The treatment response for the negative symptoms of schizophrenia is not ideal, and the efficacy of antidepressant treatment remains a matter of considerable controversy. This systematic review and meta-analysis aimed to assess the efficacy of adjunctive antidepressant treatment for negative symptoms of schizophrenia under strict inclusion criteria.

A systematic literature search (PubMed/Web of Science) was conducted to identify randomized, double-blind, effect-focused trials comparing adjuvant antidepressants with placebo for the treatment of negative symptoms of schizophrenia from database establishment to April 16, 2025. Negative symptoms were examined as the primary outcome. Data were extracted from published research reports, and the overall effect size was calculated using standardized mean differences (SMD).

A total of 15 articles, involving 655 patients, were included in this review. Mirtazapine (N = 2, n = 48, SMD −1.73, CI −2.60, −0.87) and duloxetine (N = 1, n = 64, SMD −1.19, CI −2.17, −0.21) showed significantly better efficacy for negative symptoms compared to placebo. In direct comparisons between antidepressants, mirtazapine showed significant differences compared to reboxetine, escitalopram, and bupropion, but there were no significant differences between other antidepressants or between antidepressants and placebo. No publication bias for the prevalence of this condition was observed.

These findings suggest that adjunctive use of mirtazapine and duloxetine can effectively improve the negative symptoms of schizophrenia in patients who are stably receiving antipsychotic treatment. Therefore, incorporating antidepressants into future treatment plans for negative symptoms of schizophrenia is a promising strategy that warrants further exploration.