The relationship between renin-angiotensin system-modulating medication and depression: a systematic review.

INTRODUCTION: The renin-angiotensin system (RAS) is implicated in stress, inflammation, and reward-related neurobiology, and RAS inhibition shows antidepressant-like effects in preclinical models. Whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are associated with depression outcomes in adults remains uncertain. METHODS: We searched MEDLINE, Embase, PsycINFO, APA PsycArticles, and AMED from inception to November 2024 for observational studies examining ACEI or ARB exposure and depression outcomes in adults. Risk of bias was assessed with the Quality in Prognosis Studies (QUIPS) tool. Due to methodological heterogeneity, no meta-analysis was performed, and findings were synthesised using structured direction of effect methods, with sensitivity synthesis restricted to studies at low risk of confounding. RESULTS: Fifteen studies involving more than 7 million participants were included. Eight studies reported protective associations between ACEI or ARB exposure and depression outcomes, six found no clear association, and one linked data cohort reported a modest increase in major depressive disorder with angiotensin antagonist monotherapy compared with patients not receiving antihypertensive treatment. Protective associations were more common in large registry cohorts using clinician-coded outcomes, whereas studies using symptom scales or prescription-based proxies were more often null. Among studies with stronger confounding control, findings were mixed. CONCLUSION: Observational evidence suggests a modest protective association between ACEI or ARB exposure and depression outcomes. However, heterogeneity in exposure and outcome definitions, together with residual confounding, limits causal inference. Prospective studies using bias-resistant designs and improved characterisation of incident depression, and better characterisation of drug-specific exposure are needed.