High-dose antidepressants up risk of out-of-hospital cardiac arrest

Patients on high-dose citalopram (>20 mg) and high-dose escitalopram (>10 mg) are more likely to experience out-of-hospital cardiac arrest (OHCA) than those on sertraline, while users of high-dose mirtazapine (>30 mg) have a higher OHCA rate than those on duloxetine, a study has shown.

“Our findings indicate that careful titration of citalopram, escitalopram, and mirtazapine dose may have to be considered due to drug safety issues,” the researchers said.

A nationwide nested case‒control study was conducted to examine the relationship of individual antidepressant medications within drug classes with the risk of OHCA. Cases were defined as OHCA from presumed cardiac causes.

Using Cox regression with time-dependent exposure and covariates, the researchers calculated hazard ratios (HRs) and 95 percent confidence intervals (CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. They also analysed antidepressants with and without sodium channel blocking or potassium channel blocking properties separately.

From 2001 to 2015, a total of 10,987 OHCA cases were recorded, with a higher rate seen for high-dose citalopram (HR, 1.46, 95 percent CI, 1.27‒1.69) and high-dose escitalopram (HR, 1.43, 95 percent CI, 1.16‒1.75) among selective serotonin reuptake inhibitors (SSRIs), with sertraline as the reference drug. [Br J Clin Pharmacol 2022;88: 3162-3171]

OHCA rates were also increased with high-dose mirtazapine (HR, 1.59, 95 percent CI, 1.18‒2.14) among the serotonin‒norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants compared with duloxetine.

On the other hand, no medication among tricyclic antidepressants resulted in an increased OHCA rate, with amitriptyline used as reference.

The rate of OHCA was higher for antidepressants with known potassium channel blocking properties (HR, 1.14, 95 percent CI, 1.05‒1.23) but not for those with sodium channel blocking properties. In patients without cardiac disease and cardiovascular risk factors, mirtazapine and citalopram, albeit statistically not significant, correlated with an elevated OHCA rate.

“While we observed an increased rate of OHCA among citalopram, escitalopram and mirtazapine in our main analyses, this increase in OHCA rate only occurred at high-dose, and were small to modest,” the researchers said.

Moreover, these findings were consistent with those of a previous study examining the effects of antidepressants on QT interval, which reported that QT prolongation among SSRIs were largely caused by citalopram and escitalopram. [J Clin Psychiatry 2014;75:441-449]

Careful titration

“The use of antidepressants is fundamental for the control of symptoms in depression and untreated depression more than doubles the risk of OHCA,” the researchers said. [Arch Intern Med 2006;166:195-200]

“Therefore, our findings that most of the antidepressants are not associated with OHCA are of clinical importance and indicate that careful titration may have to be considered when citalopram, escitalopram, and mirtazapine is prescribed,” they added.

The current study was limited by its observational design and the possibility of residual confounding due to the absence of data on important factors such as body mass index, alcohol use, and smoking. Information on the exact cause of OHCA was also unobtainable, leading to a potential misclassification of the outcome. [Circulation 2018;137:2689-2700]

Additionally, information on the indication for the antidepressant prescription and whether claimed medications were actually taken were not available.