Antidepressants differ in QTc effect, with no early rise in major cardiovascular events

Design

Individual participant data network meta-regression of double-blind randomised trials, plus aggregate meta-analysis

Population

35 trials, 8,679 adults with major depressive disorder (QTc); 139 trials, 52,398 participants (cardiovascular events)

Primary outcome

Change in QTcF over the first 8 weeks, compared with placebo

Effect

Escitalopram +8.7 ms (95% CrI 1.6 to 15.8); amitriptyline +5.3 ms (0.8 to 9.8)

This BMJ analysis combined individual-participant data from 35 double-blind trials (8,679 people with major depressive disorder) comparing ten antidepressants with placebo for QTc over the first eight weeks. Compared with placebo, escitalopram was associated with a QTc rise of 8.7 ms (95% credibility interval 1.6 to 15.8) and amitriptyline with 5.3 ms (0.8 to 9.8). Venlafaxine and vortioxetine were often associated with the lowest QTc values once risk factors were taken into account. There was wide variability between individuals, notably for escitalopram, fluoxetine and mirtazapine.

A second, aggregate analysis of 139 trials (52,398 participants) found no association between antidepressant use and early major adverse cardiovascular events or non-suicidal death compared with placebo (risk difference 0.01%, credibility interval -0.01% to 0.02%).

QTc is a surrogate for arrhythmia risk, not the outcome itself, and these were short trials in people selected for depression trials. The authors suggest weighing individual risk factors when choosing a drug. No guideline has been changed by this paper.

• Look at baseline QTc, potassium, kidney function and other QT-prolonging drugs before prescribing escitalopram or amitriptyline.
• Expect individual variation; a single average QTc rise does not predict one patient's response.
• No excess of early cardiovascular events or non-suicidal death was seen across 139 trials.
• Where QT risk is a concern, the data suggest venlafaxine and vortioxetine tended to have smaller effects.

Why it matters

It replaces drug-class assumptions with drug-specific QTc estimates drawn from randomised data.

Don't overread it

QTc prolongation is a surrogate marker, and the cardiovascular outcomes were short-term and rare.

The statistics, in plain English

A credibility interval is the Bayesian counterpart of a confidence interval. Escitalopram's runs from 1.6 to 15.8 ms, so the effect is clearly above zero but its size is uncertain.

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