New Data Links Angiotensin Receptor Blockers with Increased Suicide Risk

Muhammad Mamdani, PharmD

A common medication to treat various cardiovascular and other disorders increases the risk of suicide, according to new data.

A team, led by Muhammad Mamdani, PharmD, director of the Li Ka Shing Centre for Healthcare Analytics Research and Training (CHART) at St. Michael’s Hospital, examined the association between suicide and exposure to angiotensin-converting enzyme inhibitors (ACEIs) compared with angiotensin receptor blockers (ARBs).

The population-based bested case-control study involved individuals at least 66-years old that were part of an administrative claims database in Ontario from 1995-2015 and committed suicide within 100 days of receiving either medication.

They identified 4 controls for each case, matched by age (within 1 year), sex, and presence of hypertension and diabetes. They used conditional logistic regression to estimate odds ratios for the association between suicide and exposure to ARBs compared with ACEIs.

The investigators matched 964 cases to 3856 controls. The median age of cases and controls was 76, with 768 cases and 3068 controls being male. There were 260 cases exposed to ARBs and 704 cases exposed to ACEIs.

While ACEIs and ARBs are some of the most commonly used medications for hypertension, chronic kidney disease, heart failure, and diabetes, their effects on mental health outcomes, particularly suicide, is poorly understood.

This family of drugs generally work by modulating the renin-angiotensin aldosterone system to lower blood pressure. ACEIs inhibit the conversion of angiotensin I to angiotensin II (AII), while ARBs block the binding of AII to its AII type 1 receptor, resulting in unpregulation of AII and unopposed stimulation of the AII type 2 receptor.

The investigators hypothesize that ARBs would be associated with a higher risk of suicide than ACEIs are, possibly because AII-mediated increases in substance P activity and heightened hypothalamic-pituitary-adrenal axis activity, provoking stress and anxiety.

Polymorphisms associated with higher levels of AII have been associated with other mental health conditions, including major depression, bipolar disorder, panic disorder, and anxiety disorder.

“The use of ARBs may be associated with an increased risk of suicide compared with ACEIs,” the authors wrote. “Preferential use of ACEIs over ARBs should be considered whenever possible, particularly in patients with severe mental health illness.”

While both drug classes could have anti-inflammatory or neuroprotective effects as an extension of their pharmacological effects, ARB-mediated compensatory increases in brain AII could inadvertently worsen outcomes.

This assertion is supported by an increased risk of suicide in patients with ACE gene polymorphisms associated with higher levels of this peptide.

Cases were more likely to have histories of alcohol abuse (3.3% vs .6%; standardized difference, .20); anxiety or sleep disorders (42.8% vs 14.7%; standardized difference, .65); psychoses, agitation, and related disorders (41.6% vs 14.5%; standardized difference, .63); affective disorder (42.6% vs 14.7%; standardized difference, .65); and other mental health conditions (42.9% vs 17.7%; standardized difference, .66) than controls.

Cases were also more likely than controls to use antidepressants (38.0% vs 13.3%; standardized difference, .59), antipsychotics (11.7% vs 31.%; standardized difference, .34), benzodiazepines (40.1% vs 14.0%; standardized difference, .62), and mood stabilizers (3.4% vs 1.6%; standardized difference, .12).

The most common ACEIs were ramipril (38.8%) and enalapril (15.0%) and the most common ARBs were valsartan (16.7%), telmisartan (16.7%), and candesartan (16.7%).

Among controls, 741 were exposed to ARBs and 3115 were exposed to ACEIs.

“Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted OR, 1.63; 95% CI, 1.33-2.00),” the authors wrote. “The findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm (OR, 1.60; 95% CI, 1.29-1.98).”

The study, “Association Between Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, and Suicide,” was published online in JAMA Network Open.