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. 2022 Feb 25;52(1):8-35.

Protein Biomarkers in Monocytes and CD4+ Lymphocytes for Predicting Lithium Treatment Response of Bipolar Disorder: a Feasibility Study with Tyramine-Based Signal-Amplified Flow Cytometry

Keming Gao  1 , Marzieh Ayati  1 , Mehmet Koyuturk  1 , Joseph R Calabrese  1 , Stephen J Ganocy  1 , Nicholas M Kaye  1 , Hillard M Lazarus  1 , Eric Christian  1 , David Kaplan  1
Affiliations

Protein Biomarkers in Monocytes and CD4+ Lymphocytes for Predicting Lithium Treatment Response of Bipolar Disorder: a Feasibility Study with Tyramine-Based Signal-Amplified Flow Cytometry

Keming Gao et al. Psychopharmacol Bull. .

Abstract

Purpose: To determine if enhanced flow cytometry (CellPrint™) can identify intracellular proteins of lithium responsiveness in monocytes and CD4+ lymphocytes from patients with bipolar disorder.

Methods: Eligible bipolar I or II patients were openly treated with lithium for 16-weeks. Baseline levels of Bcl2, BDNF, calmodulin, Fyn, phospho-Fyn/phospho-Yes, GSK3β, phospho-GSK3αβ, HMGB1, iNOS, IRS2, mTor, NLPR3, PGM1, PKA C-α, PPAR-γ, phospho-RelA, and TPH1 in monocytes and CD4+ lymphocytes of lithium responders and non-responders were measured with CellPrint™. Their utility of discriminating responders from non-responders was explored. Protein-protein network and pathway enrichment analyses were conducted.

Results: Of the 24 intent-to-treat patients, 12 patients completed the 16-week study. Eleven of 13 responders and 8 of 11 non-responders were available for this analysis. The levels of the majority of analytes in lithium responders were lower than non-responders in both cell types, but only the level of GSK3β in monocytes was significantly different (p = 0.034). The combination of GSK3β and phospho-GSK3αβ levels in monocytes correctly classified 11/11 responders and 5/8 non-responders. Combination of GSK3β, phospho-RelA, TPH1 and PGM1 correctly classified 10/11 responders and 6/7 non-responders, both with a likelihood of ≥ 85%. Prolactin, leptin, BDNF, neurotrophin, and epidermal growth factor/epidermal growth factor receptor signaling pathways are involved in the lithium treatment response. GSK3β and RelA genes are involved in 4 of 5 these pathways.

Conclusion: CellPrint™ flow cytometry was able to detect differences in multiple proteins in monocytes and CD4+ lymphocytes between lithium responders and non-responders. A large study is warranted to confirm or refute these findings.

Keywords: biomarkers; bipolar disorder; blood mononuclear cell; lithium.

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Figures

Figure 1
Figure 1
Fold change (FC) of 17 Analytes at Baseline between Lithium Responders and Non-Responders in CD4+ Lymphocytes (blue bars) and Monocytes (brown bars). FC = log2 (median fluorescent intensity of non-responders/median fluorescent intensity of responders)
Figure 2
Figure 2
Classification of Lithium Responders and Non-responders According to Cut-off Levels of GSK3β and Phospho-GSK3αβ in Monocytes. Y-axis is the Median Fluorescent Intensities of Phosphorylated GSK3αβ, and X-axis is the Median Fluorescent Intensities of GSK3β
Figure 3
Figure 3
Results of Protein-protein Interaction Network of 14 Proteins in Monocytes
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