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

Cynthia Calkin, Christie McClelland, Kathleen Cairns, Lyna Kamintsky, Alon Friedman

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

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.

Original languageEnglish
Article number636174
JournalFrontiers in Psychiatry
Volume12
DOIs
Publication statusPublished - May 25 2021

Bibliographical note

Funding Information:
CC would like to thank the Brain & Behavior Research Foundation (NARSAD, grant # 18764 and grant # 25714), and the Stanley Medical Research Institute (grant # 14T-008) for awards supporting her research and AF would like to thank the Canadian Institutes for Health Research (grant # PJT 148896) for supporting his research.

Publisher Copyright:
© Copyright © 2021 Calkin, McClelland, Cairns, Kamintsky and Friedman.

ASJC Scopus Subject Areas

  • Psychiatry and Mental health

PubMed: MeSH publication types

  • Journal Article

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