INDIVIDUAL VARIATION IN D-2 DOPAMINE-RECEPTOR OCCUPANCY IN CLOZAPINE-TREATED PATIENTS

Objective: The objectives of this study were 1) to pursue the question of clozapine's striatal D-2 occupancy in relation to its clinical eff ectiveness; 2) to investigate the relation between schizophrenic sympt oms, clozapine blood levels, and estimated D-2 occupancy during clinic ally stable and unstable conditions; and 3) to eh amine long-term stab ility in D-2 occupancy. Method: Specific binding of the D-2 radioligan d [I-123]benzamide [I-123]IBZM) was studied with single photon emissio n computed tomography in 13 patients with schizophrenia when they were clinically stable during chronic clozapine treatment, after clozapine dose reduction of greater than or equal to 50%, and in a subgroup (N= 7) after restabilization on clozapine regimens. Clozapine's estimated D-2 occupancy was based on comparison with values from drug-free norma l subjects. Results: A wide range of estimated D-2 occupancies (18% to greater than or equal to 80%) were associated with sustained, favorab le response to clozapine without correlation with residual symptoms. C lonzapine blood levels were negatively related to [(123)]IBZM specific binding. Acute dose reduction was associated with predicted worsening in positive and negative symptoms and increases in [I-123]IBZM specif ic binding. Independent of clozapine blood level, patients with more s ymptoms showed lower [I-123]IBZM specific binding, consistent with com petition of endogenous dopamine for D-2 binding sites in patients with greater symptoms. Restabilization on clozapine regimens produced D-2 Occupancies closely correlated with baseline values. Conclusions: Ther e was no evidence for a critical degree of D-2 occupancy required to s ustain clozapine's therapeutic effects across subjects. Simple linear regression was the best-fit model for clozapine's D-2 occupancy. Longi tudinal follow-up suggests stability over time of D-2 occupancy in rel ation to dose and clinical response within individual patients.