A randomized controlled trial of 90 people with schizophrenia found that spironolactone, a medication approved decades ago for heart failure, showed potential to improve working memory and cognitive function. The findings suggest a possible new treatment avenue for cognitive impairments that have long resisted pharmaceutical intervention.

Cognitive deficits are a core feature of schizophrenia, affecting memory, attention, and everyday functioning. These impairments are among the strongest predictors of social and work-related disability in people with the condition. Despite decades of research, no effective medications have been developed specifically to treat cognitive symptoms in schizophrenia, making this potential breakthrough significant.

Why Is Spironolactone Being Tested for Schizophrenia?

Researchers identified spironolactone through a systematic drug-repurposing approach. Scientists screened a library of FDA-approved medications to find compounds that could modulate the NRG1-ERBB4 signaling pathway, which plays a role in cognitive function and is altered in schizophrenia. Spironolactone emerged as a promising candidate because it can inhibit ERBB4 activity, potentially restoring balance to neural signaling.

Before testing the drug in people, researchers confirmed its effects in animal models. When NRG1 transgenic mice received spironolactone for three weeks, they showed improvements in working memory, sensory gating, and positive symptoms like hyperactivity. These preclinical results justified moving forward with a human trial.

What Did the Clinical Trial Show?

The SPIRO-TREAT trial was a multi-site, double-blind study conducted at university hospitals in Munich and Regensburg, Germany. Researchers randomly assigned 90 patients with schizophrenia to receive one of two spironolactone doses (100 milligrams or 200 milligrams daily) or placebo for three weeks. The primary outcome measured was change in working memory performance.

The results were mixed but encouraging. While the pre-specified statistical analyses did not show a significant advantage for spironolactone over placebo, working memory performance showed substantial numerical improvements, particularly in the group receiving 200 milligrams. Post-hoc sensitivity analyses, which examined the data using different statistical approaches, revealed that spironolactone did produce a significant advantage for the primary endpoint. Both doses were well tolerated, with no safety concerns reported.

How to Interpret These Findings

• Promising but preliminary: The numerical improvements in working memory and positive results in sensitivity analyses suggest spironolactone warrants further investigation, but the initial statistical plan did not confirm superiority, indicating the effect may be modest or require larger sample sizes to detect reliably.
• Safety profile is favorable: Both spironolactone doses were well tolerated in the three-week trial, suggesting the medication is unlikely to cause serious adverse effects in this population, though longer-term safety data would be needed before clinical use.
• Study duration may have been too short: The three-week intervention period was relatively brief. Researchers suggest that longer trials or higher doses might reveal stronger effects, as cognitive improvements sometimes emerge gradually with sustained treatment.
• Addresses an unmet medical need: Current antipsychotic medications effectively treat hallucinations and delusions but do not improve cognitive symptoms, making any new option potentially valuable for patients struggling with memory and attention problems.

The researchers emphasized that these findings represent a proof-of-concept rather than a ready-to-use treatment. Confirmatory multi-center randomized controlled trials with longer intervention periods and potentially higher doses are needed before spironolactone could be offered as part of routine clinical care for schizophrenia.

This work exemplifies the National Institute of Mental Health's strategy of drug repurposing based on pathophysiological understanding. With many pharmaceutical companies withdrawing from schizophrenia research, academic investigators are increasingly turning to existing medications as a way to overcome the innovation gap in psychopharmacology. Spironolactone's low cost, established safety record, and potential cognitive benefits make it an attractive candidate for further development in this context.

The next steps will involve larger, longer trials to confirm whether spironolactone truly improves cognitive function in schizophrenia and to determine the optimal dose and duration of treatment. If confirmed, this repurposed medication could offer people with schizophrenia a new tool to address one of the most disabling aspects of their condition.