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Am J Psychiatry 1995; 152:1444-1449
Copyright © 1995 by American Psychiatric Association
D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients
AL Nordstrom, L Farde, S Nyberg, P Karlsson, C Halldin and G Sedvall
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
OBJECTIVE: Central D1, D2, and 5-HT2 receptor occupancy in schizophrenic
patients treated with clozapine was determined and related to clozapine
serum concentrations. METHOD: Seventeen patients treated with clozapine
(125-600 mg/day) were examined with positron emission tomography (PET) and
one to three of the following selective radioligands: [11C]SCH23390 (N =
11), [11C]raclopride (N = 16), and [11C]N-methylspiperone (N = 5).
Clozapine concentration in serum was determined by gas chromatography/mass
spectrometry. RESULTS: D2 receptor occupancy (20%-67%) was lower than that
previously determined in patients treated with classical neuroleptics
(70%-90%). D1 receptor occupancy (36%-59%) was higher than that induced by
classical neuroleptics (0%-44%). 5-HT2 receptor occupancy was very high
(84%- 94%), even at low clozapine doses. Despite a 20-fold range in
clozapine serum concentration (105-2121 ng/ml) at the time of PET
examination, D2 receptor occupancy was low in all patients and was not
described by the curvilinear relationship between serum drug concentration
and receptor occupancy that has been demonstrated for classical
antipsychotics. CONCLUSIONS: The results confirm in an extended series of
patients that clozapine is atypical with regard to degree of D2 receptor
occupancy, a finding that may explain the lack of extrapyramidal side
effects. The combination of relatively high D1, low D2, and very high 5-HT2
receptor occupancy values is unique to clozapine. Clozapine serum
concentrations have not been unequivocally shown to predict clinical
effects. In this study, concentration did not predict degree of occupancy
in brain. Thus, careful clinical titration cannot be replaced by monitoring
of drug concentrations for optimization of clozapine treatment in
individual patients.
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