Communications medicine · 2026
Antagonizing NRG1-ERBB4 signaling pathway with spironolactone for the treatment of schizophrenia: results of a randomized controlled drug repositioning clinical trial.
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Hasan Alkomiet, Leucht Stefan, Roeh Astrid, Langguth Berthold, Hansbauer Maximilian, Oviedo-Salcedo Tatiana, Greiner Sophie K, Papazova Irina, Löhrs Lisa, Maurus Isabel, Strube Wolfgang, Rossner Moritz J, Wehr Michael C, Bauer Ingrid, Heres Stephan, Kreuzer Peter M, Zimmermann Stephanie, Schneider-Axmann Thomas, Görlitz Thomas, Baumgartner Anja, Karch Susanne, Egert-Schwender Silvia, Blankenstein Christiane, Rothe Philipp, Wagner Elias, Aminifarsani Zahra, Downie Bryan, Leucht Claudia, Falkai Peter
Аннотация
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.
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.