A network meta-analysis of efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia
Open accessAbstract
Objective: Clozapine is considered as the standard treatment for this subgroup, but the evidence is not unequivocal. There are several potential alternatives being used because of the possible adverse effects of clozapine. We aimed to examine the efficacy and adverse events of different antipsychotics in treatment-resistant schizophrenia by performing a network meta-analysis. Methods: We searched the Cochrane Schizophrenia Group register for randomized-controlled trials (up to March 06, 2022) and MEDLINE (up to January 20, 2023). We included blinded and open studies and participants with a broad definition of treatment resistance. The primary outcome was overall symptoms of schizophrenia; secondary outcomes were response to treatment, positive and negative symptoms of schizophrenia, discontinuation, side effects, quality of life, and functioning. The study was registered in Open Science Framework ( https://osf.io/9nf2y/ ). Results: We included 60 studies involving 6838 participants in the network meta-analysis. In the primary outcome, clozapine and olanzapine were more efficacious than risperidone, haloperidol, fluphenazine, sertindole, chlorpromazine, and quetiapine (range of mean SMDs, − 0.11 to − 0.48). The difference between clozapine and olanzapine was trivial and uncertain (SMD − 0.05, 95% CI, − 0.21 to 0.11). The result of other efficacy outcomes as well as subgroup and sensitivity analyses were consistent with the primary analysis. Clozapine and olanzapine were associated with more weight gain, and clozapine was associated with more sedation events compared to many other antipsychotics. Conclusions: Clozapine remains the gold standard for patients with treatment-resistant schizophrenia. Olanzapine seems to be second-best and could be tried before switching to clozapine.
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“It is noteworthy that olanzapine was also the most efficacious drug in a NMA examining the effects of antipsychotics in long-term studies of initially acutely ill patients (Leucht et al., 2023), and that it came close to clozapine in a NMA in treatment-resistant patients(Dong et al., 2023).”
BackgroundSelf-citation
- Authors
- Dong, S., Schneider-Thoma, J., Bighelli, I., Siafis, S., Wang, D., Burschinski, A., Schestag, K., Samara, M., & Leucht, S.
- Affiliations
- TUM Klinikum (DE)
- University of Thessaly (GR)
- Corresponding author
- Leucht, Stefan
- Venue
- European Archives of Psychiatry and Clinical Neuroscience
- Published
- 2023-08-01
- Volume
- 274
- Issue
- 4
- Pages
- 917-928
- ISSN
- 0003-9373 (ISSN-L)
- 0940-1334
- 1433-8491
- PMC
- PMC11127860
- OpenAlex
- W4385442421
- Cited by
- 68
- References
- 13
- Citations by year
- 2026: 27 · 2025: 20 · 2024: 21
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- European Archives of Psychiatry and Clinical Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSF Preprints (OSF Preprints) (acceptedVersion)
- PUBLISSO (German National Library of Medicine) (submittedVersion, cc-by)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- OSF Preprints (OSF Preprints) (submittedVersion, public-domain)
- Funders
- China Scholarship Council (202006240091)
- Technische Universität München
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
- Keywords
- treatment-resistant schizophrenia, antipsychotic drugs, clozapine, olanzapine, risperidone, haloperidol, fluphenazine, sertindole, chlorpromazine, quetiapine, treatment efficacy, adverse events, weight gain, sedation, quality of life, functional outcome
- MeSH terms
- Network Meta-Analysis, Schizophrenia, Treatment-Resistant, Clozapine, Humans, Schizophrenia, Antipsychotic Agents, Outcome Assessment, Health Care
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