Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS), but more than half of patients fail to respond adequately. Antidepressant augmentation is a common strategy in clinical practice while real-world data remains limited. A recent within-subject analysis of two large nationwide cohorts from Finland and Sweden (N=23,206) examined whether concomitant use of antidepressants with clozapine impacts psychiatric relapse and somatic hospitalization rates.

Results showed that both SSRI and SNRI augmentation were associated with a significantly lower risk of relapse compared to clozapine monotherapy. This was the case especially with sertraline (adjusted hazard ratio, aHR 0.76), duloxetine (aHR 0.78), and escitalopram (aHR 0.85). The greatest reductions in relapse risk were observed at standard doses (e.g., sertraline 30–54 mg/day, aHR 0.49). High-dose antidepressant use (e.g., sertraline =105 mg/day or escitalopram >10 mg/day) was associated with increased risk of both relapse and somatic hospitalization. Importantly, no antidepressant was linked to increased somatic hospitalization at low or standard doses.

These findings support the selective use of SSRIs and SNRIs (especially sertraline, duloxetine, and escitalopram) as augmentation options in patients with ongoing negative symptoms, comorbid depression, or suicidal ideation in TRS. Importantly, clinicians should exercise caution with higher doses given the associated risks. While these results cannot establish causality, they provide valuable real-world evidence to guide augmentation strategies in clozapine-treated patients. .

Reference:

Taipale H et al. Lancet Psychiatry. 2025;12(8):568–578. Abstract