1873-24029682024Oct15Biol PsychiatrySchizophrenia Interactome-Derived Repurposable Drugs and Randomized Controlled Trials of Two Candidates.651658651-65810.1016/j.biopsych.2024.06.022S0006-3223(24)01426-4There is a substantial unmet need for effective and patient-acceptable drugs to treat severe mental illnesses such as schizophrenia (SZ). Computational analysis of genomic, transcriptomic, and pharmacologic data generated in the past 2 decades enables repurposing of drugs or compounds with acceptable safety profiles, namely those that are U.S. Food and Drug Administration approved or have reached late stages in clinical trials. We developed a rational approach to achieve this computationally for SZ by studying drugs that target the proteins in its protein interaction network (interactome). This involved contrasting the transcriptomic modulations observed in the disorder and the drug; our analyses resulted in 12 candidate drugs, 9 of which had additional supportive evidence whereby their target networks were enriched for pathways relevant to SZ etiology or for genes that had an association with diseases pathogenically similar to SZ. To translate these computational results to the clinic, these shortlisted drugs must be tested empirically through randomized controlled trials, in which their previous safety approvals obviate the need for time-consuming phase 1 and 2 studies. We selected 2 among the shortlisted candidates based on likely adherence and side-effect profiles. We are testing them through adjunctive randomized controlled trials for patients with SZ or schizoaffective disorder who experienced incomplete resolution of psychotic features with conventional treatment. The integrated computational analysis for identifying and ranking drugs for clinical trials can be iterated as additional data are obtained. Our approach could be expanded to enable disease subtype-specific drug discovery in the future and should also be exploited for other psychiatric disorders.Copyright © 2024. Published by Elsevier Inc.GanapathirajuMadhavi KMKDepartment of Biomedical Informatics and Intelligent Systems Program, University of Pittsburgh, Pittsburgh, Pennsylvania; Carnegie Mellon University in Qatar, Doha, Qatar. Electronic address: madhavi@pitt.edu.BhatiaTriptishTDepartment of Psychiatry, Centre of Excellence in Mental Health, ABVIMS - Dr. Ram Manohar Lohia Hospital, New Delhi, India.DeshpandeSmitaSDepartment of Psychiatry, St John's Medical College Hospital, Koramangala, Bengaluru, Karnataka, India.WeseskyMaribethMDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.WoodJoelJDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.NimgaonkarVishwajit LVLDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; Veterans Administration Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. Electronic address: VishwajitNL@upmc.edu.engJournal ArticleReview20240629