New analysis finds small QTc changes with some antidepressants early in treatment
A review of randomised trials found different effects on heart rhythm measurements, without evidence of more early major cardiovascular events.
High evidenceReviewSome caution advised
Medical disclaimer: This article summarizes research findings and is for informational purposes only. It is not medical advice.
Editorial illustration — not from the study.
The analysis used individual participant data from 35 trials involving 8,679 adults to examine QTc changes. It also combined results from 139 trials involving 52,398 participants to assess early major cardiovascular events and non-suicidal death.
Compared with placebo, escitalopram and amitriptyline were associated with average QTc increases of 8.7 and 5.3 milliseconds, respectively. The researchers reported substantial variation between people and medicines. The available trial data did not show an association between antidepressant use and increased early major cardiovascular events or non-suicidal death.
What the review covered
The researchers conducted an individual participant data network meta-regression and an aggregate pairwise meta-analysis of double-blind randomised trials. The studies included adults aged 18 or older with major depressive disorder diagnosed using standardised criteria. The individual-level analysis included placebo comparisons for 10 antidepressants: amitriptyline, bupropion, duloxetine, escitalopram, fluoxetine, mirtazapine, paroxetine, trazodone, venlafaxine, and vortioxetine. Researchers examined changes in QTc using the Fridericia correction during the first eight weeks and considered factors including starting QTc, age, sex assigned at birth, body mass index, blood potassium, and estimated kidney function. A separate analysis assessed early major adverse cardiovascular events and non-suicidal death.
Key conclusions
Compared with placebo, escitalopram was associated with an 8.7 millisecond increase in QTc, with a 95% credibility interval of 1.6 to 15.8 milliseconds. Amitriptyline was associated with a 5.3 millisecond increase, with a 95% credibility interval of 0.8 to 9.8 milliseconds. After considering the examined risk factors, the researchers reported the largest QTc prolongations with amitriptyline and escitalopram and the lowest QTc intervals most often with venlafaxine and vortioxetine, although the abstract does not provide a single directly comparable estimate for each medicine. Effects varied substantially, particularly for escitalopram, fluoxetine, and mirtazapine. Across 139 trials, the analysis did not identify an association between antidepressant use and higher rates of early major cardiovascular events or non-suicidal death compared with placebo; the reported risk difference was 0.01%, with a 95% credibility interval from -0.01% to 0.02%. These findings describe results in the included randomised trials and do not establish that the medicines have no cardiovascular risks in every setting or population.
Who this may apply to
The findings are most directly relevant to adults with major depressive disorder who resemble participants in the included randomised trials and who were assessed during the first eight weeks of treatment. They may be less applicable to people with substantial heart disease, abnormal blood potassium, reduced kidney function, other important medical conditions, different antidepressant combinations, or treatment lasting longer than eight weeks because the abstract does not establish how well those groups were represented. The findings do not determine the effects for children, adolescents, or people without major depressive disorder.
The significance
QTc is a measurement of the time the heart takes to reset electrically between beats. Changes in this measurement can differ between medicines and between people, so the study helps describe an early heart-rhythm outcome alongside rare cardiovascular events. The absence of an observed increase in early major cardiovascular events in these trials is reassuring within the limits of the available data, but the study was not evidence that all possible cardiovascular harms are absent, particularly beyond eight weeks or in people unlike those enrolled.
Limitations & evidence assessment
The analysis focused on the first eight weeks, so it provides limited information about longer-term cardiovascular outcomes. Individual participant data on QTc were available from only 35 of the 130 unique trials identified, meaning most identified trials could not contribute to that part of the analysis. Major cardiovascular events and non-suicidal death are uncommon, so even the larger pooled analysis may have limited ability to detect very small differences or differences in specific higher-risk groups. The abstract provides limited detail about how representative the trial participants were of people with other illnesses, different medicines, or longer treatment histories. QTc is a measured outcome and is not itself the same as a clinical cardiovascular event.
Why this evidence level: Meta-analysis pooling multiple studies sits at the top of common evidence hierarchies.
Evidence levels are editorial estimates derived from study metadata — they are not clinical appraisals.
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