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

Area of Science:

• Cardiovascular Pharmacology
• Neuroscience
• Psychiatry

Background:

• The renin-angiotensin system (RAS) plays a role in stress and reward pathways.
• RAS inhibition has demonstrated antidepressant-like effects in preclinical studies.
• The association between ACEIs and ARBs with depression in adults is not well-established.

Purpose of the Study:

• To investigate the association between angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) and depression outcomes in adults.
• To synthesize observational evidence on the link between RAS inhibitors and depression.

Main Methods:

• A systematic literature search was conducted across multiple databases (MEDLINE, Embase, PsycINFO, etc.) up to November 2024.
• Fifteen observational studies with over 7 million participants were included.
• Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool; no meta-analysis was performed due to heterogeneity.

Main Results:

• Eight studies suggested a protective association between ACEI/ARB use and depression.
• Six studies found no clear association, and one study indicated a modest increase in depression with angiotensin antagonist monotherapy.
• Findings were mixed when confounding was better controlled, with protective associations more frequent in large registry cohorts using clinician-coded outcomes.

Conclusions:

• Observational data suggest a potential modest protective effect of ACEIs and ARBs on depression outcomes.
• Heterogeneity in study designs, outcome definitions, and residual confounding limit definitive causal inference.
• Further prospective studies with robust designs and detailed characterization of drug exposure and depression are warranted.