Pharmacokinetics and time-course of D^sub 2^ receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients

The sup123I-IBZM SPECT measured Dsub2 receptor occupancy (Dsub2RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal Dsub2 receptor occupancy (Dsub2RO) and plasma concentration (Csubp) in stabilized schizophrenic patients on clinically relevant doses using sup123I-IBZM SPECT; 2) To investigate the time course of AP-induced Dsub2RO and corresponding Csubp. Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. Dsub2RO and Csubp were measured over time following a sparse-sampling experimental design, and individual PK and Dsub2RO-time profiles were estimated using a population approach. Observed striatal Dsub2RO and Csubp ranges were 28-75% and 9.4-60.5 ng/mL for risperidone, 22-84% and 8.6-89.5 ng/mL for olanzapine, 5-53% and 41.6-818.2 ng/mL for clozapine and O-64% and 37.9-719.6 ng/mL for quetiapine. A PK-Dsub2RO relationship was found for the four APs. Dsub2RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both Dsub2RO and Csubp, at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with Dsub2RO below 65%. Dsub2RO patterns over time differ between AP. These results should be considered for accurate interpretation of Dsub2RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment. [PUBLICATION ABSTRACT]