Metabolic Syndrome in Bipolar Disorder: A Review With a Focus on Bipolar Depression

Metabolic Syndrome in Bipolar Disorder: A Review With a Focus on Bipolar Depression

Susan L. McElroy, MD, and Paul E. Keck, Jr, MD

With an estimated worldwide prevalence of 2.4%,1 bipolar disorder is associated with a wide range of detrimental effects on patients’ health and functioning and is among the top 20 causes of disability worldwide.1-3 The burden of bipolar disorder includes higher rates of unemployment and dependence on public assistance,4,5 reduced work productivity among the employed,6 reduced quality of life,4 impaired cognitive function,7,8 and increased health care costs.9

In addition to the substantial psychiatric health care utilization and costs associated with bipolar illness, patients with bipolar disorder have significantly increased nonpsychiatric health care costs.9-11 The excess costs of bipolar disorder are partly due to high rates of medical comorbidities, especially increased morbidity and mortality related to cardiovascular disease, which is the foremost cause of excess death in bipolar disorder.12-15 In particular, bipolar disorder is associated with increased occurrence of metabolic syndrome, which has been linked to elevated cardiovascular morbidity.16-18 A recent meta-analysis of 37 studies (N = 6,983) concluded that 37.3% of patients with bipolar disorder had metabolic syndrome, nearly twice the rate in the general population.19 This elevated rate of metabolic syndrome has been hypothesized to underlie the increased cardiovascular morbidity and mortality of bipolar disorder.20,21

Recent studies suggest that metabolic syndrome is associated specifically with depressive symptomatology.22 Over the course of their illness, bipolar I and bipolar II patients spend substantially more time in the depressed phase than in the manic/hypomanic or cycling phases.23,24 We previously reviewed the association of bipolar disorder and obesity and discussed management options for patients with both conditions.25,26 We noted that several groups showed an association between obesity and depressive burden in patients with bipolar disorder.26 In this article, we present an overview of the co-occurrence of bipolar disorder and metabolic syndrome, the impact of metabolic dysregulation on patients with bipolar disorder, and treatment considerations, with a focus on bipolar depression. We use the term bipolar depression to indicate a major depressive episode or subsyndromal depressive symptoms that occur in the course of bipolar disorder.

METHOD

Data Sources

A search of the PubMed database was conducted on October 23, 2012, for English-language articles, published from January 1980 onward, containing the keywords bipolar AND metabolic, weight, obesity, diabetes, dyslipidemia, OR hypertension in the title or abstract. A similar search of the Cochrane Library was conducted on September 20, 2013. The searches yielded 1,817 unique citations from which case reports, conference abstracts, and pediatric/adolescent studies were excluded.

• Metabolic syndrome is often inadequately treated in patients with bipolar disorder, despite its high prevalence, association with increased cardiovascular risk, and potential negative impact on psychiatric treatment outcomes.
• All patients with bipolar disorder should be monitored regularly for body mass index, waist circumference, lipid profile, blood pressure, and blood glucose level.
• Therapeutic options for patients with bipolar disorder and metabolic risk factors include lifestyle interventions, use of bipolar disorder medications with better metabolic profiles, and adjunctive pharmacotherapy for dyslipidemia, hypertension, and/or hyperglycemia.

Study Selection

Abstracts and titles were qualitatively evaluated for evidence-based, clinically relevant answers to the following questions:

• How is metabolic syndrome defined clinically and in research studies?
• What is the prevalence of metabolic syndrome in bipolar disorder?
• What is the prevalence of metabolic syndrome in depressive disorders?
• What are the consequences of metabolic syndrome for patients with bipolar disorder?
• What hypotheses have been proposed to account for the association of metabolic syndrome with bipolar disorder? What is the evidence supporting these hypotheses?
• What is the impact of pharmacologic treatments for bipolar disorder on metabolic syndrome and its components?
• What are the best evidence-based strategies for the treatment of patients with bipolar disorder and elevated metabolic risk factors?

Full texts of 176 articles were obtained for further evaluation; additional articles were identified from the reference lists of those articles. In addition, the PubMed database was monitored during the development of this review, with relevant studies incorporated as they were published. We present our findings with the primary objective of providing clinically relevant information to clinicians who manage patients with bipolar disorder.

RESULTS AND DISCUSSION

Overview of Metabolic Syndrome

Metabolic syndrome is not a disorder per se. Rather, it is a constellation of metabolic abnormalities (ie, abdominal obesity, elevated triglyceride level, low high-density lipoprotein cholesterol [HDL-C] level, hypertension, and hyperglycemia) that has been associated with increased risk of cardiovascular disease and diabetes.18,27,28 Several organizations, including the National Cholesterol Education Program Adult Treatment Panel III (ATP III),18 International Diabetes Federation (IDF),29 and World Health Organization (WHO),30 have developed criteria for the clinical diagnosis of metabolic syndrome. Although some variation across these specific criteria sets exists, all include measures of abdominal obesity, dyslipidemia, hypertension, and hyperglycemia (Table 1).18,29-32

On the basis of the ATP III definition, patients who meet any 3 of the 5 criteria have metabolic syndrome; the IDF definition requires the presence of increased waist circumference, plus any 2 of the other 4 criteria. In 2005, the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) published updated ATP III clinical criteria for metabolic syndrome (Table 1).31 Changes from the original ATP III criteria were relatively minor; most notable was the reduction of the threshold for elevated fasting glucose from 110 mg/dL to 100 mg/dL.31 The ATP III criteria are widely used in studies evaluating metabolic syndrome31; however, not all studies cited in this review used these criteria.

On the basis of data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) and the ATP III (2001) definition, the prevalence of metabolic syndrome in the general US adult population was 23.7%.33 In an update using NHANES data from 2003 to 2006 and the AHA/NHLBI (2005) revised definition, the prevalence of metabolic syndrome was 34.3%.34

Insulin resistance, a metabolic disorder in which biological response to insulin is impaired, is recognized as a contributory factor underpinning metabolic syndrome.18,31 The term insulin resistance syndrome was previously used to describe this clustering of metabolic risk factors and is a diagnostic criterion in the WHO definition of metabolic syndrome.31 However, insulin resistance is not easily measured in clinical settings.18,31 Therefore, the ATP III and IDF criteria use fasting plasma glucose to assess for hyperglycemia.

Co-occurrence of Metabolic Syndrome and Bipolar Disorder

The association of metabolic syndrome and bipolar disorder applies globally; higher-than-expected rates of metabolic syndrome have been documented in patients with bipolar disorder in 12 countries, including the United States (Table 2).17,19,35-55 In a recent meta-analysis, the strongest moderator of metabolic syndrome prevalence was the region in which the study was conducted, with the highest rates in New Zealand and Australia (64%), followed by North America (49%), Asia (40%), South America (38%), and Europe (32%).19 Rates of metabolic syndrome in patients with bipolar disorder were generally similar to those in patients with schizophrenia.35,38,39 Higher rates of metabolic syndrome were also observed in studies with a higher mean age of patients with bipolar disorder.19

Some treatments for bipolar disorder may increase the occurrence of metabolic syndrome. In the recent meta-analysis, metabolic syndrome was significantly more prevalent in patients receiving antipsychotic medications (45.3%; n = 298) than in patients not receiving an antipsychotic agent (32.4%, n = 339).19 However, an association of obesity and bipolar depression has been noted since the time of Kraepelin (long before the development of modern psychotropics),56 and some small studies have suggested that patients with bipolar disorder may be at increased risk for metabolic syndrome before initiation of pharmacotherapy.57,58 In an Italian study, 40.8% of 76 drug-naive patients with bipolar disorder were overweight, compared with 10.8% of 65 drug-naive patients with obsessive-compulsive disorder.57 Elevated rates of insulin resistance and dyslipidemia were noted in a small study (N = 11) of unmedicated women with bipolar disorder type II, who were depressed at the time of evaluation.58 In contrast, a study of drug-naive patients (N = 56) with bipolar disorder type II in Taiwan showed a rate of metabolic syndrome similar to that in the general population.59 Additionally, in a study of metabolic control in bipolar disorder (N = 381), 51.9% of patients had glycosylated hemoglobin (HbA1c) levels > 7%, and the mean HbA1c level was similar for patients receiving versus not receiving psychotropic medications (7.5% and 7.4%, respectively).60 It may be that the high prevalence of overweight/obesity, coupled with the iatrogenic effects of medications, has amplified a predisposition for metabolic dysregulation among patients with bipolar disorder into a medical comorbidity.

Increased rates of each individual component of metabolic syndrome have also been observed in patients with bipolar disorder.44,61 In US patients, the most commonly elevated components, relative to national norms, were triglyceride level and blood pressure (Table 2).38,39,42-44 In a large national study that included 3,898 patients with bipolar disorder, 54.8% of whom were obese (body mass index [BMI] ≥ 30.0 kg/m2), 48.4% of 1,109 bipolar patients with available data had hypertriglyceridemia, 61.1% (of 1,102) had low HDL-C, 50.6% (of 3,895) had hypertension, and 31.3% (of 1,107) had fasting hyperglycemia (≥ 100 mg/dL)[1] on the basis of ATP III/AHA criteria.39 In that study, elevated triglycerides and abdominal obesity were the strongest predictors of metabolic syndrome in the overall sample of more than 2,500 psychiatric patients with available data (42% with bipolar disorder, 33% with schizophrenia, 66% with depression).39

Even though hyperglycemia is generally the least common component of metabolic syndrome in patients with bipolar disorder (Table 2), its occurrence is an important clinical marker, because the prevalence of type 2 diabetes is elevated in bipolar patients.52,62-64 In a retrospective chart review of 243 older (aged 50-74 years) psychiatric inpatients, diabetes was present in 26.4% of patients with bipolar disorder type I, 18.5% with major depression, 12.7% with schizophrenia, and 50.0% with schizoaffective disorder.65 The rate of diabetes was significantly elevated relative to the US population (NHANES III data) in patients with schizoaffective and bipolar I disorders.65 In addition, insulin resistance is an early risk factor for vascular disease in patients with bipolar disorder, even in the absence of elevated fasting glucose.66

Co-occurrence of Metabolic Syndrome and Depression

The co-occurrence of diabetes and depression is well established,67 as is the link between depression and elevated cardiovascular risk.68 In addition, a growing body of evidence has demonstrated an association between depression and metabolic syndrome.69-71 In an analysis of data from the NHANES study (N = 2,439), overweight adults with abdominal obesity were significantly more likely to have major depressive or moderate-to-severe depressive symptoms than overweight adults without abdominal obesity.72 Indeed, the association between depression and insulin resistance may be mediated, in part, by abdominal adiposity.73 In a population of generally healthy US adults (N = 5,125), the presence of depressive symptoms was associated with increased rates of abdominal obesity, hypertriglyceridemia, and low HDL-C level; in women, there was also an association with slightly elevated fasting blood glucose.74

Metabolic syndrome may have a particularly strong association with depressive symptoms characterized by neurovegetative features such as fatigue, loss of energy, sleep disruption, and concentration difficulties.75 Neurovegetative symptoms are highly prevalent among adults with bipolar depression. In a US national survey, fatigue was reported by 80.4% of 1,154 patients with bipolar I depression; sleep disturbance, by 91.2%; and concentration problems, by 90.7%.76

In addition to studies showing that metabolic syndrome is more prevalent in people with past or current depressive syndromes, evidence suggests that metabolic syndrome may increase the risk of developing a depressive disorder. In 2 population-based studies (N = 5,232; N = 520), men and women without depressive symptoms at baseline but with metabolic syndrome were more likely to report depressive symptoms at 6- to 7-year follow-up, even after controlling for potential confounders such as age, BMI, education, physical activity, smoking, alcohol use, and antidepressant exposure.77,78

In light of the association of metabolic syndrome and depression, it is possible that differences exist in the metabolic profile of patients with bipolar disorder who primarily exhibit symptoms of depression versus primarily hypomania or mania. Mood symptoms and cardiovascular risk, as measured by Framingham scores, were evaluated in a study of US veterans with bipolar disorder (N = 118).79 Patients with clinically significant depression symptoms (17% of the overall sample) had a 6-fold increased risk of developing cardiovascular disease (Framingham score of > 20%), whereas patients with clinically significant manic symptoms (33% of the overall sample) were not at increased risk.79 However, the relatively small sample size may have limited the ability to detect increased cardiovascular risk in patients with predominantly manic symptoms. Overall, elevated diastolic blood pressure, fasting glucose, and BMI (but not systolic blood pressure or dyslipidemia) were significantly associated with increased cardiovascular risk. Additional studies are needed to evaluate the relationships between manic versus depressive mood symptoms and metabolic syndrome in patients with bipolar disorder.

Ramifications of Metabolic Syndrome in Bipolar Disorder

In a large US national survey (N = 43,093), people with bipolar disorder type I (n = 1,411) were 5 times more likely than controls (n = 34,851) to have a cardiovascular disease (odds ratio = 4.95; 95% CI, 4.27-5.75); risk was also greater than for patients with major depressive disorder (n = 6,831; odds ratio = 1.80; 95% CI, 1.52-2.14).80 Among respondents with cardiovascular disease, the age of patients with bipolar disorder was, on average, 13.7 years younger than that of controls.80 As noted earlier, metabolic syndrome has been identified as a primary contributor to the increased cardiovascular risk in bipolar disorder.20

In addition, metabolic dysregulation has been associated with negative psychiatric outcomes for patients with bipolar disorder.81 In a study of patients with rapid-cycling bipolar disorder (N = 225) treated with lithium and valproate, disorders of the endocrine/metabolic system, including obesity, were associated with greater severity of depression and poorer response to treatment.82 Abdominal obesity in patients with bipolar disorder has been associated with worse scores on measures of disease severity and global functioning.43 Research in the United States has indicated that the presence of metabolic syndrome in patients with bipolar disorder is associated with a lifetime history of suicide attempts42,43; however, this association has not been confirmed by studies in other countries.54,83

Patients with bipolar disorder often have cognitive impairments, which may compromise treatment outcome.7 Metabolic syndrome has been associated with cognitive decline in older adults,84 and a recent, large, community-based study showed the greatest cognitive decline in adults who were obese and had metabolic abnormalities.85 Together, these findings raise concern about the effects of metabolic syndrome on cognitive functioning in patients with bipolar disorder. Indeed, in a post hoc analysis of 67 euthymic adults with bipolar I or bipolar II disorder, BMI was negatively correlated with measures of attention and psychomotor processing, and overweight and obese patients had impaired verbal fluency compared to normal weight patients.86

Hypotheses Accounting for the Link Between Bipolar Disorder and Metabolic Syndrome

Several putative explanations exist for the association between bipolar disorder and metabolic syndrome.87 Hypotheses include reduced access to health care,88 behavioral/phenomenological features,61,89,90 shared neurobiologic abnormalities,62 common genetic susceptibility,62 and adverse effects of psychotropic medications (Figure 1).17,26,63 Patients with bipolar disorder are generally more likely to be unemployed or permanently disabled—characteristics associated with limited access to health care.88 In addition, unemployment and disability have been associated with poor health habits in general, and obesity in particular.91-94

Symptoms of bipolar depression (eg, hyperphagia, fatigue, lethargy, hypersomnia, or insomnia) may lead to overeating and reduced physical activity.88 Inadequate sleep is associated with hyperphagia and obesity,95 and bipolar patients often have disturbed sleep.7 Bipolar I disorder has been associated with increased risk of obstructive sleep apnea,96 which, in turn, is associated with endothelial dysfunction and cardiovascular risk.97,98 Binge eating is a frequent comorbidity in patients with bipolar disorder and has been linked with depressive symptoms and obesity.99-101 Binge-eating disorder in adults and loss-of-control eating in children have been associated with development of metabolic syndrome, and the increased risk was not accounted for by obesity alone.102,103 Moreover, consumption of certain macronutrients (ie, fat) may induce a proinflammatory response.104 In contrast, regular exercise may exert a beneficial effect on biochemical markers of inflammation105,106 and on glucose homeostasis.107

Shared pathophysiology. Disruption in metabolic networks (eg, insulin-glucose homeostasis, inflammatory processes, adipokine synthesis) may be a central feature of mood disorders.108 Inflammation has been identified in several studies as a pathophysiologic link between metabolic dysregulation and both depression and bipolar disorder.75,109,110 Chronic, subclinical inflammation is associated with metabolic syndrome and decreased insulin sensitivity,111,112 and preclinical studies indicate that inflammatory cytokines induce insulin resistance.31 Levels of C-reactive protein (CRP) and other proinflammatory cytokines are elevated in acute bipolar illness and are not entirely normalized during remission.113,114 Furthermore, elevated CRP levels have been significantly associated with the presence of metabolic syndrome in patients with bipolar disorder (N = 60).115 Of note, leptin, a peptide hormone secreted by adipocytes, has been identified as a possible link between obesity and depressive disorders.116 Leptin has shown antidepressant effects in animal models; however, the potentially beneficial effects of leptin on depressive symptoms, food intake, and energy expenditure may be attenuated in obese individuals as a result of leptin resistance.116,117

Other overlapping mechanisms include vascular endothelial dysfunction, increased oxidative stress, increased sympathetic activation, increased platelet activation, and stress-related hyperactivity of the hypothalamic-pituitary-adrenal axis.10,22,63,118-120 In patients with bipolar disorder or major depressive disorder, environmental stressors such as early childhood adversity, and ongoing stressors related to the disease itself, may initiate biological events with long-term effects on mood symptoms and metabolic risk factors.62,121-123

Converging evidence supports the role of dopamine in the pathophysiology of both bipolar disorder and metabolic syndrome.124,125 Reduction in striatal dopamine transporter availability has been observed in a small study of euthymic and depressed patients with bipolar I or bipolar II disorder (N = 11),126 and dopaminergic agents appear to have therapeutic effects in bipolar depression.127-131 Dopamine dysregulation has also been implicated in obesity and binge eating.132-134 Moreover, D2 receptor agonists have been reported to improve metabolic parameters (eg, blood glucose, resting energy expenditure, systolic blood pressure) in obese patients135 and lipid levels and glycemic control in those with diabetes.125 Indeed, the dopamine agonist bromocriptine has recently received regulatory approval for the treatment of type 2 diabetes.136

In sum, the association between bipolar disorder and metabolic syndrome is complex and undoubtedly mediated by interactions of multiple mechanistic pathways.

Pharmacotherapy. Pharmacologic therapies approved by the US Food and Drug Administration for the treatment of bipolar disorder include lithium, mood-stabilizing anticonvulsant agents (ie, carbamazepine, lamotrigine, valproate), and atypical antipsychotic agents. Some of these medications are associated with weight gain and unfavorable changes in lipid parameters; however, substantial variation exists among agents regarding degree of liability for weight gain and metabolic disruption (Table 3).25,127,129,137-148

Antipsychotic agents can be characterized as conferring higher (eg, clozapine, olanzapine), intermediate (eg, risperidone, quetiapine), or lower (eg, amisulpride, asenapine, aripiprazole, lurasidone, ziprasidone) risks of metabolic abnormalities.138,141,149-151 Data are mixed, however, as to whether mood stabilizer-antipsychotic combination therapy is more likely to be accompanied by metabolic dysregulation than antipsychotic monotherapy.55,152

The weight gain associated with antipsychotic treatment is one contributor to antipsychotic-induced metabolic abnormalities. Other mechanisms for metabolic dysregulation during treatment with antipsychotic agents identified in preclinical research include oxidative stress, direct effects on glucose metabolism, and enhanced lipogenesis.153-155 The propensity for dyslipidemia among atypical antipsychotic agents parallels that for weight gain (Table 2), although there are reports of antipsychotic-treated patients for whom the association with dyslipidemia was independent of BMI or weight gain.156,157 Increased blood glucose levels have been observed consistently for olanzapine, but not for many other atypical antipsychotic agents (Table 2).

Weight gain is common during treatment with lithium or valproate; however, adverse effects on lipid and glucose levels are not observed consistently.143 For example, a 52-week study of lithium or aripiprazole for bipolar disorder type I (N = 63) showed modest weight increases in both treatment groups but small mean changes in lipid, glucose, and insulin levels.158 Similarly, a study in New Zealand showed lower HDL-C levels but similar frequency of insulin resistance in 60 overweight patients with bipolar disorder treated with valproate and 60 members of the general population matched for age, sex, BMI, and ethnicity.41 The prevalence of metabolic syndrome was numerically higher in valproate-treated patients (50.0% vs 31.7%), but the difference was not statistically significant.41 However, in a study in Taiwan, patients with bipolar disorder treated with valproate (n = 52) had significantly higher plasma insulin and triglyceride levels and lower fasting plasma glucose and HDL-C levels than healthy controls (n = 119); metabolic parameters of unmedicated patients did not differ significantly from those of healthy controls.159

Lamotrigine appears to have a low risk of causing weight gain and adverse metabolic effects.143 In two 18-month multicenter placebo-controlled studies that were enriched for lamotrigine response based on a preceding 8-week open-label phase,160 obese patients with bipolar I disorder (n = 155) lost weight with lamotrigine (mean, −4.2 kg) but gained weight with lithium (mean, +6.1 kg).161 In clinical trials of carbamazepine for bipolar disorder (N = 239 short-term, N = 77 extension study), minimal weight gain with modest increases in total cholesterol (which included both high-density and low-density lipoproteins) has been observed.162,163

Antidepressant medications are used frequently in the treatment of patients with bipolar disorder, although evidence regarding their efficacy and safety in bipolar depression is mixed.164-168 The effects of antidepressants on weight and other metabolic parameters differ by medication class (Table 3). Tricyclic antidepressants and monoamine oxidase inhibitors tend to produce weight gain, dual serotonin-norepinephrine reuptake inhibitors (SNRIs) have a generally neutral effect, and bupropion may provide weight reduction; the effects of selective serotonin reuptake inhibitors (SSRIs) vary by agent.25,169 Additionally, some antidepressants may alter glucose metabolism and insulin sensitivity.148,170 For example, some tricyclic antidepressants may promote hyperglycemia and impaired insulin sensitivity, whereas some SSRIs may have beneficial effects on glycemic control.148 SNRIs have no apparent effects on glucose homeostasis.148 Regarding selective norepinephrine reuptake inhibitors, atomoxetine[2] may produce weight loss,171 and reboxetine[3] may be associated with improvement in metabolic parameters.172

Dopaminergic agents, which may be effective for bipolar depression, are generally weight neutral or even associated with weight loss. A randomized, double-blind, placebo-controlled study of modafinil as an adjunct to mood stabilizers in patients with bipolar I or II depression (N = 85) showed weight change similar to placebo during 6 weeks of treatment.129 Similarly, in an 8-week study of patients with bipolar I depression treated with lithium, valproic acid, or olanzapine, mean weight was essentially unchanged with adjunctive armodafinil (+ 0.1 kg, N = 128), compared with mean weight gain of 1.0 kg with placebo (N = 129).127 However, information regarding the long-term effects of dopaminergic agents on mood or weight is currently lacking.

Management of Metabolic Syndrome in Patients With Bipolar Disorder

A US national cardiometabolic screening program found that 62.1% of 588 bipolar disorder patients with metabolic syndrome were not receiving treatment for any syndrome component.39 Among patients receiving treatment for dyslipidemia, hypertension, or hyperglycemia, inadequate symptom control was observed in a substantial proportion.39 Thus, there is great need for improvement in the treatment of metabolic syndrome in patients with bipolar disorder, particularly because reducing blood pressure and lipid parameters to normal levels in patients with metabolic syndrome has been shown to reduce the occurrence of cardiovascular events by 40%-50%.173

There are emerging guidelines on the treatment of common medical and psychiatric comorbidities in patients with bipolar disorder,174 including recommendations intended to improve the clinical management of metabolic abnormalities.137,175 However, in the absence of randomized controlled trials in patients with bipolar disorder, it is often necessary to draw recommendations from general treatment guidelines. We have previously proposed an assessment tool for the evaluation of metabolic risk in psychiatric patients,175 and Table 4 provides a summary of treatment goals and interventions for each metabolic syndrome component.176 Regular monitoring of BMI, waist circumference, lipid profile, and fasting plasma glucose level is clearly important, especially in patients receiving antipsychotic medications.26,137,141,177 As the occurrence of dyslipidemia may be independent of BMI,156 recommendations for regular metabolic monitoring include patients who are normal weight and do not gain weight during treatment.156,157 However, assessment for and treatment of metabolic syndrome should be tailored to meet individual patients’ needs.

Physicians are generally advised to select pharmacologic agents that are efficacious for bipolar disorder symptoms and have a low liability for weight gain and metabolic dysregulation.25,137 In selecting pharmacotherapies, it has been recommended that physicians conduct a comprehensive risk-benefit analysis considering symptoms and severity of bipolar illness, medical history (including metabolic risk), past medication efficacy, and potential adverse events.142 However, in an analysis of prescription practices at an academic medical center, factors related to metabolic risk (ie, BMI, diagnosis or treatment for hypertension or diabetes) did not appear to influence psychiatrists’ decisions regarding use of atypical antipsychotic agents with moderate-to-high liability for adverse metabolic events.178

Lifestyle modifications may have beneficial effects on both cardiovascular risk and depression. Exercise is known to reduce the incidence of metabolic syndrome and cardiovascular disease179,180 and may improve depressive symptoms in patients with a depressive disorder.181 The Mediterranean diet has been associated with decreased occurrence of cardiovascular events in older adults (aged 55-80 years; N = 7,447) at elevated risk182 and with reduced incidence of depression.183 In a recent study of overweight and obese adults with serious mental illness (eg, schizophrenia, bipolar disorder, or major depressive disorder; N = 291), a behavioral weight loss intervention consisting of nutritional counseling and group exercise produced significantly greater weight loss relative to the control group.184 Tobacco use has a substantial negative impact on cardiovascular mortality; however, smoking cessation is often associated with weight gain.185 A recent prospective, community-based study (N = 3,251) found that smoking cessation reduced the risks of cardiovascular disease despite subsequent weight gain (mean of 3.0 kg in 205 recent quitters).186 Smoking cessation is overlooked as a strategy to reduce cardiovascular risk in patients with bipolar disorder, who are often more amenable to smoking cessation interventions than clinicians assume.175 Of note, among the available medical treatments for smoking cessation, bupropion and, to a lesser extent, nicotine replacement and varenicline mitigate weight gain associated with smoking cessation.187

Weight management in patients with bipolar disorder. Behavioral weight management, also known as lifestyle modification, is the first-line treatment for obesity in bipolar disorder26,137 and includes stressing the importance of good sleep hygiene for weight management. Reduction in weight and abdominal obesity may also have beneficial effects on other components of metabolic syndrome.188

Pharmacologic treatment options for weight management include switching the patient’s bipolar disorder medication to one with a lower potential to induce weight gain.26 However, the possibility of switching medication in a patient who is clinically stable must be carefully considered. Patients respond differently to pharmacologic therapies and may not derive the same benefit from one agent as from another. Thus, when considering a medication switch, the potential for relapse must be evaluated and balanced with expected benefits to the patient’s metabolic profile.

Another pharmacologic option for weight management is initiating adjunctive therapy with an agent to reduce weight. Although the effects of pharmacotherapy on the neurovegetative symptoms of bipolar depression have not been formally assessed, it is possible that adjunctive medications that improve symptoms such as fatigue and overeating may promote increased physical activity and weight loss. For example, bupropion, which is considered an “activating antidepressant” because of its mild stimulant-like properties, has been associated with both improvement in depressive symptoms and weight loss in patients with bipolar disorder.169,189

Recommended adjunctive medications for weight control include metformin (especially if the patient is taking an antipsychotic agent), orlistat, anticonvulsants (ie, topiramate, zonisamide), and dopaminergic agents (ie, bupropion, modafinil).137 Bariatric surgery is a highly effective treatment for severe obesity and may be considered for carefully selected patients with bipolar disorder.26

Management of dyslipidemia, hypertension, and hyperglycemia. Lifestyle modification is recommended as first-line treatment for patients with dyslipidemia, hypertension, or hyperglycemia. Whether for weight loss or management of other metabolic risk factors, a multidisciplinary approach to lifestyle modification is generally recommended and may include psychotherapists, nurses, dieticians, and/or self-help groups.175 Healthy eating habits, appropriate exercise, and good sleep hygiene need to be emphasized. Adjunctive lipid lowering, antihypertensive, or antidiabetic medications should be considered if nonpharmacologic interventions are insufficient (Table 4).176

Dyslipidemia. Guidelines for the management of patients with dyslipidemia are available from the ATP III,[4] the American Association of Clinical Endocrinologists, and other organizations.18,190-194 Commonly used medications for dyslipidemia include beta-hydroxy-beta-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), fibric acid derivatives, niacin (nicotinic acid), and bile acid sequestrants (Table 4).18,137,176,191 Although concerns have been raised about increased risk of depression and suicide associated with statin use, a study of more than 20,000 patients with elevated cardiovascular risk showed no difference in the rate of suicide or attempted suicide in patients receiving statins compared with those receiving placebo.195 Moreover, statin use was associated with reduced risk of developing depression in a nested case-control analysis (n = 458 cases, n = 1,830 controls).196

Nutritional supplementation with omega-3 fatty acids has been shown to reduce triglyceride level and increase HDL-C level197,198 and may have a beneficial effect on depressive symptoms. A recent meta-analysis of 6 randomized, placebo-controlled studies (N = 291) showed that adjunctive use of omega-3 fatty acids with conventional mood stabilizers may provide improvement in bipolar depression (effect size = 0.34), although the effect on lipid profile was not reported in any of the included studies.199

In patients who require treatment with antipsychotics, switching to an agent with lower metabolic liability can provide improvement in lipid levels, including triglycerides, HDL-C, and the triglyceride/HDL-C ratio, as well as reductions in weight and BMI.200 Lipid-lowering therapy, omega-3 supplementation, or both, may be appropriate in addition to or instead of switching antipsychotic agents. In a 4-year naturalistic prospective study of antipsychotic-treated patients (N = 89), initiation of lipid-lowering therapy was associated with reduction in cardiovascular risk.201

Hypertension. Given the well-established links between both bipolar disorder and depressive disorders and cardiovascular disease, adequate treatment of hypertension is of particular importance in these patients. Treatment guidelines regarding dietary and pharmacologic interventions are available from the American Society of Hypertension.202-205 A key nutritional intervention is the DASH (Dietary Approaches to Stop Hypertension) diet, which emphasizes a diet rich in fruits, vegetables, and low-fat dairy products, with reduced consumption of sodium and saturated fat.202,206 The DASH diet has been shown to reduce blood pressure in patients with hypertension207,208 but has not yet been evaluated in hypertensive patients with bipolar disorder.

A broad range of antihypertensive agents are available, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, β-blockers, calcium channel blockers, and aldosterone blockers (Table 4).175,176,203 Lithium, mood-stabilizing anticonvulsant agents, and atypical antipsychotic agents have no apparent adverse effects on blood pressure.137 However, clinicians should be aware of the potential for lithium toxicity resulting from drug-drug interactions with thiazide or loop diuretics, ACE inhibitors, and ARBs.209-212 Of note, despite initial concerns, β-blockers are not associated with increased risk of depression.213,214

Hyperglycemia. The American Diabetes Association (2012) guidelines include recommendations regarding testing for diabetes in asymptomatic patients, prevention or delay of diabetes in patients at increased risk, and monitoring and treatment of patients with a diabetes diagnosis.215 No randomized controlled trials have evaluated the treatment of diabetes in patients with bipolar disorder or the treatment of bipolar disorder in patients with comorbid diabetes, although several studies have evaluated the treatment of depression in patients with diabetes.216,217 However, as with type 2 diabetes in general, metformin is suggested as first-line therapy for patients with bipolar disorder who have hyperglycemia; a thiazolidinedione may also slow the progression to diabetes in patients with insulin resistance (Table 4).175,176,215 With the exception of certain atypical antipsychotics, pharmacologic agents used in the treatment of bipolar disorder generally have minimal effects on plasma glucose levels (Table 4).176 For patients being treated with an atypical antipsychotic agent, metformin may reduce metabolic risks including weight, waist circumference, and insulin resistance.218 Other pharmacologic options for hyperglycemia and diabetes include sulfonylureas (eg, glipizide), glucagon-like peptide-1 (GLP-1) agonists (eg, exenatide), dipeptidyl peptidase-4 (DPP-4) inhibitors (eg, sitagliptin), and bromocriptine, as well as insulin.137,215

Summary of Key Recommendations

• Psychiatrists should conduct a comprehensive assessment of metabolic risk in patients with bipolar disorder. This evaluation should include screening for all metabolic syndrome components. An online tool is available for performing a Framingham cardiovascular risk assessment (http://cvdrisk.nhlbi.nih.gov/calculator.asp).
• Regular monitoring of BMI, waist circumference, lipid profile, and fasting plasma glucose level is important, especially in patients receiving antipsychotic medications.
• The patient’s psychiatrist and primary care provider should collaborate to provide effective treatment for components of metabolic syndrome, as indicated.
• Selection of pharmacologic treatments for bipolar disorder should take into consideration the presence of or risk for metabolic syndrome and the metabolic liability of the therapeutic regimen. Decisions regarding pharmacotherapy should be customized on the basis of constellation and severity of bipolar symptoms, medical history and comorbidities, and metabolic risk.
• Behavioral management strategies (including dietary changes such as the DASH diet for hypertension and exercise) are first-line treatments for obesity and other components of metabolic syndrome. Good sleep hygiene should be consistently promoted. Smoking cessation is also a first-line strategy for reducing cardiovascular risk. Cognitive-behavioral psychotherapy may help motivate and reinforce behavior change.
• Pharmacotherapy for obesity, dyslipidemia, hypertension, and/or hyperglycemia should be initiated when indicated, and treatment effectiveness should be monitored subsequently.

CONCLUSIONS

Metabolic syndrome is a common but widely underrecognized and undertreated comorbidity in patients with bipolar disorder. Bipolar illness is often characterized by predominance of depressive episodes compared with manic/hypomanic episodes, and metabolic syndrome is particularly associated with depressive symptomatology. Although guidelines are emerging for the clinical management of metabolic syndrome in bipolar disorder, these are not based on randomized controlled trials in patients with bipolar disorder but are typically extended from general guidelines. Psychiatrists should conduct a comprehensive assessment of metabolic risk in patients with bipolar disorder, with regular monitoring thereafter. Selection of pharmacologic treatments for bipolar disorder should take into consideration the patient’s risk for metabolic syndrome and the metabolic liability of the therapeutic regimen. Behavioral management strategies are first-line treatments for components of metabolic syndrome and may be supplemented with pharmacologic therapies as necessary. Adequate management of metabolic syndrome may improve clinical outcomes in patients with bipolar disorder, as well as prevent adverse cardiovascular events and the development of diabetes.

Drug names: aripiprazole (Abilify), armodafinil (Nuvigil), asenapine (Saphris), atomoxetine (Strattera), bromocriptine (Parlodel, Cycloset, and others), bupropion (Wellbutrin, Aplenzin, and others), carbamazepine (Carbatrol, Equetro, and others), clozapine (Clozaril, FazaClo, and others), exenatide (Byetta), glipizide (Glucotrol and others), lamotrigine (Lamictal and others), lisdexamfetamine (Vyvanse), lithium (Lithobid and others), lorcaserin (Belviq), lurasidone (Latuda), metformin (Glucophage and others), modafinil (Provigil), olanzapine (Zyprexa), orlistat (Xenical), phentermine (Adipex-P, Suprenza, and others), pramipexole (Mirapex and others), quetiapine (Seroquel), risperidone (Risperdal and others), sitagliptin (Januvia), topiramate (Topamax and others), valproic acid (Depakene, Stavzor, and others), varenicline (Chantix), ziprasidone (Geodon), zonisamide (Zonegran and others).

Author affiliations: Lindner Center of HOPE, Mason, Ohio; and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Potential conflicts of interest: Dr McElroy is a consultant to or member of the scientific advisory boards of Alkermes, Bracket, Corcept, MedAvante, Shire, Sunovion, and Teva; is a principal or coinvestigator for studies sponsored by the Agency for Healthcare Research & Quality, Alkermes, AstraZeneca, Cephalon (now Teva), Forest, Lilly, Marriott Foundation, National Institute of Mental Health (NIMH), Orexigen, Pfizer, Shire, Takeda, and Transcept; and is an inventor on United States Patent No. 6,323,236 B2: Use of Sulfamate Derivatives for Treating Impulse Control Disorders and along with the patent’s assignee, University of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & Johnson, which has exclusive rights under the patent. Dr Keck is employed by the University of Cincinnati College of Medicine and University of Cincinnati Physicians; is presently or has been in the past year a principal or co-investigator on research studies sponsored by Alkermes, AstraZeneca, Cephalon, Marriott Foundation, NIMH, Orexigen, Pfizer, and Shire; has been reimbursed for consulting to, in the past year, Bristol-Myers Squibb, Teva, Otsuka, Forest, and Merck (2012) and Sunovion, Alkermes, Shire, and Forest (2013); and is a coinventor on United States Patent No. 6,387,956: Shapira NA, Goldsmith TD, Keck, PE Jr. (University of Cincinnati) Methods of Treating Obsessive-Compulsive Spectrum Disorder Comprises the Step of Administering an Effective Amount of Tramadol to an Individual. Filed March 25, 1999; approved May 14, 2002. Dr Keck has received no financial gain from this patent.

100. McElroy SL, Frye MA, Hellemann G, et al. Prevalence and correlates of eating disorders in 875 patients with bipolar disorder. J Affect Disord. 2011;128(3):191-198. PubMed doi:10.1016/j.jad.2010.06.037

101. Wildes JE, Marcus MD, Fagiolini A. Prevalence and correlates of eating disorder co-morbidity in patients with bipolar disorder. Psychiatry Res. 2008;161(1):51-58. PubMed doi:10.1016/j.psychres.2007.09.003

102. Hudson JI, Lalonde JK, Coit CE, et al. Longitudinal study of the diagnosis of components of the metabolic syndrome in individuals with binge-eating disorder. Am J Clin Nutr. 2010;91(6):1568-1573. PubMed doi:10.3945/ajcn.2010.29203

103. Tanofsky-Kraff M, Shomaker LB, Stern EA, et al. Children’s binge eating and development of metabolic syndrome. Int J Obes (Lond). 2012;36(7):956-962. PubMed doi:10.1038/ijo.2011.259

104. Esser D, Oosterink E, op ‘ t Roodt J, et al. Vascular and inflammatory high fat meal responses in young healthy men; a discriminative role of IL-8 observed in a randomized trial. PLoS ONE. 2013;8(2):e53474. PubMed doi:10.1371/journal.pone.0053474

105. Ford ES. Does exercise reduce inflammation? physical activity and C-reactive protein among US adults. Epidemiology. 2002;13(5):561-568. PubMed doi:10.1097/00001648-200209000-00012

106. Kasapis C, Thompson PD. The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. J Am Coll Cardiol. 2005;45(10):1563-1569. PubMed doi:10.1016/j.jacc.2004.12.077

107. Boulé NG, Weisnagel SJ, Lakka TA, et al; HERITAGE Family Study. Effects of exercise training on glucose homeostasis: the HERITAGE Family Study. Diabetes Care. 2005;28(1):108-114. PubMed doi:10.2337/diacare.28.1.108

108. McIntyre RS, Soczynska JK, Konarski JZ, et al. Should depressive syndromes be reclassified as “metabolic syndrome type II”? Ann Clin Psychiatry. 2007;19(4):257-264. PubMed doi:10.1080/10401230701653377

109. Leboyer M, Soreca I, Scott J, et al. Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Disord. 2012;141(1):1-10. PubMed doi:10.1016/j.jad.2011.12.049

110. Soczynska JK, Kennedy SH, Woldeyohannes HO, et al. Mood disorders and obesity: understanding inflammation as a pathophysiological nexus. Neuromolecular Med. 2011;13(2):93-116. PubMed doi:10.1007/s12017-010-8140-8

111. Hanley AJ, Festa A, D’ Agostino RB Jr, et al. Metabolic and inflammation variable clusters and prediction of type 2 diabetes: factor analysis using directly measured insulin sensitivity. Diabetes. 2004;53(7):1773-1781. PubMed doi:10.2337/diabetes.53.7.1773

112. Festa A, D’ Agostino R Jr, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102(1):42-47. PubMed doi:10.1161/01.CIR.102.1.42

113. Goldstein BI, Kemp DE, Soczynska JK, et al. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry. 2009;70(8):1078-1090. PubMed doi:10.4088/JCP.08r04505

114. Tsai SY, Chung KH, Wu JY, et al. Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J Affect Disord. 2012;136(1-2):110-116. PubMed doi:10.1016/j.jad.2011.08.022

115. Vuksan-Cusa B, Sagud M, Jakovljević M. C-reactive protein and metabolic syndrome in patients with bipolar disorder compared to patients with schizophrenia. Psychiatr Danub. 2010;22(2):275-277. PubMed

116. Lu XY. The leptin hypothesis of depression: a potential link between mood disorders and obesity? Curr Opin Pharmacol. 2007;7(6):648-652. PubMed doi:10.1016/j.coph.2007.10.010

117. Yamada N, Katsuura G, Ochi Y, et al. Impaired CNS leptin action is implicated in depression associated with obesity. Endocrinology. 2011;152(7):2634-2643. PubMed doi:10.1210/en.2011-0004

118. Moretti R, Bernobich E, Esposito F, et al. Depression in vascular pathologies: the neurologist’s point of view. Vasc Health Risk Manag. 2011;7:433-443. PubMed doi:10.2147/VHRM.S20147

119. Rybakowski JK, Wykretowicz A, Heymann-Szlachcinska A, et al. Impairment of endothelial function in unipolar and bipolar depression. Biol Psychiatry. 2006;60(8):889-891. PubMed doi:10.1016/j.biopsych.2006.03.025

120. Schins A, Honig A, Crijns H, et al. Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link? Psychosom Med. 2003;65(5):729-737. PubMed doi:10.1097/01.PSY.0000088596.42029.10

121. McIntyre RS, Soczynska JK, Liauw SS, et al. The association between childhood adversity and components of metabolic syndrome in adults with mood disorders: results from the International Mood Disorders Collaborative Project. Int J Psychiatry Med. 2012;43(2):165-177. PubMed doi:10.2190/PM.43.2.e

122. Ohaeri JU, Akanji AO. Metabolic syndrome in severe mental disorders. Metab Syndr Relat Disord. 2011;9(2):91-98. PubMed doi:10.1089/met.2010.0053

123. Post RM, Altshuler LL, Leverich GS, et al. Role of childhood adversity in the development of medical co-morbidities associated with bipolar disorder. J Affect Disord. 2013;147(1-3):288-294. PubMed doi:10.1016/j.jad.2012.11.020

124. Cousins DA, Butts K, Young AH. The role of dopamine in bipolar disorder. Bipolar Disord. 2009;11(8):787-806. PubMed doi:10.1111/j.1399-5618.2009.00760.x

125. Pijl H, Romijin JA. Obesity, dopamine and the metabolic syndrome: potential of dopaminergic agents in the control of metabolism. Curr Opin Endocrinol Diabetes. 2006;13(2):179-184. doi:10.1097/01.med.0000216967.74622.9c

126. Anand A, Barkay G, Dzemidzic M, et al. Striatal dopamine transporter availability in unmedicated bipolar disorder. Bipolar Disord. 2011;13(4):406-413. PubMed doi:10.1111/j.1399-5618.2011.00936.x

127. Calabrese JR, Ketter TA, Youakim JM, et al. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71(10):1363-1370. PubMed doi:10.4088/JCP.09m05900gry

128. Carlson PJ, Merlock MC, Suppes T. Adjunctive stimulant use in patients with bipolar disorder: treatment of residual depression and sedation. Bipolar Disord. 2004;6(5):416-420. PubMed doi:10.1111/j.1399-5618.2004.00132.x

129. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242-1249. PubMed doi:10.1176/appi.ajp.2007.06060981

130. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161(3):564-566. PubMed doi:10.1176/appi.ajp.161.3.564

131. Mah L, Zarate CA Jr, Nugent AC, et al. Neural mechanisms of antidepressant efficacy of the dopamine receptor agonist pramipexole in treatment of bipolar depression. Int J Neuropsychopharmacol. 2011;14(4):545-551. PubMed doi:10.1017/S1461145710001203

132. Mathes WF, Brownley KA, Mo X, et al. The biology of binge eating. Appetite. 2009;52(3):545-553. PubMed doi:10.1016/j.appet.2009.03.005

133. Wang GJ, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet. 2001;357(9253):354-357. PubMed doi:10.1016/S0140-6736(00)03643-6

134. Wang GJ, Geliebter A, Volkow ND, et al. Enhanced striatal dopamine release during food stimulation in binge eating disorder. Obesity (Silver Spring). 2011;19(8):1601-1608. PubMed doi:10.1038/oby.2011.27

135. Kok P, Roelfsema F, Frölich M, et al. Activation of dopamine D2 receptors simultaneously ameliorates various metabolic features of obese women. Am J Physiol Endocrinol Metab. 2006;291(5):E1038-E1043. PubMed doi:10.1152/ajpendo.00567.2005

136. Defronzo RA. Bromocriptine: a sympatholytic, D2-dopamine agonist for the treatment of type 2 diabetes. Diabetes Care. 2011;34(4):789-794. PubMed doi:10.2337/dc11-0064

137. McIntyre RS, Alsuwaidan M, Goldstein BI, et al; Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid metabolic disorders. Ann Clin Psychiatry. 2012;24(1):69-81. PubMed

138. Citrome L. Lurasidone for the acute treatment of adults with schizophrenia: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed? Clin Schizophr Relat Psychoses. 2012;6(2):76-85. PubMed doi:10.3371/CSRP.6.2.5

139. McIntyre RS, Wong R. Asenapine: a synthesis of efficacy data in bipolar mania and schizophrenia. Clin Schizophr Relat Psychoses. 2012;5(4):217-220. PubMed doi:10.3371/CSRP.5.4.6

140. De Hert M, Yu W, Detraux J, et al. Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis. CNS Drugs. 2012;26(9):733-759. PubMed doi:10.2165/11634500-000000000-00000

141. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists, et al. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-272. PubMed doi:10.4088/JCP.v65n0219

142. Bell PF, McKenna JP, Roscoe BM. Treatment of bipolar disorders and metabolic syndrome: implications for primary care. Postgrad Med. 2009;121(5):140-144. PubMed doi:10.3810/pgm.2009.09.2060

143. Fagiolini A, Chengappa KN. Weight gain and metabolic issues of medicines used for bipolar disorder. Curr Psychiatry Rep. 2007;9(6):521-528. PubMed doi:10.1007/s11920-007-0071-1

144. Narula PK, Rehan HS, Unni KE, et al. Topiramate for prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia: a double-blind, placebo-controlled trial. Schizophr Res. 2010;118(1-3):218-223. PubMed doi:10.1016/j.schres.2010.02.001

145. Chuang YC, Chuang HY, Lin TK, et al. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia. 2012;53(1):120-128. PubMed doi:10.1111/j.1528-1167.2011.03316.x

146. Remick RA, Froese C. Monoamine oxidase inhibitors: clinical review. Can Fam Physician. 1990;36:1151-1155. PubMed

147. Licht CM, de Geus EJ, Seldenrijk A, et al. Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension. Hypertension. 2009;53(4):631-638. PubMed doi:10.1161/HYPERTENSIONAHA.108.126698

148. McIntyre RS, Soczynska JK, Konarski JZ, et al. The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms. Expert Opin Drug Saf. 2006;5(1):157-168. PubMed doi:10.1517/14740338.5.1.157

149. Chaggar PS, Shaw SM, Williams SG. Effect of antipsychotic medications on glucose and lipid levels. J Clin Pharmacol. 2011;51(5):631-638. PubMed doi:10.1177/0091270010368678

150. Baptista T, De Mendoza S, Beaulieu S, et al. The metabolic syndrome during atypical antipsychotic drug treatment: mechanisms and management. Metab Syndr Relat Disord. 2004;2(4):290-307. PubMed doi:10.1089/met.2004.2.290

151. Potkin SG. Asenapine: a clinical overview. J Clin Psychiatry. 2011;72(suppl 1):14-18. PubMed doi:10.4088/JCP.10075su1.03

152. Kim B, Kim SJ, Son JI, et al. Weight change in the acute treatment of bipolar I disorder: a naturalistic observational study of psychiatric inpatients. J Affect Disord. 2008;105(1-3):45-52. PubMed doi:10.1016/j.jad.2007.04.006

153. Baig MR, Navaira E, Escamilla MA, et al. Clozapine treatment causes oxidation of proteins involved in energy metabolism in lymphoblastoid cells: a possible mechanism for antipsychotic-induced metabolic alterations. J Psychiatr Pract. 2010;16(5):325-333. PubMed doi:10.1097/01.pra.0000388627.36781.6a

154. Houseknecht KL, Robertson AS, Zavadoski W, et al. Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology. 2007;32(2):289-297. PubMed doi:10.1038/sj.npp.1301209

155. Vestri HS, Maianu L, Moellering DR, et al. Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology. 2007;32(4):765-772. PubMed doi:10.1038/sj.npp.1301142

156. Birkenaes AB, Birkeland KI, Engh JA, et al. Dyslipidemia independent of body mass in antipsychotic-treated patients under real-life conditions. J Clin Psychopharmacol. 2008;28(2):132-137. PubMed doi:10.1097/JCP.0b013e318166c4f7

157. Bobo WV, Bonaccorso S, Jayathilake K, et al. Prediction of long-term metabolic effects of olanzapine and risperidone treatment from baseline body mass index in schizophrenia and bipolar disorder. Psychiatry Res. 2011;189(2):200-207. PubMed doi:10.1016/j.psychres.2011.07.008

158. McIntyre RS, McElroy SL, Eudicone JM, et al. A 52-week, double-blind evaluation of the metabolic effects of aripiprazole and lithium in bipolar I disorder. Prim Care Companion CNS Disord. 2011;13(6). PubMed

159. Chang HH, Yang YK, Gean PW, et al. The role of valproate in metabolic disturbances in bipolar disorder patients. J Affect Disord. 2010;124(3):319-323. PubMed doi:10.1016/j.jad.2009.12.011

160. Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65(3):432-441. PubMed doi:10.4088/JCP.v65n0321

161. Bowden CL, Calabrese JR, Ketter TA, et al. Impact of lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder. Am J Psychiatry. 2006;163(7):1199-1201. PubMed doi:10.1176/appi.ajp.163.7.1199

162. Ketter TA, Kalali AH, Weisler RH; SPD417 Study Group. A 6-month, multicenter, open-label evaluation of beaded, extended-release carbamazepine capsule monotherapy in bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004;65(5):668-673. PubMed doi:10.4088/JCP.v65n0511

163. Weisler RH, Keck PE Jr, Swann AC, et al; SPD417 Study Group. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2005;66(3):323-330. PubMed doi:10.4088/JCP.v66n0308

164. Amit BH, Weizman A. Antidepressant treatment for acute bipolar depression: an update. Depress Res Treat. 2012; 2012:684725. doi:10.1155/2012/684725 PubMed

165. Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry. 2004;161(9):1537-1547. PubMed doi:10.1176/appi.ajp.161.9.1537

166. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders. Am J Psychiatry. 2013;170(11):1249-1262. PubMed doi:10.1176/appi.ajp.2013.13020185

167. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722. PubMed doi:10.1056/NEJMoa064135

168. Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 2011;72(2):156-167. PubMed doi:10.4088/JCP.09r05385gre

169. McIntyre RS, Mancini DA, McCann S, et al. Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord. 2002;4(3):207-213. PubMed doi:10.1034/j.1399-5618.2002.01189.x

170. Derijks HJ, Meyboom RH, Heerdink ER, et al. The association between antidepressant use and disturbances in glucose homeostasis: evidence from spontaneous reports. Eur J Clin Pharmacol. 2008;64(5):531-538. PubMed doi:10.1007/s00228-007-0441-y

171. Gadde KM, Yonish GM, Wagner HR 2nd, et al. Atomoxetine for weight reduction in obese women: a preliminary randomised controlled trial. Int J Obes (Lond). 2006;30(7):1138-1142. PubMed doi:10.1038/sj.ijo.0803223

172. Paslakis G, Gilles M, Lederbogen F, et al. The effect of a 4-week treatment with reboxetine on metabolic parameters of depressed inpatients. Eur Arch Psychiatry Clin Neurosci. 2011;261(3):173-177. PubMed doi:10.1007/s00406-010-0164-4

173. Wong ND, Pio JR, Franklin SS, et al. Preventing coronary events by optimal control of blood pressure and lipids in patients with the metabolic syndrome. Am J Cardiol. 2003;91(12):1421-1426. PubMed doi:10.1016/S0002-9149(03)00392-8

174. McIntyre RS, Rosenbluth M, Ramasubbu R, et al; Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force. Managing medical and psychiatric comorbidity in individuals with major depressive disorder and bipolar disorder. Ann Clin Psychiatry. 2012;24(2):163-169. PubMed

175. Bermudes RA, Keck PE, McElroy SL. Metabolic risk assessment, monitoring, and interventions. In: Bermudes RA, Keck PE, McElroy SL, eds. Managing Metabolic Abnormalities in the Psychiatrically Ill: A Clinical Guide for Psychiatrists. Washington, DC: American Psychiatric Publishing, Inc; 2007:277-302.

176. Bermudes RA. Metabolic syndrome: 5 risk factors guide therapy. Curr Psychiatr. 2005;4(4):73-88.

177. Citrome L, Holt RI, Walker DJ, et al. Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder. Clin Drug Investig. 2011;31(7):455-482. PubMed doi:10.2165/11589060-000000000-00000

178. Prabhakar M, Haynes WG, Coryell WH, et al. Factors associated with the prescribing of olanzapine, quetiapine, and risperidone in patients with bipolar and related affective disorders. Pharmacotherapy. 2011;31(8):806-812. PubMed doi:10.1592/phco.31.8.806

179. Mora S, Cook N, Buring JE, et al. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation. 2007;116(19):2110-2118. PubMed doi:10.1161/CIRCULATIONAHA.107.729939

180. Thompson PD, Buchner D, Pina IL, et al; American Heart Association Council on Nutrition, Physical Activity, and Metabolism Subcommittee on Physical Activity. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation. 2003;107(24):3109-3116. PubMed doi:10.1161/01.CIR.0000075572.40158.77

181. Rimer J, Dwan K, Lawlor DA, et al. Exercise for depression. Cochrane Database Syst Rev. 2012;7:CD004366. PubMed

182. Estruch R, Ros E, Salas-Salvadó J, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279-1290. doi:10.1056/NEJMoa1200303

183. Sánchez-Villegas A, Delgado-Rodr×­guez M, Alonso A, et al. Association of the Mediterranean dietary pattern with the incidence of depression: the Seguimiento Universidad de Navarra/University of Navarra follow-up (SUN) cohort. Arch Gen Psychiatry. 2009;66(10):1090-1098. PubMed doi:10.1001/archgenpsychiatry.2009.129

184. Daumit GL, Dickerson FB, Wang NY, et al. A behavioral weight-loss intervention in persons with serious mental illness. N Engl J Med. 2013;368(17):1594-1602. PubMed doi:10.1056/NEJMoa1214530

185. Berlin I. Smoking-induced metabolic disorders: a review. Diabetes Metab. 2008;34(4, pt 1):307-314. PubMed doi:10.1016/j.diabet.2008.01.008

186. Clair C, Rigotti NA, Porneala B, et al. Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes. JAMA. 2013;309(10):1014-1021. PubMed doi:10.1001/jama.2013.1644

187. Farley AC, Hajek P, Lycett D, et al. Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev. 2012;1:CD006219. PubMed

188. Sacks FM. Metabolic syndrome: epidemiology and consequences. J Clin Psychiatry. 2004;65(suppl 18):3-12. PubMed

189. Wellbutrin (bupropion hydrochloride) tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011.

190. Grundy SM, Cleeman JI, Merz CN, et al;; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239. PubMed doi:10.1161/01.CIR.0000133317.49796.0E

191. Jellinger PS, Smith DA, Mehta AE, et al; AACE Task Force for Management of Dyslipidemia and Prevention of Atherosclerosis. American Association of Clinical Endocrinologists’ Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract. 2012;18(suppl 1):1-78. PubMed doi:10.4158/EP.18.S1.1

192. Berglund L, Brunzell JD, Goldberg AC, et al; Endocrine society. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(9):2969-2989. PubMed doi:10.1210/jc.2011-3213

193. Reiner Z, Catapano AL, De Backer G, et al; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769-1818. PubMed doi:10.1093/eurheartj/ehr158

194. Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of dyslipidemia. http://www.healthquality.va.gov/lipids/lip05_950_final2.pdf. Updated 2006. Accessed September 30, 2013.

195. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22. PubMed doi:10.1016/S0140-6736(02)09327-3

196. Yang CC, Jick SS, Jick H. Lipid-lowering drugs and the risk of depression and suicidal behavior. Arch Intern Med. 2003;163(16):1926-1932. PubMed doi:10.1001/archinte.163.16.1926

197. Bernstein AM, Ding EL, Willett WC, et al. A meta-analysis shows that docosahexaenoic acid from algal oil reduces serum triglycerides and increases HDL-cholesterol and LDL-cholesterol in persons without coronary heart disease. J Nutr. 2012;142(1):99-104. PubMed doi:10.3945/jn.111.148973

198. von Schacky C. A review of omega-3 ethyl esters for cardiovascular prevention and treatment of increased blood triglyceride levels. Vasc Health Risk Manag. 2006;2(3):251-262. PubMed doi:10.2147/vhrm.2006.2.3.251

199. Sarris J, Mischoulon D, Schweitzer I. Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression. J Clin Psychiatry. 2012;73(1):81-86. PubMed doi:10.4088/JCP.10r06710

200. Chen Y, Bobo WV, Watts K, et al. Comparative effectiveness of switching antipsychotic drug treatment to aripiprazole or ziprasidone for improving metabolic profile and atherogenic dyslipidemia: a 12-month, prospective, open-label study. J Psychopharmacol. 2012;26(9):1201-1210. PubMed doi:10.1177/0269881111430748

201. Mackin P, Waton T, Watkinson HM, et al. A four-year naturalistic prospective study of cardiometabolic disease in antipsychotic-treated patients. Eur Psychiatry. 2012;27(1):50-55. PubMed doi:10.1016/j.eurpsy.2010.08.011

202. Appel LJ, Giles TD, Black HR, et al; American Society of Hypertension Writing Group. ASH Position Paper: dietary approaches to lower blood pressure. J Clin Hypertens (Greenwich). 2009;11(7):358-368. PubMed doi:10.1111/j.1751-7176.2009.00136.x

203. Ferdinand KC. A compendium of antihypertensive therapy. J Clin Hypertens (Greenwich). 2011;13(9):636-638. PubMed doi:10.1111/j.1751-7176.2011.00506.x

204. Gradman AH, Basile JN, Carter BL, et al; American Society of Hypertension Writing Group. Combination therapy in hypertension. J Clin Hypertens (Greenwich). 2011;13(3):146-154. PubMed doi:10.1111/j.1751-7176.2010.00397.x

205. Hill MN, Miller NH, Degeest S, et al; American Society of Hypertension Writing Group. Adherence and persistence with taking medication to control high blood pressure. J Am Soc Hypertens. 2011;5(1):56-63. PubMed doi:10.1016/j.jash.2011.01.001

206. Karanja N, Erlinger TP, Pao-Hwa L, et al. The DASH diet for high blood pressure: from clinical trial to dinner table. Cleve Clin J Med. 2004;71(9):745-753. PubMed doi:10.3949/ccjm.71.9.745

207. Sacks FM, Svetkey LP, Vollmer WM, et al; DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med. 2001;344(1):3-10. PubMed doi:10.1056/NEJM200101043440101

208. Svetkey LP, Simons-Morton D, Vollmer WM, et al; ASH Research Group. Effects of dietary patterns on blood pressure: subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med. 1999;159(3):285-293. PubMed doi:10.1001/archinte.159.3.285

209. Sica DA, Carter B, Cushman W, et al. Thiazide and loop diuretics. J Clin Hypertens (Greenwich). 2011;13(9):639-643. PubMed doi:10.1111/j.1751-7176.2011.00512.x

210. Finley PR, O’ Brien JG, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol. 1996;16(1):68-71. PubMed doi:10.1097/00004714-199602000-00011

211. Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother. 2011;9(6):364-377. PubMed doi:10.1016/j.amjopharm.2011.10.004

212. Smith TG. ABCD of hypertension treatment: ask about lithium, too. BMJ. 2011;342(2):d2718. PubMed doi:10.1136/bmj.d2718

213. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288(3):351-357. PubMed doi:10.1001/jama.288.3.351

214. van Melle JP, Verbeek DE, van den Berg MP, et al. Beta-blockers and depression after myocardial infarction: a multicenter prospective study. J Am Coll Cardiol. 2006;48(11):2209-2214. PubMed doi:10.1016/j.jacc.2006.07.056

215. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35(suppl 1):S11-S63. PubMed

216. Petrak F, Herpertz S. Treatment of depression in diabetes: an update. Curr Opin Psychiatry. 2009;22(2):211-217. PubMed doi:10.1097/YCO.0b013e3283207b45

217. van der Feltz-Cornelis CM, Nuyen J, Stoop C, et al. Effect of interventions for major depressive disorder and significant depressive symptoms in patients with diabetes mellitus: a systematic review and meta-analysis. Gen Hosp Psychiatry. 2010;32(4):380-395. PubMed doi:10.1016/j.genhosppsych.2010.03.011

218. Ehret M, Goethe J, Lanosa M, et al. The effect of metformin on anthropometrics and insulin resistance in patients receiving atypical antipsychotic agents: a meta-analysis. J Clin Psychiatry. 2010;71(10):1286-1292. PubMed doi:10.4088/JCP.09m05274yel