Baseline in the Study in (n=170) 20 to 80 mg/ (n=175) All Patients Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a carcinogenicity study conducted with lurasidone in rats and mice. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive. S6

7 Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 7. Table 7: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies 20 to 120 mg/ Mean Change from Baseline (mg/dl) n=303 n=321 Total cholesterol Triglycerides Proportion of Patients with Shifts Total cholesterol ( 240 mg/dl) Triglycerides ( 200 mg/dl) 5.7% (15/263) 8.6% (21/243) 5.4% (15/276) 10.8% (28/260) Patients were randomized to flexibly dosed 20 to 120 mg/ or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dl at week 24, respectively. In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dl for 20 to 80 mg/ (n=144) and -1.4 mg/dl for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dl for 20 to 80 mg/ (n=144) and +5.9 mg/dl for placebo (n=145). Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 8. The mean weight gain was kg for -treated patients compared to -2 kg for placebo-treated patients. Change in weight from baseline for olanzapine was kg and for quetiapine extended-release was kg in Studies 3 and 5, respectively. The proportion of patients with a 7% increase in body weight (at Endpoint) was 4.8% for -treated patients and 3.3% for placebo-treated patients. Table 8: Mean Change in Weight (kg) from Baseline in Adult Studies (n=696) 20 mg/ (n=71) 40 mg/ (n=484) 80 mg/ (n=526) 120 mg/ (n=291) 160 mg/ (n=114) All Patients In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), was associated with a mean change in weight of kg at week 24 (n=755), kg at week 36 (n=443) and kg at week 52 (n=377). Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 9. The mean change in weight gain was +0.5 kg for -treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 3.3% for -treated patients and 4.5% for placebo-treated patients. Table 9: Mean Change in Weight (kg) from Baseline in the Adolescent Study (n=111) 40 mg/ (n=109) 80 mg/ (n=104) All Patients Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 10. The mean change in weight gain was kg for -treated patients compared to -4 kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 2.4% for -treated patients and 0.7% for placebo-treated patients. Table 10: Mean Change in Weight (kg) from Baseline in the Adult Study (n=151) 20 to 60 mg/ (n=143) 80 to 120 mg/ (n=147) All Patients Patients were randomized to flexibly dosed 20 to 60 mg/, 80 to 120 mg/, or placebo. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -2 kg at week 24 (n=130). Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 11. The mean change in weight gain was kg for -treated patients compared to kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 3.1% for -treated patients and 0.3% for placebo-treated patients. Table 11: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Studies (n=307) 20 to 120 mg/ (n=327) All Patients Patients were randomized to flexibly dosed 20 to 120 mg/ or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of kg at week 24 (n=86). Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 12. The mean change in weight gain was +0.7 kg for -treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 4.0% for -treated patients and 5.3% for placebo-treated patients. Table 12: Mean Change in Weight (kg) from Baseline in the Study in (n=170) 20 to 80 mg/ (n=175) All Patients Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a carcinogenicity study conducted with lurasidone in rats and mice. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive. S7

8 In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for -treated patients was +0.4 ng/ml and was -1.9 ng/ml in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/ml and for females was -0.2 ng/ml. Median changes for prolactin by dose are shown in Table 13. Table 13: Median Change in Prolactin (ng/ml) from Baseline in Adult Studies All Patients -1.9 (n=672) Females -5.1 (n=200) Males -1.3 (n=472) 20 mg/ -1.1 (n=70) -0.7 (n=19) -1.2 (n=51) 40 mg/ -1.4 (n=476) -4.0 (n=149) -0.7 (n=327) 80 mg/ -0.2 (n=495) -0.2 (n=150) -0.2 (n=345) 120 mg/ +3.3 (n=284) +6.7 (n=70) +3.1 (n=214) 160 mg/ +3.3 (n=115) +7.1 (n=36) +2.4 (n=79) The proportion of patients with prolactin elevations 5 upper limit of normal (ULN) was 2.8% for -treated patients and = 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 5.7% for -treated patients and = 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 1.6% and 0.6% for placebo-treated male patients. In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), was associated with a median change in prolactin of -0.9 ng/ml at week 24 (n=357), -5.3 ng/ml at week 36 (n=190) and -2.2 ng/ml at week 52 (n=307). In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for -treated patients was +1.1 ng/ml and was +0.1 ng/ml for placebo-treated patients. For -treated patients, the median change from baseline to endpoint for males was +1.0 ng/ml and for females was +2.6 ng/ml. Median changes for prolactin by dose are shown in Table 14. Table 14: Median Change in Prolactin (ng/ml) from Baseline in the Adolescent Study All Patients (n=103) Females (n=39) Males 0 (n=64) 40 mg/ (n=102) (n=42) (n=60) 80 mg/ (n=99) (n=33) (n=66) The proportion of patients with prolactin elevations 5x ULN was 0.5% for treated patients and 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 1.3% for -treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% for treated patients and 1.6% for placebo-treated male patients. The median change from baseline to endpoint in prolactin levels, in the adult shortterm, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/ml and +3.5 ng/ml with 20 to 60 mg/ and 80 to 120 mg/, respectively compared to +0.3 ng/ml with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/ml and for females was +3.1 ng/ml. Median changes for prolactin by dose range are shown in Table 15. Table 15: Median Change in Prolactin (ng/ml) from Baseline in the Adult Study All Patients +0.3 (n=147) Females (n=82) Males +0.4 (n=65) 20 to 60 mg/ 80 to 120 mg/ +1.7 (n=140) +1.8 (n=78) +1.2 (n=62) +3.5 (n=144) +5.3 (n=88) +1.9 (n=56) Patients were randomized to flexibly dosed 20 to 60 mg/, 80 to 120 mg/, or placebo. The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 0.4% for -treated patients and % for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0.6% for -treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% and 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of ng/ml at week 24 (n=130). The median change from baseline to endpoint in prolactin levels, in the adult shortterm, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/ml with 20 to 120 mg/ compared to ng/ml with placebotreated patients. The median change from baseline to endpoint for males was +2.4 ng/ml and for females was +3.2 ng/ml. Median changes for prolactin across the dose range are shown in Table 16. Table 16: Median Change in Prolactin (ng/ml) from Baseline in the Adult Adjunctive Therapy Studies All Patients (n=301) Females +0.4 (n=156) Males -0.1 (n=145) 20 to 120 mg/ +2.8 (n=321) +3.2 (n=162) +2.4 (n=159) Patients were randomized to flexibly dosed 20 to 120 mg/ or placebo as adjunctive therapy with lithium or valproate. The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was % for -treated patients and % for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0% for -treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% and 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with, as adjunctive therapy with either lithium or valproate, in the shortterm and continued in the longer-term study, had a median change in prolactin of -2.9 ng/ml at week 24 (n=88). In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, the median change from baseline to endpoint in prolactin levels for treated patients was ng/ml and was ng/ml for placebo-treated patients. For -treated patients, the median change from baseline to endpoint for males was ng/ml and for females was ng/ml. Median changes for prolactin are shown in Table 17. Table 17: Median Change in Prolactin (ng/ml) from Baseline in the Bipolar Depression Study in All Patients (n=157) Females (n=78) Males (n=79) 20 to 80 mg/ (n=165) (n=83) (n=82) The proportion of patients with prolactin elevations 5x ULN was 0% for -treated patients and 0.6% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0% for -treated patients and 1.3% for placebo-treated female patients. No male patients in the placebo or treatment groups had prolactin elevations 5x ULN. Leukopenia, Neutropenia and Agranulocytosis Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should be discontinued at the first sign of decline in WBC, in the absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm 3 ) should discontinue and have their WBC followed until recovery. S8