Angiotensin receptor blockers (ARBs) may be associated with a higher risk for suicide compared with angiotensin-converting enzyme inhibitors (ACEIs) among individuals aged ≥66 years in Ontario, Canada, according to a study published in JAMA Open Network.
In this population-based, nested, case-control study, researchers analyzed administrative claims databases for individuals aged ≥66 years from Ontario, Canada, between January 1, 1995, and December 31, 2015. Researchers defined cases as patients who died by suicide within 100 days of receiving a prescription for an ACEI or ARB (n=964). Up to 4 age- and sex-matched controls (n=3856) were also required to have been exposed to an ACEI or ARB within the 100 days preceding the index date.
Among the cases, 26.0% were exposed to ARBs (n=260) and 18.4% were exposed to ACEIs (n=704). Among controls, 74.0% were exposed to ARBs (n=741) and 81.6% were exposed to ACEIs (n=3115). ARB exposure was associated with a higher risk for suicide (adjusted odds ratio [aOR], 1.63; 95% CI, 1.33-2.00). In a sensitivity analysis excluding individuals with a history of deliberate self-harm, there were consistent findings (OR, 1.60; 95% CI, 1.29-1.98).
Limitations of this study included the inability to assess clinically important comorbidities and behaviors such as substance abuse, although the researchers do not anticipate any major differences in such characteristics between exposure groups. The researchers did not have reliable data on hospital admissions related to mental health and emergency department visits. The generalizability of these findings for younger populations and women is not known because the population studied was elderly and predominantly men. Suicide may be misclassified, but there is no apparent reason why this would be differentially influenced by ACEI or ARB exposure, which would likely bias these findings toward a null hypothesis. This study also had insufficient power to explore potential interclass differences in suicide risk.
“The mechanisms by which ARBs or ACEIs might impart differential risks for suicide are unknown,” the researchers noted. “Another possible explanation for a higher risk for suicide among users of ARBs is associated with the upregulation of [angiotensin I to angiotensin II (AII)] and resulting unopposed stimulation of AII type 2 receptors. These effects have been associated with nuclear factor–κB pathway activation, a process increasingly recognized as being involved in the pathophysiology of mood disorders. The mechanisms linking ARBs to mental health conditions and whether these effects are common to all members of this class are areas where further research is required.”
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Mamdani M, Gomes T, Greaves S, et al. Association between angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and suicide. JAMA Netw Open. 2019;2(10):e1913304.