Adding antidepressants raises serious rhythm risk Starting selective serotonin reuptake inhibitor antidepressants while taking an antipsychotic was linked to higher risk of dangerous heart rhythm problems or sudden death, though events were rare.
*Retrospective cohort study (target-trial emulation); Level 2b (OCEBM).

Citation

Chien H-T, Lin S-W, Kung T-J, et al. Ventricular Arrhythmia and Sudden Death Risk With Concomitant Antipsychotic and Selective Serotonin Reuptake Inhibitor Use. JAMA Network Open. 2026;9(4):e266028. doi:10.1001/jamanetworkopen.2026.6028

Background

Antipsychotics and some antidepressants can affect the heart’s electrical system. Whether combining them increases dangerous rhythm problems or sudden death has had limited real-world evidence.

Patients

Adults (18+) with a recorded psychotic disorder starting an outpatient antipsychotic in the US (2010-2023) or Taiwan (2010-2021); excluded if they used these antidepressants in the prior year or had prior dangerous rhythm problems or sudden death.

Intervention

Starting a selective serotonin reuptake inhibitor antidepressant within 52 weeks after antipsychotic start.

Control

Continuing antipsychotic treatment without starting that antidepressant class.

Outcome

First dangerous heart rhythm problem or sudden death (combined outcome).

Follow-up Period

Up to 1 year.

Results

Comparison US relative risk over time (95% CI) Taiwan relative risk over time (95% CI)
Any selective serotonin reuptake inhibitor antidepressant added vs not added (primary) 1.51 (1.04-2.19) 3.32 (2.26-4.88)
Citalopram or escitalopram added vs not added 2.20 (1.39-3.46) 2.84 (1.75-4.62)
Other drugs in this antidepressant class added vs not added NS 2.85 (1.79-4.54)
NS = not statistically significant.

Absolute risk was low: about 0.1% (US) and 0.2% (Taiwan). The reported absolute differences were roughly 1 per 10,000 (US) and 3 per 10,000 (Taiwan), implying approximate numbers needed to harm of 10,000 and 3,333, respectively.

Limitations

Observational claims data may miss important risk factors (for example, smoking or detailed clinical measurements). Events were rare, limiting precision and drug-by-drug comparisons. The combined outcome cannot show whether rhythm problems or sudden death drove results. Death recording in US data was incomplete after 2015, and intention-to-treat estimates were smaller than per-protocol estimates.

Funding

Taiwan National Science and Technology Council grant; Xin Chen Foundation scholarship; no funder role.

Clinical Application

When adding these antidepressants to antipsychotics, prefer lower-risk options and monitor closely (electrocardiogram, electrolytes), especially early and during dose changes.