Membrane transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are efflux pumps that remove drugs from the brain back to the peripheral blood compartment, serving as a functional component of the blood-brain barrier (BBB). We report here that coadministration of the P-gp and BCRP inhibitor ketoconazole with risperidone may preferentially increase D2 receptor occupancy in the striatum compared to pituitary. Four male patients with schizophrenia or schizoaffective disorder who had received at least 4 prior injections of the long-acting risperidone at a stable dose of 25 to 50 mg participated in this positron emission tomography study. Multiple-dose ketoconazole coadministration reduced the P-gp activity as shown by fexofenadine oral challenge. Importantly, we found a strong statistical trend in this sample of 4 subjects who consistently showed a decrease in striatal fluorine 18 (F)-fallypride binding (an indication of increased D2 receptor occupancy) after ketoconazole coadministration (P = 0.057), whereas the pituitary (a region that lies outside the BBB) F-fallypride binding did not change (P = 0.99). These observations warrant further research with selective drug transporter inhibitors. We suggest that in neuroimaging studies, the pituitary drug occupancy can serve as a useful new "positive control" to evaluate whether drug occupancy is preferentially increased in brain regions that fall inside the BBB after cotreatment with P-gp and BCRP inhibitors. This is a noteworthy study design consideration regarding the future clinical testing of novel adjunct interventions aimed at modulating membrane transporter function at the BBB, with the goal of augmenting drug access into the brain compartment, particularly in treatment-resistant psychiatric illness.