Key result
Genetically proxied ACE inhibitors were associated with an increased risk of schizophrenia in Europeans (OR 2.10) and East Asians (OR 2.51), while beta blockers and calcium channel blockers showed no protective effects.
Why the study?
Existing evidence regarding the repurposing of antihypertensives for mental disorder treatment is conflicting and cannot establish causation.
Do genetically proxied antihypertensive drugs (ACEIs, BBs, CCBs) affect the risk of mental disorders (BD, MDD, SCZ) in European and East Asian populations?
Observational (n=1,296,997)
Yes
Do genetically proxied antihypertensive drugs (ACEIs, BBs, CCBs) affect the risk of mental disorders (BD, MDD, SCZ) in European and East Asian populations?
Odds Ratio: 2.1 (95% CI 1.54–2.87)
p-value: p=<0.0033
Genetically proxied ACE inhibitors are associated with an increased risk of schizophrenia, suggesting potential harm rather than protection for mental disorders.
MR findings on antihypertensives and psychiatric risk remain hypothesis-generating; leaves open need for confirmatory trials.
BACKGROUND: Mental disorders are among the top causes of disease burden worldwide. Existing evidence regarding the repurposing of antihypertensives for mental disorders treatment is conflicting and cannot establish causation. METHODS: We used Mendelian randomization to assess the effects of angiotensin-converting-enzyme inhibitors (ACEIs), beta blockers (BBs), and calcium channel blockers (CCBs) on risk of bipolar disorder (BD), major depression disorder (MDD), and schizophrenia (SCZ). We used published genetic variants which are in antihypertensive drugs target genes and correspond to systolic blood pressure (SBP) in Europeans and East Asians, and applied them to summary statistics of BD (cases = 41,917; controls = 371,549 in Europeans), MDD (cases = 170,756; controls = 329,443 in Europeans and cases = 15,771; controls = 178,777 in East Asians), and SCZ (cases = 53,386; controls = 77,258 in Europeans and cases = 22,778; controls = 35,362 in East Asians) from the Psychiatric Genomics Consortium. We used inverse variance weighting with MR-Egger, weighted median, weighted mode, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. We performed gene-specific analysis and utilized various methods to address potential pleiotropy. RESULTS: After multiple testing correction, genetically proxied ACEIs were associated with an increased risk of SCZ in Europeans (odds ratio (OR) per 5 mmHg lower in SBP 2.10, 95% CI 1.54 to 2.87) and East Asians (OR per 5 mmHg lower in SBP 2.51, 95% CI 1.38 to 4.58). Genetically proxied BBs were not associated with any mental disorders in both populations. Genetically proxied CCBs showed no benefits on mental disorders. CONCLUSIONS: Antihypertensive drugs have no protection for mental disorders but potential harm. Their long-term use among hypertensive patients with, or with high susceptibility to, psychiatric illness needs careful evaluation.
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Fan et al. (2024) conducted an observational in Mental disorders (bipolar disorder, major depression disorder, schizophrenia) (n=1,296,997). Genetically proxied ACE inhibitors vs. Genetically higher systolic blood pressure was evaluated on Risk of schizophrenia per 5 mmHg lower in systolic blood pressure (OR 2.10, 95% CI 1.54 to 2.87, p=<0.0033). Genetically proxied ACE inhibitors were associated with an increased risk of schizophrenia in Europeans (OR 2.10) and East Asians (OR 2.51), while beta blockers and calcium channel blockers showed no protective effects.
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