Angiotensin-converting enzyme (ACE) inhibitors may be associated with an increased risk for schizophrenia and may affect psychiatric symptoms, new research suggests.
Investigators found individuals who carry a genetic variant associated with lower levels of the ACE gene and protein have increased liability to schizophrenia, suggesting that drugs that lower ACE levels or activity may do the same.
“Our findings warrant further investigation into the role of ACE in schizophrenia and closer monitoring by clinicians of individuals, especially those with schizophrenia, who may be on medication that lower ACE activity, such as ACE inhibitors,” Sonia Shah, PhD, Institute for Biomedical Sciences, University of Queensland, Brisbane, Australia, told Medscape Medical News.
The study was published online March 10 in JAMA Psychiatry.
Antihypertensives and Mental Illness
Hypertension is common in patients with psychiatric disorders and observational studies have reported associations between antihypertensive medication and these disorders, although the findings have been mixed.
Shah and colleagues estimated the potential of different antihypertensive drug classes on schizophrenia, bipolar disorder, and major depressive disorder.
In a two-sample Mendelian randomization study, they evaluated ties between a single-nucleotide variant (SNV) and drug target gene expression derived from expression quantitative trait loci data in blood (sample 1) and the SNV-disease association from published case-control, genome-wide association studies (sample 2).
The analyses 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.
The major finding was that a one-standard deviation (1-SD) lower expression of the ACE gene in blood was associated with lower systolic blood pressure of 4.0 mm Hg (95% CI, 2.7 – 5.3), but also an increased risk of schizophrenia (odds ratio [OR], 1.75; 95% CI, 1.28 – 2.38).
Could ACE Inhibitors Worsen Symptoms or Trigger Episodes?
In their article, the researchers note that in most patients, onset of schizophrenia occurs in late adolescence or early adult life, ruling out ACE inhibitor treatment as a potential causal factor for most cases.
“However, if lower ACE levels play a causal role for schizophrenia risk, it would be reasonable to hypothesize that further lowering of ACE activity in existing patients could worsen symptoms or trigger a new episode,” they write.
Shah emphasized that evidence from genetic analyses alone is “not sufficient to justify changes in prescription guidelines.”
“Patients should not stop taking these medications if they are effective at controlling their blood pressure and they don’t suffer any adverse effects. But it would be reasonable to encourage greater pharmacovigilance,” she told Medscape Medical News.
“One way in which we are hoping to follow up these findings,” said Shah, “is to access electronic health record data for millions of individuals to investigate if there is evidence of increased rates of psychotic episodes in individuals who use ACE inhibitors, compared to other classes of blood pressure-lowering medication.”
Reached for comment, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences at Staten Island University Hospital in New York City, noted that this is an “extremely complicated” study and urged caution in interpreting the results.
“Since most people develop schizophrenia earlier in life, before they usually develop problems with blood pressure, it’s not so much that these drugs might cause schizophrenia,” Sullivan said.
“But because of their effects on this particular gene, there’s a possibility that they might worsen symptoms or in somebody with borderline risk might cause them to develop symptoms later in life. This may apply to a relatively small number of people who develop symptoms of schizophrenia in their 40s and beyond,” he added.
That’s where “pharmacovigilance” comes into play, Sullivan said.
“In other words,” he suggested, “we should be looking at people we’re treating with these drugs to see — might we be tipping some of them into illness states that they otherwise wouldn’t experience?”
Support for the study was provided by the National Health and Medical Research Council (Australia) and US National Institute for Mental Health. Shah and Sullivan ha ve disclosed no relevant financial relationships.
JAMA Psychiatry. Published online March 10, 2021. Abstract