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Background: <p>The (NRG1)-<i>ERBB4</i> 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.</p> Methods: <p>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 (<a href="http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE">http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE</a>).</p> Results: <p>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.</p> Conclusions: <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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

摘要

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.