Mineralocorticoid Receptor Antagonists and Cognitive Outcomes in Cardiovascular Disease and Beyond: A Systematic Review

Background/Objectives: Cognitive impairment is a debilitating comorbidity affecting diverse patient populations, yet the cognitive effects of therapies like mineralocorticoid receptor antagonists (MRAs) remain underexplored. Preclinical evidence suggests that MRAs, particularly spironolactone, may reduce cognitive decline by modulating aldosterone-dependent pathways and targeting hippocampal receptors. However, evidence in humans is fragmented, and no systematic review has consolidated these findings. This review evaluates the cognitive effects of MRAs, synthesizes current data, and identifies research gaps. Methods: A literature search using terms related to MRAs and cognitive outcomes was performed in PubMed and Web of Science from 1979 to 2023. A total of 143 articles were identified and 85 were screened after removing duplicates. Ultimately, 44 studies were included and were classified based on study design and population focus (preclinical, healthy controls, patients with psychiatric disorders, and cardiovascular patients). Results: Spironolactone demonstrated mixed effects on cognition. In healthy participants, it improved spatial memory under stress and prevented stress-related suppression of medial temporal activity, but impaired working memory and selective attention. In patients with psychiatric conditions, spironolactone reduced cognitive empathy deficits in major depressive disorder and improved working memory in bipolar I disorder. In cardiovascular patients, spironolactone improved cognitive scores and hippocampal memory but had no effect on non-hippocampal memory. Conclusions: Spironolactone exhibits potential cognitive benefits across diverse populations. However, its effects on cognition are mixed, highlighting the need for further research to understand its mechanisms and therapeutic potential, particularly in patients with heart failure and other related conditions.