OBJECTIVE: This study sought to determine the relationships between
serum clozapine levels and therapeutic response. METHOD: Fifty-six
inpatients who met the DSM-III-R criteria for chronic schizophrenia and who
had not responded to extended treatment with classical antipsychotics were
randomly assigned to 12 weeks of double-blind treatment with clozapine at
one of three serum level ranges: low (50- 150 ng/ml), medium (200-300
ng/ml), or high (350-450 ng/ml). Baseline clinical assessments were
completed before the patients' regular antipsychotic and anticholinergic
drugs were discontinued. During clozapine treatment, serum levels were
ascertained weekly to allow adjustment of clozapine doses so as to maintain
each patient near the midpoint of his or her assigned serum level range.
Clinical assessments were completed after 6 and 12 weeks of treatment.
RESULTS: The analyses of the results of treatment supported the superior
efficacy of the 200- 300 ng/ml and 350-450 ng/ml serum clozapine level
ranges over the 50- 150 ng/ml range, with no advantage for 350-450 ng/ml
over 200-300 ng/ml. Sleepiness increased with increasing serum levels.
CONCLUSIONS: Serum clozapine levels per unit of daily dose were at the
lower end of the range noted in previous reports, possibly reflecting the
current study's dosing schedules of twice or three times a day, the 11- to
13- hour postdose sampling time, and the moderate doses given. Serum
clozapine levels, if interpreted in relation to daily clozapine dosing
schedules, postdose sampling time, and total daily dose, may help to guide
dosing to provide adequate opportunities for therapeutic response and to
limit certain side effects of clozapine treatment.