Antagonizing NRG1-ERBB4 signaling pathway with spironolactone for the treatment of schizophrenia: results of a randomized controlled drug repositioning clinical trial

BACKGROUND: The (NRG1)-ERBB4 signaling pathway has been identified to be pathophysiologically meaningful for cognitive impairments in schizophrenia. The in the 1960s approved mineralocorticoid antagonist spironolactone has been shown to be effective to modulate (NRG1)-ERBB4 signaling in preclinical and animal models. Thus, a proof-of-concept drug repurposing trial in patients with schizophrenia was justified. METHODS: We conducted a multi-site proof-of-concept randomized controlled trial. 90 patients with schizophrenia were randomized to a three-week trial of two different spironolactone dosages (100 mg or 200 mg) or placebo. The primary endpoint was predefined as change in working memory performance after three weeks of treatment. A naturalistic follow-up was performed nine weeks after the end of intervention. The trial was registered at the WHO International Clinical Trials Registry platform ( http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE ). RESULTS: Despite large numerical improvements in working memory functions, particularly in the spironolactone 200 mg group, the pre-specified analyses do not demonstrate significant superiority of either intervention over placebo. However, post-hoc sensitivity analyses suggest a significant advantage of spironolactone for the primary endpoint. Safety measures show that both interventions are well tolerated. CONCLUSIONS: This finding suggests a potential positive effect of spironolactone on working memory in people with schizophrenia and the good safety outcomes may justify further trials with longer intervention periods or higher spironolactone dosages.

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Journal
Communications Medicine
Published
2026-06-16
DOI
https://doi.org/10.1038/s43856-026-01714-3
Primary Topic
Estrogen and related hormone effects
Type
article
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article

Antagonizing NRG1-ERBB4 signaling pathway with spironolactone for the treatment of schizophrenia: results of a randomized controlled drug repositioning clinical trial

Stefan Leucht, Tatiana Oviedo-Salcedo, Christiane Blankenstein, Thomas Görlitz et al.
Communications Medicine
Estrogen and related hormone effects
article

Antagonizing NRG1-ERBB4 signaling pathway with spironolactone for the treatment of schizophrenia: results of a randomized controlled drug repositioning clinical trial

Stefan Leucht, Tatiana Oviedo-Salcedo, Christiane Blankenstein, Thomas Görlitz, Isabel Maurus, Moritz J. Rossner, Maximilian Hansbauer, Astrid Roeh, Berthold Langguth, Stephan Heres, Irina Papazova, Peter Falkai, Anja Baumgartner, Elias M. Wagner, Susanne Karch, Claudia Leucht, Wolfgang Strube, Michael C. Wehr, Lisa Löhrs, Bryan Downie, Alkomiet Hasan, Thomas Schneider-Axmann, Zahra Aminifarsani, Silvia Egert-Schwender, Ingrid Bauer, Philipp Rothe, Stephanie Zimmermann, Sophie K. Greiner, Peter M. Kreuzer
article en

Abstract

BACKGROUND: The (NRG1)-ERBB4 signaling pathway has been identified to be pathophysiologically meaningful for cognitive impairments in schizophrenia. The in the 1960s approved mineralocorticoid antagonist spironolactone has been shown to be effective to modulate (NRG1)-ERBB4 signaling in preclinical and animal models. Thus, a proof-of-concept drug repurposing trial in patients with schizophrenia was justified. METHODS: We conducted a multi-site proof-of-concept randomized controlled trial. 90 patients with schizophrenia were randomized to a three-week trial of two different spironolactone dosages (100 mg or 200 mg) or placebo. The primary endpoint was predefined as change in working memory performance after three weeks of treatment. A naturalistic follow-up was performed nine weeks after the end of intervention. The trial was registered at the WHO International Clinical Trials Registry platform ( http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE ). RESULTS: Despite large numerical improvements in working memory functions, particularly in the spironolactone 200 mg group, the pre-specified analyses do not demonstrate significant superiority of either intervention over placebo. However, post-hoc sensitivity analyses suggest a significant advantage of spironolactone for the primary endpoint. Safety measures show that both interventions are well tolerated. CONCLUSIONS: This finding suggests a potential positive effect of spironolactone on working memory in people with schizophrenia and the good safety outcomes may justify further trials with longer intervention periods or higher spironolactone dosages.

Communications MedicineVol. 6(1)
University of Augsburg (DE), Universität Ulm (DE), University Hospital Augsburg (DE), University Hospital Regensburg (DE), German Center for Infection Research (DE), Munich Security Conference (DE), Columbus Center (US), German Centre for Cardiovascular Research (DE), Max Planck Institute of Psychiatry (DE), Max Planck Institute of Biochemistry (DE), Bezirkskrankenhaus Augsburg (DE), University of Regensburg (DE), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE)
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Estrogen and related hormone effects
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