Investigating the potential effect of antihypertensive medication on psychiatric disorders: a mendelian randomisation study

Background There is growing evidence from observational studies that drugs used for the prevention and treatment of CVD may cause, exacerbate, or relieve neuropsychiatric symptoms. Aim Use Mendelian randomisation (MR) analysis to investigate the potential effect of different antihypertensive drugs on schizophrenia, bipolar disorder and major depressive disorder. Methods We conduct two sample MR using expression quantitative trait loci (eQTLs) for antihypertensive drug target genes as genetic instruments, together with summary data from published genome-wide association studies, to investigate the causal effect of changes in drug target gene expression (as proxies of drug exposure) on psychiatric disorders. Results A 1 standard deviation lower expression of the ACE gene in blood was associated with 4.0 mmHg (95% CI = 2.7 – 5.3) lower systolic blood pressure, but increased risk of schizophrenia (OR (95% CI) = 1.75 (1.28 – 2.38)). A concordant direction of effect was observed with ACE expression in brain tissue. Conclusions Findings suggest an adverse effect of lower ACE expression on schizophrenia risk. This warrants further investigation to determine if lowering ACE activity for treatment of hypertension using ACE inhibitors (particularly centrally-acting drugs) may worsen symptoms in patients with schizophrenia, and whether there is any association between ACE inhibitor use and risk of (mainly late-onset) schizophrenia.