Managing Multiple Comorbidities in Bipolar Disorder

Transcription

1 SECOND IN A SERIES OF 3 NEWSLETTERS A SUPPLEMENT TO This promotional, non-cme program is intended only for health care professionals involved in the treatment of adult patients with bipolar disorder. Managing Multiple Comorbidities in Bipolar Disorder 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 Larry Culpepper, MD, MPH Professor Department of Family Medicine Boston University School of Medicine Boston, Massachusetts Andrew J. Cutler, MD Executive Vice President and Chief Medical Officer Meridien Research Bradenton, Florida James Sloan Manning, MD Adjunct Associate Professor Department of Family Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Co-Director Mood Disorders Clinic Moses Cone Family Practice Center Greensboro, North Carolina Anna M. O Kinsky, MSN, APN Psychiatric Nurse Practitioner Catholic Charities Delaware House Westampton, New Jersey Princeton Healthcare Princeton, New Jersey DISCLOSURES Drs. Cutler and Manning and Ms. O Kinsky serve or have served as consultants, speakers, and researchers for various pharmaceutical companies, including Sunovion. Dr. Culpepper serves or has served as a consultant for, and receives royalties and payment from, 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. 07/17 LAT Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. INDICATIONS is indicated for treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate in adults. 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 behaviors in patients aged 24 years and younger compared to placebo. Monitor for clinical worsening and emergence of suicidal thoughts and behavior. is not approved for use in pediatric patients with depression. 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. The Cost of Bipolar Disorder Bipolar disorder is a serious psychiatric illness associated with a considerable medical and economic burden. In the United States (US), the estimated lifetime prevalence of bipolar disorder is 2% to 4%, with about 1% of US adults having a lifetime history of bipolar I disorder. 1,2 It has been estimated that in 2009, the direct and indirect costs associated with bipolar disorder amounted to at least $151 billion in the US. 3 In addition, costs for patients with comorbid medical, mental health, and substance use disorders may be 2 to 3 times those for patients without these comorbid conditions, with most of the increased cost going to medical services rather than to behavioral health care. 4 Medical comorbidities occur often in bipolar disorder. 5 One study reviewed medical charts of 309 patients with bipolar disorder and found that 55% of patients had at least 1 comorbid medical condition, the most common being endocrine/metabolic disorders (23%) and vascular disease (21%). 6 Watch a video about the impact of lifestyle factors on adherence and outcomes. Visit S1

2 MANAGING MULTIPLE COMORBIDITIES IN BIPOLAR DISORDER AN EXPERT S PERSPECTIVE Commentary by James Sloan Manning, MD T he high prevalence rate of comorbid general medical conditions (GMCs) among patients with bipolar disorder has been well documented and illustrates the importance of integrating behavioral health and primary care services. Using data from the National Epidemiologic Survey on Alcohol and Related Conditions, Perron and colleagues reported that a diagnosis of bipolar I disorder was a significant risk factor for GMCs such as those noted in this newsletter. 1 These comorbid GMCs added to physical, mental, and psychosocial disability, as measured by the 12-Item Short-Form Health Survey, Version 2. 1 In addition, a meta-analysis of 2634 studies with 106,785 patients revealed that the estimated prevalence of unexplained somatic symptoms in patients with bipolar spectrum disorders was 47.8% nearly double the rate of those in the general population. 2 These data suggest important challenges to populationbased health care, and there is a movement toward creating collaborative care models to meet these challenges. A review by Bradford and colleagues assessed models that integrated behavioral health and primary care services and found positive effects on prevention and management of chronic disease for patients with serious mental illness. 3 Although more large trials are needed to confirm the effectiveness of those care models, creating an integrated, community-supported, chronic illness focused, teambased care delivery system may help clinicians identify and track chronically ill patients and improve preventive care. Furthermore, patient education on metabolic issues and risk factors, as well as incorporation of lifestyle interventions, such as healthy cooking classes, nutrition counseling, and exercise, into individualized treatment plans may also help mitigate the risk of comorbid GMCs. 4 In my opinion, by assuming that relapse and chronicity are realities of illness and acknowledging the impact that bipolar disorder and comorbid GMCs have on patient motivation and volition, clinicians may be able to improve the management and overall health of patients. James Sloan Manning, MD References 1. Perron BE, et al. Prevalence and burden of general medical conditions among adults with bipolar I disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2009;70(10): Edgecomb JB, et al. Medically unexplained somatic symptoms and bipolar spectrum disorders: a systematic review and meta-analysis. J Affect Disord. 2016;204: Bradford DW, et al. An evidence synthesis of care models to improve general medical outcomes for individuals with serious mental illness: a systematic review. J Clin Psychiatry. 2013;74(8):e754-e Bauer IE, et al. Lifestyle interventions targeting dietary habits and exercise in bipolar disorder: a systematic review. J Psychiatr Res. 2016;74:1-7. Mortality and Comorbid CVD Cardiovascular risk is increased in patients with bipolar disorder, even among those who are treatment naïve. 7 The onset of cardiovascular disease (CVD) in patients with bipolar disorder occurs approximately 10 years earlier and with a mortality rate about twice that of the general population. 8,9 Even among those who do not have CVD at baseline, the risk of developing new-onset CVD is more than twice that of matched control subjects or patients with major depressive disorder. 8 On average, patients with bipolar disorder die about 9 to 10 years earlier than the general population. 10,11 Although some of this excess mortality is attributable to an increased risk of suicide, it is known that comorbid CVD contributes to greater mortality in this patient population. 11 Monitoring and Managing Metabolic Risks As with CVD, patients with bipolar disorder are at risk of weight and body mass index (BMI) increases even when they are not overweight at baseline. 12 Therefore, these individuals should receive regular monitoring of these and other metabolic parameters with the goal of identifying these trends before reaching diagnosable comorbidities. 13 In fact, many clinical practice guidelines emphasize the importance MONITORING METABOLIC RISK IN BIPOLAR DISORDER In light of the increased risk for medical comorbidities in people with bipolar disorder, several guidelines recommend regular monitoring of metabolic parameters, including weight, body mass index, waist circumference, blood pressure, glucose, and lipids in this patient population. Guidelines have been developed and published by the following organizations: British Association for Psychopharmacology (2016) 14 Royal Australian and New Zealand College of Psychiatrists (2015) 15 Canadian Network for Mood and Anxiety Treatment and the International Society for Bipolar Disorders (2013) 16 American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity (2004) 17 Although the suggested interval for the measurement of each parameter varies, all of the guidelines emphasize the importance of cardiometabolic monitoring in patients with bipolar disorder. Overall, health care professionals should consider physical health in their clinical assessment and treatment planning based on an individual s specific needs and circumstances of closely monitoring metabolic measures in patients with bipolar disorder (Box) However, evidence suggests that these patients often fail to receive such routine preventive care. 18 In the Understanding Patients Needs, Interactions, Treatment, and Expectations Global Survey, preventive care practices received by patients with bipolar disorder and schizophrenia were assessed. Researchers discovered that only about 30% of patients received appropriate weight and blood pressure monitoring, while only 20% underwent regular physical examinations. 18 To help ensure that patients with bipolar disorder receive the appropriate monitoring, follow-up, and preventive care, a collaborative and holistic approach, which includes a focus on lifestyle modifications and patient education, may be effective. 12,19,20 S2 Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5.

3 : A Treatment Option for is indicated 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. 21 Each phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled adult 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. 22,23 Patients in the monotherapy study were randomized to flexibly dosed (N=166), flexibly dosed (N=169), or placebo (N=170). 22 Patients in the adjunctive therapy study were randomized to flexibly dosed plus lithium or valproate (N=183) or placebo plus lithium or valproate (N=165). 23 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. 22,23 Efficacy Efficacy was measured by the change from baseline to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) score, the 2 trials primary efficacy endpoint. monotherapy achieved a 44% greater reduction in MADRS score at Week 6 versus placebo (Figure 1). 22 The mean decrease in MADRS score between baseline and Week 6 was 15.4 points for patients randomized to or versus 10.7 points for patients randomized to placebo (P<.001). 22 The higher dose range ( ) did not provide additional efficacy, on average, compared to the lower dose range (20-60 ). 21 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 versus 13.5 points for patients randomized to placebo (P<.01) (Figure 1). 23 Safety and Tolerability 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. 21 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. 21 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. 21, 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, 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: MADRS SCORE LS Mean Change From Baseline Baseline Baseline mean = mg (n=161) 22 * ** Time (Weeks) Effect size: mg: mg: 0.51 * ** mg (n=162) ** *** *** *** *** *** (n=162) LS Mean Change From Baseline Baseline Adjunctive Therapy 23 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 ( ) did not provide additional efficacy, on average, compared to the lower dose range (20-60 ). MADRS scale range, Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. S3

4 MANAGING MULTIPLE COMORBIDITIES IN BIPOLAR DISORDER FIGURE 2. MONOTHERAPY AND ADJUNCTIVE THERAPY: WEIGHT AND LABORATORY PARAMETERS Mean Change From Baseline* Weight 21 (lb) Total Cholesterol 21 (mg/dl) Glucose 21 (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 24, : 0.3 lb (n=153) -0.1 mg/dl (n=154) 1.5 mg/dl (n=153) Adjunctive Therapy Mean Change From Baseline* Weight 21 (lb) Total Cholesterol 21 (mg/dl) (n=327) (n=307) -1 (n=321) (n=303) mg + Li/VPA Glucose 21 (mg/dl) (n=319) (n=302) + Li/VPA Longer-term, Open-label Extension Study Change from open-label baseline 24, : 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. akathisia, insomnia, anxiety, headache, and nausea. 24 Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk. 21 Changes in weight and laboratory parameters during both the short-term and longer-term monotherapy and adjunctive therapy studies are presented in Figure 2. 21,24 Overall, the clinical trials demonstrated that at 6 weeks, metabolic changes were similar in the and placebo groups, 21 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. 24 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 longerterm 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. 21,24 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. 21,24 References 1. Frye MA, et al. Healthcare resource utilization in bipolar depression compared with unipolar depression: results of a United States population-based study. CNS Spectr. 2006;11(9): American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; Dilsaver SC. An estimate of the minimum economic burden of bipolar I and II disorders in the United States: J Affect Disord. 2011;129(1-3): Melek SP, et al. Economic Impact of Integrated Medical- Behavioral Healthcare: Implications for Psychiatry. Denver, CO: Milliman, Inc.; April Hirschfeld RM, et al. Bipolar disorder costs and comorbidity. Am J Manag Care. 2005;11(3 suppl): S85-S Maina G, et al. General medical conditions are associated with delay to treatment in patients with bipolar disorder. Psychosomatics. 2013;54(5): Leboyer M, et al. Can bipolar disorder be viewed as a multisystem inflammatory disease? J Affect Disord. 2012; 141(1): Goldstein BI, et al. Excessive and premature new-onset cardiovascular disease among adults with bipolar disorder in the US NESARC cohort. J Clin Psychiatry. 2015;76(2): Westman J, et al. Cardiovascular mortality in bipolar disorder: a population-based cohort study in Sweden. BMJ Open. 2013;3(4). 10. Crump C, et al. Comorbidities and mortality in bipolar disorder: a Swedish national cohort study. JAMA Psychiatry. 2013;70(9): Weiner M, et al. Cardiovascular morbidity and mortality in bipolar disorder. Ann Clin Psychiatry. 2011;23(1): Lipkovich I, et al. Early predictors of substantial weight gain in bipolar patients treated with olanzapine. J Clin Psychopharmacol. 2006;26(3): Culpepper L. The diagnosis and treatment of bipolar disorder: decision-making in primary care. Prim Care Companion CNS Disord. 2014;16(3). 14. Goodwin GM, 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, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aus N Z J Psychiatry. 2015;49(12): Yatham LN, 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): American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2): McIntyre RS. Understanding needs, interactions, treatment, and expectations among individuals affected by bipolar disorder or schizophrenia: the UNITE global survey. J Clin Psychiatry. 2009;70(suppl 3): Bauer IE, et al. Lifestyle interventions targeting dietary habits and exercise in bipolar disorder: a systematic review. J Psychiatr Res. 2016;74: Susman JL. Improving outcomes in patients with bipolar disorder through establishing an effective treatment team. Prim Care Companion J Clin Psychiatry. 2010;12(suppl 1): [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals Inc.; February Loebel A, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2): Loebel A, 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 from clinical worsening, and for emergence of suicidal thoughts and behaviors. is not approved for use in pediatric patients with depression. INDICATIONS AND USAGE is indicated for: Treatment of adult and adolescent patients age 13 to 17 years with schizophrenia. treatment of adult patients with major depressive episodes associated with bipolar I disorder (bipolar depression). Adjunctive treatment with lithium or valproate in adult patients with major depressive episodes 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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. 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 placebo-treated patients. The drugplacebo 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 is not approved for use in pediatric patients with depression. 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. 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 health care 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 (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported. 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. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, 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. S5

6 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 treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because was not marketed at the time these studies were performed, it is not known if is associated with this increased risk. 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. Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 2. Table 2: Change in Fasting Glucose in Adult Studies Mean Change from Baseline (mg/dl) n=680 n=71 n=478 n=508 n=283 n=113 Serum Glucose Proportion of Patients with Shifts to 126 mg/dl Serum Glucose ( 126 mg/dl) 8.3% (52/628) 11.7% (7/60) 12.7% (57/449) 6.8% (32/472) 1% (26/260) 5.6% (6/108) In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), was associated with a mean change in glucose of +1.8 mg/dl at week 24 (n=355), +0.8 mg/dl at week 36 (n=299) and +2.3 mg/dl at week 52 (n=307). In studies of adolescents and adults with schizophrenia, changes in fasting glucose were similar. In the short-term, placebo-controlled study of adolescents, fasting serum glucose mean values were -1.3 for placebo (n=95), +0.1 for 40 mg (n=90), and +1.8 for 80 mg (n=92). Data from the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 3. Table 3: Change in Fasting Glucose in the Adult Bipolar Depression Study 20 to to 120 Mean Change from Baseline (mg/dl) n=148 n=140 n=143 Serum Glucose Proportion of Patients with Shifts to 126 mg/dl Serum Glucose ( 126 mg/dl) 4.3% (6/141) 2.2% (3/138) 6.4% (9/141) Patients were randomized to flexibly dosed 20 to 60, 80 to 120, or placebo. who received as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dl at week 24 (n=129). Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 4. Table 4: Change in Fasting Glucose in the Adult Adjunctive Therapy Studies 20 to 120 Mean Change from Baseline (mg/dl) n=302 n=319 Serum Glucose Proportion of Patients with Shifts to 126 mg/dl Serum Glucose ( 126 mg/dl) 1.0% (3/290) 1.3% (4/316) Patients were randomized to flexibly dosed 20 to 120 or placebo as adjunctive therapy with lithium or valproate. 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 glucose of +1.7 mg/dl at week 24 (n=88). Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 5. Table 5: Change in Fasting Lipids in Adult Studies Mean Change from Baseline (mg/dl) n=660 n=71 n=466 n=499 n=268 n=115 Total Cholesterol Triglycerides Proportion of Patients with Shifts Total Cholesterol ( 240 mg/dl) Triglycerides ( 200 mg/dl) 5.3% (30/571) 10.1% (53/526) 13.8% (8/58) 14.3% (7/49) 6.2% (25/402) 10.8% (41/379) 5.3% (23/434) 6.3% (25/400) 3.8% (9/238) 10.5% (22/209) 4.0% (4/101) 7.0% (7/100) In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and (n=357) mg/dl at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dl at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dl at week 52, respectively. In the adolescent short-term, placebo-controlled study, fasting serum cholesterol mean values were -9.6 for placebo (n=95), -4.4 for 40 mg (n=89), and +1.6 for 80 mg (n=92), and fasting serum triglyceride mean values were +0.1 for placebo (n=95), -0.6 for 40 mg (n=89), and +8.5 for 80 mg (n=92). Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 6. Table 6: Change in Fasting Lipids in the Adult Bipolar Depression Study 20 to to 120 Mean Change from Baseline (mg/dl) n=147 n=140 n=144 Total cholesterol Triglycerides Proportion of Patients with Shifts Total cholesterol ( 240 mg/dl) Triglycerides ( 200 mg/dl) 4.2% (5/118) 4.8% (6/126) 4.4% (5/113) 10.1% (12/119) 4.4% (5/114) 9.8% (12/122) Patients were randomized to flexibly dosed 20 to 60, 80 to 120, or placebo. who received as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 (n=130) and -1.0 (n=130) mg/dl at week 24, respectively. 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 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 or placebo as adjunctive therapy with lithium or valproate. 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. 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 versus 3.3% for placebo-treated patients. Table 8: Mean Change in Weight (kg) from Baseline in Adult Studies (n=696) 20 (n=71) 40 (n=484) 80 (n=526) 120 (n=291) 160 (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 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 versus 4.5% for placebo-treated patients. Table 9: Mean Change in Weight (kg) from Baseline in the Adolescent Study (n=111) 40 (n=109) 80 (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 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 versus 0.7% for placebo-treated patients. Table 10: Mean Change in Weight (kg) from Baseline in the Adult Study (n=151) 20 to 60 (n=143) 80 to 120 (n=147) All Patients Patients were randomized to flexibly dosed 20 to 60, 80 to 120, or placebo. 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 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 versus 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 (n=327) All Patients Patients were randomized to flexibly dosed 20 to 120, or placebo as adjunctive therapy with lithium or valproate. 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). 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. 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 12. Table 12: 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) (n=70) -0.7 (n=19) -1.3 (n=472) (n=476) -4.0 (n=149) -0.7 (n=327) (n=495) -0.2 (n=150) -0.2 (n=345) (n=284) +6.7 (n=70) +3.1 (n=214) (n=115) +7.1 (n=36) +2.4 (n=79) The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 2.8% for -treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 5.7% for -treated patients versus 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 1.6% versus 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 13. S7

8 Table 13: Median Change in Prolactin (ng/ml) from Baseline in the Adolescent Study All Patients (n=103) Females (n=39) Males 0 (n=64) (n=102) (n=42) (n=60) (n=99) (n=33) (n=66) The proportion of patients with prolactin elevations 5x ULN was 0.5% for -treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 1.3% for -treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% versus 1.6% for placebo-treated male patients. The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/ml and +3.5 ng/ml with 20 to 60 and 80 to 120, 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 14. Table 14: Median Change in Prolactin (ng/ml) from Baseline in the Adult Study 20 to to 120 All Patients +0.3 (n=147) +1.7 (n=140) +3.5 (n=144) Females (n=82) +1.8 (n=78) +5.3 (n=88) Males +0.4 (n=65) +1.2 (n=62) +1.9 (n=56) Patients were randomized to flexibly dosed 20 to 60, 80 to 120, or placebo. The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 0.4% for -treated patients versus % for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0.6% for -treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% versus 0% for placebo-treated male 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 short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/ml with 20 to 120 compared to ng/ml with placebo-treated 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 15. Table 15: 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 (n=321) +3.2 (n=162) +2.4 (n=159) Patients were randomized to flexibly dosed 20 to 120 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 versus % for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0% for -treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% versus 0% for placebo-treated male 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 median change in prolactin of -2.9 ng/ml at week 24 (n=88). 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. Orthostatic Hypotension and Syncope may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs. Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: 20 mm Hg decrease in systolic blood pressure and 10 bpm increase in pulse from sitting to standing or supine to standing position. The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was ( incidence, placebo incidence): orthostatic hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)]. In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with 40 mg, 2.1% with 80 mg, 1.7% with 120 mg and 0.8% with 160 mg compared to 0.7% with placebo. The incidence of orthostatic hypotension reported as adverse events from the short-term, placebo-controlled adolescent schizophrenia study was 0.5% (1/214) in -treated patients and 0% (0/112) in placebo-treated patients. No syncope event was reported. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0% with 40 mg and 2.9% with 80 mg, compared to 1.8% with placebo. In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with 20 to 60 mg and 0.6% with 80 to 120 mg compared to 0% with placebo. In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with 20 to 120 mg compared to 0.9% with placebo. Falls may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. Seizures As with other antipsychotic drugs, should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer s dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older. In adult short-term, placebo-controlled schizophrenia studies, seizures/ convulsions occurred in 0.1% (2/1508) of patients treated with compared to 0.1% (1/708) placebo-treated patients. S8