Use of antidepressants are generally safe in terms of heart rate corrected QT interval (QTc) prolongation, but differences exist across antidepressants and risk factors among adults with major depressive disorder, according to a study.
Moreover, antidepressant use shows no significant association with early major adverse cardiovascular events (MACE) and nonsuicidal sudden death.
“Matching individual characteristics with potential benefits and harms associated with a treatment are essential components of personalized approaches and shared decision making,” said the investigators.
Individual participant data (IPD) and aggregate data were derived from randomized controlled trials identified using the databases of Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, Medline, Medline In-Process, PsycINFO, the websites of regulatory agencies, and international registers.
The investigators analysed IPD using network meta-regression to explore the interactions with baseline QTc, age, sex assigned at birth, BMI, serum potassium level, and estimated glomerular filtration rate (eGFR). They analysed aggregate data on early MACE using pairwise meta-analysis comparing antidepressant with placebo.
A total of 130 trials were identified, of which 35 (27 percent) included IPD (n=8,679) on QTc with placebo and 10 antidepressants (ie, amitriptyline, bupropion, duloxetine, escitalopram, fluoxetine, mirtazapine, paroxetine, trazodone, venlafaxine, vortioxetine). [BMJ 2026;394:e100600]
Use of escitalopram and amitriptyline, compared with placebo, correlated with higher QTc intervals (8.7 ms, 95 percent credibility interval [CrI], 1.6‒15.8 and 5.3 ms, 95 percent CrI, 0.8‒9.8, respectively).
QTc prolongation
When considering risk factors, escitalopram and amitriptyline also correlated with the highest QTc prolongations (21.3 percent and 58.8 percent, respectively). On the other hand, venlafaxine and vortioxetine were associated with the lowest QTc intervals (24.1 percent and 9.7 percent, respectively).
Significant effect variability was also noted across antidepressants, particularly for escitalopram, fluoxetine, and mirtazapine.
In the aggregate analysis of 139 trials (52,398 participants), no association was observed between antidepressant use and increased rates of early MACE and nonsuicidal death compared with placebo (risk difference, 0.01 percent, 95 percent CrI, ‒0.01 to 0.02).
“The present findings call for mental health guidelines to take into consideration the differences across antidepressants in terms of QTc prolongation,” the investigators said. [https://tinyurl.com/3x4xyzhn]
“Our results are in line with [the caution by the UK Medicines and Healthcare Products Regulatory Agency] when prescribing escitalopram, considering how drug performance varied based on the risk factors of sex, age, QTc interval before starting an antidepressant, potassium level, BMI, and eGFR, instead of relying on average effects,” they added. [https://www.gov.uk/drug-safety-update/citalopram-and-escitalopram-qt-interval-prolongation]
Shiny App
The investigators also developed the Shiny App (https://egostinelli.shinyapps.io/QTcF) to aid in identifying specific QTc prolongation risk for each patient, depending on clinical and personal characteristics.
“We believe this app is an important step in allowing patients and clinicians to consider the trade-off with potential benefits and harms in a shared decision-making process, as recommended by the UK National Institute for Health and Care Excellence,” they said.