Aside from the bipolar diagnosis itself and its consequences such as disability and unemployment, there is a large array of comorbid psychiatric conditions associated with bipolar disorder. Up to 75% of patients with bipolar disorder have at least one other psychiatric disorder, with anxiety, substance abuse, and eating disorder among the most common.42,43
In the past, excess deaths associated with bipolar disorder were attributed to unnatural causes such as suicide, homicide, and accidents. Increased evidence now reveals that patients with bipolar disorder are, in fact, mainly at risk of premature death because of medical disorders, with excess mortality ranging from 35% to twofold higher than the general population and higher than those with major depression.44
The most common causes of natural death for bipolar patients are cardiovascular and cerebrovascular diseases which occur at twice the rate of the general population.44
Bipolar patients are at greater risk for cardiovascular mortality than patients with other mental illnesses, including unipolar depression and schizophrenia. Bipolar patients have a higher prevalence of medical disorders which are themselves cardiovascular risk factors, such as diabetes mellitus underlined by impaired glucose tolerance and insulin resistance, obesity (and in particular increased rates of abdominal obesity), hypertension associated with higher sympathetic tone and lower heart rate variability, and thyroid failure.45
Obesity is correlated with a poorer outcome in patients with bipolar I disorder. Preventing and treating obesity in bipolar disorder patients could thus decrease the morbidity and mortality related to physical illness and possibly improve the course of bipolar illness.46
Identification of these risk factors should be performed early in the course of bipolar disorder as it is noteworthy that the increase in mortality is most prominent in the first 10 years after admission for a mood episode. In pediatric bipolar disorder, comorbid medical conditions such as obesity, type 2 diabetes, and cardiovascular disorders were more prevalent and preceded the diagnosis of bipolar disorder.47
Excess mortality from natural causes among bipolar patients may result from several mechanisms. Bipolar disorder is associated with excess burden of cardiovascular risk factors such as smoking (70% of outpatients with bipolar disorder are nicotine dependent), alcoholism, poor diet, and sedentary lifestyle.48
In the STEP-BD program, substance abuse and smoking were found to be associated with more lifetime mood episodes and greater severity of symptoms, as well as rapid cycling, comorbid psychiatric disorders, and demographic factors such as being male, having less education, and having lower income.43
In addition, nearly all antipsychotics and mood stabilizers cause some amount of weight gain from minimal to significant amounts. Their role in the metabolic syndrome may be substantial, as is their benefit in the treatment of psychiatric illness. Until more is known about the source of increased risk of cardiovascular disorder and of other risks such as diabetes, it is the responsibility of the physician to provide careful monitoring of these risk factors, for example, by providing help for smoking cessation or reinforcing the need to do structured exercise49
and to make a careful selection of treatments, antipsychotics, and/or mood stabilizers, according to the expected riskbenefit ratio for a given patient.
In addition to an unhealthy lifestyle which may contribute to the risk of medical disorders, elucidating the mechanisms underlying the links between specific medical illness and bipolar disorder may provide new insights into its pathophysiology. Alterations in interacting metabolic, inflammatory, and oxidative systems appear likely to contribute to the cumulative “organ damage,” e.g., allostatic load.50
For example, major stressors have been reported during the childhood of bipolar patients17
and often precede mood episodes. Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, central to stress response, have been reported during mood episodes, during euthymic periods, and in unaffected relatives of patients with bipolar disorder, thus suggesting that HPA axis dysfunction may be a vulnerability marker.51
HPA dysfunction may in turn increase insulin resistance leading to hyperglycemia, increased oxidative stress, metabolic syndrome, and atherosclerosis. Hyperactivity of the HPA axis may also be associated with hyperactivity of the autonomous system, commonly observed in patients with bipolar disorder and their relatives.14
Dysregulation of the autonomic system may lead to insulin resistance and may worsen metabolic syndrome, leading to increased risk of sudden cardiac death.48
Recently, attention has shifted to the importance of inflammation in the pathophysiology and treatment of bipolar disorder. Indeed, several studies have shown that bipolar disorder is associated with increased expression of pro-inflammatory markers (particularly CRP, soluble IL- 2 receptor, IL-6, and TNF): genetic findings suggest that bipolar disorder is associated with IL-1 and IL-6 genes, and comorbid medical burden may contribute to the pro-inflammatory milieu. Lithium may modulate the inflammation milieu in bipolar disorder and anti-inflammatory therapies may possess symptom-alleviating effects among acutely ill patients.51
For example, bipolar patients have elevated levels of interleukin-6, a potent stimulator of corticotrophinreleasing hormone production which may also lead to HPA axis hyperactivity and hypercortisolemia acting synergistically to worsen cardiovascular outcome. In turn, elevation of cortisol can increase levels of proinflammatory cytokines and down-regulate cellular and humoral responses. Inflammation has also been hypothesized to signal the brain to produce neurobiological changes in the face of stress.52
There is an urgent need for further research to understand the putative role of inflammation in bipolar disorder.
A clear role for basic research is required in the previously described areas. First, identification of core markers of the disorder would help phenotypic refinement and might improve the impact of basic neuroscience tools such as brain imaging techniques or molecular biology to elucidate pathophysiology of bipolar disorder. Second, bipolar disorder is increasingly recognized as being a multi-system disorder that affects endocrine, vascular, immunologic, and neural functions. Elucidating the links between specific medical illnesses and bipolar disorder may provide new approaches to better understand and to better treat the disorder. In addition, this approach should stimulate the identification of biomarkers or biosignatures of the disorder that would enable us to better identify diagnostic risk and protective factors at the individual level (as opposed to population level) and to develop a new set of personalized interventions. These factors would span genetic, neurobiological, behavioral, and environmental markers along with age, gender, ethnicity, culture, and socioeconomic background, either alone or in combination, in order to build personalized approaches to treatment.