Lancet Psychiatry

SSRIs and SNRIs may reduce relapse risk when added to clozapine

August 5, 2025

Study details: A large, register-based study analyzed data from >23,000 patients with schizophrenia across Finland and Sweden. Using a within-subject design, researchers compared relapse rates during clozapine monotherapy vs. clozapine augmented with specific antidepressants. Antidepressant use was categorized by dose, and outcomes included psychiatric and somatic hospital admissions.

Results: Augmentation with SSRIs and SNRIs was associated with significantly reduced relapse risk. The strongest effects were seen with sertraline (adjusted hazard ratio [aHR], 0.76; 95% confidence interval [CI], 0.69–0.83), duloxetine (aHR, 0.78; 95% CI, 0.68–0.89), and escitalopram (aHR, 0.85; 95% CI, 0.79–0.92). When stratified by dose, standard-dose regimens showed even greater benefit—sertraline 30–54 mg/day (aHR 0.49), escitalopram 6–10 mg/day (aHR 0.57), and duloxetine 18–32 mg/day (aHR 0.59). High-dose antidepressants were linked to increased hospitalization risk, though most estimates weren’t statistically significant.

Clinical impact: These findings support the use of SSRIs and SNRIs as an augmentation strategy for patients with treatment-resistant schizophrenia on clozapine, especially at standard doses. The data reinforce the importance of dose optimization and caution against high-dose regimens due to potentially elevated risk.

Source:

Taipale H, et al. (2025, August). Lancet Psychiatry. Real-world effectiveness of clozapine augmentation with antidepressants: within-subject data evidence from two European nationwide cohorts. https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(25)00163-4/abstract