ArticleSchizophrenia (Heidelberg, Germany)2022
Spironolactone alleviates schizophrenia-related reversal learning in Tcf4 transgenic mice subjected to social defeat.
Article in Schizophrenia (Heidelberg, Germany), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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The trial behind it
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Who cites it
7 citing papers in PubMed, 10 citations in OpenAlex.
- Efficacy of spironolactone as adjunctive therapy to sodium valproate in bipolar-I disorder: A double-blind, randomized, placebo-controlled clinical trial.Brain and behavior · 2023Trial
- Antagonizing NRG1-ERBB4 signaling pathway with spironolactone for the treatment of schizophrenia: results of a randomized controlled drug repositioning clinical trial.Communications medicine · 2026Article
- Mice lacking two alleles of the schizophrenia risk geneFrontiers in cellular neuroscience · 2026Article
- A second act for spironolactone: cognitive benefits in renal dysfunction - a critical review.Metabolic brain disease · 2025Review
- Mineralocorticoid Receptor Antagonists and Cognitive Outcomes in Cardiovascular Disease and Beyond: A Systematic Review.Journal of personalized medicine · 2025Review
- Profiling of ERBB receptors and downstream pathways reveals selectivity and hidden properties of ERBB4 antagonists.iScience · 2024Article
- IntelliCage: the development and perspectives of a mouse- and user-friendly automated behavioral test system.Frontiers in behavioral neuroscience · 2023Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Cognitive deficits are a hallmark of schizophrenia, for which no convincing pharmacological treatment option is currently available. Here, we tested spironolactone as a repurposed compound in Tcf4 transgenic mice subjected to psychosocial stress. In this '2-hit' gene by environment mouse (GxE) model, the animals showed schizophrenia-related cognitive deficits. We had previously shown that spironolactone ameliorates working memory deficits and hyperactivity in a mouse model of cortical excitatory/inhibitory (E/I) dysbalance caused by an overactive NRG1-ERBB4 signaling pathway. In an add-on clinical study design, we used spironolactone as adjuvant medication to the standard antipsychotic drug aripiprazole. We characterized the compound effects using our previously established Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling (PsyCoP). PsyCoP is a widely applicable analysis pipeline based on the Research Domain Criteria (RDoC) framework aiming at facilitating translation into the clinic. In addition, we use dimensional reduction to analyze and visualize overall treatment effect profiles. We found that spironolactone and aripiprazole improve deficits of several cognitive domains in Tcf4tg x SD mice but partially interfere with each other's effect in the combination therapy. A similar interaction was detected for the modulation of novelty-induced activity. In addition to its strong activity-dampening effects, we found an increase in negative valence measures as a side effect of aripiprazole treatment in mice. We suggest that repurposed drug candidates should first be tested in an adequate preclinical setting before initiating clinical trials. In addition, a more specific and effective NRG1-ERBB4 pathway inhibitor or more potent E/I balancing drug might enhance the ameliorating effect on cognition even further.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.