{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:20:23Z","timestamp":1789129223050,"version":"build-2803163510"},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:00:00Z","timestamp":1780790400000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Modern psychiatric treatment often necessitates polypharmacy, yet combination regimens carry significant risks of metabolic burden and drug\u2013drug interactions. There is growing interest in and clinical acceptance of rational, mechanism\u2010based drug combinations that are designed around desirable pharmacological properties rather than trial and error. The repurposing of D\u2010cycloserine (DCS) is an example of this shift. An analog of d\u2010alanine, DCS was originally developed as an antibiotic but failed to gain widespread use due to its propensity to induce psychotic symptoms such as hallucinations. More recently, DCS has emerged as a pharmaceutical with multifunctional actions including bimodal N\u2010methyl\u2010D\u2010aspartate (NMDA) receptor modulation. At low doses (50\u2013100\u2009mg), it functions as a partial agonist that can enhance synaptic plasticity, whereas at higher doses (&gt;\u2009500\u2009mg), it acts as a functional antagonist. NRX\u2010101, a fixed\u2010dose combination of high\u2010dose DCS and the second\u2010generation antipsychotic lurasidone, is currently being evaluated in clinical trials for bipolar depression with acute suicidality. In this combination, lurasidone offsets the psychotic effects of DCS, supporting its potential reconsideration for multidrug\u2010resistant urinary tract infections. NRX\u2010101 thus represents a case of rational polypharmacy in which complementary pharmacologic properties expand therapeutic possibilities for seemingly unrelated indications. More broadly, mechanism\u2010based rational polypharmacy may continue to revive previously abandoned compounds for difficult\u2010to\u2010treat psychiatric and medical conditions.<\/jats:p>","DOI":"10.1111\/cts.70624","type":"journal-article","created":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T16:03:37Z","timestamp":1780848217000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanism\u2010Based Polypharmacy as a Repurposing Strategy: The Case of D\u2010Cycloserine and Lurasidone"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6287-4999","authenticated-orcid":false,"given":"Avery D.","family":"Franzen","sequence":"first","affiliation":[{"name":"Department of Psychiatry University of Iowa Carver College of Medicine  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John 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