Non-Clozapine interventions in treatment-resistant schizophrenia: a systematic review and meta-analysis

Journal article : Review

Background and hypothesis: Clozapine is the only licensed pharmacotherapy for treatment resistant schizophrenia (TRS), but in some cases is not a suitable treatment option. A review of the efficacy of non-clozapine interventions in TRS may help inform clinical decision making when clozapine treatment is not feasible. Study design: A systematic review and meta-analysis was performed investigating the efficacy of non-clozapine augmentation of antipsychotic treatment in TRS on positive, negative, and total symptoms. The review protocol is registered at PROSPERO (ID: CRD42023418053). PsycInfo, PubMed and EMBASE were searched up until July 2023. Cochrane Risk of Bias tool (v2) was used to assess study quality. Data were pooled using a random-effects model for each class of intervention to give an estimate of effect size (Hedges’ g). Results: 78 studies were included, of which 68 were included in the meta-analysis, comprising 3241 patients. High-dose antipsychotics (7 studies, 467 participants) did not improve any symptom domain. Augmentation of antipsychotics with glycine modulatory site agonists (9 studies, 187 participants) improved positive (g = −0.56 [−0.81, −0.31], GRADE rating Low), negative (g = −1.18 [−1.49, −0.87], GRADE rating Low) and total (g = −1.17 [−1.75, −0.59], GRADE rating Very Low) symptoms. Non-invasive stimulation (26 studies, 893 participants) moderately benefited positive symptoms (g = −0.42 [−0.65, −0.18], GRADE rating Low). Psychotherapy (10 studies, 565 participants) moderately improved positive symptoms (g = −0.56 [−1.01, −0.10], GRADE rating Low). Augmentation with antidepressants (3 studies, 187 participants) improved negative (g = −0.74 [−1.46, −0.02], GRADE rating Very Low) and total (g = −0.69 [−1.00, −0.38], GRADE rating Low) symptoms. Sample sizes were small, and publication bias was apparent for non-invasive stimulation studies. Conclusions: Several augmentation strategies, including pharmacotherapy, non-invasive stimulation, and psychotherapy demonstrated benefit in small studies, however no intervention reached the threshold of evidence to be routinely recommended as a viable alternative to clozapine. High-quality trials are needed for definitive recommendations.

Authors: Carr, R; Cannon, A; Finelli, V; Bukala, B; Cimen, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature [academic journals on nature.com]
• Journal: Molecular Psychiatry
• Volume: 31
• Issue: 1
• Pages: 526-544
• Publication date: 2025-10-03
• Acceptance date: 2025-09-05
• DOI: 10.1038/s41380-025-03255-y
• EISSN: 1476-5578
• ISSN: 1359-4184
• Language: English
• Subtype: Review