Effects of antipsychotic drug on dopamine synthesis in humans measured by PET with [C-11]DOPA

Objectives Effects of antipsychotic drugs have been considered to be mediated by blockade of dopamine D2 receptors. In this study, changes in dopamine synthesis rate by administration of second-generation antipsychotics were measured by PET.

Methods PET studies were performed on 12 healthy men under resting condition (baseline study) and oral administration of single dose of antipsychotic drug, risperidone of 0.5-2.0 mg, (drug challenge study) on separate days. In each study, both PET scans with [C-11]raclopride and [C-11]DOPA were performed sequentially. The occupancy of dopamine D2 receptors by risperidone was calculated from binding potential values in the striatum for baseline and drug challenge studies with [C-11]raclopride determined by the SRTM method. The uptake rate constant, Ki, for [C-11]DOPA in the striatum indicating the dopamine synthesis rate was estimated by the graphical analysis.

Results The occupancies of dopamine D2 receptors were 39%-75%. The dopamine synthesis rate Ki were 0.0136±0.0017 and 0.0142±0.0010 (1/min) for the baseline and drug challenge studies, respectively, and no significant change in Ki by risperidone was observed. A significant negative correlation was observed between the baseline Ki and the change in Ki by risperidone (r=-0.87).

Conclusions The negative correlation between the baseline Ki and the change in Ki by risperidone, and smaller coefficient of variation of Ki in drug challenge studies than in baseline studies indicate that risperidone can be considered to stabilize the level of dopamine synthesis rate. Therapeutic effects of risperidone on schizophrenia might be related to stabilizing effects on dopaminergic neurotransmission responsivity in dopamine release.