Previous studies investigating the effectiveness of augmentation therapy have been limited.

To evaluate the effectiveness of antipsychotic augmentation therapies among patients with treatment-resistant depression.

We included patients diagnosed with depression receiving two antidepressant courses within 1 year between 2009 and 2020 and used the clone-censor-weight approach to address time-lag bias. Participants were assigned to either an antipsychotic or a third-line antidepressant. Primary outcomes were suicide attempt and suicide death. Cardiovascular death and all-cause mortality were considered as safety outcomes. Weighted pooled logistic regression and non-parametric bootstrapping were used to estimate approximate hazard ratios and 95% confidence intervals.

The cohort included 39 949 patients receiving antipsychotics and the same number of matched antidepressant patients. The mean age was 51.2 (standard deviation 16.0) years, and 37.3% of participants were male. Compared with patients who received third-line antidepressants, those receiving antipsychotics had reduced risk of suicide attempt (sub-distribution hazard ratio 0.77; 95% CI 0.72–0.83) but not suicide death (adjusted hazard ratio 1.08; 95% CI 0.93–1.27). After applying the clone-censor-weight approach, there was no association between antipsychotic augmentation and reduced risk of suicide attempt (hazard ratio 1.06; 95% CI 0.89–1.29) or suicide death (hazard ratio 1.22; 95% CI 0.91–1.71). However, antipsychotic users had increased risk of all-cause mortality (hazard ratio 1.21; 95% CI 1.07–1.33).

Antipsychotic augmentation was not associated with reduced risk of suicide-related outcomes when time-lag bias was addressed; however, it was associated with increased all-cause mortality. These findings do not support the use of antipsychotic augmentation in patients with treatment-resistant depression.