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

内容摘要

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. 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 ). 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. 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. Individuals diagnosed with schizophrenia frequently experience cognitive deficits, including challenges related to everyday memory and attention. We evaluated whether spironolactone, a drug available since the 1960s and today used to treat heart failure is effective in treating cognitive impairment in people with schizophrenia. For that, we conducted a placebo-controlled clinical trial where participants received either 100 mg or 200 mg spironolactone or placebo for three weeks. Before and after this intervention, we tested cognition. We were able to show that our intervention with spironolactone has the potential to improve cognition in people with schizophrenia. Further trials are needed before this intervention can be offered as part of the clinical routine.