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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 <jats:italic>AMSTAR-2<\/jats:italic> checklist. Of the 112 meta-analyses included in our review, 61 (54.5%) had an overall high methodological quality according to <jats:italic>AMSTAR-2<\/jats:italic>. 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\u2019s 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.<\/jats:p>","DOI":"10.1038\/s41398-021-01613-2","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T06:03:05Z","timestamp":1632290585000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":182,"title":["Efficacy and safety of clozapine in psychotic disorders\u2014a systematic quantitative meta-review"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7147-6167","authenticated-orcid":false,"given":"Elias","family":"Wagner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spyridon","family":"Siafis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyumi","family":"Fernando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Falkai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G.","family":"Honer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"R\u00f6h","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Siskind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Leucht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alkomiet","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"1613_CR1","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/BF00606409","volume":"11","author":"J Idanpaan-Heikkila","year":"1977","unstructured":"Idanpaan-Heikkila J, Alhava E, Olkinuora M, Palva IP. 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WGH has received consulting fees or sat on paid advisory boards for: AlphaSights, Guidepoint, In Silico, Translational Life Sciences, Otsuka, AbbVie and Newron, and holds\/held shares in Translational Life Sciences, AbCellera and Eli Lilly. PF was honorary speaker for Janssen-Cilag, Astra-Zeneca, Eli Lilly, Bristol Myers-Squibb, Lundbeck, Pfizer, Bayer Vital, SmithKline Beecham, Wyeth, and Essex. During the last 5 years he was a member of the advisory boards of Janssen-Cilag, AstraZeneca, Eli Lilly, and Lundbeck. Presently, he is a member of the advisory boards of Richter Pharma, B\u00f6hringer-Ingelheim and Otsuka. SL has received honoraria as a consultant\/advisor and\/or for lectures from Angelini, B\u00f6hringer Ingelheim, Geodon & Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, SanofiAventis, Sandoz, Sunovion, TEVA. AH has been invited to scientific meetings by Lundbeck, Janssen-Cilag, and Pfizer, and he received paid speakerships from Desitin, Janssen-Cilag, Otsuka and Lundbeck. He was member of Roche, Otsuka, Lundbeck and Janssen-Cilag advisory boards.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"487"}}