The Bipolar Depression Bulletin

Transcription

1 The Bipolar Depression Bulletin Insights in the Diagnosis and Treatment of Bipolar Depression Please see Important Safety Information,, on page 15 INDICATIONS AND USAGE LATUDA 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 LATUDA 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 LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established. IMPORTANT SAFETY INFORMATION AND INDICATIONS FOR LATUDA 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. LATUDA is not approved for use in pediatric patients with depression. Bipolar disorder is a serious disease. The 12-month prevalence of bipolar disorder in the US is about 5.7 million American adults (or about 2.6 percent of people aged 18 and older in the United States). 1-3 People with bipolar I disorder may experience difficulties returning to normal work function after having a depressive episode. 1 They may suffer from cognitive impairment which can also contribute to vocational and interpersonal difficulties, even during euthymic periods. 1 This interactive newsletter will focus on the challenges of adults living with bipolar I disorder from a patient perspective, as well as a treatment option for bipolar depression, LATUDA (lurasidone HCl). The newsletter will follow a hypothetical psychiatric nurse practitioner, Lewis, and a hypothetical patient, Mary, as Lewis interviews Mary about the impact of bipolar I disorder on her life. Hypothetical Patient Case Mary, 33 years old Mary is a 33-year-old warehouse worker at a large distribution center. She went straight to community college after graduating high school. During her first year at college, Mary had an episode of inflated grandiosity; she took a loan and went on a buying spree. Mary recalls: I felt I was better than everyone else at the college and wanted to dress accordingly. I used up all the money to buy expensive jewelry and designer clothing. In her second year, Mary found it hard to concentrate on her studies and her grades dropped. She switched majors multiple times and became very depressed. Eventually, Mary dropped out of college and returned to live with her parents. She was initially diagnosed with unipolar depression and was treated with antidepressants for 7 years. Mary says: I was treated for depression for such a long time, but the medication didn t work. It was very frustrating. Mary was diagnosed with bipolar I disorder at age 27 and received treatment, which improved her condition. She started working at the distribution center a couple of years ago and recently got married. LAT

2 Newsletter 2 Page 2 Lewis: Mary, you were diagnosed with bipolar I disorder about 6 years ago. Can you please tell me what led to this diagnosis? Mary: I was initially diagnosed with depression and was treated with antidepressants for almost 7 years. All the doctors I saw back then focused on my depressive symptoms. The depressive symptoms started during my second year at college, when I found it difficult to concentrate, and my grades were getting worse. I remember staying in my room for weeks at a time, feeling very depressed. I changed my major many times and eventually dropped out of college. After dropping out, I returned home to live with my parents and applied for jobs. Keeping a job was very hard for me; even when I found a job and was hired, the longest I stayed employed was six months. Only after my current doctor asked me questions about my past was I finally diagnosed with bipolar I disorder. The doctor explained that the questions helped to identify manic episodes, or what she called periods of elevated mood, which can help to differentiate bipolar depression from unipolar depression. I told my doctor that during my first year in college I felt an urge to buy very expensive jewelry and clothing. I even took a loan and spent all the money in just a couple of weeks, which got me into some big financial trouble. Lewis: Your story illustrates how challenging the diagnosis of bipolar disorder can be. By one Rate of Correct Diagnosis of Bipolar Disorder 8 Click to Expand Your Knowledge What is the burden of untreated bipolar disorder on the patient? estimate, about a third of the people with bipolar disorder are misdiagnosed as having unipolar depression and may wait 10 years or more before receiving a correct diagnosis. 4 The diagnosis of bipolar I disorder requires the occurrence of at least one manic episode, which may be preceded or followed by a major depressive episode. 1 However, people with bipolar I disorder spend most of their time in a depressive state, and some people may not experience a manic episode in 5 years or more. 5,6 Your psychiatrist probably asked you questions from the Mood Disorders Questionnaire (MDQ) to identify your past manic episode. 7 Mary: It sounds familiar, but I m not sure. Can you please explain what the MDQ is? Lewis: The MDQ is a single-page questionnaire which asks about the lifetime history of 13 symptoms or behaviors that may indicate mania, including irritability, distractibility, energy level, involvement in risky activity, and other manic symptoms. 7 In addition, the MDQ asks if these symptoms occurred during the same time period Check Your Knowledge: Click the Right Answer 49.0% Received Neither Diagnosis of Bipolar nor Unipolar Depression 19.8% Received Correct Diagnosis 31.2% Received Diagnosis of Unipolar Depression Which of the following is true about the MDQ? 7 A) It is a screening tool to detect past depressive symptoms B) It was originally developed in the 1980s for inpatient assessments C) It is a screening tool that can assist in detection of a history of manic symptoms The rate of correct diagnosis in one analysis of individuals who met the criteria of bipolar I and II disorders on the MDQ. 8 D) All of the above

3 Newsletter 2 Page 3 and the degree to which the symptoms affected a patient s life. 7 The MDQ is a very useful screening tool designed to identify previous manic symptoms, although it is not designed as a diagnostic tool. 7,8 This means the psychiatrist might need to conduct further interviews or use other tools to get to a final diagnosis. 7,8 Can you share with me how you felt when you were diagnosed with bipolar I disorder? Mary: It was good to at least know what I have so we could figure out how to manage it. I was also embarrassed about my behavior when I was manic and how it impacted my parents and friends. A lot of my friends distanced themselves from me, and I was afraid I d end up all alone. There are things about myself I don t tell anyone, then I feel guilty because I have to lie about myself. Lewis: I m sorry to hear that. Untreated or improperly treated bipolar disorder may often lead to relationship problems. 4 According to one study, 80% of adults with bipolar disorder reported having relationship problems during the time their illness was untreated or improperly treated. 4 However, after receiving effective treatment for bipolar disorder, their relationships with friends and family may improve. 4 How did the diagnosis of bipolar disorder affect the relationship with your family? Mary: After the diagnosis, my parents became very protective. I felt like they were always looking for signs of recurrence. I m truly grateful for them being there when I needed support, but they made me feel like I lost my independence. I got married Rate of Unemployment in People With Bipolar Disorder 10 Employed 35% Unemployed 65% Click to Expand Your Knowledge What symptoms may be suggestive of bipolar depression? What are some of the psychiatric comorbidities associated with bipolar disorder? last year; my husband knew about my diagnosis before we got married, but he had never seen me at my worst. I love him very much, but I don t think he knew what he was getting himself into. He is always very anxious about signs I m getting depressed or manic again. If I start cleaning the house or buy some new clothes, my husband will suggest calling the doctor. Lewis: It sounds like your family really cares about you, which may explain why they are so protective. You mentioned earlier experiencing difficulties in maintaining a job before being diagnosed with bipolar disorder. 4 That's not unusual. Maintaining employment with mental health issues may be challenging. According to a national survey conducted between 2009 and 2010, people with mental health issues are employed less often than adults with no reported mental health issues. 9 For adults with bipolar disorder, one study reported an unemployment rate of 65%. 10 According to a different study, 73% of people with bipolar disorder experienced problems with their job and school during the time their illness was untreated or mistreated 4 ; even after receiving treatment for bipolar disorder, 53% report job- and schoolrelated problems. 4 Mary, you currently work at a large distribution center. Can you tell me more about the challenges you currently face at work? Mary: One of the challenges I face at work is dealing with the mood episodes, in particular the depressive episodes. There is always uncertainty about when I will be depressed next. I worry that it will lead to me missing more work or performing poorly, which might mean I could lose my job. During depressive episodes, I avoid making eye contact with people

4 Newsletter 2 Page 4 at work and try to keep to myself. Sometimes if I am too depressed or nervous, I just call in sick and stay home. Lewis: Can you share with me your strategies for managing your condition at the workplace? Mary: I find maintaining a daily routine very useful to keep me on track. I try to get 8-9 hours of sleep and set the alarm clock to the same time every day. I also have my meals at set times. At work, I try to go for short walks outside a couple of times a day. I was told that exercise may help in re-energizing me, and may also help to keep my mind and body healthy. Lewis: These are very good strategies for managing bipolar depression at work or at home. Adhering to treatment and maintaining a healthy lifestyle can be very helpful in preventing relapse. 11 Mary: I ve been pretty good at adhering to my treatment and trying to keep a healthy lifestyle. However, I still have those bad days where I m very depressed. Lewis: I understand your concern. A suggestion I have is to try LATUDA (lurasidone HCl), which is one of the FDA-approved medications for bipolar depression. LATUDA 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. 12 It is important to read the Medication Guide,, and Important Safety Information for LATUDA. Commonly observed adverse reactions ( 5% incidence and at least twice the rate of placebo) for LATUDA in adults with bipolar depression were akathisia, extrapyramidal symptoms, and somnolence. 12 Click to Expand Your Knowledge Click here to view the LATUDA monotherapy pivotal trial in adults Click here to view the LATUDA adjunctive pivotal trial in adults Click here to view the safety and tolerability data for the LATUDA monotherapy study in adults Click here to view the safety and tolerability data for the LATUDA adjunctive therapy study in adults Click here to learn about LATUDA dose modifications in special populations Click here to view the full Prescribing Information for LATUDA

5 Newsletter 2 Page 5 EXPAND YOUR KNOWLEDGE

6 Newsletter 2 Page 6 The Burden of Untreated Bipolar Depression on the Patient The diagnosis of bipolar disorder, and specifically bipolar depression, can be very challenging. Based on one study, nearly 70% of people with bipolar disorder consult between one to four physicians before receiving a correct diagnosis. 4 The most commonly reported (60%) misdiagnosis for people with bipolar disorder is unipolar depression. Other frequently mentioned misdiagnoses include anxiety disorder (26%), schizophrenia (18%), borderline personality disorder (17%), alcohol or substance abuse (14%), and schizoaffective disorder (11%). 4 By one estimate, people with bipolar disorder may wait more than 10 years from onset of symptoms to receiving an accurate diagnosis of bipolar disorder. 4 During the time their illness was untreated or improperly treated, people frequently (80%) experienced relationship problems. 4 In addition, untreated or improperly treated illness may lead to employment-related problems and physical health problems. 4 After receiving a correct diagnosis and appropriate treatment plan, the reported rate of relationship problems and employment-related problems was reduced. 4 Click to Expand Your Knowledge What symptoms may be suggestive of bipolar depression? What are some of the psychiatric comorbidities associated with bipolar disorder? Burden of Bipolar Disorder During the Period of Misdiagnosis 4 0% 10% 20% 30% 40% 50% 60% 70% 80% Interpersonal Conflicts 53% 68% Misdiagnosis Correct Diagnosis Marital Difficulties 30% 49% Job-/School-Related Problems Financial Difficulties 53% 55% 51% 73% Alcohol/Substance Abuse 14% 37% Physical/Health Problems 46% 48% Results of the National Depressive and Manic- Depressive Association (NDMDA) 2000 survey of 600 individuals with bipolar disorder. 4

7 Newsletter 2 Page 7 Cluster of Symptoms and Features Suggestive of Bipolar Depression Depressive episodes of unipolar depression and bipolar disorder often have similar presentation. 1 However, some clusters of symptoms and features may suggest bipolar depression versus unipolar depression. These characteristics, which are listed below, include symptoms of any atypical depression (eg, hypersomnia, hyperphagia, and fatigue); melancholic features, including the loss of pleasure in all, or almost all, activities and a lack of reactivity to usually pleasurable stimuli; history of antidepressant-induced mania or hypomania; history of bipolar disorder in a first-degree relative; poor response to antidepressant therapy; psychotic features; and multiple, brief episodes of depression or a recurrent pattern of illness with abrupt onset and end In the DSM-5, mixed states are recognized both with unipolar depression and with bipolar disorder, so corroborating information that specifies length and severity of symptoms is especially important. 1 Atypical depression Psychomotor retardation Melancholic features Psychotic features High trait or state anxiety; agitation Symptoms Antidepressant-induced mania or hypomania Bipolar disorder in first-degree relative Poor response to antidepressants Medical History 19-21,23 Early onset; troubled development Recurrent pattern; abrupt onset and end of depressive episode Onset or Illness Pattern Other Comorbid substance use Work- and relationshiprelated stress

8 Newsletter 2 Page 8 Psychiatric Comorbidities in Bipolar Disorder It has been estimated that 65% of people with bipolar disorder suffer from at least one comorbid disorder. 15,16 Furthermore, an estimated 42% of people with bipolar disorder have at least two comorbid disorders and nearly a quarter have three comorbid disorders. 16 The most common comorbidities in bipolar disorder, occurring at higher rates than in the general population, are substance use disorder and anxiety disorders, including generalized anxiety disorder, and posttraumatic stress disorder. 16 During their lifetime, 42% of people with bipolar I disorder will have a comorbid anxiety disorder. 16,17 Of patients who have received a bipolar disorder diagnosis, 42% have a comorbid substance use disorder, with 33% having alcohol use disorder. 15 Others who suffer from bipolar disorder may also have stimulant, opioid, cocaine, or marijuana use disorders. 16 symptoms that remain once substances are no longer being used, as they can confound or amplify symptoms that are the result of the underlying bipolar disorder. 1 How can the extensive overlap between bipolar disorder and these psychiatric comorbidities be explained? One explanation is that psychiatric disorders may represent risk factors for each other or share similar end states from different mechanisms. 16 There is some evidence for inheritance of substance use disorder, suggesting inheritance of several illnesses in some patients. 16 Another possibility is that bipolar disorder is related to substance use and anxiety, and by extension, all of these disorders may be related and share a common pathophysiology. 16 There is preliminary research indicating that dysregulation in several common neurotransmitter systems including the dopaminergic, serotonergic, noradrenergic, and GABAergic systems may be important in the pathophysiology of all of these disorders. 16 It is important to note that the diagnosis of bipolar disorder can only be established based on the Summary of Some Psychiatric Comorbidities in BD 1,16,17 Impulse Control Disorder Substance Use Disorder Bipolar Disorder ADHD Eating Disorder Anxiety Disorder

9 Newsletter 2 Page 9 Screening for Manic Symptoms: The Mood Disorder Questionnaire (MDQ) The MDQ is a screening tool that is designed to identify previous manic symptoms. 7 The MDQ includes three questions: the first question is comprised of 13 yes/no items derived from both DSM-IV criteria and clinical experience 7 ; the second question asks if any of the symptoms marked in the first question occurred during the same time period 7 ; the third question assesses, on a 4-response scale, how problematic the symptoms were. 7 A positive screen includes answering yes to seven or more of the 13 symptoms in question one, a yes to question two, and a moderate to serious problematic effect of these symptoms on a patient s life. 7 In combination with the Patient Health Questionnaire-9 (PHQ-9), which identifies the presence and severity of a depressive episode, Check Your Knowledge Which of the following is true about the MDQ? 7 A) It is a screening tool to detect past depressive symptoms B) It was originally developed in the 1980s for inpatient assessments D) All of the above these screening tools can point a clinician in the direction of a bipolar disorder diagnosis, but should not be used as diagnostic tools. 7 Mary s Responses to the MDQ 7* 1. Has there ever been a period of time when you were not your usual self and Yes No you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble? you were so irritable that you shouted at people or started fights or arguments? you felt much more self-confident than usual? you got much less sleep than usual and found you didn t really miss it? you were much more talkative or spoke much faster than usual? thoughts raced through your head or you couldn t slow your mind down? you were so easily distracted by things around you that you had trouble concentrating or staying on track? you had much more energy than usual? you were much more active or did many more things than usual? you were much more social or outgoing than usual, for example, you telephoned friends in the middle of the night? you were much more interested in sex than usual? you did things that were unusual for you or that other people might have thought were excessive, foolish, or risky? spending money got you or your family into trouble? 2. If you checked YES to more than one of the above, have several of these ever happened during the same time period? 3. How much of a problem did any of these cause you like being unable to work; having family, money, or legal troubles; getting into arguments or fights? Please circle one response only. No Problem Minor Problem Moderate Problem Serious Problem *The above is an example of a completed MDQ from a hypothetical patient.

10 Newsletter 2 Page 10 Study Design for LATUDA Monotherapy in Adults 12,13,18 Screening Baseline Double-blind Core Study LATUDA mg/day* LATUDA mg/day Placebo Open-label Extension LATUDA mg/day ǂ 3-14 Days 6 Weeks 24 Weeks *Dosing: started at 20 mg x 7 days, then flexibly dosed mg/day. Dosing: started at 20 mg x 2 days, then increased by 20 mg every 2 days until 80 mg, then flexibly dosed mg/day. ǂ Dosing: started at 60 mg, then flexibly dosed. Efficacy of LATUDA (lurasidone HCl) Monotherapy in Adults In the monotherapy study, LATUDA was statistically significant as compared to placebo in reduction of MADRS total scores at Week 6 12,13 The high-dose range ( mg/day) did not provide additional efficacy, on average, compared to the low-dose range (20-60 mg/day) 12,13 LATUDA was also proven statistically significant as compared to placebo in the key secondary measure of Clinical Global Impressions scale for use in bipolar illness (CGI-BP) on Weeks 2 to 6 12,13 MADRS=Montgomery-Åsberg Depression Rating Scale. Click to Expand Your Knowledge Safety and tolerability data for the LATUDA monotherapy study in adults LS Mean Change From Baseline Efficacy of LATUDA Monotherapy in Adults: MADRS Total Score 12, LATUDA mg (n=161) Time (Weeks) Baseline Effect size: LATUDA mg: 0.51 LATUDA mg: 0.51 * ** * ** ** *** LATUDA mg (n=162) *** *** *** *** Placebo (n=162) Baseline mean =

11 Newsletter 2 Page 11 Safety and Tolerability of LATUDA (lurasidone HCl) Monotherapy in Adults The most common adverse events with LATUDA monotherapy in either dose group, with rates at least 5% and at least twice the placebo rate, were akathisia, EPS, somnolence, nausea, vomiting, diarrhea, and anxiety 12 Atypical antipsychotics have been associated with metabolic changes, including changes in lipids, glucose and body weight. 12 Monitoring of weight, and symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness are recommended 12 Mean Change in Metabolic Parameters From Baseline to Week 6* 12 Total Cholesterol (mg/dl) Triglycerides (mg/dl) Glucose (mg/dl) Weight (lb) LATUDA mg 1.2 (n=140) 5.6 (n=140) -0.8 (n=140) 1.2 (n=143) LATUDA mg -4.6 (n=144) 0.4 (n=144) 1.8 (n=143) 0.0 (n=147) Placebo -3.2 (n=147) 6.0 (n=147) 1.8 (n=148) -0.1 (n=151) The proportion of patients with 7% weight gain at Week 6 was 2.4% for LATUDA-treated patients versus 0.7% for placebo-treated patients 12 The proportion of patients with prolactin elevation 5x upper limit of normal was 0.4% for LATUDAtreated patients and 0.0% for placebo-treated patients 12 Prolactin (ng/ml) Median Change in Prolactin From Baseline to Week 6* 12 LATUDA mg 1.7 (n=140) LATUDA mg 3.5 (n=144) *Last observation carried forward (LOCF) analysis. Placebo 0.3 (n=147) Adverse Reactions in 2% of LATUDA-Treated Adult Patients and at Greater Incidence Than Placebo 12 Patients (%) 100 LATUDA mg (n=164) LATUDA mg (n=167) Placebo (n=168) <1 <1 <1 <1 1 EPS, extrapyramidal symptoms; UTI, urinary tract infection. Note: Figures rounded to the nearest integer. Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence. ǂ EPS includes bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus.

12 Newsletter 2 Page 12 Study Design for LATUDA Adjunctive Therapy in Adults 12,14,18 Screening Li or VPA 28 days 3-14 Days Baseline Double-blind Core Study Open-label Extension LATUDA mg/day * + Li or VPA LATUDA mg/day Placebo + Li or VPA 6 Weeks + Li or VPA 24 Weeks *Dosing: started at 20 mg 3 days, increased to 40 mg 3 days, increased to 60 mg at Day 7, then flexibly dosed. Therapeutic range: lithium, meq/l; valproate, µg/ml. Baseline mean plasma concentrations: lithium (LATUDA group, 0.7 meq/l; placebo group, 0.7 meq/l); valproate (LATUDA group, 75.0 µg/ml; placebo group, 72.0 µg/ml). Dosing: started at 60 mg, then flexibly dosed. Efficacy of LATUDA (lurasidone HCl) Adjunctive Therapy in Adults In the adjunctive study of LATUDA with lithium or valproate, LATUDA was statistically significant as compared to placebo in reduction of MADRS scores at Week 6 12,14 LATUDA was also proven statistically significant as compared to placebo in the key secondary measure of Clinical Global Impressions scale for use in bipolar illness (CGI-BP) on Weeks 3 to 6 12,14 MADRS=Montgomery-Åsberg Depression Rating Scale. Click to Expand Your Knowledge Safety and tolerability data for the LATUDA adjunctive therapy study in adults Efficacy of LATUDA Adjunctive Therapy in Adults: MADRS Total Score 12,14 LS Mean Change From Baseline Time (Weeks) Baseline Effect size: 0.34 *** LATUDA mg + Li/VPA (n=179) *** * ** Placebo + Li/VPA (n=161) Baseline mean = Li, lithium; VPA, valproate

13 Newsletter 2 Page 13 Safety and Tolerability of LATUDA (lurasidone HCl) Adjunctive Therapy in Adults The most commonly observed adverse events ( 5% and at least twice the placebo rate) with LATUDA as an adjunctive therapy with lithium or valproate were: somnolence and akathisia 12 Atypical antipsychotics have been associated with metabolic changes, including changes in lipids, glucose and body weight. 12 Monitoring of weight and symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness, are recommended 12 The proportion of patients with 7% weight gain at Week 6 was 3.1% for LATUDA-treated patients versus 0.3% for placebo-treated patients 12 The proportion of patients with prolactin elevation 5x upper limit of normal (ULN) was 0.4% for LATUDA-treated patients versus 0.0% for placebotreated patients 12 Mean Change in Metabolic Parameters From Baseline to Week 6* 12 Total Cholesterol (mg/dl) Triglycerides (mg/dl) Glucose (mg/dl) Weight (lb) LATUDA mg + Li/VPA -3.1 (n=321) 4.6 (n=321) 1.2 (n=319) 0.2 (n=327) Median Change in Prolactin From Baseline to Week 6* 12 LATUDA mg + Li/VPA Placebo + Li/VPA -2.9 (n=303) -4.6 (n=303) -0.9 (n=302) 0.4 (n=307) Placebo + Li/VPA Prolactin (ng/ml) 2.8 (n=327) 0.0 (n=307) *Last observation carried forward (LOCF) analysis. Adverse Reactions in 2% of LATUDA-Treated Adult Patients and at Greater Incidence Than Placebo 12 Patients (%) LATUDA mg + Li/VPA (n=360) Placebo + Li/VPA (n=334) < <1 EPS, extrapyramidal symptoms. Note: Figures rounded to the nearest integer. EPS includes bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus. Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence.

14 Newsletter 2 Page 14 LATUDA (lurasidone HCl) Dosage and Administration in Bipolar Depression LATUDA has once-daily flexible dosing, which starts at 20 mg/day and may be increased up to 120 mg/day as needed 12 Recommended starting dose of 20 mg/day for monotherapy and adjunctive therapy 12 Initial dose titration is not required 12 Maximum recommended daily dose is 120 mg/day 12 In the monotherapy study, the higher dose range ( mg/day) did not provide additional efficacy, on average, compared to the lower dose range (20-60 mg/day) 12 LATUDA should be taken with food (at least 350 calories) 12 The effectiveness of LATUDA 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 LATUDA for extended periods should periodically re-evaluate the longterm usefulness of the drug for the individual patient 12 The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established 12 LATUDA Dose Modification in Special Populations For patients with moderate renal impairment (creatinine clearance of 30 ml/min to >50 ml/ min) as well as for those with severe renal impairment (creatinine clearance of >30 ml/min), the recommended starting dose is 20 mg/day, and the dose should not exceed 80 mg/day 12 For patients with moderate hepatic impairment (Child-Pugh score=7 to 9), the dose should not exceed 80 mg/day. 11 For patients with severe hepatic impairment (Child-Pugh score=10 to 15), the dose should not exceed 40 mg/day 12 LATUDA Dose Modifications Due to Drug Interactions LATUDA should not be administered with strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc) or strong CYP3A4 inducers (eg, rifampin, avasimibe, St. John s wort, phenytoin, carbamazepine, etc) 12 When a moderate CYP3A4 inhibitor (eg, diltiazem, atazanavir, erythromycin, fluconazole, verapamil, etc) is added to therapy with LATUDA, the LATUDA dose should be reduced to half of the original dose level 12 When LATUDA is added to therapy with a moderate CYP3A4 inhibitor, the recommended starting dose is 20 mg/day and the maximum recommended dose is 80 mg/day 12 If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose after chronic treatment (at least 7 days) with the CYP3A4 inducer 12 Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations 12 Once-daily Flexible Dosing 12 * 20 mg 40 mg 60 mg 80 mg 120 mg *Pills shown are not actual size.

15 Newsletter 2 Page 15 Important Safety Information and Indications 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. LATUDA is not approved for use in pediatric patients with depression. Contraindications: LATUDA is contraindicated in the following: Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone Strong CYP3A4 inhibitors (e.g., ketoconazole) Strong CYP3A4 inducers (e.g., rifampin) Cerebrovascular Adverse Reactions, Including Stroke: In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. LATUDA is not approved for the treatment of patients with dementiarelated psychosis. Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported with administration of antipsychotic drugs. Clinical signs 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. Manage NMS with immediate discontinuation of antipsychotic drugs, including LATUDA, intensive symptomatic treatment and monitoring. Tardive Dyskinesia (TD): The risk of developing TD (a syndrome of abnormal involuntary movements) and potential for it to become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Metabolic Changes: Atypical antipsychotic drugs have caused metabolic changes including: 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. Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo fasting blood glucose testing at the beginning of 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 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. Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Hyperprolactinemia: As with other drugs that antagonize dopamine D 2 receptors, LATUDA elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/neutropenia has been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Monitor complete blood count in patients with a pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) or history of drug-induced leukopenia/neutropenia. Discontinue LATUDA at the first sign of a decline in WBC in the absence of other causative factors. Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest at the beginning of treatment and when increasing dose. Monitor patients vulnerable to hypotension, and those with cardiovascular and cerebrovascular disease. Falls: Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with disease, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy. Seizures: LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold. Potential for Cognitive and Motor Impairment: Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely. Body Temperature Regulation: Use LATUDA with caution in patients who may experience conditions that increase body temperature (e.g., exercising strenuously, exposure to extreme heat, concomitant medication with anticholinergic activity, or being subject to dehydration). Dysphagia: Antipsychotics, including LATUDA, have been associated with esophageal dysmotility and aspiration, and should be used with caution in patients at risk for aspiration pneumonia. Most Commonly Observed Adverse Reactions: The most commonly observed adverse reactions ( 5% incidence and at least twice the rate of placebo) for LATUDA were akathisia, extrapyramidal symptoms, and somnolence. To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc. at or FDA at FDA-1088 ( INDICATIONS LATUDA 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 in adults. Before prescribing LATUDA, please read the full Prescribing Information, including Boxed Warning.

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