SynthesisMolecular psychiatry2026
Non-Clozapine interventions in treatment-resistant schizophrenia: a systematic review and meta-analysis.
Synthesis in Molecular psychiatry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
1 citing paper in PubMed.
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
background and hypothesisClozapine 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
designA 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).
results78 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.
conclusionsSeveral 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.
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