Antihypertensive Drug Targets and the Potential Effects on Psychiatric Disorders

Antihypertensive Drug Targets and the Potential Effects on Psychiatric Disorders
David Bunch, PharmD, Geritom Medical, Inc.

Background: There have been observational studies that suggest an association between antihypertensive medications and psychiatric disorders. There have also been reports of hallucinations and reversible psychosis after angiotensin converting enzyme (ACE) inhibitor treatment. Given that many patients with psychiatric disorders have higher risk for cardiovascular morbidity and mortality and require antihypertensive medications, there is value in exploring this association.

Objective: The purpose of this study was to identify an association between antihypertensive treatment and psychiatric disorders.

Study Design: This study utilized a 2-sample mendelian randomization (MR) analysis using publicly available expression quantitative trait loci data and summary data from the most recent genome-wide association study (GWAS) of psychiatric disorders. The study authors defined an MR analysis as a “statistical genetics approach that uses genetic variants that are robustly associated with an exposure as potentially unconfounded instruments to infer whether observed association between the exposure and outcome is causal or not.” The authors identified genes whose protein products were targeted by an active ingredient in different classes of antihypertensive medications. Genes that did not reflect a decrease in systolic blood pressure were excluded. Using GWAS summary data for schizophrenia, bipolar disorder, and major depressive disorder, summary-based MR analysis was run to determine the association of a one standard-deviation (SD) change in drug target blood gene expression level with outcomes of disease. A default heterogeneity independent instrument (HEIDI) P < 0.01 was used to exclude pleiotropic single nucleotide variants. 

Results: In total there were 110 genes that were identified whose encoded protein activity had been shown to be modified by one or more antihypertensive medications. Only 61 of these genes were able to be queried due to one gene not being expressed in blood and lack of data for the other 48 genes. A one SD decrease in ACE expression in blood was associated with a decrease in systolic blood pressure of 4.0 [95% CI 2.7-5.3] mmHg and a higher risk of schizophrenia 1.75 [ 95% CI 1.28-2.38; P = 3.95 x 10-4]. Similar association was seen in the prefrontal cortex 1.33 [95%CI 1.13-1.56, cerebral spinal fluid 1.12 [95% CI 1.05-1.19], and plasma 1.04 [95% CI 1.01-1.07]. Other gene targets that were associated with schizophrenia and bipolar disorder were ruled out due to the significant HEIDI P values suggesting these associations were likely due to linkage.

Conclusions: Based on the findings in this study, there may be an association between lower ACE messenger RNA and protein levels and an increased risk of schizophrenia. If lower ACE levels have an effect on schizophrenia risk, then it could be hypothesised that inhibiting ACE may also have a similar effect, thus worsening schizophrenia symptoms. In light of these statistical findings, further research into the role of ACE in schizophrenia may be warranted.

Key Point: This study brings to light the potential for lower ACE levels, and potentially ACE inhibitors, contributing to worsening symptoms in schizophrenia.



  1. Chauquet S, Zhu Z, O’Donovan MC, Walters JT, Wray NR, Shah S. Association of Antihypertensive Drug Target Genes With Psychiatric Disorders. JAMA Psychiatry. 2021. doi:10.1001/jamapsychiatry.2021.0005