Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D Receptor Occupancy and Peripheral Blood Concentration of Antipsychotics: A Systematic Review

Objective: The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D receptor occupancy with antipsychotics and their peripheral blood concentrations. Data Sources: MEDLINE and Embase were searched using the following keywords : (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). Study Selection: The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D occupancy with antipsychotics and their blood concentrations. Data Extraction: The ratios of D occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. Results: Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D occupancy-dependent fashion. It contrarily increased in a time-dependent manner. Conclusions: The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.