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Background and hypothesis <p>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.</p> Study design <p>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’ <i>g</i>).</p> Results <p>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,&#xa0;565 participants) moderately improved positive symptoms (g = −0.56 [−1.01, −0.10], GRADE rating Low).&#xa0;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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • Richard Carr,
  • Alistair Cannon,
  • Valeria Finelli,
  • Bernard Bukala,
  • Yesim Cimen,
  • Patritsiya Filipova,
  • Connor Cummings,
  • Toby Pillinger,
  • Oliver D. Howes,
  • Robert A. McCutcheon

摘要

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.