Insulin Resistance and Blood-Brain Barrier Dysfunction Underlie Neuroprogression in Bipolar Disorder.

Bipolar disorder (BD) often progresses to a more chronic and treatment resistant (neuroprogressive) course. Identifying which patients are at risk could allow for early intervention and prevention. Bipolar disorder is highly comorbid with metabolic disorders including type II diabetes mellitus (T2DM), hypertension, obesity, and dyslipidemia. Our studies have shown that insulin resistance (IR) is present in over 50% of patients with BD and that IR might underlie the progression of BD. While no confirmed predictors exist for identifying which patients with BD are likely to develop a more chronic course, emerging evidence including our own studies suggest that IR and related inflammatory pathways lead to impairments in blood-brain barrier (BBB) functioning. For the first time in living psychiatric patients, we have shown that the severity of BBB leakage is proportional to BD severity and is associated with IR. In this hypothesis paper we (i) highlight the evidence for a key role of IR in BD, (ii) show how IR in BD relates to shared inflammatory pathways, and (iii) hypothesize that these modulations result in BBB leakage and worse outcomes in BD. We further hypothesize that (iv) reversing IR through lifestyle changes or the actions of insulin sensitizing medications such as metformin, or optimizing BBB function using vascular protective drugs, such as losartan, could provide novel strategies for the prevention or treatment of neuroprogressive BD.