Studying cellular functions in bipolar disorder: Are there specific predictors of lithium response?

Background: Lithium is the first-line mood stabilizer for the treatment of bipolar disorder (BD). In order to interrogate cellular phenotypes related to disease and lithium treatment response, this study used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs) from BD patients who are well characterized for clinical lithium response. Methods: BD patients diagnosed according to the DSM-IV criteria; were recruited from the outpatient services of the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Clinical lithium response was assessed using the Alda scale and NIMH Retrospective Life chart method. The controls were ethnically matched healthy subjects with no family history of neuropsychiatric illness. NPCs from two BD patients from the same family who clearly differed in their clinical response to lithium were chosen, and compared with healthy population controls. Whole transcriptome sequencing (RNA-Seq) and analysis were performed, with and without in vitro lithium (1mM for 7 days). In addition, mitochondrial membrane potential (MMP), cell viability and cell proliferation parameters were examined. Experiments were also performed in 25 LCLs from BD patients (16 lithium responders and 9 lithium non-responders), and 12 healthy control LCLs, to evaluate them in a system amenable to clinical translation. Results: RNA-Sequencing and analysis did not reveal differences in NPCs on in vitro lithium treatment. MMP was lower in BD, both in NPCs and LCLs; reversal with in vitro lithium happened only in LCLs and was unrelated to lithium response. Cell proliferation was higher in BD compared to controls, and there was no change on lithium addition. Cell viability assays indicated greater cell death in BD; which could only be rescued in LCLs of clinical lithium responders. The latter finding was associated with enhanced BCL2 and GSK3B expression with in vitro lithium. Discussion: Overall, our study findings indicate that there are cellular phenotypes related to the disease (mitochondrial potential, cell proliferation) in NPCs and LCLs. We also observed clinical lithium response related phenotypes (cell viability, BCL2/ GSK3B expression) in LCLs. The next step would be to evaluate a larger set of PBMCs from clinical lithium response groups of BD to derive cellular phenotypes related to direct clinical application.