A critical review of the early clozapine trials published in German and a discussion of the many unresolved issues left by these trials.

Clozapine was (1) first introduced in Austria and Switzerland in 1972, (2) associated with 8 Finnish deaths due to agranulocytosis in 1975 (almost leading to its withdrawal), and (3) approved in the United States (US) for treatment-resistant schizophrenia in 1989 (resulting in a worldwide resurrection). 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.