Dissociation in Pharmacokinetic Attenuation Between Central Dopamine D₂ 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 D2 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 D2 occupancy with antipsychotics and their blood concentrations.

Data Extraction: The ratios of D2 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 D2 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.