¹Yale School of Medicine, Psychiatry, New Haven, United States, ²University College London, Biomedical Engineering, London, United Kingdom, ³Yale School of Medicine, Genetics, New Haven, United States, ⁴Yale School of Medicine, Medicine, New Haven, United States

Background: Bipolar disorder (BD) is highly prevalent, with global rates estimated to be up to about four percent of the population. It causes tremendous suffering owing to its acute mood episodes and its high suicide rate, among the highest rate of all disorders. Yet, its causes are not clear, and methods for its early detection and effective treatment are limited. The study of new candidate early detection and treatment target mechanisms and use of emerging technologies research advances can be important to advance the field. Increasing evidence supports the central importance of energy-related symptoms in the suffering associated with BD and its high suicide risk. Energy-related symptoms are also often early indicators of impending acute episodes and may be linked to vulnerability to the switch to acute mood episodes in BD. Mitochondrial dysfunction has been implicated, but the specific mitochondrial mechanisms involved in BD are not clear.

Aims & Objectives: The aims of the line of research to be presented are to identify energy-related brain differences in BD and the contributing mitochondrial mechanisms.

Method: In this presentation, data will be presented from approaches that include the study of the relationship between energy-related symptoms and brain system abnormalities identified in magnetic resonance imaging data in a cohort (>300 individuals with BD). In a modest subset of these individuals, data on mitochondrial dysfunction in the brain will be presented from using the recently developed non-invasive optical neuroimaging technique, broadband near-infrared spectroscopy (bNIRS), integrated with data from brain organoids generated from blood samples of the scanned individuals. Data will also be presented from a clinical trial assessing a psychotherapeutic approach that empowers individuals to improve their brain health, as well as reduce their symptoms and suicide risk by regularizing sleep and other daily behavior rhythms.

Results: Results presented will include significant neuroimaging findings in individuals with BD in brain regions that subserve emotion regulation, psychomotor activity, and circadian rhythms. Abnormal mitochondrial complex activity shown by bNIRS, in addition to findings of elevated blood lactate, implicate greater use of aerobic glycolysis in individuals with BD. The mitochondrial mechanisms are supported by organoid findings that demonstrate involvement of specific mechanisms, including an ATP synthase leak mechanism, that importantly show reversal with lithium and novel potential therapeutic agents. Data also support the potential for individuals to have beneficial effects on their brain health by modifying their behavior.

Discussion & Conclusions: The data support important links between the brain system differences of BD, specific mitochondrial mechanisms in BD’s brain pathophysiology and as novel treatment targets, and the promise of bNIRS as a scalable technology to detect brain mitochondrial dysfunction, as well as the beneficial effects of behavioral changes that could inform global health efforts.