Molecular signatures of hyperexcitability and lithium responsiveness in bipolar disorder patient neurons provides alternative therapeutic strategies

Bipolar Disorder (BD) is a chronic psychiatric illness affecting ~3% of the global population. It is one of the top 10 causes of disability and mortality worldwide, largely due to high suicide, cardiovascular, and metabolic comorbidity. Typically, BD has life-long presentation characterized by alternations of extreme mania and depression, associated with psychosis and self-harm. Given the complex heritability and symptoms of BD, long term clinical management of some patients remains unsatisfactory. Thus, there is a major unmet need for new clinical treatment strategies and drug options to help these patients. Lithium (Li) remains the gold standard mood stabilizer and first-line treatment for manic/depressive episodes, reducing suicide and overall mortality rates. Two major questions stand out i) how Li is effective, and ii) why for only a subset of patients? To address this, we studied the biology and lithium effects in iPSC-derived neurons from people with a known clinical and genetic profile, comparing healthy individuals, BD Li-responders, and BD Li-non responders. We combined cell imaging, electrophysiology, biochemistry, , phosphoproteomic and whole transcriptome sequencing approaches to provide mechanistic insights and guide the search for BD biomarkers and Li responsiveness. Overall design: To identify cellular processes underlying hyperexcitability in BD neurons, and effects of Li that are general or specific to BD LR neurons. we performed whole transcriptome sequencing from all patient lines. iPSC-derived neurons of Ctl vs. BD, and BD LR vs. BD LNR -/+ Li were compared. Data from 4-5 lines per group/condition.