Positron emission tomography (PET) studies of dopamine receptor occupancy can be used to assess dosing of antipsychotics. Typically, studies of antipsychotics have applied pharmacodynamic (PD) modeling alone to characterize the relationship between antipsychotic dose and its effect on the brain. However, a limitation of this approach is that it does not account for the discrepancy between the time courses of plasma concentration and receptor occupancy by antipsychotics. Combined pharmacokinetic-PD (PK-PD) modeling, by incorporating the time dependence of occupancy, is better suited for the reliable analysis of the concentration-occupancy relationship. To determine the effect of time on the concentration-occupancy relationship as a function of analysis approach, we measured dopamine receptor occupancy after the administration of aripiprazole using [(11)C]raclopride PET and obtained serial measurements of the plasma aripiprazole concentration in 18 volunteers. We then developed a PK-PD model for the relationship, and compared it with conventional approach (PD modeling alone). The hysteresis characteristics were observed in the competitor concentration-occupancy relationship and the value of EC(50) was different according to the analysis approach (EC(50) derived from PD modeling alone=11.1 ng/mL (95% confidence interval (CI)=10.1 to 12.1); while that derived from combined PK-PD modeling=8.63 ng/mL (95% CI=7.75 to 9.51)). This finding suggests that PK-PD modeling is required to obtain reliable prediction of brain occupancy by antipsychotics.