{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:28:56Z","timestamp":1790742536115,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T00:00:00Z","timestamp":1709596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brain and Behavior Research Foundation","award":["#24487"],"award-info":[{"award-number":["#24487"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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 \u2265 0.6 mEq\/L) for 16 weeks were divided into two groups, responders (\u226550% 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.<\/jats:p>","DOI":"10.3390\/jcm13051491","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T05:31:19Z","timestamp":1709616679000},"page":"1491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Possible Role of Correlation Coefficients and Network Analysis of Multiple Intracellular Proteins in Blood Cells of Patients with Bipolar Disorder in Studying the Mechanism of Lithium Responsiveness: A Proof-Concept Study"],"prefix":"10.3390","volume":"13","author":[{"given":"Keming","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University Hospitals Cleveland Medical Center, 10524 Euclid Avenue, 12th Floor, Cleveland, OH 44106, USA"},{"name":"Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5280-5738","authenticated-orcid":false,"given":"Marzieh","family":"Ayati","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Texas Rio Grande Valley, Edinburg, TX 78539, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2933-8908","authenticated-orcid":false,"given":"Nicholas M.","family":"Kaye","sequence":"additional","affiliation":[{"name":"CellPrint Biotechnology LLC, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Koyuturk","sequence":"additional","affiliation":[{"name":"Department of Computer and Data Sciences, Center for Proteomics and Bioinformatics, Case Wester Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University Hospitals Cleveland Medical Center, 10524 Euclid Avenue, 12th Floor, Cleveland, OH 44106, USA"},{"name":"Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Christian","sequence":"additional","affiliation":[{"name":"CellPrint Biotechnology LLC, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1159-5607","authenticated-orcid":false,"given":"Hillard M.","family":"Lazarus","sequence":"additional","affiliation":[{"name":"CellPrint Biotechnology LLC, Cleveland, OH 44106, USA"},{"name":"Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA"},{"name":"Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7069-9254","authenticated-orcid":false,"given":"David","family":"Kaplan","sequence":"additional","affiliation":[{"name":"CellPrint Biotechnology LLC, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/bdi.12609","article-title":"Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder","volume":"20","author":"Yatham","year":"2018","journal-title":"Bipolar Disord."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"223","DOI":"10.4088\/JCP.08m04152","article-title":"Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: A multicenter, double-blind, placebo-controlled trial","volume":"70","author":"Mulder","year":"2009","journal-title":"J. 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