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This article reviews the 1960s\/1970s trials published in German that brought about the first approval of clozapine; they are not included in PubMed and received no attention in previous historical articles. Prior historical manuscripts and the references of identified articles provide us with 13 early trials published in German. The first was unsuccessful. Randomization, double-blindness, and control antipsychotic agents were used in 1 of 10 single-center trials and a multicenter trial. Most trials focused on schizophrenia. The efficacy of clozapine in (1) mania was proposed by Angst in the Swiss trials, and (2) aggression across psychiatric diagnoses by an Austrian trial. These trials did not discuss titrations; a study by Blum and Mauruschat focused on physiological changes and first identified fever in the absence of infection during clozapine titrations (called benign hyperthermia in the US). These limited early trials leading to the introduction of clozapine in the 1970s in German-speaking countries produced many unresolved issues. Our discussion reviews the most important aspects that were clarified but not completely resolved in later years, including (1) risk of agranulocytosis, (2) titration and dosing, and (3) indications. Further clarifications and advances are limited by the lack of funding, as clozapine is a generic drug.<\/jats:p>","DOI":"10.1007\/s00210-026-05742-7","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T01:40:50Z","timestamp":1785548450000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A critical review of the early clozapine trials published in German and a discussion of the many unresolved issues left by these trials"],"prefix":"10.1007","author":[{"given":"Stefano","family":"Ferrea","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7756-2314","authenticated-orcid":false,"given":"Jose","family":"de Leon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6253-5225","authenticated-orcid":false,"given":"Pierre","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otto","family":"Benkert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanfried","family":"Helmchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7254-5646","authenticated-orcid":false,"given":"Christoph U.","family":"Correll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3851-4117","authenticated-orcid":false,"given":"Georgios","family":"Schoretsanitis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"5742_CR1","first-page":"984","volume":"24","author":"M Ackenheil","year":"1974","unstructured":"Ackenheil M, Beckmann H, Hoffmann G, Markianos E, Nystr\u00f6m I, Raese J (1974) Einfluss von Clozapin auf die MHPG-, HVS- und 5-HIES-Ausscheidung im Urin und Liquor cerebrospinalis [Effect of clozapine on the excretion of 3-methoxy-4-hydroxy-phenylglycol, homovanillic acid and 5-hydroxy-indole acetic acid in urine and cerebrospinal fluid]. 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CUC has been a consultant and\/or advisor to or has received honoraria from: AbbVie, Alkermes, Allergan, Angelini, Aristo, Autobahn, Aytu, Axsome, Boehringer-Ingelheim, Brandaris, Bristol-Meyers Squibb, Cardio Diagnostics, Casasco, Cerevel, CNX Therapeutics, Cogstate, Compass Pathways, Darnitsa, Delpor, Denovo, Draig, Eli Lilly, Eumentis Therapeutics, Gedeon Richter, GH Research, Hetero, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen\/J&J, Karuna, LB Pharma, Lundbeck, Mapi, Maplight, MedInCell, MedLink Global, Merck, Mindpax, Mitsubishi Tanabe Pharmaceuticals, Mylan, Neumora Therapeutics, Neuraxpharm, Neurocrine, Neurelis, Neurosterix, NeuShen, Neusignal Therapeutics, Newron, Noven, Novo Nordisk, Orion Pharma, Om, Oruka, Otsuka, Phrenix, PPD Biotech, qCell, Recognify Life Science, Recordati, Relmada, Response Pharmaeutical, Reviva, Roemmers, Rovi, Saladax, Sanofi, Seqirus, Serina, Servier, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Syremis, Tabuk, Takeda, Teva, Terran, Tolmar, Vertex, Viatris and Xenon Pharmaceuticals. He provided expert testimony for Janssen, Lundbeck, Neurocrine, and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, IntraCellular Therapies, Relmada, Reviva, Rovi and Teva. He has received grant support from Boehringer-Ingelheim, Janssen and Takeda. He received royalties from UpToDate and is also a stock option or stock holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharmaceuticals, Medincell, MedLink Global, Mindpax, Quantic, Terran. GS has served as a consultant for Dexcel Pharma, HLS Therapeutics, Lundbeck\/Otsuka, Roche and Thermo Fisher Scientific and has received speaker\u2019s fees from HLS Therapeutics, Lundbeck\/Otsuka, OM Suisse and Sadalax. He holds shares of Medincell and Maplight.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}