Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome.

Psychiatric comorbidity is a prevailing hallmark of bipolar disorder. Over 97% of patients with bipolar I disorder meet criteria for a concurrent psychiatric illness, and the co-occurrence of three or more disorders is dramatically higher than comorbidity with only one disorder across the bipolar spectrum (1). General medical conditions also cluster heavily within bipolar populations (2-4) and result in an earlier and increased mortality from cardiovascular, respiratory, and endocrine causes (5). Of increasing concern, clinical and epidemiologic studies reveal more than half of bipolar disorder patients are either overweight or obese (6, 7), a finding that appears independent of treatment with weight-promoting psychotropic medications (8). A full one-third of patients with bipolar disorder also meet criteria for metabolic syndrome, a group of risk factors prominently associated with the development of heart disease, stroke, and type II diabetes (9). Among patients receiving atypical antipsychotics, metabolic syndrome is now recognized to occur at an equivalent rate in bipolar disorder as in schizophrenia (10). These cardiometabolic risk factors also appear to herald the presence of greater psychiatric symptom severity. For instance, attempted suicides are more common among patients with concurrent metabolic syndrome (9). Similarly, poorer treatment outcomes are more likely in the setting of generalized obesity (11). Not only do obese patients experience an increased lifetime number of depressive and manic episodes, but they also relapse more quickly following stabilization, primarily into depressive episodes (12). Although metabolic-related illnesses may be associated with more complex illness presentations and greater severity of mood symptoms, there is incongruity as to the role comorbid medical conditions play in moderating or predicting treatment response. Some authors have found significant associations between the absolute number of comorbid medical illnesses and worsened bipolar outcomes (13, 14), whereas others have identified no such relationships (15). Thompson and colleagues (16), studying patients with bipolar I or schizoaffective disorder, found the presence of a high number of baseline medical comorbidities to be associated with depressive episodes of greater severity and longer duration. Moreover, patients with greater baseline medical burden in that study improved more slowly throughout the course of treatment. The most common medical illnesses afflicting patients with bipolar disorder include those of cardiovascular (e.g., hypertension) and endocrine/metabolic origin (e.g., obesity, hyperlipidemia, and type II diabetes) (2, 3, 17). Rather than simply representing a pharmacological side effect or the sequelae of a complex and unpredictable disorder, it is highly probable that the pathophysiology underlying bipolar disorder fosters the development of a variety of medical disorders (18). For instance, women with bipolar disorder store a greater proportion of fat in visceral or abdominal regions than obese controls (19). Visceral fat is metabolically active, secreting proinflammatory cytokines and other acute phase reactants that have been correlated with increased severity of depressive symptoms (20). Abnormalities in other metabolic-inflammatory networks suggest that biological mechanisms common to bipolar disorder and metabolic syndrome include abnormal glucocorticoid signaling, oxidative stress, autonomic dysregulation, and altered energy biosynthesis (21). Thus, medical comorbidity may represent a core feature of bipolar disorder, rather than an incidental event or side effect of treatment (18). The primary objective of this report was to evaluate the multifaceted relationship between medical comorbidity, indicators of mood disorder severity, and response to treatment with lithium and valproate. We hypothesized that illnesses of the endocrine/metabolic system would be associated with greater psychiatric symptom burden and would negatively influence acute treatment response. Our hypothesis was based on clinical experiences with bipolar patients and published literature relating obesity to an increased risk for bipolar disorder, attempted suicide, and earlier relapses. Given that prior studies of medical comorbidity in bipolar populations have generally excluded (2, 16) or focused entirely on patients with substance use disorders (SUDs) (17), a secondary objective was to compare the burden of medical comorbidity among two cohorts with rapid-cycling bipolar disorder differing only in a recent history of an alcohol or drug use disorder.