Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates

Background: Despite its clinical relevance, comprehensive estimates on the prevalence of treatment resistance in schizophrenia-spectrum disorders are missing. This study aimed to systematically assess the prevalence and correlates of treatment-resistant schizophrenia (TRS). Method: An electronic search was conducted in PubMed and EMBASE for articles published until 05/17/2022, following PRISMA guidelines. Included studies were of patients with schizophrenia-spectrum disorders providing TRS prevalence information or allowing its calculation. Estimates within intent-to-treat and observed cases analyses were calculated via random-effects model meta-analysis. Sensitivity, subgroup and meta-regression analyses were performed. Findings: Across 49 studies (n=28392, mean age=38·3±6·2 years, males=64·8±12·1%, mean illness duration=14·3±5·3 years) the overall TRS prevalence was 36·7% (95%CI=33·0-40·5%, I2=97·3%, p<0·0001), ranging from 15·4% (95%CI=13·4-17·5%) to 75·6% (95%CI=69·1-81·3%). For first-episode psychosis samples (n=10579), the prevalence was 22·0% (95%CI=18·4-25·8%) vs. 39·5% (95%CI=32·2-47·0%) in multiple-episode schizophrenia (n=4685) (Q=18·27, p<0·0001). The pooled estimate of early-onset/primary (without any treatment response) TRS was 23.6% (3 studies; n=694; 95%CI=20·5-26·8%; I2=36·5%, p=0·207) vs. 9.3% (2 studies; n=450; 95%CI=6·8-12·2%; I2=0, p=0·6125) for later-onset/secondary (≥6 months after initial treatment response) TRS. In subgroup analyses, higher TRS frequency was associated with longer illness duration and recruitment from long-term hospitals or clinics specialized in clozapine. In meta-regression analysis, older age and poor functioning were associated with greater TRS. In sensitivity analyses of low-risk of bias studies, the TRS prevalence was 27.8%. This study is registered with PROSPERO, CRD42018092033. Interpretation: Between 22% of first-episode and 40% of multi-episode patients with schizophrenia have TRS, with heterogeneity explained by different study designs, settings and populations. At least two distinct trajectories of TRS, i.e., early-onset/primary and later-onset/secondary, with relevance for clinical practice and neurobiological studies, but only. few studies specifically addressed early-onset/primary vs late-onset/secondary TRS. Additional epidemiological studies of TRS are needed to disentangle different trajectories and inform health policies and clinical decision-making. Funding Information: No funding source. Declaration of Interests: Dr. Gadelha has been a consultant and/or advisor to or has received honoraria from: Aché, Daiichi-Sankyo, Torrent, Bayer, Cristalia, and Janssen. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. Dr. Bressan has received research grants from Janssen Cilag, Novartis, Roche and the following governmental funding research agencies: CAPES, CNPq and FAPESP (2016/022465 and 22 2011/50740-5); he has been a forum consultant for Janssen, Novartis and Roche and has participated in speaker bureaus for Ache, Janssen, Lundbeck, and Novartis. Dr. André Russowski Brunoni reports grants from Sao Paulo Research State Foundation (2018/10861-7, 2019/06009-6), Brazilian National Council of Scientific Development productivity support (PQ-1B), and University of Sao Paulo Medical School productivity support (PIPA-A), and Newton Advanced Fellowship (NAFR 2012\1010), and in-kind support from Flow Neuroscience and MagVenture, unrelated to the present work. All other authors do not have any conflict of interest to report with regards to the topic of this manuscript.

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