Am J Psychiatry 1996; 153:1571-1578
Copyright © 1996 by American Psychiatric Association
Individual variation in D2 dopamine receptor occupancy in clozapine- treated patients
D Pickar, TP Su, DR Weinberger, R Coppola, AK Malhotra, MB Knable, KS Lee, J Gorey, JJ Bartko, A Breier and J Hsiao
Experimental Therapeutics Branch, NIMH, Bethesda, MD 20892-1380, USA.
OBJECTIVE: The objectives of this study were 1) to pursue the question of
clozapine's striatal D2 occupancy in relation to its clinical
effectiveness; 2) to investigate the relation between schizophrenic
symptoms, clozapine blood levels, and estimated D2 occupancy during
clinically stable and unstable conditions; and 3) to examine long-term
stability in D2 occupancy. METHOD: Specific binding of the D2 radioligand
[123I]benzamide ([123I]IBZM) was studied with single photon emission
computed tomography in 13 patients with schizophrenia when they were
clinically stable during chronic clozapine treatment, after clozapine dose
reduction of > or = 50%, and in a subgroup (N = 7) after restabilization
on clozapine regimens. Clozapine's estimated D2 occupancy was based on
comparison with values from drug-free normal subjects. RESULTS: A wide
range of estimated D2 occupancies (18% to > or = 80%) were associated
with sustained, favorable response to clozapine without correlation with
residual symptoms. Clozapine blood levels were negatively related to
[123I]IBZM specific binding. Acute dose reduction was associated with
predicted worsening in positive and negative symptoms and increases in
[123I]IBZM specific binding. Independent of clozapine blood level, patients
with more symptoms showed lower [123I]IBZM specific binding, consistent
with competition of endogenous dopamine for D2 binding sites in patients
with greater symptoms. Restabilization on clozapine regimens produced D2
occupancies closely correlated with baseline values. CONCLUSIONS: There was
no evidence for a critical degree of D2 occupancy required to sustain
clozapine's therapeutic effects across subjects. Simple linear regression
was the best-fit model for clozapine's D2 occupancy. Longitudinal follow-up
suggests stability over time of D2 occupancy in relation to dose and
clinical response within individual patients.
