(CSPOT13) Association between Antipsychotic Therapy and Suicide Risk in Patients with Treatment-Resistant Depression – A clone-censor-weight Approach to Address Immortal Time Bias

Background: When emulating a target trial to evaluate the effectiveness of antipsychotic therapy in patients with treatment-resistant depression (TRD), to determine the time zero would be important. The clone-censor-weight approach eliminates the immortal time bias since outcomes may occur before patients receiving antipsychotic therapy.

Objectives: To evaluate the suicide risk of antipsychotic therapy in patients with TRD, employing the clone-censor-weight approach.

Methods: We emulated a target trial using Taiwan’s National Health Insurance Research Database (NHIRD). Patients diagnosed with depression who had received two antidepressant courses within one year between 2009 and 2020. Excluded were dementia, schizophrenia, bipolar disorder and alcohol or drug abuse history within the previous year, to avoid misclassification of antipsychotic exposure. We followed up patients from the first date of receiving either an antipsychotic or a third-line antidepressant. The primary outcomes were either attempted suicide or successful suicide. Additionally, cardiovascular death and all-cause mortality were evaluated as safety outcomes. We applied propensity score matching to mimic randomization in the emulated trial. Specifically, we also employed the clone-censor-weight approach to address immortal time bias. Cox proportional hazard models and non-parametric bootstrap were applied to estimate approximate hazard ratios (HRs) and their 95% confidence intervals (95% CIs).

Results: This cohort included 39,949 patients receiving antipsychotics, and the same number of matched antidepressant patients. The mean age was 51.2 (SD 16.0) years, and 37.3% were male. Compared to patients receiving antidepressants, patients receiving antipsychotics were associated with a reduced risk of attempted suicide (sub-distribution HR: 0.77; 95% CI: 0.72-0.83), but not with a reduced risk of successful suicide (adjusted HR: 1.08; 95% CI: 0.93-1.27). After applying the clone-censor-weight approach, we found no association of antipsychotic therapy with reduced risk for attempted suicide (HR: 1.01; 95% CI: 0.86-1.16) and successful suicide (HR: 0.85; 95% CI: 0.61-1.16). Moreover, patients receiving antipsychotics were associated with an increased risk of all-cause mortality (HR: 1.14; 95% CI: 1.06-1.26).

Conclusions: We initially found that antipsychotic therapy was associated with a reduced risk of suicide, however, this association was no longer observed after we controlled for immortal time bias by using the clone-censor-weight approach. These results highlight the need to address potential immortal time bias in previous observational studies.