The Bipolar Depression Bulletin A Collaborative Care Approach to Diagnosing Bipolar Depression

Transcription

1 The Bipolar Depression Bulletin A Collaborative Care Approach to Diagnosing Bipolar Depression Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page 16. 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. The efficacy of LATUDA 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 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 Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. LATUDA is not approved for use in patients under the age of 18 years. Depressive episodes of major depressive disorder (MDD) and bipolar disorder (BD) often have a similar presentation. 1,2 Patients with bipolar depression (BPD) can often be misdiagnosed with MDD, which may lengthen the time to diagnosis and implementation of an appropriate treatment plan. 1-5 Once an appropriate treatment plan is put in place, care of patients with BPD can be complex, due to the numerous medical and psychiatric comorbidities some patients have. 6 Collaborative care, which employs a multidisciplinary approach to patient care, may increase the efficacy of a treatment plan. 6 This interactive newsletter will focus on some characteristics of BPD and collaborative care, as well as a treatment option for BPD, LATUDA (lurasidone HCl). The newsletter will follow two fictional nurse practitioners (NPs), Mr. Krinsky and Mrs. Carter, as Mr. Krinsky interviews Mrs. Carter about the diagnosis of a fictional patient, Rebecca, who is suffering from depressive symptoms. Patient Case Rebecca, 28 years old (hypothetical patient) Rebecca is a paralegal who just divorced her husband of 4 years. Recently, she has been having trouble finding the energy to care for herself and has been feeling depressed for the past month: I feel like I m moving in slow motion and have no energy. I just can t get out of bed or concentrate on anything. Her ex-husband has noticed Rebecca s depression. He mentions that she has lost quite a bit of weight. When asked if she has ever felt depressed before, Rebecca mentions that as a senior in high school, she went through a period of about 2 weeks where she was feeling worthless and hopeless. She even attempted suicide. She was hospitalized for a short time but did not receive any pharmacological treatment. Rebecca eventually graduated high school and she says her life got better, especially around age 23 when she first starting dating her now exhusband. A few months after they got married, Rebecca says: I felt wired and was sleeping less than 3 hours most nights. I also cheated on my husband a couple of times and was going out and partying a lot. I was a bit out of control. Rebecca s infidelity and decreased need for sleep lasted for about 3 weeks. A few years later, Rebecca s husband learned of her infidelity and the couple divorced 6 months ago. While she was initially saddened by her divorce, she says that her depression has gotten much worse over the past month. LAT983-16

2 Newsletter 2 Page 2 Mr. Krinsky: Rebecca s depression seems severe, and during one of her past Major Depressive Episodes (MDEs), she even attempted suicide. It s possible that her MDEs could be either MDD or BPD. Can you discuss some of the symptoms and characteristics NPs can look out for when trying to distinguish BPD from MDD? Mrs. Carter: The road to proper treatment is often long for patients with BD. 7 On average, a patient who initially presents with depression waits about 10.5 years for a proper treatment, whereas BD patients initially presenting with manic symptoms wait an average of 6.5 years for a proper treatment. 7 Early detection and proper diagnosis are critical for implementing appropriate treatment. In some studies, untreated BD led to an increased lifetime history of suicide attempts, a higher number of major mood episodes, and an increased incidence of self-harm. 7,8 Diagnosis of BPD requires the occurrence and identification of a manic episode that could be preceded or followed by a hypomanic episode or an MDE. 1 Generally, the essential feature of a manic episode is a distinct period during which there is an abnormally, persistently elevated, expansive, or irritable mood that lasts for more than a week. 1 Please consult the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, or the DSM-5, for a complete description of the diagnostic criteria for BPD. 1 Recognizing depressive and past manic symptoms in the clinic can help clinicians diagnose BD. 9,10 The Patient Health Questionnnaire-9, or PHQ-9, can help determine the severity of a patient s depression. 9 The Mood Disorder Questionnaire, or MDQ, can help identify previous manic or hypomanic symptoms. 10 It is important to be aware that the majority of patients with BD also tend to suffer from at least one psychiatric or medical comorbid disorder. 1 Years Average Duration of Untreated Bipolar Disorder Depressive Manic Type of First Episode Click to Expand Your Knowledge What are the psychiatric and medical comorbidities associated with BD? Comorbid conditions in BD can obscure and delay the diagnosis, predict and hasten earlier onset of illness, and detract from short- and long-term recovery. 11 Mr. Krinsky: As NPs, once a proper diagnosis is made, there are several aspects of managing BD that we can help a patient with. What are some of the priorities in care for, and ways that we can educate, BPD patients? Mrs. Carter: BPD is a chronic illness that patients have to manage throughout their life. 12 Collaborative care is a treatment model designed to treat chronic medical conditions through patient education and participation in decision-making, evidence-based guidelines, and use of a clinical team approach. 6 The treatment team can include a variety of healthcare professionals, including NPs, who can help through teaching patients how to handle their depressive or manic symptoms, and additionally, about any medications they are taking. 6,12 Check Your Knowledge: Click the Right Answer Based on a clinical study, what factors or life events, aside from increased self-harm or suicide attempts, are more likely in patients with BD than with MDD? 8

3 Newsletter 2 Page 3 NPs may utilize several intervention strategies to help patients succeed in coping with their symptoms. 12,13 The priorities for care may vary depending on whether a patient is in an inpatient or outpatient setting. 13 In an inpatient setting, top priorities may include preventing harm to self or others, ensuring basic needs are met, monitoring medication effects, and planning for long-term management. 13 If a patient is in an inpatient setting, NPs can help by ensuring that a patient is taking their medication properly and monitoring their efficacy and any resulting adverse effects. 12,13 By contrast, in an outpatient setting, top priorities may include assessing for mood symptoms and suicidal ideation, creating an action plan for suicidal ideation, and monitoring coping strategies. 13 As mentioned before, the risk of suicide and selfharm is increased for BD patients. 7,8 NPs can help prevent these types of events by being vigilant of suicidal ideation or planning, or red flags that include psychotic symptoms, feelings of helplessness or hopelessness, extreme anxiety, alcohol or drug abuse, and family history of suicide attempts. 12,13 BD Intervention Strategies for Nurses 12 Administer medications and monitor the patient s response Medication schedule Drug-drug interactions Ensure safety Suicide prevention Stabilize mood in structured environment Enlist help Psychiatric clinical nurse Social worker Provide education about all aspects of medication therapy Adverse reactions Expected effects Provide education about coping with the disease Identify triggers Encourage healthy lifestyle Click to Expand Your Knowledge What specific roles can NPs play in the care of patients with BPD? What is collaborative care and what are the benefits of using it in the treatment of BPD patients? Lastly, NPs can enlist help by delegating and educating social workers, other nurses, and caregivers on the various aspects of caring for BD patients we just discussed. 12,13 The support of a social worker and/or caregiver could be beneficial in helping a patient to participate in work, school, and family activities. Mr. Krinsky: There have been some positive outcomes in using collaborative care for the treatment of BD patients. Can you explain more about collaborative care? Mrs. Carter: The collaborative care treatment model, in addition to being designed to address chronic medical conditions, was also designed to address treatment gaps and improve outcomes in the primary care environment. 6 In addition, the model seeks to improve outcomes for patients in the primary care setting. 6 The key elements include collaborative decision-making with patients and with other physicians, and use of supportive technology to facilitate monitoring and follow-up of patient outcomes. 6 There are several different models for collaborative care treatment teams. For the treatment of mental health conditions, several studies have included the patient, primary care physicians, specialists, NPs, nurses, psychologists, and social workers. 6 Check Your Knowledge: Click the Right Answer Collaborative care of patients with BPD is associated with what types of outcomes? 14

4 Newsletter 2 Page 4 Mr. Krinsky: In our case study, here, Rebecca s symptoms seem to be suggestive of BPD. For example, she appears to have had at least 1 prior MDE and manic episode, and is in the midst of a current MDE. Is there a treatment option for Rebecca or patients who may currently be taking mood stabilizers, such as lithium or valproate, but may be continuing to suffer from breakthrough depressive episodes? Mrs. Carter: One of the FDA-approved treatment options indicated for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) that could be helpful to Rebecca is LATUDA (lurasidone HCl). LATUDA is indicated as monotherapy and as adjunctive therapy with lithium or valproate. It is important to read the full Prescribing Information, including Boxed Warning, and Important Safety Information for LATUDA. 15 Mr. Krinsky: How was the efficacy of LATUDA established? Mrs. Carter: The efficacy of LATUDA for the treatment of MDEs associated with BPD as monotherapy and as adjunctive therapy with lithium or valproate was established in 2 short-term clinical trials The primary efficacy endpoint for the 2 trials was change from baseline to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled Efficacy of LATUDA MADRS Total Score Monotherapy: 15,16,18 LS Mean Change From Baseline to Week 6 Placebo (n=162) LATUDA mg (n=161) LATUDA mg (n=162) Adjunctive Therapy 15,17,18 LS Mean Change From Baseline to Week 6 Placebo + Li/VPA (n=161) LATUDA + Li/VPA mg (n=161) LS, least squares; MADRS, Montgomery-Åsberg Depression Rating Scale; Li, lithium; VPA, valproate Click to Expand Your Knowledge What is the Montgomery-Åsberg Depression Rating Scale (MADRS) total score? What was the pivotal trial design and efficacy for LATUDA monotherapy? What was the pivotal trial design and efficacy for LATUDA adjunctive therapy? 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. In addition, the efficacy of LATUDA in the treatment of mania associated with BD has not been established. 15 Mr. Krinsky: What were the results of these pivotal trials? Mrs. Carter: Use of LATUDA in monotherapy and adjunctive therapy shows significant improvement in depressive symptoms, as measured by the MADRS total score In LATUDA monotherapy, dosing between mg/day and dosing between mg/day were investigated. 15,16,18 The higher dose didn t provide any additional efficacy, on average, than the lower dose. 15,16,18 Both doses were associated with a statistically significant reduction in depressive symptoms (-15.4 for both LATUDA treatment groups vs for the placebo group). 15,16,18 In LATUDA adjunctive therapy, dosing between mg/day was investigated. 15,17,18 LATUDA added to lithium or valproate was associated with a statistically significant reduction from baseline in depressive symptoms compared with placebo (-17.1 for the LATUDA treatment group vs for the placebo group). 15,17,18 Mr. Krinsky: What was the safety of LATUDA in the monotherapy and adjunctive therapy? Mrs. Carter: 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, extrapyramidal symptoms (EPS), somnolence (including hypersomnia,

5 Newsletter 2 Page 5 Adverse Events (incidence 5%, with incidence greater for the LATUDA group versus placebo) for LATUDA monotherapy, adjunctive therapy, and placebo 16,17 Placebo (n=168) LATUDA Monotherapy (%) LATUDA Adjunctive Therapy (%) LATUDA mg (n=164) LATUDA mg (n=167) Placebo + Li/VPA (n=163) LATUDA mg + Li/VPA (n=183) Nausea Headache Akathisia Somnolence Sedation Dry mouth Vomiting Extrapyramidal events Tremor Insomnia hypersomnolence, sedation, and somnolence), nausea, vomiting, diarrhea, and anxiety. 15,18 The most common treatment-emergent adverse events among patients taking LATUDA as adjunctive therapy with lithium or valproate (at least 5% for LATUDA and at least twice the placebo rate) were somnolence and akathisia. 15,18 Overall, in the combined LATUDA monotherapy 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. 15,18 In the LATUDA adjunctive therapy group, 5.8% (21/360) of patients discontinued treatment due to adverse reactions, compared with 4.8% (16/334) of patients in the placebo group. 15,18 For patients and healthcare professionals involved in collaborative or other types of care, it is important to understand all adverse events and/or changes that may occur to metabolism or weight as a result of medication. 6 Atypical antipsychotics can be associated with metabolic changes; changes in weight, lipids, and glucose were assessed in the LATUDA clinical trials. Before prescribing LATUDA, please read the full Prescribing Information, including Boxed Warning. Click to Expand Your Knowledge Use of LATUDA as a monotherapy treatment option has been associated with what kind of metabolic changes? Click here to view the LATUDA monotherapy safety data Click here to view the LATUDA adjunctive therapy safety data Mean change from baseline to the 6-week endpoint in lipids and glucose in patients with BPD taking LATUDA monotherapy, adjunctive therapy, or placebo 15 Placebo LATUDA Monotherapy LATUDA mg LATUDA mg LATUDA Adjunctive Therapy Placebo + Li/VPA LATUDA mg + Li/VPA Total Cholesterol (mg/dl) -3.2 (n=147) 1.2 (n=140) -4.6(n=144) -2.9 (n=303) -3.1 (n=321) Triglycerides (mg/dl) 6.0 (n=147) 5.6 (n=140) 0.4 (n=144) -4.6 (n=303) 4.6 (n=321) Glucose (mg/dl) 1.8 (n=148) -0.8 (n=140) 1.8 (n=143) -0.9 (n=302) 1.2 (n=319) Weight (lb) -0.1 (n=151) 1.2 (n=143) 0.0 (n=147) 0.4 (n=307) 0.2 (n=327)

6 Newsletter 2 Page 6 APPENDIX

7 Newsletter 2 Page 7 Check Your Knowledge Based on a clinical study, what factors or life events, aside from increased self-harm or suicide attempts, are more likely in patients with BD than with MDD? 8 D) All of the Above Discriminating between MDD and BPD can be difficult. 3,8 Determining particular life events or factors that occur more frequently in BD patients than MDD patients may help clinicians determine the proper diagnosis. 8 BD patients were more likely than MDD patients to make a suicide/self-harm attempt, be hospitalized, experience bullying at school, and have a family history of BD. 8 BD patients were less likely than MDD patients to be clinically judged as having problematic personality traits. 8 Clusters of Symptoms and Features Suggestive of BPD Although both BPD and MDD may manifest identically as major depressive episodes, some clusters of symptoms and features may suggest the former versus the latter. These characteristics, which are listed below, include symptoms of any atypical depression (eg, hypersomnia, hyperphagia, weight increase, 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 with MDD as well as BD, 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 1 relative Poor response to antidepressants Medical History 19,20,22,23 Early onset; troubled development Recurrent pattern; abrupt onset and end of depressive episode Onset or Illness Pattern Other 20,21 Work- and relationship-related stress Comorbid substance use

8 Newsletter 2 Page 8 Psychiatric Comorbidities in BD It has been estimated that 65% of those with BD have at least 1 comorbid disorder. 24 In addition, 42% of BD patients have at least 2 comorbid disorders and nearly a quarter have 3 comorbid disorders. 24 The most common comorbidities in BD, occurring at higher rates than in the general population, are substance use disorder and anxiety disorders, including generalized anxiety disorder, and posttraumatic stress disorder. 11 Of patients who have received a BD diagnosis, 42% have a comorbid substance use disorder, with 33% having alcohol use disorder. 11 Others who suffer from BD may also have stimulant, opioid, cocaine, or marijuana use disorders. 11 It is important to note that diagnosis of BD can only be established based on the symptoms that remain once substances are no longer being used, as they can confound or amplify symptoms that are the result of the underlying BD. 1 BD patients also have an increased risk, approximately 35-fold higher than the general population, of many anxiety disorders, including generalized anxiety disorder, simple phobia, social phobia, panic disorder, and post-traumatic stress disorder. 11 During their lifetime, 65% to 90% of patients with BPD have or will have a comorbid anxiety disorder. 11 How can the extensive overlap between BD and these psychiatric comorbidities be explained? Some evidence indicates that BD is related to substance use and anxiety, and by extension, all of these disorders may be related and share a common pathophysiology. 24 Medical Comorbidities and Medical Mortality in BD Patients with BD have approximately 2-fold increased mortality and die up to 9 years prematurely, compared to the general population. 25 The leading causes of mortality for those suffering from BD is suicide and comorbid cardiovascular disease. Other medical comorbidities include Psychiatric Comorbidities in BD 11* Personality Disorders Cardiovascular disease Substance Use Disorder COPD Impulse Control Disorders Bipolar Disorder Influenza or pneumonia Anxiety Disorder Diabetes mellitus ADHD Metabolic syndrome Medical Comorbidities in BD 11,25* *Adapted from Figure 2 in McIntyre RS, et al. Human Psychopharmacology. 2004; 19: This is not a full list of BD comorbidities. diabetes, chronic obstructive pulmonary disease (COPD), influenza or pneumonia, unintentional injuries, and cancer. 25,26 Patients who had their BD diagnosed earlier in their lifetime have decreased mortality, compared to patients who had their BD diagnosed later, due to chronic disease such as diabetes, COPD, cancer, and heart disease. 25 This data may be suggestive of the underlying mechanism of the increased mortality seen with BD. Patients suffering with BD may be less likely to seek out and receive primary or preventative medical care. 25 In addition, BD patients have higher rates of engaging in unhealthy lifestyle factors, including smoking and substance misuse. Several cardiovascular risk factors are more common in individuals with bipolar disorder than in the general population, which may help explain the elevated risk of cardiovascular mortality. 26 These risk factors include: obesity, hypertension, diabetes, and hyperlipidemia. 26 Each could contribute to excess cardiovascular mortality. 26

9 Newsletter 2 Page 9 Nursing and the Management of BD Patients Nurses and NPs can help in the treatment of BD patients by understanding the causes, signs, and symptoms of BD. In addition, understanding the potential adverse reactions and the effect of medications used to treat BD can give them a firsthand view of how a patient is reacting to the treatment. The priorities and goals for nurses and NPs in managing BD patients may change depending on the stage of treatment a patient is in. 13 In the short-term, the primary goals for treatment may be the stabilization and safety of a patient. 13 For the long-term maintenance of a BD patient, goals may include preventing relapse and limiting the duration and severity of manic or depressive symptoms. 13 The goals of treatment may also be different for BD patients in an inpatient setting or an outpatient setting. 13 For inpatient treatment, signs and symptoms of depression or mania determine the goals and focus of management. Safety is the first priority, and patients in the midst of an MDE are at a high risk for self-harm. 13 For outpatient management, goals include reestablishing the patient s previous functioning level, identifying triggers, preventing relapse or reducing its severity, limiting the duration of future episodes, and monitoring responses to treatment. 13 The chart below compares care priorities for patients with BD in inpatient and outpatient settings. 13 Nursing Management Priorities for BD 13* Inpatient setting Outpatient setting Interventions: Prevent patient from harming self or others Assess for suicidal ideation and suicide planning Ensure that patient s basic needs are met Create action plan for suicidal ideation Monitor medication effects Assess for hypomanic, manic, and depressive episodes Plan for long-term management Monitor coping strategies Focus on: Nutritional status Nutritional status Sleep Sleep Compliance with treatment plan and medications Compliance with treatment plan and medications Activities of daily living Activities of daily living Thought processes and content communication Thought processes and content communication Social interaction Social interaction Self-esteem Self-esteem Quality of life Quality of life Knowledge of BD and its treatment Participation in work, school, and family Knowledge of BD and its treatment *Adapted from Wieseke A. Am Nurse Today. 2011;6(7):8-12.

10 Newsletter 2 Page 10 Check Your Knowledge Collaborative care of patients with BPD is associated with what types of outcomes? 14 C) Both A and B Collaborative care involves the formation of a treatment team that includes the patient, caregivers, and nurses, and can include a multitude of other healthcare professionals. The objective of this team is to create a patientspecific treatment plan to educate both the patient and caregiver, amongst other things. 14 Studies have found that collaborative care substantially reduced the duration of time and the severity of depressive symptoms experienced by BD patients. 14 Collaborative Care for the Management of BD Because medical management of BD patients is often confounded by medical or psychiatric comorbidities, as well as side effects associated with complex medication regimens, there can sometimes be a gap between the efficacy of BD treatments and the effectiveness of the care that patients receive. 6 Several studies have documented the successes of a collaborative care model for the treatment of BD and other mental health disorders. 6 The key elements of collaborative care include the use of evidence-based treatment guidelines, patient psychoeducation, collaborative decision-making with patients and their treatment team, and follow-up on patient outcomes. 6 Studies that have used collaborative care for the treatment of BD have found significant reduction in the severity of manic symptoms in study populations. 6 Other studies documented substantial reduction in the duration of time and the severity of depressive symptoms in BD patients. 14 The goal of this team-based, patient-oriented method of treatment is to achieve patient recovery, returning patients to their level of functioning prior to the onset of illness. 6 Improving Outcomes in Chronic Illnesses Using Collaborative Care 6* Clinical Guidelines Evidence-Based, Planned Care Practice Redesign Patient Education Expert System Information Appointments Roles Follow-up Self-management Behavioral change Psychological support Patient participation Provider education Decision support Consultation Reminders Outcomes Feedback Care planning Informed, Activated Patient Improved Functional and Clinical Outcomes Prepared, Proactive Practice Team *Adapted from Susman JL. Prim Care Companion J Clin Psychiatry. 2010;12(Suppl 1):30-34.

11 Newsletter 2 Page 11 Measuring Depression Severity: The Montgomery-Åsberg Depression Rating Scale (MADRS) total score The MADRS is a 10-item questionnaire to rate the severity of depressive episodes and should be administered by an healthcare professional during a clinical interview. 27 Each question asks about a different symptom of depression and its severity on a scale of 0 to The score for each individual question is added together to give an overall score ranging from 0 to The higher the total score is, the more severe the depression symptoms. 18 MADRS total score 27* 1. Apparent Sadness: Representing despondency, gloom and despair, (more than just ordinary transient low spirits) reflected in speech, facial expression, and posture. Rate by depth and inability to brighten up. 2. Reported Sadness: Representing reports of depressed mood, regardless of whether it is reflected in appearance or not. Includes low spirits, despondency or feeling of being beyond help without hope. Rate according to intensity, duration and the extent to when the mood is reported to be influenced by events. 3. Inner Tension: Representing feelings of ill-defined discomfort, edginess, inner turmoil mounting to either panic, dread or anguish. Rate according to intensity, frequency, duration and the extent of reassurance called for. 4. Reduced Sleep: Representing the experience of reduced duration or depth of sleep compared to the subject s own normal pattern when well. 5. Reduced Appetite: Representing the feeling of loss of appetite compared with when well. Rate by loss of desire for food or the need to force oneself to eat. 6. Concentration Difficulties: Representing difficulties in collecting one s thoughts mounting to incapacitating lack of concentration. Rate according to intensity, frequency, and degree of incapacity produced. 7. Lassitude: Representing a difficulty getting started or slowness initiating and performing everyday activities. Rating scale for each symptom: Severity of Depressive Symptoms 8. Inability to Feel: Representing the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure. The ability to react with adequate emotion to circumstances or people is reduced. 9. Pessimistic Thoughts: Representing thoughts of guilt. Inferiority, selfreproach, sinfulness, remorse and ruin. 10. Suicidal Thoughts: Representing the feeling that life is not worth living, that a natural death would be welcome, suicidal thoughts, and the preparations for suicide. Suicidal attempts should not in themselves influence the rating. *For each of the 10-items, the MADRS has distinct definitions (not shown here) for scale steps 0, 2, 4, and Please see the full test for precise rating of symptom severity (Br J Psychiatry. 1979;134: ). 27

12 Newsletter 2 Page 12 Short-Term Efficacy of LATUDA Monotherapy A total of 505 subjects from multiple sites throughout the world, including the United States, were randomized in the pivotal monotherapy trial of LATUDA in patients with BPD. 16 In this trial, subjects were evaluated for eligibility during a screening period of 3 to 14 days, during which they were tapered off all psychotropic medications. After screening, washout, and baseline evaluation, patients in the monotherapy double-blind study were randomized to flexibly dosed LATUDA mg/day (N=166), flexibly dosed LATUDA mg/day (N=169), or placebo (N=170). 16 The efficacy of LATUDA as monotherapy with BPD was measured by the change from baseline to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and served as the primary efficacy endpoint for this study. 16 In the monotherapy study, LATUDA mg/ day and mg/day were associated with a statistically significant reduction in MADRS total score from baseline to the 6-week endpoint compared with placebo, indicating a 44% greater reduction. 16,17 The high-dose range ( mg/ day) did not provide additional efficacy, on average, compared to the low-dose range (20-60 mg/day). 15 LS Mean Change From Baseline Efficacy of LATUDA Monotherapy: MADRS Total Score 16, LATUDA mg (n=161) Time (Weeks) Baseline Effect size: LATUDA mg: 0.51 LATUDA mg: 0.51 Click to Expand Your Knowledge * ** * ** ** *** LATUDA mg (n=162) *** *** *** *** Placebo (n=162) Baseline mean = Safety Information for LATUDA Monotherapy Study Study Design for LATUDA Monotherapy 16,18 Double-blind Core Study Screening Baseline LATUDA mg/day* LATUDA mg/day Placebo Open-label Extension LATUDA mg/day ǁ 3-14 Days 6 Weeks *Dosing: started at 20 mg 7 days, then flexibly dosed mg/day. Dosing: started at 20 mg 2 days, then increased by 20 mg every 2 days until 80 mg, then flexibly dosed mg/day. ǁ Dosing: started at 60 mg, then flexibly dosed. 24 Weeks

13 Newsletter 2 Page 13 Short-Term Efficacy of LATUDA Adjunctive Therapy In the multicenter, pivotal adjunctive therapy study of LATUDA in patients with bipolar depression, 348 subjects were randomized. 17 In this trial, subjects were evaluated for eligibility during a screening period of 3 to 14 days, during which they were tapered off all psychotropic medications, unless they were on lithium or valproate. 17,18 This washout period concluded at least 3 days prior to study randomization. 17,18 These patients were to remain stable within the protocol-specified therapeutic range of lithium or valproate (lithium, meq/l; valproate, µg/ml) for at least 28 days prior to randomization. Patients in the double-blind adjunctive therapy study were randomized to flexibly dosed LATUDA mg/ day plus lithium or valproate (N=183) or placebo plus lithium or valproate (N=165). 17 The efficacy of LATUDA as an adjunctive therapy added to either lithium or valproate in patients with bipolar depression was measured by the change from baseline to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, the 2 trials primary efficacy endpoint. 15 In the adjunctive therapy study, at the 6-week endpoint, LATUDA added to lithium or valproate was associated with a statistically significant reduction from baseline in the MADRS total score compared with placebo (-17.1 vs -13.5; P<0.01). 17 LS Mean Change From Baseline Efficacy of LATUDA Adjunctive Therapy: MADRS Total Score 17, Time (Weeks) Baseline LATUDA mg + Li/VPA (n=179) Effect size: 0.34 *** *** * ** Placebo + Li/VPA (n=161) Baseline mean = Click to Expand Your Knowledge Safety Information for LATUDA Adjunctive Therapy Study Study Design for LATUDA Adjunctive Therapy 17,18 Screening Li or VPA 28 days Baseline Double-blind Core Study Placebo + Li or VPA Open-label Extension LATUDA mg/day + Li or VPA LATUDA mg/day ǁ + Li or VPA 3-14 Days Li, lithium; VPA, valproate. 6 Weeks 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). ǁ Dosing: started at 60 mg, then flexibly dosed.

14 Newsletter 2 Page 14 Short-Term Safety of LATUDA Monotherapy 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. 15 Weight gain has been observed with atypical antipsychotic use. 15 Clinical monitoring of weight is recommended. 15 Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactinelevating compounds. 15 Placebo-treated patients (N=151) LATUDA-treated patients (N=290) Weight Gain During Study Period 15 Mean Weight Gain (lbs) Patients With a 7% Increase in Body Weight (%) Median Change in Prolactin From Baseline to Endpoint 15 Treatment Group Males Females Click to Expand Your Knowledge Placebo 0.4 ng/ml (N=65) 0.0 ng/ml (N=82) Short-Term Efficacy for LATUDA Monotherapy Study LATUDA mg LATUDA mg 1.2 ng/ml (N=62) 1.9 ng/ml (N=56) 1.8 ng/ml (N=78) 5.3 ng/ml (N=88) Adverse Reaction in 2% of LATUDA-Treated Patients and at Greater Incidence Than Placebo 15 Patients (%) LATUDA mg (n=164) LATUDA mg (n=167) Placebo (n=168) <1 < <1 <1 2 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. 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.

15 Newsletter 2 Page 15 Short-Term Safety of LATUDA Adjunctive Therapy The most common treatment-emergent adverse events among patients taking LATUDA as adjunctive therapy with lithium or valproate (at least 5% for LATUDA and at least twice the placebo rate) were somnolence and akathisia. 15 Weight gain has been observed with atypical antipsychotic use. 15 Clinical monitoring of weight is recommended. 15 Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactinelevating compounds. 15 Placebo + Li/VPAtreated patients (N=307) LATUDA + Li/ VPA-treated patients (N=327) Weight Gain During Study Period 15 Mean Weight Gain (lbs) Patients With a 7% Increase in Body Weight (%) Click to Expand Your Knowledge Median Change in Prolactin From Baseline to Endpoint 15 Treatment Group Males Females Short-Term Efficacy for LATUDA Adjunctive Therapy Study Placebo + Li/VPA LATUDA mg + Li/VPA -0.1 ng/ml (N=145) 2.4 ng/ml (N=159) 0.4 ng/ml (N=156) 3.2 ng/ml (N=162) 100 Adverse Reaction in 2% of LATUDA-Treated Patients and at Greater Incidence Than Placebo 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.

16 Newsletter 2 Page 16 Important Safety Information and Indications Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. LATUDA is not approved for use in patients under the age of 18 years. 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) WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions, Including Stroke: 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. LATUDA is not approved for the treatment of patients with dementia-related psychosis Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including LATUDA. NMS can cause 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. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems Tardive Dyskinesia (TD): TD is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients with antipsychotic drugs. There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. The risk of developing TD 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. Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of TD. If signs and symptoms appear in a patient on LATUDA, drug discontinuation should be considered Metabolic Changes 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 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 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 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 D2 receptors, LATUDA elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds In the short-term, placebo-controlled monotherapy study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated females was 3.1 ng/ml and was 1.5 ng/ml for males. The proportion of female patients with prolactin elevations 5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated male patients In the short-term, placebo-controlled adjunctive therapy with lithium or valproate study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated females was 3.2 ng/ml and was 2.4 ng/ml for males. The proportion of female patients with prolactin elevations 5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated male patients 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. Patients with a preexisting low white blood cell count (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 LATUDA should be discontinued at the first sign of a decline in WBC in the absence of other causative factors Orthostatic Hypotension and Syncope: LATUDA may cause orthostatic hypotension. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, in patients with known cardiovascular disease or history of cerebrovascular disease, and in patients who are antipsychotic-naïve Seizures: LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold (e.g., Alzheimer s dementia) 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: Disruption of the body s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration Suicide: The possibility of suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer s dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia ADVERSE REACTIONS Commonly observed adverse reactions ( 5% incidence and at least twice the rate of placebo) for LATUDA were akathisia, extrapyramidal symptoms, and somnolence 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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