Insulin resistance in bipolar disorder: relevance to routine clinical care.

Bipolar disorder (BD) is associated with significant morbidity. Patients are symptomatic for almost one-half of their lives and experience significant disability (1). Many patients go on to have a more progressive form of BD with greater illness burden. These patients have a more chronic course, are refractory to treatment and have poorer outcomes. They require intensive and prolonged care due to lack of remission in an illness that for others is episodic. Obesity, type II diabetes (T2D), and now insulin resistance (IR) have been found to be associated with this more severe form of BD. Together, they contribute significantly to comorbid cardiovascular disease (CVD), the leading cause of death in BD (2). The key difference between IR and the other risk factors is that it does not show up on routine laboratory testing—one has to go looking for it. In a cross-sectional study of 121 patients who were not acutely unwell with bipolar I or bipolar II disorder at the time of study, we found very high rates of IR (32% of patients had IR, 22% had T2D, and only 46% were euglycemic). We made a new diagnosis of T2D in 39% of those with T2D (8% of the total sample), highlighting the high rates of undiagnosed T2D in BD, and none of the patients had been previously diagnosed with IR. Together, this represents 40% of all patients in our sample who had a previously unidentified metabolic disturbance; one that may be affecting clinical outcome. Patients with BD and either T2D or IR had three times higher odds of a chronic course compared to euglycemic patients [50% and 49% versus 27%, respectively; odds ratio (OR) = 3.07, p = 0.007], three times higher odds of rapid cycling (39% and 40% versus 18%, respectively; OR = 3.13, p = 0.012), and were more likely to be refractory to lithium treatment (37% and 37% versus 3%, respectively; OR = 8.40, p < 0.0001), even after controlling for antipsychotic exposure and body mass index (BMI) (3). Of note, patients with IR had equally poor psychiatric outcomes as those with T2D. Our findings suggest that IR may be a factor in the progression of BD to a more advanced stage of disease, even before T2D manifests. This is important, as patients are not screened for IR by either their family physician or their psychiatrist, even when their BD fails to remit. Association does not imply causation, however, and our results do not allow us to determine the direction of a possible causal relationship between IR/T2D and poor outcome in BD. For that, we need prospective studies examining the relationship between IR, glycemic control and outcome in BD. It is not surprising that we find an association between IR and poor outcomes in BD. In our earlier cross-sectional studies we found that patients with BD and T2D had higher rates of rapid cycling, a more chronic course of illness, poorer functioning and greater disability. They had greater medical comorbidity (higher rates of obesity and hypertension) (4). Patients with BD and elevated BMI also had a more chronic course, with longer duration of illness, more anxiety, poorer functioning, greater disability and higher rates of T2D and hypertension (5). We have studied response to lithium (the principal treatment for BD) in relation to BMI. We found that those