Managing Multiple Comorbidities in Bipolar Disorder

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1 Available at CurrentPsychiatry.com/BipolarDepression A SUPPLEMENT TO This promotional, non-cme program is intended only for health care professionals involved in the treatment of adult patients with bipolar disorder. SECOND IN A SERIES OF 3 NEWSLETTERS FEBRUARY 2017 Managing Multiple Comorbidities in Bipolar Disorder This newsletter series was developed and brought to you by Sunovion Pharmaceuticals Inc. It did not undergo peer review by Current Psychiatry. Newsletter content was developed in collaboration with the faculty. Faculty Larry Culpepper, MD, MPH Professor Department of Family Medicine Boston University School of Medicine Boston, Massachusetts Andrew J. Cutler, MD Executive Vice President and Chief Medical Officer Meridien Research Bradenton, Florida James Sloan Manning, MD Adjunct Associate Professor Department of Family Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Co-Director Mood Disorders Clinic Moses Cone Family Practice Center Greensboro, North Carolina Anna M. O Kinsky, MSN, APN Psychiatric Nurse Practitioner Catholic Charities Delaware House Westampton, New Jersey Princeton Healthcare Princeton, New Jersey DISCLOSURES Drs. Cutler and Manning and Ms. O Kinsky serve or have served as consultants, speakers, and researchers for various pharmaceutical companies, including Sunovion. Dr. Culpepper serves or has served as a consultant for, and receives royalties and payment from, various pharmaceutical companies, including Sunovion. The clinical expert commentary reflects the view of an actual licensed clinician who has been engaged by Sunovion. The information contained herein is intended for general informational purposes only and is not a substitute for your professional medical advice and judgment. This supplement is sponsored by LATUDA, 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. 1/17 LAT Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. 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. A multidisciplinary panel of Clinical Experts contributed to the development of this 3-part newsletter series. Each issue explores strategies for the management of patients with bipolar disorder and features expert commentary from the psychiatry, primary care, or nurse-practitioner/physician-assistant perspective. The Cost of Bipolar Disorder Bipolar disorder is a serious psychiatric illness associated with a considerable medical and economic burden. In the United States (US), the estimated lifetime prevalence of bipolar disorder is 2% to 4%, with about 1% of US adults having a lifetime history of bipolar I disorder. 1,2 It has been estimated that in 2009, the direct and indirect costs associated with bipolar disorder amounted to at least $151 billion in the US. 3 In addition, costs for patients with comorbid medical, mental health, and substance use disorders may be 2 to 3 times those for patients without these comorbid conditions, with most of the increased cost going to medical services rather than to behavioral health care. 4 Medical comorbidities occur often in bipolar disorder. 5 One study reviewed medical charts of 309 patients with bipolar disorder and found that 55% of patients had at least 1 comorbid medical condition, the most common being endocrine/metabolic disorders (23%) and vascular disease (21%). 6 Supplement to Current Psychiatry Vol 16, No 2 February 2017 S1

2 MANAGING MULTIPLE COMORBIDITIES IN BIPOLAR DISORDER AN EXPERT S PERSPECTIVE Commentary by James Sloan Manning, MD T he high prevalence rate of comorbid general medical conditions (GMCs) among patients with bipolar disorder has been well documented and illustrates the importance of integrating behavioral health and primary care services. Using data from the National Epidemiologic Survey on Alcohol and Related Conditions, Perron and colleagues reported that a diagnosis of bipolar I disorder was a significant risk factor for GMCs such as those noted in this newsletter. 1 These comorbid GMCs added to physical, mental, and psychosocial disability, as measured by the 12-Item Short-Form Health Survey, Version 2. 1 In addition, a meta-analysis of 2634 studies with 106,785 patients revealed that the estimated prevalence of unexplained somatic symptoms in patients with bipolar spectrum disorders was 47.8% nearly double the rate of those in the general population. 2 These data suggest important challenges to populationbased health care, and there is a movement toward creating collaborative care models to meet these challenges. A review by Bradford and colleagues assessed models that integrated behavioral health and primary care services and found positive effects on prevention and management of chronic disease for patients with serious mental illness. 3 Although more large trials are needed to confirm the effectiveness of those care models, creating an integrated, community-supported, chronic illness focused, teambased care delivery system may help clinicians identify and track chronically ill patients and improve preventive care. Furthermore, patient education on metabolic issues and risk factors, as well as incorporation of lifestyle interventions, such as healthy cooking classes, nutrition counseling, and exercise, into individualized treatment plans may also help mitigate the risk of comorbid GMCs. 4 In my opinion, by assuming that relapse and chronicity are realities of illness and acknowledging the impact that bipolar disorder and comorbid GMCs have on patient motivation and volition, clinicians may be able to improve the management and overall health of patients. James Sloan Manning, MD References 1. Perron BE, et al. Prevalence and burden of general medical conditions among adults with bipolar I disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2009;70(10): Edgecomb JB, et al. Medically unexplained somatic symptoms and bipolar spectrum disorders: a systematic review and meta-analysis. J Affect Disord. 2016;204: Bradford DW, et al. An evidence synthesis of care models to improve general medical outcomes for individuals with serious mental illness: a systematic review. J Clin Psychiatry. 2013;74(8):e754-e Bauer IE, et al. Lifestyle interventions targeting dietary habits and exercise in bipolar disorder: a systematic review. J Psychiatr Res. 2016;74:1-7. Mortality and Comorbid CVD Cardiovascular risk is increased in patients with bipolar disorder, even among those who are treatment naïve. 7 The onset of cardiovascular disease (CVD) in patients with bipolar disorder occurs approximately 10 years earlier and with a mortality rate about twice that of the general population. 8,9 Even among those who do not have CVD at baseline, the risk of developing new-onset CVD is more than twice that of matched control subjects or patients with major depressive disorder. 8 On average, patients with bipolar disorder die about 9 to 10 years earlier than the general population. 10,11 Although some of this excess mortality is attributable to an increased risk of suicide, it is known that comorbid CVD contributes to greater mortality in this patient population. 11 Monitoring and Managing Metabolic Risks As with CVD, patients with bipolar disorder are at risk of weight and body mass index (BMI) increases even when they are not overweight at baseline. 12 Therefore, these individuals should receive regular monitoring of these and other metabolic parameters with the goal of identifying these trends before reaching diagnosable comorbidities. 13 In fact, many clinical practice guidelines emphasize the importance MONITORING METABOLIC RISK IN BIPOLAR DISORDER In light of the increased risk for medical comorbidities in people with bipolar disorder, several guidelines recommend regular monitoring of metabolic parameters, including weight, body mass index, waist circumference, blood pressure, glucose, and lipids in this patient population. Guidelines have been developed and published by the following organizations: British Association for Psychopharmacology (2016) 14 Royal Australian and New Zealand College of Psychiatrists (2015) 15 Canadian Network for Mood and Anxiety Treatment and the International Society for Bipolar Disorders (2013) 16 American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity (2004) 17 Although the suggested interval for the measurement of each parameter varies, all of the guidelines emphasize the importance of cardiometabolic monitoring in patients with bipolar disorder. Overall, health care professionals should consider physical health in their clinical assessment and treatment planning based on an individual s specific needs and circumstances of closely monitoring metabolic measures in patients with bipolar disorder (Box) However, evidence suggests that these patients often fail to receive such routine preventive care. 18 In the Understanding Patients Needs, Interactions, Treatment, and Expectations Global Survey, preventive care practices received by patients with bipolar disorder and schizophrenia were assessed. Researchers discovered thatonly about 30% of patients received appropriate weight and blood pressure monitoring, while only 20% underwent regular physical examinations. 18 To help ensure that patients with bipolar disorder receive the appropriate monitoring, follow-up, and preventive care, a collaborative and holistic approach, which includes a focus on lifestyle modifications and patient education, may be effective. 12,19,20 S2 Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. February 2017 Vol 16, No 2 Supplement to Current Psychiatry

3 LATUDA: A Treatment Option for Bipolar Depression LATUDA is indicated for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate. 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 has not been established for longer-term use (more than 6 weeks) or for the treatment of mania associated with bipolar disorder. 21 Each phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled adult patients with major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features. All psychotropic medications were tapered off, and patients were randomly assigned to a treatment group. 22,23 Patients in the monotherapy study were randomized to flexibly dosed LATUDA mg/day (N=166), flexibly dosed LATUDA mg/day (N=169), or placebo (N=170). 22 Patients in the 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). 23 LATUDA dose adjustments within the assigned dosing range were permitted to optimize efficacy and tolerability. Study medication was taken once daily in the evening by mouth with a meal (eg, dinner) or within 30 minutes after eating. 22,23 Efficacy Efficacy was measured by the change from baseline to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) score, the 2 trials primary efficacy endpoint. LATUDA monotherapy achieved a 44% greater reduction in MADRS score at Week 6 versus placebo (Figure 1). 22 The mean decrease in MADRS score between baseline and Week 6 was 15.4 points for patients randomized to LATUDA mg/day or mg/day versus 10.7 points for patients randomized to placebo (P<.001). 22 The higher dose range ( mg/day) did not provide additional efficacy, on average, compared to the lower dose range (20-60 mg/day). 21 With LATUDA 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 LATUDA mg/day versus 13.5 points for patients randomized to placebo (P<.01) (Figure 1). 23 Safety and Tolerability Adverse reactions occurring in at least 2% of patients in either LATUDA 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 LATUDA treatment groups, 6.0% (20/331) of patients discontinued treatment due to adverse reactions compared with 5.4% (9/168) of patients in the placebo group. 21 The safety and tolerability of adjunctive LATUDA 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 LATUDA-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 LATUDA as adjunctive therapy with lithium or valproate and by 4.8% of patients (16/334) in the placebo group. 21 Patients from both the LATUDA and placebo groups of the 6-week monotherapy and adjunctive therapy trials were eligible to continue into a 6-month, uncontrolled, open-label, flexible-dose extension study. 21, The adverse reactions in at least 5% of patients who continued on LATUDA monotherapy in the longer-term study were headache, nausea, nasopharyngitis, akathisia, insomnia, and anxiety. Of those who continued on LATUDA adjunctive therapy plus lithium or valproate in the longer-term The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. FIGURE 1. PRIMARY EFFICACY ENDPOINT: MADRS SCORE LS Mean Change From Baseline Baseline Baseline mean = LATUDA mg (n=161) Monotherapy 22 * ** Time (Weeks) Effect size: LATUDA mg: 0.51 LATUDA mg: 0.51 * ** LATUDA mg (n=162) ** *** *** *** *** *** Placebo (n=162) LS Mean Change From Baseline Baseline Adjunctive Therapy 23 Time (Weeks) LATUDA mg + Li/VPA (n=179) Effect size: 0.34 *** *** * ** Placebo + 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/day) did not provide additional efficacy, on average, compared to the lower dose range (20-60 mg/day). MADRS scale range, Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. Supplement to Current Psychiatry Vol 16, No 2 February 2017 S3

4 MANAGING MULTIPLE COMORBIDITIES IN BIPOLAR DISORDER FIGURE 2. LATUDA MONOTHERAPY AND ADJUNCTIVE THERAPY: WEIGHT AND LABORATORY PARAMETERS Mean Change From Baseline* Monotherapy Weight 21 (lb) Total Cholesterol 21 (mg/dl) Glucose 21 (mg/dl) (n=143) (n=147)(n=151) (n=140)(n=144)(n=147) (n=140)(n=143)(n=148) LATUDA mg LATUDA mg Placebo Longer-term, Open-label Extension Study Change from open-label baseline 24, : 0.3 lb (n=153) -0.1 mg/dl (n=154) 1.5 mg/dl (n=153) Adjunctive Therapy Mean Change From Baseline* Weight 21 (lb) Total Cholesterol 21 (mg/dl) (n=327) (n=307) -1 (n=321) (n=303) LATUDA mg + Li/VPA Glucose 21 (mg/dl) (n=319) (n=302) Placebo + Li/VPA Longer-term, Open-label Extension Study Change from open-label baseline 24, : 1.7 lb (n=173) 0.4 mg/dl (n=182) -0.5 mg/dl (n=181) Abbreviations: Li, lithium; VPA, valproate. *Last observation carried forward. Observed cases; patients who continued on LATUDA. 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. study, at least 5% experienced parkinsonism, somnolence, akathisia, insomnia, anxiety, headache, and nausea. 24 Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk. 21 Changes in weight and laboratory parameters during both the LATUDA short-term and longer-term monotherapy and adjunctive therapy studies are presented in Figure 2. 21,24 Overall, the clinical trials demonstrated that at 6 weeks, metabolic changes were similar in the LATUDA and placebo groups, 21 and at 24 weeks, no clinically significant changes in body weight or clinically relevant changes or shifts from open-label baseline in lipid parameters and glucose were observed. 24 For prolactin in the short-term monotherapy study, the median change in concentration was +1.7 ng/ml, +3.5 ng/ml, and +0.3 ng/ml for the low-dose LATUDA, high-dose LATUDA, and placebo groups, respectively, and -1.1 ng/ml for those who continued on LATUDA in the longerterm trial. In the short-term adjunctive therapy studies, the median change was +2.8 ng/ml in the LATUDA group and ng/ml in the placebo group, and in the longer-term trial, it was -1.3 ng/ml in patients who continued on LATUDA. 21,24 Changes from baseline to endpoint in EPS, akathisia, and tardive dyskinesia were also evaluated in the LATUDA 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 LATUDAtreated patients was comparable to placebo on all 3 movement scales. 21,24 References 1. Frye MA, et al. Healthcare resource utilization in bipolar depression compared with unipolar depression: results of a United States population-based study. CNS Spectr. 2006;11(9): American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; Dilsaver SC. An estimate of the minimum economic burden of bipolar I and II disorders in the United States: J Affect Disord. 2011;129(1-3): Melek SP, et al. Economic Impact of Integrated Medical- Behavioral Healthcare: Implications for Psychiatry. Denver, CO: Milliman, Inc.; April Hirschfeld RM, et al. Bipolar disorder costs and comorbidity. Am J Manag Care. 2005;11(3 suppl): S85-S Maina G, et al. General medical conditions are associated with delay to treatment in patients with bipolar disorder. Psychosomatics. 2013;54(5): Leboyer M, et al. Can bipolar disorder be viewed as a multisystem inflammatory disease? J Affect Disord. 2012; 141(1): Goldstein BI, et al. Excessive and premature new-onset cardiovascular disease among adults with bipolar disorder in the US NESARC cohort. J Clin Psychiatry. 2015;76(2): Westman J, et al. Cardiovascular mortality in bipolar disorder: a population-based cohort study in Sweden. BMJ Open. 2013;3(4). 10. Crump C, et al. Comorbidities and mortality in bipolar disorder: a Swedish national cohort study. JAMA Psychiatry. 2013;70(9): Weiner M, et al. Cardiovascular morbidity and mortality in bipolar disorder. Ann Clin Psychiatry. 2011;23(1): Lipkovich I, et al. Early predictors of substantial weight gain in bipolar patients treated with olanzapine. J Clin Psychopharmacol. 2006;26(3): Culpepper L. The diagnosis and treatment of bipolar disorder: decision-making in primary care. Prim Care Companion CNS Disord. 2014;16(3). 14. Goodwin GM, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6): Malhi GS, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aus N Z J Psychiatry. 2015;49(12): Yatham LN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update Bipolar Disord. 2013;15(1): American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2): McIntyre RS. Understanding needs, interactions, treatment, and expectations among individuals affected by bipolar disorder or schizophrenia: the UNITE global survey. J Clin Psychiatry. 2009;70(suppl 3): Bauer IE, et al. Lifestyle interventions targeting dietary habits and exercise in bipolar disorder: a systematic review. J Psychiatr Res. 2016;74: Susman JL. Improving outcomes in patients with bipolar disorder through establishing an effective treatment team. Prim Care Companion J Clin Psychiatry. 2010;12(suppl 1): LATUDA [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals Inc.; Loebel A, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2): Loebel A, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2): Data on file. Sunovion Pharmaceuticals Inc. S4 Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. February 2017 Vol 16, No 2 Supplement to Current Psychiatry

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