Objective: The aim of this systematic review and meta-analysis was to characterize ultra-treatment-resistant Schizophrenia also known as clozapine-resistant schizophrenia (CRS) patients across clozapine combination and augmentation trials through demographic and clinical baseline data. Furthermore, we investigated the variability and consistency in CRS definitions between studies.
Methods: Systematic searches of articles indexed in PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and PsycINFO were conducted in March 2020. 1541 randomized and non-randomized clinical trials investigating pharmacological and non-pharmacological clozapine add-on strategies were screened and a total of 71 studies were included. The primary outcome was the overall symptom score at baseline, measured with Positive and Negative Syndrome Scale (PANSS) total or Brief Psychiatric Rating Scale (BPRS) total scores.
Results: Data from 2731 patients were extracted. Patients were overall moderately ill with a mean PANSS total score at baseline of 79.16 (±7.52), a mean duration of illness of 14.64 (±4.14) years with a mean clozapine dose of 436.94 (±87.47) mg/day. Illness severity data were relatively homogenous among patients independently of the augmentation strategy involved, although stark geographical differences were found. Overall, studies showed a large heterogeneity of CRS definitions and insufficient guidelines implementation.
Conclusions: This first meta-analysis characterizing CRS patients and comparing CRS definitions revealed a lack of consistent implementation of a CRS definition from guidelines into clinical trials, compromising the replicability of the results and their applicability in clinical practice. We offer a new score modeled on a best practice definition to help future trials increase their reliability.
Keywords: Clozapine; Meta-analysis; Schizophrenia; Ultra-treatment-resistance.
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