Summary
An analysis of double-blind trials found small average QTc increases with escitalopram and amitriptyline, with effects varying by individual risk factors. A separate analysis found no evidence of increased early sudden-death rates compared with placebo.
A BMJ analysis of double-blind randomised trials found that escitalopram and amitriptyline were associated with small average increases in the heart’s corrected QT interval during the first eight weeks of treatment for major depressive disorder. The effects varied with patient characteristics; a separate analysis of 139 trials found no evidence that antidepressants increased early non-suicidal sudden-death rates compared with placebo.
The study combined individual participant data from 35 trials, covering 8,679 adults, with trial-level safety data from a larger group of studies. Its findings point to differences between medicines in their effects on cardiac electrical activity, while the short-term event data offer limited evidence about rare outcomes.
QTc changes varied between medicines and risk profiles
The QT interval on an electrocardiogram reflects the time taken for the heart’s lower chambers to electrically recover between beats. Because this interval changes with heart rate, the researchers used the Fridericia correction, or QTcF. A longer QTc can be a marker of delayed ventricular repolarisation and potential arrhythmia risk, but a change in the measurement is not itself a cardiovascular event.
The researchers compared QTcF changes with placebo at the trial timepoint closest to four weeks, within a range of one to eight weeks. After accounting for average values of age, sex assigned at birth, baseline QTcF, body mass index, serum potassium and kidney function, escitalopram was associated with an average increase of 8.7 milliseconds (95% credibility interval 1.6 to 15.8). For amitriptyline, the increase was 5.3 ms (0.8 to 9.8).
The analysis also modelled combinations of these risk factors. The researchers found substantial variation between individual profiles, particularly for escitalopram, fluoxetine and mirtazapine. Across the modelled combinations, escitalopram and amitriptyline were among the medicines most often associated with the largest QTc increases. These combinations describe modelled scenarios, not the proportion of patients expected to experience a particular change.
Sudden-death events were rare in the trial data
In the 35-trial group with individual QTc data, no participant experienced torsades de pointes or non-suicidal sudden death during trial participation. Ten participants experienced syncope, or fainting. For a broader comparison of sudden-death events, the researchers analysed aggregate data from 139 trials involving 52,398 participants. There were nine events among 34,575 participants assigned antidepressants and three among 17,823 assigned placebo. The estimated risk difference was 0.01 percentage points (95% credibility interval −0.01 to 0.02).
The results provide a short-term comparison from randomised trials, not a measure of long-term cardiovascular risk. Sudden cardiac events are rare, and the authors say the available trial data were likely underpowered to give definitive answers about them. QTc changes are also a proxy measure: they can indicate a factor relevant to arrhythmia risk without establishing that an arrhythmia will occur.
What the analysis can—and cannot—inform
The individual-data analysis included ten antidepressants, but citalopram was not represented because QTc data were unavailable. Escitalopram was represented by 186 participants, fewer than several other medicines in the analysis. The researchers also could not assess dose effects, and the trials focused on acute treatment rather than longer-term use.
The findings support considering patient characteristics alongside average drug effects when comparing antidepressants. They do not rank medicines by overall suitability: the study examined cardiac measurements and early safety events, rather than weighing cardiovascular effects against antidepressant benefits for an individual.