The introduction of clozapine at the Nathan Kline Institute in New York and its long-term consequences

Nathan S. Kline was a pioneer in psychopharmacology in the United States (US). In 1952, Kline started a research unit at Rockland State Hospital, New York. Kline brought clozapine from Switzerland since it was not yet available in the US. At Rockland State Hospital, George Simpson had conducted antipsychotic trials and had developed scales to assess movement disorders. In 1974, Simpson published the first US clozapine trial. In 1978, he published on 1) the effect of clozapine on tardive dyskinesia and 2) high plasma clozapine concentrations in two patients with seizures. His experience of clozapine withdrawal symptoms in his first 2 trials led in the future to more articles in this area. In Philadelphia, Simpson designed a double-blind randomized clinical trial (RCT) with 3 doses (100, 300 and 600 mg/day) which was published in 1999. From the 50 patients started on the RCT, 47 provided repeated plasma clozapine concentrations every other week of the RCT. This rich database of plasma clozapine concentrations under controlled conditions has contributed to many of the advances in clozapine pharmacokinetics in the last 5 years including: 1) obesity can be associated with clozapine poor metabolism (PM) status, 2) a clozapine ultrarapid metabolizer (UM) with a minimum therapeutic dose of 1591 mg/day, 3) a case of clozapine intoxication dropped from the RCT due to pneumonia, 4) cases of increased plasma concentrations during clozapine-induced fever, 5) the possibility that African-Americans may need higher clozapine doses than those of European ancestry, and 6) three indices of non-adherence.