Angiotensin-converting enzyme (ACE) inhibitors, particularly those that are centrally acting, may be associated with an increased risk of schizophrenia and may affect psychiatric symptoms in patients with the disorder, genetic analyses suggest. In a Mendelian randomization analysis, lower ACE messenger RNA and protein levels were associated with an increased risk of schizophrenia, researchers found. "I want to emphasize that the evidence from genetic analyses alone is insufficient to justify any changes in prescription guidelines," Dr. Sonia Shah of the University of Queensland, Australia, told Reuters Health by email. "If ACE inhibitors are effective at controlling blood pressure in patients and there are no adverse side effects, then clinicians should continue to follow the current prescription guidelines." Further, she noted, "our findings from the analysis of large genetic datasets of individuals with European and East Asian were consistent. However, as we were unable to get access to suitable genetic datasets for other ancestries, it is difficult to extrapolate these findings." "Previous studies have shown that ACE inhibitors are not as efficient at lowering blood pressure in individuals with African ancestry compared to those of European ancestry," she noted. "Therefore, it is possible that any effect of ACE inhibitors is likely to vary between people of different ancestries, and we would need large datasets from difference ancestries to investigate this further." As reported in JAMA Psychiatry, the two-sample Mendelian randomization study assessed the association between a single-nucleotide variant (SNV) and drug-target gene expression derived from expression quantitative trait loci (eQTL) data in blood (sample 1) and the SNV-disease association from published case-control genome-wide association studies (sample 2). Participants included 40,675 patients with schizophrenia and 64,643 controls; 20,352 with bipolar disorder and 31,358 controls; and 135,458 with major depressive disorder and 344,901 controls. Blood eQTL levels were measured in 31,684 individuals; prefrontal cortex eQTLs were measured in 1,387; and protein QTLs were measured in cerebral spinal fluid from 544 participants and in plasma from 818. Expression levels of antihypertensive drug target genes were proxies for drug exposure. A one-standard deviation (1-SD) lower expression of the ACE gene in blood was associated with a 4.0 mm Hg lower systolic blood pressure, but an increased risk of schizophrenia (odds ratio, 1.75). A concordant direction of association was also seen between ACE expression in the prefrontal cortex (OR, 1.33) and ACE protein levels in cerebral spinal fluid (OR per 1-SD decrease, 1.12) and plasma (OR per 1-SD decrease, 1.0). No association was detected between genetically estimated systolic blood pressure and schizophrenia risk. Summing up, the authors state, "Findings suggest an adverse association of lower ACE messenger RNA and protein levels with schizophrenia risk. These findings warrant greater pharmacovigilance and further investigation into the effect of ACE inhibitors, particularly those that are centrally acting, on psychiatric symptoms in patients with schizophrenia, as well as the role of ACE inhibitor use in late-onset schizophrenia." Dr. Robert Shulman, Acting Chair, Department of Psychiatry and Behavioral Sciences at Rush University Medical Center in Chicago told Reuters Health by email, "The study notes only an association between the angiotensin-converting enzyme and schizophrenia. There is no evidence for causation. "To date," he said, "the only identified genetic marker for schizophrenia is the C4 complement gene seen in 50% of individuals who suffer from schizophrenia." "The paper really is out on a limb when they note visual hallucinations and reversible psychosis in patients treated with ACE-inhibiting medications as possibly reflecting the association between lower ACE mRNA and schizophrenia," he said. "Many medications can cause visual hallucinations and reversible psychosis. This is not unique to the mechanism of action of ACE inhibitors." "In my own experience treating patients who suffer schizophrenia and other psychiatric disorders for over thirty years, I have not seen the ACE inhibitors class of medication induce psychosis or worsen underlying psychiatric illness," he said. "The benefits seen in the use of these medications for hypertension and cardiovascular disease in our patients with psychiatric illness far outweigh the known risks as well (the) hypothesized risk for use." —Marilynn Larkin S0urce
