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.