Mechanism-Based Polypharmacy as a Repurposing Strategy: The Case of D-Cycloserine and Lurasidone.

Modern psychiatric treatment often necessitates polypharmacy, yet combination regimens carry significant risks of metabolic burden and drug-drug interactions. There is growing interest in and clinical acceptance of rational, mechanism-based drug combinations that are designed around desirable pharmacological properties rather than trial and error. The repurposing of D-cycloserine (DCS) is an example of this shift. An analog of d-alanine, 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-methyl-D-aspartate (NMDA) receptor modulation. At low doses (50-100 mg), it functions as a partial agonist that can enhance synaptic plasticity, whereas at higher doses (> 500 mg), it acts as a functional antagonist. NRX-101, a fixed-dose combination of high-dose DCS and the second-generation 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-resistant urinary tract infections. NRX-101 thus represents a case of rational polypharmacy in which complementary pharmacologic properties expand therapeutic possibilities for seemingly unrelated indications. More broadly, mechanism-based rational polypharmacy may continue to revive previously abandoned compounds for difficult-to-treat psychiatric and medical conditions.