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

Avery D Franzen; John S Svendsen; Cassidy J Kline; Susan Q Shen

doi:10.1111/cts.70624

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

Journal article

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

Avery D Franzen, John S Svendsen, Cassidy J Kline and Susan Q Shen

Clinical and translational science, Vol.19(6), e70624

06/2026

DOI: 10.1111/cts.70624

PMCID: PMC13242789

PMID: 42251640

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Abstract

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.

Animals

Antipsychotic Agents - adverse effects

Antipsychotic Agents - pharmacology

Antipsychotic Agents - therapeutic use

Cycloserine - administration & dosage

Cycloserine - adverse effects

Cycloserine - pharmacology

Cycloserine - therapeutic use

Drug Repositioning - methods

Humans

Lurasidone Hydrochloride - adverse effects

Lurasidone Hydrochloride - pharmacology

Lurasidone Hydrochloride - therapeutic use

Polypharmacy

Receptors, N-Methyl-D-Aspartate - agonists

Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors

Receptors, N-Methyl-D-Aspartate - metabolism

Details

Title: Subtitle: Mechanism-Based Polypharmacy as a Repurposing Strategy: The Case of D-Cycloserine and Lurasidone
Creators: Avery D Franzen - University of Iowa
John S Svendsen - University of Iowa
Cassidy J Kline - University of Iowa
Susan Q Shen - University of Iowa
Resource Type: Journal article
Publication Details: Clinical and translational science, Vol.19(6), e70624
DOI: 10.1111/cts.70624
PMID: 42251640
PMCID: PMC13242789
NLM abbreviation: Clin Transl Sci
ISSN: 1752-8054
eISSN: 1752-8062
Publisher: Wiley
Grant note: NIEHS/NIH: P30 ES005605 NIDA/NIH: DP1DA063504
C.J.K. is supported by NIEHS/NIH P30 ES005605. SQS is supported by NIDA/NIH DP1DA063504.
Language: English
Date published: 06/2026
Academic Unit: Psychiatry
Record Identifier: 9985172993802771

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