Augmentation Strategies for Partial or Non-responders to Clozapine in Patients with Schizophrenia: A Bayesian Network Meta-analysis of Randomized Controlled Trials
Archana Mishra1, Rituparna Maiti1, Biswa Ranjan Mishra2, Anand Srinivasan1
1Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
2Department of Psychiatry, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, India
Correspondence to: Rituparna Maiti
Department of Pharmacology, Academic Block, All India Institute of Medical Sciences (AIIMS), Sijua, PO Dumuduma, Bhubaneswar 751019, Odisha, India
Received: August 2, 2023; Revised: September 3, 2023; Accepted: October 19, 2023; Published online: November 30, 2023.
© The Korean College of Neuropsychopharmacology. All rights reserved.

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Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a lack of evidence regarding the most effective therapy. This network meta-analysis was conducted to evaluate the efficacy of pharmacological agents used in the augmentation strategies in patients who were partial/ non-responders to clozapine. Relevant data were extracted from 30 randomized controlled trials through searches of electronic databases (MEDLINE/PubMed, Embase, Cochrane, clinical trial registries). PRISMA guidelines were followed for the extraction, management, analysis, and reporting of the data. The outcome measure in this study was a reduction in symptom severity according to total PANSS/BPRS and was reported as the standardized mean difference with a 95% credible interval. Bayesian network meta-analysis with random effects model and uninformative priors was conducted, and the ranking probability of each intervention was done. Meta-regression was done to assess the effect of duration on the reduction in symptom severity scores. Mirtazapine (−5.2 [95%CrI: −7.7, −2.7]) and memantine (−2.1 [95%CrI: −4.0, −0.19]] were more efficacious than placebo for augmentation of clozapine in partial/non-responders and were the most effective adjunctive agents as per SUCRA scores. Both drugs did not cause a significant increase in frequency of adverse events compared to placebo. There was a significant effect of duration on the reduction in symptom severity. There was no evident publication bias. Mirtazapine and memantine may prove beneficial for augmentation of clozapine in non/partial responders to monotherapy.
Keywords: Clozapine; Schizophrenia; Clozapine-resistant; Augmentation therapy.

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