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.