|Roger S. McIntyre, MD, FRCPC
Associate Professor of Psychiatry
University of Toronto
Head of Mood Disorders Psychopharmacology Unit
University Health Network
Toronto, Ontario, Canada
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Release Date: April 25, 2011
Expiration Date: April 24, 2012
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|This activity has been designed to meet the educational needs of psychiatrists and other mental health care providers involved in the management of patients with bipolar disorder.
|Patients with bipolar disorder have a high prevalence of medical comorbidities, particularly cardiometabolic diseases. The impact of these conditions is significant in terms of quality of life, delivery of psychiatric and medical services, and mortality. Biologic factors associated with bipolar disorder, adverse pharmacologic effects, disparities in health care, and other risk factors, such as unhealthy lifestyles, may contribute to the burden of disease.
|After participating in this activity, participants should be better able to:
- Identify factors that increase the risk of cardiometabolic diseases in patients with bipolar disorder
- Describe how medical comorbidities impact the course of bipolar illness and patient outcomes
- Implement treatment strategies to manage medical comorbidities in patients with bipolar disorder
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Roger S. McIntyre, MD, FRCPC Advisory boards: AstraZeneca, Biovail, Bristol-Myers Squibb, Eli Lilly and Company, France Foundation, GlaxoSmithKline, Lundbeck, Organon, Ortho-McNeil-Janssen, Pfizer Inc, Schering-Plough, Shire, Solvay/Wyeth
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The materials for this activity were peer reviewed by Robert M. Post, MD, and Joseph McEvoy, MD. Drs. Post and McEvoy disclosed the following financial relationships with commercial interests:
Robert M. Post, MD
Consultant: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Puretech
Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline.
Joseph McEvoy, MD
Consultant: Roche, Sunovion
Speakers bureau: Eli Lilly and Company, Merck & Co, Inc, Sunovion
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Prevalence of Medical Comorbidities
Medical comorbidities are more common and more likely to be multiple in patients with bipolar disorder compared with control individuals matched for age, gender, rurality, and health care utilization.1 In the past, early mortality in patients with bipolar disorder was attributed primarily to unnatural causes, such as suicide, homicide, and accidents. However, there is increasing evidence that the majority of excess deaths in this population is caused by general medical disorders. The mortality rates from natural causes are from 35% to 2.5-fold higher among patients with bipolar illnesses compared with the general population, and cardiovascular disease is responsible for the majority of excess deaths.2
The prevalence of obesity is higher in patients with bipolar disorder than in the general population. The number of previous depressive episodes correlates with the likelihood of being overweight (body mass index [BMI] of 25-29 kg/m2) or obese (BMI ≥30 kg/m2).3 Patients with bipolar disorder are likely to be overweight or obese even when their mood is euthymic.4 Other cardiovascular disease risk factors that comprise the metabolic syndrome—diabetes, dyslipidemia, and hypertension—are common in patients with bipolar disorder.5 There is also an increased prevalence of disorders related to glucose metabolism, including impaired glucose tolerance, insulin resistance, and frank diabetes mellitus, in patients with bipolar disorder, independent of the effects of body mass.6 The estimated prevalence of diabetes mellitus type 2 and metabolic syndrome is reported at twice the rate of the general population.7-9
Factors Contributing to Medical Comorbidities
Multiple patient-, treatment-, and disease-related factors contribute to the increased risk of medical comorbidities in patients with bipolar disorder. Many of these comorbid medical conditions are the result of preventable or modifiable behaviors, such as unhealthy diet, smoking, and sedentary lifestyle.1 In addition, disease-specific symptoms and behaviors, particularly those that occur during depressive episodes, such as increased appetite, decreased physical activity, and reduced energy expenditure, increase the risk for obesity.4,10 Other factors may contribute to the increased morbidity and mortality associated with medical comorbidities, including social deprivation; living alone or being homeless or single; poor access to and less effective use of health services; poor adherence to medical regimens; biased attitudes among health care providers; failure of psychiatric providers to ask about or address medical problems; and the "competing needs" theory (the precedence given by health care providers to conditions that need immediate attention while delaying or disregarding the management of other conditions).2
Metabolic side effects of pharmacotherapies used to treat bipolar illness also increase the risk of morbidity and mortality due to co-occurring medical conditions in these patients.2 Evidence shows that some atypical antipsychotics used in the treatment of bipolar disorder are associated with weight gain (Figure 1), hyperglycemia, dyslipidemia, and other metabolic abnormalities, which may lead to diabetes and vascular disease.11 Mood stabilizers, such as lithium, are also associated with increased risks of obesity and metabolic syndrome.2
Biologic factors associated with bipolar illness may also contribute to the increased mortality risk from natural causes. Chronic stress, which patients experience during both the manic and the depressive phases of bipolar disorder, is associated with increased cortisol levels, lack of cortisol suppression, and changes in hypothalamic-pituitary-adrenal axis responses. This metabolic dysregulation may increase insulin resistance and can lead to hyperglycemia, increased oxidative stress, metabolic syndrome, and atherosclerosis. In addition, patients with bipolar illness have increased activity of the sympathetic nervous system, which may also lead to insulin resistance, metabolic syndrome, and increased risk of sudden cardiac death.2
Depressive syndromes may be neurotoxic. Abnormalities in cellular plasticity, cellular resilience, and intracellular signaling, as well as alterations in the size, shape, and density of neurons and glia, have been found. Studies employing neuroimaging and neuropsychological tests have demonstrated abnormalities in brain morphology and function in patient populations with depressive syndromes and in those with diabetes. Common physiologic mechanisms have been implicated, including insulin-glucose homeostasis, immuno-inflammatory processes, and oxidative stress mechanisms.12
Consequences of Medical Comorbidities
Medical comorbidities in patients with bipolar disorder are a source of substantial economic burden related to costs from nonmental health care, including laboratory and radiologic diagnostic services and treatments. Although many patients with affective disorders perceive substantial barriers to medical care, including lack of transportation, inability to afford prescription medications, and delays in obtaining care,13 chronic medical disorders in patients with bipolar disorder are associated overall with more frequent medical service utilization. The number of physician-diagnosed chronic medical disorders is directly related to a patient’s dependency on others for activities of daily living, inability to work, frequent hospitalizations for mental health care, consultations with more mental health professionals, and use of psychotropic medications.14 Indirect costs due to morbidity and premature mortality also contribute to the cost of illness in patients with bipolar disorder.15
The medical comorbidities afflicting patients with bipolar disorder affect nearly every organ system, and the high rate of cardiometabolic conditions, such as diabetes, cardiovascular disease, and dyslipidemia, is of particular concern. Studies have shown that medically ill hospitalized patients with bipolar disorder are more likely to be older and to experience a lower rate of recovery from affective episodes.16 Baseline severity of bipolar illness is related to the number of comorbid medical problems,17 and medical illness correlates with poorer prognosis manifested by longer duration of lifetime depression and slower improvement in depressive symptoms.18
Obesity is associated with poorer outcomes in patients with bipolar disorder. Studies have noted higher body mass index (BMI) scores in patients with lower scores on the Global Assessment of Functioning Scale and longer durations of bipolar illness. In addition, patients who achieve complete remission of symptoms on lithium have significantly lower BMI scores.19 Obese patients with bipolar disorder experience a greater number of lifetime depressive and manic episodes; present with more severe and difficult-to-treat symptoms during their first affective episode; and have significantly earlier recurrence of affective episodes, primarily depressive, during maintenance-phase treatment (Figure 2). Obesity also has psychosocial consequences, including discrimination and stigmatization, which may contribute to the severity of bipolar disorder by negatively impacting patients’ general physical health and functioning, quality of life, self-esteem, and psychological well-being.10 Obese patients have an increased risk of sleep apnea, which causes sleep disruptions and may lead to mood destabilization in patients with bipolar disorder.20 Obesity may also impact effectiveness of pharmacotherapies by altering the distribution and elimination of medications.21 Obesity, as in the general population, is linked to medical illnesses in patients with bipolar disorder. Truncal obesity, which is most common, increases the risk of type 2 diabetes mellitus, dyslipidemia, hypertension, stroke, ischemic heart disease, and early death.
Diabetes, a risk factor for cardiovascular disease, can also impact the course of bipolar illness. Patients with both bipolar disorder and comorbid diabetes have more lifetime psychiatric hospitalizations than patients with bipolar disorder who do not have diabetes.9 The association between these 2 disorders underscores the importance of screening for diabetes in patients with bipolar illness, particularly because early detection and initiation of treatment to control glycemia may prevent diabetes-related complications.22 Studies have demonstrated cerebrovascular lesions involving small intraparenchymal cerebral vessels and focal infarctions in patients with diabetes. These lesions predominantly occur in areas providing blood supply to the base of the pons, thalamus, and basal ganglia. Diabetes has been implicated as a risk factor for subcortical white-matter lesions observed on magnetic resonance imaging (MRI) scans; similar MRI findings have been noted in patients with bipolar disorder. Cerebral microvascular disease may lead to greater frequency of manic episodes, another reason to minimize diabetes-related complications in patients with comorbid bipolar disorder.9
Metabolic syndrome, which is characterized by dysregulation of glucose and lipids, is associated with the development of cardiovascular disease as well as type 2 diabetes. The cardiometabolic risk factors that comprise the syndrome include abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance with or without glucose intolerance, a prothrombotic state, and a proinflammatory state.23 Comorbid metabolic syndrome impacts the presentation and course of bipolar disorder as well as the response to treatment. Patients with comorbid metabolic syndrome have more complex illness presentations, less favorable responses to treatment, and more adverse courses and outcomes of their bipolar disorder.
Management of Medical Comorbidities
The increased prevalence of risk factors (eg, obesity, smoking, and unhealthy dietary habits) and the inadequate utilization of preventative and primary health care in patients with bipolar disorder underscore the importance of comprehensive medical and behavioral assessments. Patients should have baseline weight and BMI measured, as well as laboratory studies to screen for diabetes, lipid abnormalities, and thyroid disease. In addition, inquiries concerning exercise habits, eating patterns, caffeine usage, and smoking should be included in an initial evaluation.7
Weight loss is a particular challenge for patients with mental illness.24 Diet and exercise counseling should be provided to all patients with bipolar disorder, preferably before weight gain, and definitely once weight gain has occurred.10 Behavioral therapies are also effective adjuncts in weight loss treatment.24,25 If weight gain is clearly related to a specific medication, switching to an alternative agent or lowering the drug dose, if possible, should be considered.26 Pharmacotherapy for obesity may be appropriate for obese patients who have failed to lose weight through diet and exercise alone. Surgical treatment, such as gastric bypass, should be considered in patients with a BMI >40 kg/m2 who have not responded to other methods of weight reduction and who present with obesity-related comorbid conditions such as hypertension, diabetes, and obstructive sleep apnea.27 Patients who smoke should be provided with smoking cessation support, counseling, and pharmacologic treatment, if appropriate.28
The National Cholesterol Education Program recommends screening of all adults over age 20 with a fasting lipoprotein profile every 5 years.29 Since patients with bipolar disorder who take atypical antipsychotics associated with weight gain tend to have a greater prevalence of metabolic syndrome (Figure 3),30 more frequent metabolic monitoring has been recommended in this patient population. A consensus development conference was convened with members of the American Diabetes Association, the American Psychiatric Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity to develop guidelines for monitoring patients treated with atypical antipsychotic medications. Modifiable risk factors should be evaluated at or near baseline and serially after prescription of antipsychotics. Patients should have their weight and BMI evaluated at baseline and assessed at 4, 8, and 12 weeks after initiating or changing an atypical antipsychotic medication (then quarterly thereafter at the time of routine visits). Fasting plasma glucose, lipid levels, and blood pressure also should be assessed 3 months after initiation of antipsychotic medications. Thereafter, blood pressure and plasma glucose values should be obtained annually, or more frequently in those who have a higher baseline risk for the development of diabetes or hypertension. In patients with a normal lipid profile at 3 months, repeat testing should be performed at 5-year intervals, or more frequently if clinically indicated (Table).31
Optimal management in patients with bipolar disorder involves coordination between psychiatric and general medical care.32 Patients should be encouraged to follow up with a primary care provider. However, psychiatrists may need to assume responsibility for monitoring and lifestyle counseling, including education about healthy habits, especially when prescribing medications with potential for metabolic complications.
- Carney CP, Jones LE. Medical comorbidity in women and men with bipolar disorders: a population-based controlled study. Psychosom Med. 2006;68(5)684-691.
- Roshanaei-Moghaddam B, Katon W. Premature mortality from general medical illnesses among persons with bipolar disorder: a review. Psychiatr Serv. 2009;60(2):147-156.
- Fagiolini A, Frank E, Houck PR, et al. Prevalence of obesity and weight change during treatment in patients with bipolar I disorder. J Clin Psychiatry. 2002;63(6):528-533.
- McLaren KD, Marangell LB. Special considerations in the treatment of patients with bipolar disorder and medical co-morbidities. Ann Gen Hosp Psychiatry. 2004;3(1):7.
- Fagiolini A, Frank E, Scott JA, et al. Metabolic syndrome in bipolar disorder: findings from the Bipolar Disorder Center for Pennsylvanians. Bipolar Disord. 2005;7(5):424-430.
- Regenold WT, Thapar RK, Marano C, et al. Increased prevalence of type 2 diabetes mellitus among psychiatric inpatients with bipolar I affective and schizoaffective disorders independent of psychotropic drug use. J Affect Disord. 2002;70(1):19-26.
- McIntyre RS, Konarski JZ, Misener VL, Kennedy SH. Bipolar disorder and diabetes mellitus: epidemiology, etiology, and treatment implications. Ann Clin Psychiatry. 2005;17(2):83-93.
- McIntyre RS, Danilewitz M, Liauw SS, et al. Bipolar disorder and metabolic syndrome: an international perspective. J Affect Disord. 2010;126(3):366-387.
- Cassidy F, Ahearn E, Carroll BJ. Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients. Am J Psychiatry. 1999;156(9):1417-1420.
- Fagiolini A, Kupfer DJ, Houck PR, et al. Obesity as a correlate of outcome in patients with bipolar I disorder. Am J Psychiatry. 2003;160(1):112-117.
- Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68(suppl 1):20-27.
- McIntyre RS, Socynska JK, Konarski JZ, et al. Should depressive syndromes be reclassified as "Metabolic Syndrome Type II"? Ann Clin Psychiatry. 2007;19(4):257-264.
- Dickerson FB, McNary SW, Brown CH, et al. Somatic healthcare utilization among adults with serious mental illness who are receiving community psychiatric services. Med Care. 2003;41(4):560-570.
- McIntyre RS, Konarski JZ, Socynzska JK, et al. Medical comorbidity in bipolar disorder: implications for functional outcomes and health service utilization. Psychiatr Serv. 2006;57(8):1140-1144.
- Kleinman L, Lowin A, Flood E, et al. Costs of bipolar disorder. Pharmacoeconomics. 2003;21(9):601-622.
- Black DW, Winokur G, Bell S, et al. Complicated mania. Comorbidity and immediate outcome in the treatment of mania. Arch Gen Psychiatry. 1988;45(3):232-236.
- Beyer J, Kuchibhatla M, Gersing K, Krishnan KR. Medical comorbidity in a bipolar outpatient clinical population. Neuropsychopharmacology. 2005;30(2):401-404.
- Thompson WK, Kupfer DJ, Fagiolini A, et al. Prevalence and clinical correlates of medical comorbidities in patients with bipolar I disorder: analysis of acute-phase data from a randomized controlled trial. J Clin Psychiatry. 2006;67(5):783-788.
- Calkin C, van de Velde C, Ruzickova M, et al. Can body mass index help predict outcome in patients with bipolar disorder? Bipolar Disord. 2009;11(6):650-656.
- Plante DT, Winkelman JW. Sleep disturbance in bipolar disorder: therapeutic implications. Am J Psychiatry. 2008;165(7):830-843.
- Cheymol G. Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet. 2000;39(3):215-231.
- Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589.
- Grundy SM, Brewer HB Jr, Cleeman JI, et al; American Heart Association; National Heart, Lung, and Blood Institute. Circulation. 2004;109(3):433-438.
- Devlin MJ, Yanovski SZ, Wilson GT. Obesity: what mental health professionals need to know. Am J Psychiatry. 2000;157(6);854-866.
- McElroy SL. Obesity in patients with severe mental illness: overview and management. J Clin Psychiatry. 2009;70(suppl 3):12-21.
- Newcomer JW. Comparing the safety and efficacy of atypical antipsychotics in psychiatric patients with comorbid medical illnesses. J Clin Psychiatry. 2009;70(suppl 3):30-36.
- Snow V, Barry P, Fitterman N, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005;142(7):525-531.
- Newcomer JW. Metabolic syndrome and mental illness. Am J Manag Care. 2007;13(7 suppl):S170-S177.
- Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497.
- Fiedorowicz JG, Palagummi NM, Forman-Hoffman VL, et al. Elevated prevalence of obesity, metabolic syndrome, and cardiovascular risk factors in bipolar disorder. Ann Clin Psychiatry. 2008;20(3):131-137.
- 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):596-601.
- McIntyre RS. Overview of managing medical comorbidities in patients with severe mental illness. J Clin Psychiatry. 2009;70(6):e17.