Antidepressant treatment duration and risk of sudden cardiac death: A nationwide cohort study

Antidepressants (ADs) are among the most widely prescribed medications worldwide. Although previous studies suggest associations between AD use and adverse cardiovascular outcomes, the impact of treatment duration and recency on sudden cardiac death (SCD) risk remains unclear, limiting clinical risk stratification.

This study aimed to investigate whether cumulative duration and recency of AD treatment are associated with SCD risk and whether associations differ across drug classes.

We conducted a nationwide cohort study of 4.3 million Danish residents aged 18-90 years during 2010. AD exposure was ascertained from the national prescription registry (1999-2009). Deaths were adjudicated as SCD or non-SCD. Multivariable Cox models estimated hazard ratios (HRs). AD use was defined as ≥2 prescriptions within 1 calendar year and categorized by cumulative duration (1-5 years vs ≥6 years) and recency (remote, recent, or current).

Among 6002 SCDs, 1907 (32%) occurred in AD users. Adjusted HRs were 1.41 (95% confidence interval [CI] 1.31-1.51) for 1-5 years and 1.74 (95% CI 1.59-1.90) for ≥6 years of use. A temporal gradient emerged: current users showed the highest risk (HR 1.71; 95% CI 1.59-1.83) vs recent (HR 1.24; 95% CI 1.09-1.42) and remote users (HR 1.11; 95% CI 0.97-1.27). Associations were consistent across drug classes: selective serotonin reuptake inhibitors (HR 1.38; 95% CI 1.28-1.49; HR 1.57; 95% CI 1.42-1.75) and tricyclic ADs (HR 1.24; 95% CI 1.09-1.42; HR 1.40; 95% CI 1.15-1.71) for 1-5 and ≥6 years, respectively.

Long-term AD treatment was associated with increased SCD risk in a duration- and recency-dependent manner across major drug classes. Although causality cannot be inferred, these findings identify patients receiving prolonged AD therapy as a population at elevated cardiovascular risk, warranting further investigation.