Abstract
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.
Highlights
Bipolar disorder is a mood disorder affecting up to 5% of the population, leading to significant morbidity and premature mortality
Expanding on our earlier hypothesis that insulin resistance (IR) plays a role in the development of neuroprogression in Bipolar disorder (BD) [3], we propose that both IR and BBBD are biomarkers for neuroprogression and advancement of the illness process
We have highlighted the evidence for a key role for IR and shared inflammatory pathways leading to BBBD and neuroprogression of BD
Summary
Bipolar disorder is a mood disorder affecting up to 5% of the population, leading to significant morbidity and premature mortality. A relationship between IR in the periphery and the brain in Alzheimer’s disease suggests that peripheral IR might precede accumulation of amyloid ß protein in Alzheimer’s [97] Applying this concept to the current body of evidence in IR and BD, we postulate that BBBD is likely to be a key mechanism contributing to BD neuroprogression, as mediated by IR and shared inflammatory pathways (Figure 1B). Neuroinflammatory signaling cascades may amplify the circadian dysregulation in BD patients, by favoring the production of kynurenine (and quinolinic acid) over serotonin (and melatonin) [102,103,104] Together, these pathways demonstrate the tight interplay between HPA activity, systemic inflammation, BBBD, neuroinflammation and BD neuroprogression, with the BBB being the interface between systemic and CNS processes/manifestations. We suggest that utilizing these two biomarkers (IR, and BBBD once clinically available) will be important in identifying bipolar patients with neuroprogression and for following treatment response
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