6G-06 - Assessing the Risk of Ventricular Arrhythmia and Sudden Death in Patients Receiving Concomitant Treatment with Antipsychotics and Selective Serotonin Reuptake Inhibitors: A Sequential Target Trial Emulation Study

Background: Antipsychotics and selective serotonin reuptake inhibitors (SSRIs) are each associated with increased risk of ventricular arrhythmia (VA) and sudden death (SD). Their concurrent use may further elevate the risk due to interactive effects. However, real-world evidence remains limited.

Objectives: To evaluate the risk of VA or SD in patients concurrently prescribed with antipsychotics and SSRIs.

Methods: Using the Merative MarketScan Databases (2010–2023) in the US and National Health Insurance Research Database in Taiwan (2010-2021), we emulated 52 sequential target trials to assess VA/SD risk after SSRI initiation in patients started on antipsychotics. Individuals were classified as SSRI initiators or non-initiators weekly from the first to the 52nd week post-antipsychotic initiation. A per-protocol approach was applied, censoring patients who deviated from their initial SSRI use status. Inverse probability weighting was used to ensure baseline comparability, with further adjustments for time-varying covariates. We estimated hazard ratios (HRs), with robust variance estimators for 95% confidence intervals (CIs).
We analyzed SSRI-specific risk stratified by CredibleMeds torsades de pointes (TdP) classification. Subgroup analyses assessed variation by sex, age, baseline depression, and antipsychotic characteristics (CYP2D6 substrate status and TdP risk). Sensitivity analyses were conducted using an intension-to-treat approach, varying treatment grace period (to 90 days) and follow-up duration (26, 104 weeks, or no restriction). Unmeasured confounding was assessed using serotonin-norepinephrine reuptake inhibitors as a negative control, tricyclic antidepressants as a positive control, and carditis as a negative control outcome.

Results: Among 4,370,289 person-trials (307,818 patients) in the US and 1,997,468 person-trials (171,676 patients) in Taiwan, 17.2% and 14.7% were SSRI initiators, respectively. Adjusted HRs for VA/SD associated with concurrent SSRIs use, compared with antipsychotic use alone, were 1.51 (95% CI 1.04–2.19) in the US and 3.37 (2.29–4.95) in Taiwan. For high-risk SSRIs (citalopram, escitalopram), HRs were 2.20 (1.39–3.46) and 2.84 (1.75–4.63), respectively. Increased risk was observed in female and those under 65 years. Sensitivity analyses showed consistent results and positive and negative control analyses suggested minimal unmeasured confounding.

Conclusions: SSRI initiation among antipsychotic users was associated with increased risk of VA/SD, supporting the need for cautious use and monitoring in patients receiving these combinations.