Background: The mechanism of
lithium treatment responsiveness in
bipolar disorder (BD) remains unclear. The aim of this study was to explore the utility of correlation coefficients and
protein-to-
protein interaction (PPI) network analyses of intracellular
proteins in monocytes and CD4+ lymphocytes of patients with BD in studying the potential mechanism of
lithium treatment responsiveness. Methods: Patients with bipolar I or II disorder who were diagnosed with the MINI for DSM-5 and at any phase of the illness with at least mild symptom severity and received
lithium (serum level ≥ 0.6 mEq/L) for 16 weeks were divided into two groups, responders (≥50% improvement in Montgomery-Asberg Depression Rating Scale and/or Young
Mania Rating Scale scores from baseline) and non-responders. Twenty-eight intracellular
proteins/analytes in CD4+ lymphocytes and monocytes were analyzed with a
tyramine-based signal-amplified flow cytometry procedure. Correlation coefficients between analytes at baseline were estimated in both responders and non-responders and before and after
lithium treatment in responders. PPI network, subnetwork, and pathway analyses were generated based on fold change/difference in studied
proteins/analytes between responders and non-responders. Results: Of the 28 analytes from 12
lithium-responders and 11
lithium-non-responders, there were more significant correlations between analytes in responders than in non-responders at baseline. Of the nine
lithium responders with pre- and post-
lithium blood samples available, the correlations between most analytes were weakened after
lithium treatment with cell-type specific patterns in CD4+ lymphocytes and monocytes. PPI network/subnetwork and pathway analyses showed that
lithium response was involved in four pathways, including
prolactin,
leptin,
neurotrophin, and
brain-derived neurotrophic factor pathways.
Glycogen synthase kinase 3 beta and nuclear factor
NF-kappa-B p65 subunit genes were found in all four pathways. Conclusions: Using correlation coefficients, PPI network/subnetwork, and pathway analysis with multiple intracellular
proteins appears to be a workable concept for studying the mechanism of
lithium responsiveness in BD. Larger sample size studies are necessary to determine its utility.