People taking angiotensin receptor blockers (ARBs) appear to be more likely to die by suicide

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A common type of blood pressure medication might be associated with an increased risk of suicide, a new study suggests.

People taking angiotensin receptor blockers (ARBs) appear to be more likely to die by suicide, compared to those who take another type of blood pressure drug called ACE inhibitors, researchers found.

Patients using ARBs had a 63% increased risk of death by suicide over people on ACE inhibitors, the findings showed.

But the study could not prove a cause-and-effect relationship.

“There is reason for some concern,” said lead researcher Muhammad Mamdani, director of the Applied Health Research Center of the Li Ka Shing Knowledge Institute at St. Michael’s Hospital, in Toronto. “Now would I be going en masse and change everybody’s prescriptions? No, not just yet. We should have more work done in this area.”

“But certainly if I had a choice as a patient, I would be choosing the ACE inhibitor over the ARB,” Mamdani concluded.

ARBs and ACE inhibitors both work by interfering with the action of angiotensin II, a hormone in the body that causes blood vessels to constrict.

ARBs work by blocking the ability of angiotensin II to bind with receptors and command blood vessels to narrow, while ACE inhibitors actually lower the amount of the hormone produced within the body.

Both drugs are widely used to treat high blood pressure, chronic kidney disease, heart failure and diabetes, the study authors said in background notes.

Mamdani and his colleagues pursued their new research based on earlier studies suggesting ARBs might be linked to suicide risk.

Using Canadian health databases, the investigators identified 964 people who died by suicide within 100 days of being prescribed either an ARB or an ACE inhibitor.

They then compared those people to a control group of just over 3,000 people also taking either type of blood pressure medication.

The results showed that people taking ARBs had a statistically significant higher risk of suicide than those on an ACE inhibitor.

“It is a fairly commonly used set of drugs, and lots of people would be affected by it. Certain people, especially if you’re susceptible to mood disorders, may be even more at risk,” Mamdani said.

He noted that ARBs might cause levels of angiotensin II to increase in the brain.

“That could be related to mood disorders, and that could trigger suicidal-type behavior,” Mamdani suggested.

However, there’s currently no evidence that angiotensin II has anything to do with moods or suicidal intent, said Dr. Robert Carey, dean emeritus of the University of Virginia School of Medicine.

“I think those speculations are exactly that,” Carey said. “There is no realistic mechanism to which one could attribute that difference in suicide risk.”

Carey noted that other factors that could influence suicide risk might have come into play with these patients. For example, some were taking antidepressants or benzodiazepines, “which might have had an influence on the suicide rate,” he said.

The study also didn’t assess underlying substance abuse, prior mental health hospitalizations, or previous emergency department visits, said Dr. Suzanne Steinbaum, a cardiologist with the Mount Sinai Hospital in New York City.

The study was published online Oct. 16 in JAMA Network Open.

“I don’t think this could be construed as evidence to switch from ARBs to ACE inhibitors,” Carey concluded. “The mechanism is absolutely up in the air and needs more basic study.”


Importance  The renin-angiotensin system has been implicated in mood disorders. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most commonly used medications, yet their effects on mental health outcomes, particularly suicide, are poorly understood. This study examined the association between suicide and exposure to ACEIs and ARBs. Because of differences in their mode of action, it was speculated that ARBs would be associated with a higher risk of suicide than ACEIs.

Objective  To examine the association between suicide and exposure to ARBs compared with ACEIs.

Design, Setting, and Participants  This population-based nested case-control study of individuals aged 66 years and older used administrative claims databases in Ontario, Canada, from January 1, 1995, to December 31, 2015. Data analysis was performed from January to April 2019. Cases were individuals who died by suicide within 100 days of receiving an ACEI or ARB. The date of death served as the index date. For each case, 4 controls were identified and matched by age (within 1 year), sex, and presence of hypertension and diabetes. All individuals received an ACEI or ARB within 100 days before the index date.

Exposures  Use of an ACEI or ARB.

Main Outcomes and Measures  Conditional logistic regression was used to estimate odds ratios for the association between suicide and exposure to ARBs compared with ACEIs.

Results  Nine hundred sixty-four cases were matched to 3856 controls. The median (interquartile range) age of cases and controls was 76 (70-82) years. Most cases (768 [79.7%]) and controls (3068 [79.6%]) were men. Among cases, 260 (26.0%) were exposed to ARBs, and 704 (18.4%) were exposed to ACEIs. Among controls, 741 (74.0%) were exposed to ARBs, and 3115 (81.6%) were exposed to ACEIs. Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00). The findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm (odds ratio, 1.60; 95% CI, 1.29-1.98).

Conclusions and Relevance  The use of ARBs may be associated with an increased risk of suicide compared with ACEIs. Preferential use of ACEIs over ARBs should be considered whenever possible, particularly in patients with severe mental health illness.Introduction

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used for the management of hypertension, chronic kidney disease, heart failure, and diabetes. These drugs lower blood pressure by modulating the renin-angiotensin aldosterone system in distinct ways. Angiotensin-converting enzyme inhibitors inhibit the conversion of angiotensin I to angiotensin II (AII), whereas ARBs block the binding of AII to its AII type 1 receptor, resulting in upregulation of AII and unopposed stimulation of the AII type 2 receptor.1

Although peripheral AII does not cross the blood-brain barrier, AII is also generated in the central nervous system.2 Its central effects include modulation of neurotransmitter release and activation of proinflammatory pathways that may influence mental health.2,3 Because ACEI and ARBs can cross the blood-brain barrier to various degrees, these drugs may interfere with central AII activity.

The effect of these drugs on mental health outcomes, particularly suicide, is of increasing interest because of the bidirectional association between depression and cardiovascular disease.4 

Although 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.5,6

 The mechanisms by which AII may be associated with a higher risk of suicide remain largely unclear. Possible explanations include AII-mediated increases in substance P activity and heightened hypothalamic-pituitary-adrenal axis activity, provoking stress and anxiety.79

 Moreover, 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.7,8,1012

 Furthermore, recent data13 suggest that users of ARBs, but not ACEIs, may have an increased risk of suicide compared with nonusers.

The objective of our study was to examine the association between suicide and exposure to ARBs compared with ACEIs. We hypothesized that exposure to ARBs would be associated with a higher risk of suicide compared with ACEIs.

Results

Over the 18-year study period, we matched 964 cases to 3856 controls exposed to either an ACEI or ARB within 100 days before the index date. Most cases (768 [79.7%]) and controls (3068 [79.6%]) were men, and the median (interquartile range) age was 76 (70-82) years. As expected, comorbidities and psychotropic drug use were more common among cases. For example, cases were more likely than controls to have histories of alcohol abuse (3.3% vs 0.6%; standardized difference, 0.20); anxiety or sleep disorders (42.8% vs 14.7%; standardized difference, 0.65); psychoses, agitation, and related disorders (41.6% vs 14.5%; standardized difference, 0.63); affective disorder (42.6% vs 14.7%; standardized difference, 0.65); and other mental health conditions (42.9% vs 17.7%; standardized difference, 0.66) (Table 1). Cases were also more likely than controls to use antidepressants (38.0% vs 13.3%; standardized difference, 0.59), antipsychotics (11.7% vs 31.%; standardized difference, 0.34), benzodiazepines (40.1% vs 14.0%; standardized difference, 0.62), and mood stabilizers (3.4% vs 1.6%; standardized difference, 0.12). The most common ACEIs were ramipril (38.8%) and enalapril (15.0%). The most common ARBs were valsartan (16.7%), telmisartan (16.7%), and candesartan (16.7%).

Among cases, 260 (26.0%) were exposed to ARBs, and 704 (18.4%) were exposed to ACEIs. Among controls, 741 (74.0%) were exposed to ARBs, and 3115 (81.6%) were exposed to ACEIs. In the primary analysis, compared with ACEIs, ARB exposure was associated with a higher risk of suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00) (Table 2). We observed consistent findings in our sensitivity analysis excluding individuals with a history of deliberate self-harm (odds ratio, 1.60; 95% CI, 1.29-1.98).Discussion

We found that ARBs were associated with a higher risk of suicide compared with ACEIs among individuals aged 66 years and older in Ontario, Canada. Previous studies5,6 have linked ACE polymorphisms to suicide, and 1 study13 reported a greater than 3-fold increased risk of suicide among ARB users compared with nonusers.

However, that study was not intended to specifically examine the association between ACEIs, ARBs, and suicide and was limited by a very small number of patients being exposed to ARBs. The mechanisms by which ARBs or ACEIs might impart differential risks of suicide are unknown.

As noted earlier, higher levels of AII may increase levels of substance P, which may, in turn, promote stress and anxiety.7,9 

Similarly, animal studies1719 have found that AII induces panic and stress when injected into stress-sensitive brain structures such as the dorsomedial hypothalamus and amygdala. However, because these effects were reversible after AII type 1 receptor blockade with an ARB, it is unlikely that this is the mechanism associating these drugs with suicide.

Another possible explanation for a higher risk of suicide among users of ARBs is associated with the upregulation of AII and resulting unopposed stimulation of AII type 2 receptors.1 These effects have been associated with nuclear factor–κB pathway activation,20 a process increasingly recognized as being involved in the pathophysiology of mood disorders.21,22 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.


More information: The American Heart Association has more about blood pressure medications.

Journal information: JAMA Network Open

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