A recent increase in the literature regarding the evidence base for
clozapine has made it increasingly difficult for clinicians to judge "best evidence" for
clozapine use. As such, we aimed at elucidating the state-of-the-art for
clozapine with regard to efficacy, effectiveness, tolerability, and management of
clozapine and
clozapine-related adverse events in neuropsychiatric disorders. We conducted a systematic
PRISMA-conforming quantitative meta-review of available meta-analytic evidence regarding
clozapine use. Primary outcome effect sizes were extracted and transformed into relative risk ratios (RR) and standardized mean differences (SMD). The methodological quality of meta-analyses was assessed using the AMSTAR-2 checklist. Of the 112 meta-analyses included in our review, 61 (54.5%) had an overall high methodological quality according to AMSTAR-2.
Clozapine appears to have superior effects on positive, negative, and overall symptoms and relapse rates in
schizophrenia (treatment-resistant and non-treatment-resistant subpopulations) compared to first-generation
antipsychotics (FGAs) and to pooled FGAs/second-generation
antipsychotics (SGAs) in
treatment-resistant schizophrenia (TRS). Despite an unfavorable metabolic and hematological adverse-event profile compared to other
antipsychotics, hospitalization, mortality and all-cause discontinuation (ACD) rates of
clozapine surprisingly show a pattern of superiority. Our meta-review outlines the superior overall efficacy of
clozapine compared to FGAs and most other SGAs in
schizophrenia and suggests beneficial efficacy outcomes in
bipolar disorder and
Parkinson's disease psychosis (PDP). More clinical studies and subsequent meta-analyses are needed beyond the application of
clozapine in
schizophrenia-spectrum disorders and future studies should be directed into multidimensional
clozapine side-effect management to foster evidence and to inform future guidelines.