Bipolar disorder is a recurrent and lifelong illness, with episodes

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1 Available at CurrentPsychiatry.com/BipolarDepression This promotional, non-cme newsletter is intended only for health care professionals involved in the treatment of adult patients with bipolar disorder. A SUPPLEMENT TO This newsletter 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 Catherine R. Judd, MS, PA-C, CAQ- Psychiatry, DFAAPA Clinical Assistant Professor Department of Physician Assistant Studies University of Texas Southwestern Medical Center School of Health Professions Physician Assistant Mental Health and Behavioral Medicine Parkland Health and Hospital System Dallas, TX DISCLOSURES Ms. Judd serves or has served as a consultant, speaker, or researcher for various pharmaceutical companies, including Sunovion. The clinical expert commentary reflects the view of an actual licensed clinician who has been engaged by Sunovion. The information contained herein is intended for general informational purposes only and is not a substitute for your professional medical advice and judgment. Bipolar Disorder: Beyond Recognizing Depressive Symptoms Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S7. INDICATIONS is indicated for monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) and adjunctive treatment with lithium or valproate in adult patients with bipolar depression. The effectiveness of for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. The efficacy of in the treatment of mania associated with bipolar disorder has not been established. IMPORTANT SAFETY INFORMATION FOR Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. 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. 06/18 LAT A clinical expert, Catherine R. Judd, MS, PA-C, CAQ-Psychiatry, DFAAPA, shares practical insights on recognizing signs of bipolar depression. Additionally, clinical data on, a treatment option for bipolar depression, are summarized. Bipolar disorder is a recurrent and lifelong illness, with episodes of depression interspersed with at least one episode of mania or hypomania. The depressive phase of bipolar I disorder is commonly known as bipolar depression. 1 Recognizing bipolar depression, and differentiating it from other forms of depression, including those associated with general medical Supplement to Current Psychiatry S1

2 INSIGHTS IN DIFFERENTIATING BIPOLAR DEPRESSION conditions, substance abuse, or major depressive disorder, can be challenging. 1 Bipolar depression is commonly misdiagnosed, most often as unipolar depression, followed by anxiety disorders, schizophrenia, personality disorders, and substance abuse and/or alcohol use disorder. 2 Ms. Judd, a practicing physician assistant from the University of Texas Southwestern Medical Center and Parkland Health & Hospital System, noted that such conditions frequently occur as comorbidities with bipolar disorder. Other mood states may also be present and could possibly be distractors from honing in on the bipolar disorder diagnosis. she added. Diagnosis can be particularly challenging as the depressive symptoms of unipolar depression may be indistinguishable from those of bipolar depression. 1 Additionally, symptoms of mania are often underreported or may not be reported at all. 2 Many patients wait more than 10 years from the onset of symptoms to receive an accurate diagnosis of bipolar disorder. 2 Differentiating bipolar and unipolar depression To help differentiate bipolar depression from unipolar depression, several factors, including symptoms, history, course of illness, and associated features, may offer helpful clues. 3-5 Characteristic symptoms that may be exhibited in bipolar depression include melancholia and psychomotor retardation. Patients may report low energy or atypical depressive symptoms such as excessive sleep and appetite. Psychotic features or comorbid anxiety within a major depressive episode are also a clue to bipolarity. 3,5,6,7 Ms. Judd emphasized the importance of listening for different ways a patient may be describing symptoms during an office visit, noting that a patient may talk about low energy, feeling tired, sleeping 18 hours a, or being less productive. Equally important in differentiating bipolar depression is an assessment of patient and family history. 4 Patients with bipolar Compared with unipolar depression, the course of illness for bipolar depression often has an earlier age of onset, with a recurrent or even seasonal pattern. 3,4,8 disorder typically present with a depressive episode rather than mania or hypomania, so assessing whether bipolar disorder exists in a first-degree relative may be an important clue. Ms. Judd acknowledged the importance of collecting comprehensive patient and family history. As a part of screening, she often asks patients, Does anybody else in the family have these kinds of problems? Further, a family history of bipolar disorder across multiple consecutive generations and among several biological relatives may be an indicator of bipolar disorder, as does a patient or family history of substance use and anxiety disorders. 3,5,6 Past treatment for multiple depressive episodes or a transient or poor response to traditional antidepressants may also be indicative of bipolar disorder. Antidepressant-induced mania, hypomania, mixed state, or rapid cycling; rapid response to antidepressants with complete remission of depressive symptoms in 3 to 4 s instead of the typical 4 to 6 weeks; or lack of response to 3 or more antidepressant trials may be additional clues. 4,7 Past improvement of depressive symptoms in response to mood stabilizers should also raise suspicion of bipolar disorder. 4 Further, compared with unipolar depression, the course of illness for bipolar depression often has an earlier age of onset, with a recurrent or even seasonal pattern. 3,4,8 Abrupt start and end of depressive episodes may also be an important sign. 5 Half of patients with bipolar disorder experience depression at the onset of bipolar disorder symptoms. 8 On average, patients with bipolar disorder experience 3 times more depression than mania when symptomatic. 9 Ms. Judd pointed out that while patients more commonly present with depressive symptoms, it is important for clinicians to be aware of the elevated mood symptoms that help distinguish a patient with bipolar disorder. Few people come in complaining about being in an elevated mood state. she said. They aren t going to seek help when they are feeling more energetic than their normal self. And so consequently, clinicians end up drilling down into the depressive episodes. This highlights that it may be beneficial to have a caregiver, family member, or significant other present at the appointment to help uncover a possible manic episode. Patients may not selfreport a past elevated mood, but another person close to them may S2 Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S7. Supplement to Current Psychiatry

3 provide information related to an episode of mania. 10 Ms. Judd explained that she has found it helpful to use both formal and informal methods of screening: It depends on the time, the setting, and whether a patient is willing to respond to a questionnaire. Screening tools such as the Mood Disorder Questionnaire (MDQ) and Composite International Diagnostic Interview (CIDI) 3.0 have been developed to help clinicians identify different mood symptoms. 11,12 These screeners can also help determine the severity of symptoms. Additionally, there are some screening tools that can be used to learn more about a patient s life. Patients may use the MDQ to selfreport symptoms of mania and the impact these symptoms have. 11 The CIDI 3.0 uses two stem questions to help uncover instances of notably elevated or persistently irritable mood, and then uses additional screening questions to check for associated symptoms of mania. 12 Ms. Judd shared that she uses the MDQ during patient screening to learn about the magnitude of a patient s symptoms. 11 Ms. Judd explained, Building from a patient s responses to the MDQ questions, I usually ask, `Have these symptoms caused you any problems? How much of an impact have these problems had on you, and for how long? And those Frequent job and relationship changes, excessive impulsive behaviors, and/or comorbid substance abuse may be other indicators of bipolar disorder. 5 problems could be interpersonal relationship problems or problems at work. And this is what can lead the clinician to start thinking about whether the patient may be describing hypomania or mania. She further explained, When asking patients about their lives, one may observe that they are not getting along with others. Patients may describe behaviors that are impulsive or related to poor decision-making. Frequent job and relationship changes, excessive impulsive behaviors, and/or comorbid substance abuse may be other indicators of bipolar disorder. 5 For these reasons, according to Ms. Judd, exploring patient history is an especially important area of focus during initial evaluation. Taking the next step A detailed clinical interview is a critical next step in diagnosis. Because an accurate diagnosis can guide the prescription and management of appropriate treatment, differentiation between unipolar and bipolar depression is especially important. Watch A Practical Guide to Recognizing. Visit Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S7. Supplement to Current Psychiatry S3

4 INSIGHTS IN DIFFERENTIATING BIPOLAR DEPRESSION : 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 longerterm use (more than 6 weeks) or for the treatment of mania associated with bipolar disorder. 13 Each phase 3, multicenter, randomized, double-blind, placebocontrolled 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. 14,15 Patients in the monotherapy study were randomized to flexibly dosed mg/ (N=166), flexibly dosed mg/ (N=169), or placebo (N=170). 14 Patients in the adjunctive therapy study were randomized to flexibly dosed mg/ plus lithium or valproate (N=183) or placebo plus lithium or valproate (N=165). 15 dose adjustments within the assigned dosing range were permitted to optimize efficacy and tolerability. Study medication was taken once daily in the evening by mouth with a meal (eg, dinner) or within 30 minutes after eating. 14,15 Efficacy 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). 14 The mean decrease in MADRS score between baseline and Week 6 was 15.4 points for patients randomized to mg/ or mg/ versus 10.7 points for patients randomized to placebo (P<.001). 14 The higher dose range ( mg/) did not provide additional efficacy, on average, compared to the lower dose range (20-60 mg/). 13 With as adjunctive therapy with lithium or valproate, the mean decrease in the MADRS score between baseline and Week 6 was 17.1 points for patients randomized to adjunctive mg/ versus 13.5 points for patients randomized to placebo (P<.01) (Figure 1). 15 FIGURE 1. PRIMARY EFFICACY ENDPOINT: MADRS SCORE LS Mean Change From Baseline Baseline Baseline mean = mg (n=161) 14 * ** Time (Weeks) Effect size: mg: mg: 0.51 * ** mg (n=162) ** *** *** *** *** *** (n=162) LS Mean Change From Baseline Baseline Adjunctive Therapy 15 Time (Weeks) mg + Li/VPA (n=179) Effect size: 0.34 *** *** * ** + Li/VPA (n=161) Baseline mean = Reduction in severity of depression *P<.05; **P<.01; ***P<.001. Abbreviations: Li, lithium; LS, least squares; MADRS, Montgomery-Åsberg Depression Rating Scale; VPA, valproate. The higher dose range ( mg/) did not provide additional efficacy, on average, compared to the lower dose range (20-60 mg/). MADRS scale range, S4 Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S7. Supplement to Current Psychiatry

5 FIGURE 2. MONOTHERAPY AND ADJUNCTIVE THERAPY: WEIGHT AND LABORATORY PARAMETERS Mean Change From Baseline* Weight 15 (lb) Total Cholesterol 15 (mg/dl) Glucose 15 (mg/dl) (n=143) (n=147)(n=151) (n=140)(n=144)(n=147) (n=140)(n=143)(n=148) mg mg Longer-term, Open-label Extension Study Change from open-label baseline 16, : 0.3 lb (n=153) -0.1 mg/dl (n=154) 1.5 mg/dl (n=153) Adjunctive Therapy Mean Change From Baseline* Weight 15 (lb) Total Cholesterol 15 (mg/dl) (n=327) (n=307) (n=321) (n=303) mg + Li/VPA Glucose 15 (mg/dl) (n=319) (n=302) + Li/VPA Longer-term, Open-label Extension Study Change from open-label baseline 16, : 1.7 lb (n=173) 0.4 mg/dl (n=182) -0.5 mg/dl (n=181) Abbreviations: Li, lithium; VPA, valproate. *Last observation carried forward. Observed cases; patients who continued on. Safety population. Notes: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. 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. 13 The safety and tolerability of adjunctive with lithium or valproate compared with placebo were examined in 2 short-term, randomized clinical trials of patients with bipolar depression. The adverse reactions that occurred in at least 2% of -treated patients and at a greater incidence than placebo in the 2 studies combined were nausea, EPS, somnolence, akathisia, nasopharyngitis, vomiting, restlessness, fatigue, increased appetite, and increased weight. Overall, treatment was discontinued due to adverse reactions by 5.8% of patients (21/360) receiving as adjunctive therapy with lithium or valproate and by 4.8% of patients (16/334) in the placebo group. 13 Patients from both the and placebo groups of the 6-week monotherapy and adjunctive therapy trials were eligible to continue into a 6-month, uncontrolled, open-label, flexibledose extension study. 16, The adverse reactions in at least 5% of patients who continued on monotherapy in the longer-term study were headache, nausea, nasopharyngitis, akathisia, insomnia, and anxiety. Of those who continued on adjunctive therapy plus lithium or valproate in the longer-term study, at least 5% experienced parkinsonism, somnolence, akathisia, insomnia, anxiety, headache, and nausea. 16 Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk. 13 Changes in weight and laboratory parameters during both the short-term and longerterm monotherapy and adjunctive therapy studies are presented in Figure 2. 13,16 Overall, the clinical trials demonstrated that at 6 weeks, metabolic changes were similar in the and placebo groups, and at 24 weeks, no clinically significant changes in body weight or The effectiveness of for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S7. Supplement to Current Psychiatry S5

6 INSIGHTS IN DIFFERENTIATING BIPOLAR DEPRESSION clinically relevant changes or shifts from open-label baseline in lipid parameters and glucose were observed. 13,16 For prolactin in the short-term monotherapy study, the median change in concentration was +1.7 ng/ml, +3.5 ng/ml, and +0.3 ng/ml for the low-dose, high-dose, and placebo groups,respectively, and -1.1 ng/ml for those who continued on in the longer-term trial. In the short-term adjunctive therapy studies, the median change was +2.8 ng/ml in the group and 0.0 ng/ml in the placebo group, and in the longer-term trial, it was -1.3 ng/ml in patients who continued on. 13,16 Changes from baseline to endpoint in EPS, akathisia, and tardive dyskinesia were also evaluated in the monotherapy and adjunctive therapy short-term and longer-term trials using the Simpson-Angus Scale (SAS), the Barnes Akathisia Scale (BAS), and the Abnormal Involuntary Movement Scale (AIMS), respectively. Categorical change was defined as a shift from normal at baseline to abnormal at study endpoint for the SAS, or as worsening from baseline to study endpoint for the BAS and AIMS. The mean change from baseline for -treated patients was comparable to placebo on all 3 movement scales. 13,16 References: 1. Hirschfeld RMA. Why care about bipolar disorder? A primary care physician s guide to screening and referral. Adv Stud Med. 2003; 3(4): Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64(2): Galvão F, Sportiche S, Lambert J, et al. Clinical differences between unipolar and bipolar depression: interest of BDRS ( Rating Scale). Compr Psychiatry. 2013;54(6): Motovsky B, Pecenak J. Psychopathological characteristics of bipolar and unipolar depression potential indicators of bipolarity. Psychiatr Danub. 2013;25(1): Parker G, McCraw S, Hadzi-Pavlovic D, Hong M, Barrett M. Bipolar depression: prototypically melancholic in its clinical features. J Affect Disord. 2013;147(1-3): Ghaemi SN, Bauer M, Cassidy F, et al. Diagnostic guidelines for bipolar disorder: a summary of the International Society for Bipolar Disorders Diagnostic Guidelines Task Force Report. Bipolar Disord. 2008;10: Perlis RH, Brown E, Baker RW, Nierenberg AA. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials. Am J Psychiatry Feb;163(2): Suppes T, Leverich GS, Keck PE, et al. The Stanley Foundation Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. J Affect Disord. 2001;67(1-3): Judd LL, Akiskal HS, Schettler PJ, et al. The longterm natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6): American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157(11): Kessler RC, Akiskal HS, Angst J, et al. Validity of the assessment of bipolar spectrum disorders in the WHO CIDI 3.0. J Affect Disord Dec;96(3): (lurasidone HCl) prescribing information. Marlborough, MA: Sunovion Pharmaceuticals Inc.; March Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebocontrolled study. Am J Psychiatry. 2014;171(2): Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2): Data on file. Sunovion Pharmaceuticals Inc. S6 Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S7. Supplement to Current Psychiatry

7 BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION* WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. is not approved for the treatment of patients with dementia-related psychosis. Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. INDICATIONS AND USAGE is indicated for: Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia. treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression). Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression). CONTRAINDICATIONS Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone. Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.). Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John s wort, phenytoin, carbamazepine, etc.). WARNINGS AND PRECAUTIONS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. is not approved for the treatment of patients with dementia-related psychosis. Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebotreated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. Table 1: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled -Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug- Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to <18 14 additional patients additional patients Decreases Compared to fewer patient 65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression. *Note: Read the full Prescribing Information before prescribing. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue and provide intensive symptomatic treatment and monitoring. Tardive Dyskinesia Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on, drug discontinuation should be considered. However, some patients may require treatment with despite the presence of the syndrome. Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Supplement to Current Psychiatry S7

8 Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 2. Table 2: Change in Fasting Glucose in Adult Studies 20 mg/ 40 mg/ 80 mg/ 120 mg/ 160 mg/ 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) 10.0% (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 mg/dl for placebo (n=95), +0.1 mg/dl for 40 mg/ (n=90), and +1.8 mg/dl 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 60 mg/ 80 to 120 mg/ 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 mg/, 80 to 120 mg/, or placebo. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received as monotherapy in the short-term study and continued in the longerterm 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 Bipolar Depression Studies 20 to 120 mg/ 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 mg/ or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dl at week 24 (n=88). In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dl for 20 to 80 mg/ (n=145) and -0.5 mg/dl for placebo (n=145). 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: Change in Fasting Lipids in Adult Studies. Table 5: Change in Fasting Lipids in Adult Studies 20 mg/ 40 mg/ 80 mg/ 120 mg/ 160 mg/ 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 mg/dl for placebo (n=95), -4.4 mg/dl for 40 mg/ (n=89), and +1.6 mg/dl for 80 mg/ (n=92), and fasting serum triglyceride mean values were +0.1 mg/dl for placebo (n=95), -0.6 mg/dl for 40 mg/ (n=89), and +8.5 mg/dl 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 60 mg/ 80 to 120 mg/ 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 mg/, 80 to 120 mg/, or placebo. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 mg/dl (n=130) and -1.0 mg/dl (n=130) at week 24, respectively. S8 Supplement to Current Psychiatry

9 Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 7. Table 7: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies 20 to 120 mg/ Mean Change from Baseline (mg/dl) n=303 n=321 Total cholesterol Triglycerides Proportion of Patients with Shifts Total cholesterol ( 240 mg/dl) Triglycerides ( 200 mg/dl) 5.7% (15/263) 8.6% (21/243) 5.4% (15/276) 10.8% (28/260) Patients were randomized to flexibly dosed 20 to 120 mg/ or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dl at week 24, respectively. In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dl for 20 to 80 mg/ (n=144) and -1.4 mg/dl for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dl for 20 to 80 mg/ (n=144) and +5.9 mg/dl for placebo (n=145). Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 8. The mean weight gain was kg for -treated patients compared to kg for placebo-treated patients. Change in weight from baseline for olanzapine was kg and for quetiapine extended-release was kg in Studies 3 and 5, respectively. The proportion of patients with a 7% increase in body weight (at Endpoint) was 4.8% for -treated patients and 3.3% for placebo-treated patients. Table 8: Mean Change in Weight (kg) from Baseline in Adult Studies (n=696) 20 mg/ (n=71) 40 mg/ (n=484) 80 mg/ (n=526) 120 mg/ (n=291) 160 mg/ (n=114) All Patients In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), was associated with a mean change in weight of kg at week 24 (n=755), kg at week 36 (n=443) and kg at week 52 (n=377). Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 9. The mean change in weight gain was +0.5 kg for -treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 3.3% for -treated patients and 4.5% for placebo-treated patients. Table 9: Mean Change in Weight (kg) from Baseline in the Adolescent Study (n=111) 40 mg/ (n=109) 80 mg/ (n=104) All Patients Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 10. The mean change in weight gain was kg for -treated patients compared to kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 2.4% for -treated patients and 0.7% for placebo-treated patients. Table 10: Mean Change in Weight (kg) from Baseline in the Adult Study (n=151) 20 to 60 mg/ (n=143) 80 to 120 mg/ (n=147) All Patients Patients were randomized to flexibly dosed 20 to 60 mg/, 80 to 120 mg/, or placebo. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of kg at week 24 (n=130). Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 11. The mean change in weight gain was kg for -treated patients compared to kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 3.1% for -treated patients and 0.3% for placebo-treated patients. Table 11: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Studies (n=307) 20 to 120 mg/ (n=327) All Patients Patients were randomized to flexibly dosed 20 to 120 mg/ or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of kg at week 24 (n=86). Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 12. The mean change in weight gain was +0.7 kg for -treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 4.0% for -treated patients and 5.3% for placebo-treated patients. Table 12: Mean Change in Weight (kg) from Baseline in the Study in (n=170) 20 to 80 mg/ (n=175) All Patients Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a carcinogenicity study conducted with lurasidone in rats and mice. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive. Supplement to Current Psychiatry S9

10 In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for -treated patients was +0.4 ng/ml and was -1.9 ng/ml in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/ml and for females was -0.2 ng/ml. Median changes for prolactin by dose are shown in Table 13. Table 13: Median Change in Prolactin (ng/ml) from Baseline in Adult Studies All Patients -1.9 (n=672) Females -5.1 (n=200) Males -1.3 (n=472) 20 mg/ -1.1 (n=70) -0.7 (n=19) -1.2 (n=51) 40 mg/ -1.4 (n=476) -4.0 (n=149) -0.7 (n=327) 80 mg/ -0.2 (n=495) -0.2 (n=150) -0.2 (n=345) 120 mg/ +3.3 (n=284) +6.7 (n=70) +3.1 (n=214) 160 mg/ +3.3 (n=115) +7.1 (n=36) +2.4 (n=79) The proportion of patients with prolactin elevations 5 upper limit of normal (ULN) was 2.8% for -treated patients and = 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 5.7% for -treated patients and = 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 1.6% and 0.6% for placebo-treated male patients. In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), was associated with a median change in prolactin of -0.9 ng/ml at week 24 (n=357), -5.3 ng/ml at week 36 (n=190) and -2.2 ng/ml at week 52 (n=307). In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for -treated patients was +1.1 ng/ml and was +0.1 ng/ml for placebo-treated patients. For -treated patients, the median change from baseline to endpoint for males was +1.0 ng/ml and for females was +2.6 ng/ml. Median changes for prolactin by dose are shown in Table 14. Table 14: Median Change in Prolactin (ng/ml) from Baseline in the Adolescent Study All Patients (n=103) Females (n=39) Males 0.00 (n=64) 40 mg/ (n=102) (n=42) (n=60) 80 mg/ (n=99) (n=33) (n=66) The proportion of patients with prolactin elevations 5x ULN was 0.5% for treated patients and 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 1.3% for -treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% for treated patients and 1.6% for placebo-treated male patients. The median change from baseline to endpoint in prolactin levels, in the adult shortterm, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/ml and +3.5 ng/ml with 20 to 60 mg/ and 80 to 120 mg/, respectively compared to +0.3 ng/ml with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/ml and for females was +3.1 ng/ml. Median changes for prolactin by dose range are shown in Table 15. Table 15: Median Change in Prolactin (ng/ml) from Baseline in the Adult Study All Patients +0.3 (n=147) Females 0.0 (n=82) Males +0.4 (n=65) 20 to 60 mg/ 80 to 120 mg/ +1.7 (n=140) +1.8 (n=78) +1.2 (n=62) +3.5 (n=144) +5.3 (n=88) +1.9 (n=56) Patients were randomized to flexibly dosed 20 to 60 mg/, 80 to 120 mg/, or placebo. The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 0.4% for -treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0.6% for -treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% and 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of ng/ml at week 24 (n=130). The median change from baseline to endpoint in prolactin levels, in the adult shortterm, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/ml with 20 to 120 mg/ compared to 0.0 ng/ml with placebotreated patients. The median change from baseline to endpoint for males was +2.4 ng/ml and for females was +3.2 ng/ml. Median changes for prolactin across the dose range are shown in Table 16. Table 16: Median Change in Prolactin (ng/ml) from Baseline in the Adult Adjunctive Therapy Studies All Patients 0.0 (n=301) Females +0.4 (n=156) Males -0.1 (n=145) 20 to 120 mg/ +2.8 (n=321) +3.2 (n=162) +2.4 (n=159) Patients were randomized to flexibly dosed 20 to 120 mg/ or placebo as adjunctive therapy with lithium or valproate. The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 0.0% for -treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0% for -treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% and 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with, as adjunctive therapy with either lithium or valproate, in the shortterm and continued in the longer-term study, had a median change in prolactin of -2.9 ng/ml at week 24 (n=88). In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, the median change from baseline to endpoint in prolactin levels for treated patients was ng/ml and was ng/ml for placebo-treated patients. For -treated patients, the median change from baseline to endpoint for males was ng/ml and for females was ng/ml. Median changes for prolactin are shown in Table 17. Table 17: Median Change in Prolactin (ng/ml) from Baseline in the Bipolar Depression Study in All Patients (n=157) Females (n=78) Males (n=79) 20 to 80 mg/ (n=165) (n=83) (n=82) The proportion of patients with prolactin elevations 5x ULN was 0% for -treated patients and 0.6% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0% for -treated patients and 1.3% for placebo-treated female patients. No male patients in the placebo or treatment groups had prolactin elevations 5x ULN. Leukopenia, Neutropenia and Agranulocytosis Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should be discontinued at the first sign of decline in WBC, in the absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm 3 ) should discontinue and have their WBC followed until recovery. S10 Supplement to Current Psychiatry