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Bipolar Disorder and Its Comorbidities

Authors: Zubin Bhagwagar, MD, PhD  Faculty and Disclosures


Comorbid medical and psychiatric conditions that complicate the assessment and management of bipolar disorder have drawn growing interest within the field of bipolar disorder. Conditions such as obesity, metabolic syndrome, substance abuse, and anxiety -- among many others -- have a significant impact on the presentation and management of bipolar disorders. Clinicians need to be aware of these conditions to both accurately diagnose and effectively treat the complex presenting symptoms.

Comorbid Medical Conditions

Bipolar Disorder and Mortality

Gary S. Sachs, MD, from Massachusetts General Hospital Boston, elegantly set the scene by describing key issues in the interface between bipolar disorder and medical comorbidities. He emphasized that bipolar disorder is a severe illness, which is characterized by increased mortality rates compared with the general population. He referred to work done by Urban Osby and colleagues and Jules Angst and colleagues to clarify the issue of mortality rates in bipolar disorder. Osby and colleagues studied over 15,000 patients with a hospital diagnosis of bipolar disorder in Sweden and linked their records with the national Cause-of-Death Register to determine the date and cause of death.[1] The authors calculated standardized mortality ratios (SMR) by dividing the observed deaths by the number of expected deaths in the bipolar group. A SMR greater than 1 implies greater risk in the bipolar population. The SMRs for all deaths in the bipolar group was 2.5 in males and 2.7 in females. The most frequent cause of death in bipolar disorder was cardiovascular disease (31% of observed deaths in the cohort of bipolar patients in the study), followed by suicide (19%), and cancer (14%). Jules Angst and colleagues followed up on a cohort of 406 patients with affective disorder for 22 years to determine SMRs.[2] In keeping with Osby's study, he showed that SMRs for patients were especially elevated, for suicide and cardiovascular disorders in both men and women, and that the most frequent cause of death was cardiovascular morbidity. In addition, the value of treatment of the disorder was underlined by the fact that the SMR for all-cause mortality of bipolar patients dropped from 2.2 for untreated patients to 1.3 for treated ones. Treatment had an even greater impact on suicides in the study population. The SMR for suicide dropped from 29 in untreated patients to 6.5 in treated patients, underscoring the need for effective treatment of patients.

Obesity and Bipolar Disorder

Susan McElroy MD, University of Cincinnati College of Medicine, spoke eloquently about the interrelationship between obesity and bipolar disorder. The overlap between bipolar disorder and eating disorders was highlighted in a recent study that examined the prevalence and correlates of eating disorders from the National Comorbidity Replication [study].[3] In this study, 12.5% of patients with binge eating disorder, 10.5% patients with sub-threshold binge eating disorder, and 18% of patients with bulimia nervosa had a comorbid diagnosis of bipolar disorder.

The scope of the problem is also highlighted in a recent population study of 9125 respondents who provided complete data on psychiatric disorder, height, and weight to evaluate the relationship between obesity and a range of mood, anxiety, and substance use disorders.[4] Obesity was defined as body mass index (weight in kilograms divided by the square of height in meters) of ≥ 30. Bipolar disorder had the highest odds ratio of all psychiatric disorders studied in patients with obesity. Obesity was associated with significant increases in lifetime diagnosis of bipolar disorder (odds ratio 1.47), panic disorder major depression (1.21), or agoraphobia (1.27), but a lower lifetime risk of substance use disorder (OR, 0.78; 95% CI, 0.65-0.93).

Obesity is also associated with a poorer outcome in bipolar patients. In a cohort of 175 patients with bipolar I disorder who were treated for an acute affective episode, 35% met the criteria for obesity.[5] At baseline assessment, significant differences were observed between the obese and non-obese patients for years of education, numbers of previous depressive and manic episodes, baseline scores on the Hamilton Rating Scale for Depression, and durations of the acute episode. A Kaplan-Meier survival analysis indicated a significantly shorter time to recurrence during the maintenance phase among obese patients. The number of patients experiencing a depressive recurrence was significantly higher in the obese than in the non-obese group.

Treatment for this comorbid group remains relatively unexplored, although there are some data available from which one can draw inferences. While there may be a particular choice of treatment based on efficacy, these treatments also have a differential effect on weight gain. A recent re-examination studied the effect of lamotrigine, lithium, and placebo administration on body weight in obese and non-obese patients with bipolar disorder.[6] Mean changes in weight among obese patients after 1 year's treatment showed the maximum weight gain for lithium-treated patients (+6.1 kg), while lamotrigine-treated patients lost weight (-4.2 kg), and placebo-treated patients were relatively weight neutral (-0.6 kg). There were no statistically significant differences among nonobese patients; mean changes in weight (kg) at week 52 being -0.5, +1.1, and +0.7 with lamotrigine, lithium, and placebo, respectively, among this population.

The Metabolic Syndrome

Andrea Fagiolini MD, University of Pittsburgh Medical School, brought together a number of diverse elements and addressed the issue of various medical comorbidities in bipolar disorder. A wide range of medical problems has been cited in the few studies focused on medical illness in this population; the most common being cardiovascular disease, diabetes mellitus, obesity, and thyroid disease.[7]

Recent interest has focused on the metabolic syndrome, especially in relation to drug treatment in psychiatry. In 2001, the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) suggested a working definition of this syndrome based on the presence of 3 or more of the following characteristics: abdominal obesity (waist circumference), hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), high blood pressure, and fasting hyperglycemia.[8] A recent study evaluated the presence of the metabolic syndrome in a group of 171 patients with bipolar disorder. Thirty percent of the sample met the full criteria for the metabolic syndrome, although a larger number of patients met other criteria. The breakdown was: 49% met the criterion for abdominal obesity, 41% for hypertriglyceridemia, 48% for hypertriglyceridemia or were on a cholesterol-lowering medication, 23% for low high-density lipoprotein cholesterol, 39% for hypertension, and 8% for high fasting glucose or antidiabetic medication use. These issues also had a functional consequence in that patients with the metabolic syndrome and patients endorsing the obesity criterion were more likely to report a lifetime history of suicide attempts. In addition to psychotropic drugs, a sedentary lifestyle, overeating, physiologic changes resulting in an increased need for sleep, and possible endocrine disruptions due to additives in food material were hypothesized to be the cause of the syndrome. Risk reduction interventions were cited as an effort to bring about change in this subset of patients, with integrated care between the psychiatrist, nurse practitioner, primary care physician, medical specialists, and the patient being the cornerstone of change. Assessing medical comorbidity should be part of the routine care of patients with bipolar disorder.

Comorbid Psychiatric Disorders

Comorbid Substance Abuse

Michael J Ostacher, MD, from Massachusetts General Hospital in Boston, described the interface of comorbid substance abuse disorders with bipolar disorder. He outlined the scope of the problem by highlighting recent studies comparing the epidemiology of the 2 conditions. Data from the 1990 Epidemiological Catchment Area (ECA) study found that among subjects with either an alcohol or other drug disorder, the odds of having the other addictive disorder were 7 times greater than in the rest of the population.[9] A little over half of the patients with bipolar disorder had a comorbid substance abuse issue. Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) program showed that subjects with bipolar disorder had increased rates of drug or alcohol abuse irrespective of age of onset of illness.[10] Subjects were divided into 3 groups based on age of onset of illness: onset before 13 years, onset between 13 and 18 years, and onset after the age of 18. All 3 groups had a significant (35%-45%) rate of comorbid alcohol or substance abuse or dependence; only the over 18-year onset group had a marginally lower (15%) comorbid drug abuse/dependence problem.

Touching upon patient treatment issues, Dr. Ostacher stressed that although the conditions were severe and caused great dysfunction, there were no US Food and Drug Administration (FDA)-approved drugs currently available to treat patients with the comorbid condition. In the STEP-BD program, subjects were classified into 3 groups on the basis of whether they had a current or past substance use disorder or no lifetime diagnosis of substance use disorder.[11] The need for appropriate treatment is highlighted by the fact that patients with bipolar disorder in STEP-BD who experienced sustained remission from comorbid substance use disorders fared much better overall compared with patients with current substance use disorders. Specific measures included quality of life, role functioning, and suicide attempts. Patients with current substance use disorders fared worst while those with no history of substance use disorders fared the best on these outcomes.

Turning to treatment strategies, Salloum and colleagues evaluated the efficacy of divalproex sodium in decreasing alcohol use and stabilizing mood symptoms in acutely ill patients with bipolar disorder and alcoholism.[12] They studied 59 subjects with diagnoses of bipolar I disorder and alcohol dependence who received treatment as usual, including lithium carbonate and psychosocial interventions, and were randomized to receive valproate or placebo. They found potential utility for the use of valproate in this population on a large number of outcome variables. Compared with the placebo group, the valproate group had a significantly lower proportion of heavy drinking days and a trend toward fewer drinks per heavy drinking day (P = .055). Even after controlling for medication adherence, the valproate group had significantly fewer drinks per heavy drinking day and fewer drinks per drinking day (P = .02). They found that higher valproate serum concentration significantly correlated with improved alcohol use outcomes, and that manic and depressive symptoms improved equally in both groups. The results suggest that the observed effect was not directly the result of an improvement in mental state. Interestingly, when they studied levels of gamma-glutamyl transpeptidase, a marker of recent alcohol use, there were significantly higher levels in the placebo group compared with the valproate group, thus providing a biomarker to substantiate the results. Therefore effectively treating bipolar patients with comorbid alcohol dependence with valproate significantly decreases morbidity. In a study in bipolar adolescents with concurrent substance use disorders (predominantly alcohol and marijuana), the addition of double-blind lithium resulted in a statistically significant decrease in affective symptoms and concurrent substance use.[13] The mean lithium level in responders was 0.9 mEq/L, once more underscoring the need for effective treatment of the condition.

While pharmacologic treatments have a clear place in the treatment of patients with comorbid substance use disorder and bipolar disorder, there is also a clear role for psychosocial interventions. Weiss and colleagues[14] randomly allocated 62 patients with bipolar disorder and current substance dependence to integrated group therapy (N = 31) or group drug counseling (N = 31). They had 2 primary outcome measures: one for substance use and the other for the mood disorder. The primary outcome measure for substance use disorders was the number of days of substance use, while the primary mood outcome was the number of weeks ill with a mood episode. The authors found that integrated group therapy had significantly better substance use outcomes than group drug counseling, despite more mood symptoms. This suggests that integrated group therapy may be a useful intervention in these difficult-to-treat bipolar patients with comorbid substance use disorders.

Suicide and Bipolar Disorder

Lauren Marangell MD, Baylor College, presented data on the interface between suicide, suicide attempts, and bipolar disorder. She emphasized that suicide was an important issue in the assessment, management, and treatment of bipolar disorder, and offered data to underscore the point. As demonstrated previously, the SMR for suicide in bipolar disorder has been reported to be 12.3 and there is a significant difference in SMRs for suicide between treated (N = 29) and untreated (N = 6.4) patients.[2] A number of factors can be identified as risk factors for suicide in bipolar patients. The STEP-BD program examined the association between baseline clinical and demographic variables and subsequent suicide attempts and completions through 2 years of follow-up of 1556 patients.[15] Of these patients, 50 attempted suicide and 7 completed suicide. History of a suicide attempt and patient estimates of the number of days spent depressed in the prior year were the only variables to predict subsequent completed or attempted suicide after controlling for other variables. In a secondary analysis of 1014 patients, only history of suicide attempt independently predicted subsequent completed or attempted suicide.

More data from the STEP-BD program shows that lifetime comorbid anxiety disorders are common in patients with bipolar disorder. They occur in over 50% of the STEP-BD population; they were associated with younger age at onset, decreased likelihood of recovery, poorer role functioning and quality of life, less time euthymic, and greater likelihood of suicide attempts.[16] Although substance abuse disorders were particularly prevalent among patients with anxiety disorders, comorbid anxiety appeared to exert an independent, deleterious effect on functioning, including history of suicide attempts.

Predicting suicide in individual patients is difficult -- in the STEP-BD cohort, suicide attempters or completers had a greater history of attempted suicide, more suicidal ideation at baseline, and more days spent depressed, anxious, or irritable over the past year than those who did not experience an event over the 24 months of observation.[17] Dr. Marangell highlighted the need for an ongoing risk assessment, vigorously treating the underlying bipolar disorder, assessing and treating the comorbid conditions and careful follow-up as good clinical practice tips for dealing with the issue in bipolar disorder. She also highlighted the connection of lithium and its putative antisuicide effect in patients with severe psychiatric disorders. However, the effects of lithium on suicide are uncertain because the low event rate means that individual randomized trials are invariably underpowered to investigate any potential benefit. A recent meta-analysis of randomized controlled trials of lithium treatment studied the effect of lithium in the prevention of all-cause mortality and suicidal behavior in patients with mood disorders.[18] Based on data from 2069 patients treated with compounds other than lithium compared with 1389 patients treated with lithium, the authors found that lithium-treated patients were less likely to die by suicide. The composite measure of suicide plus deliberate self-harm was also lower in patients who received lithium, and there were fewer deaths overall in patients who received lithium. However, the pitfalls of these data were also highlighted, including the fact that randomized controlled trials of pharmacologic agents tend to exclude patients with serious suicidal thoughts or intent.

Suicide and Posttraumatic Disorder

Another frequent, although less studied, comorbid condition is posttraumatic disorder. Lori Davis MD, VA Medical Center Alabama, put the spotlight on the relationship between these 2 conditions, in particular, the role of early childhood trauma. In a study of 330 veterans (91% male) with bipolar I or II disorder, childhood abuse was reported by nearly half of the subjects.[19] Female veterans reported more sexual abuse (27%) and less physical abuse (6.7%). Subjects with abuse were more likely to have current posttraumatic stress disorder (PTSD) and lifetime diagnoses of panic disorder and alcohol use disorders. Abuse was associated with lower SF-36 mental scores, higher likelihood of current PTSD, and lifetime diagnoses of alcohol use disorders, as well as more lifetime episodes of major depression, and a higher likelihood of at least 1 suicide attempt. In addition, a younger age at study entry was associated with a history of abuse. Clearly, a history of childhood abuse acts as a disease course modifier in male veterans with bipolar disorder. Dr. Davis suggested that clinicians should routinely seek information regarding abuse and be aware that these patients may be more difficult to treat than bipolar patients who have no abuse histories.

The effect of the traumatic events of September 11, 2001 was studied in a small cohort of STEP BD patients. Twenty percent of a cohort of 137 patients in the STEP-BD program reported development of new-onset PTSD in response to the September 11 attacks.[20] Mania/hypomania remained a significant predictor of PTSD in response to the September 11 attacks after controlling for peri-traumatic exposure and distress variables, suggestive of a substantial increase in risk compared with those in recovery. While there are no specific treatments for the comorbid condition, it was suggested that both conditions be vigorously treated with appropriate medications.


Bipolar disorder commonly has comorbid conditions and correlates which, if not assessed, complicate its management. Common conditions include obesity, metabolic syndrome, substance abuse, and anxiety disorders. The most frequent cause of mortality in patients with bipolar disorder seems to be related to cardiovascular causes and special attention is warranted to that condition. Suicide is an overarching concern with all mood disorders, including bipolar disorder, and ongoing risk assessment and appropriate treatment with mood stabilizers are essential aspects of treatment.

Supported by independent educational grants from Janssen, Bristol-Myers Squibb, and Shire



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