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Is Regionally Selective D₂/D₃ Dopamine Occupancy Sufficient for Atypical Antipsychotic Effect? An In Vivo Quantitative [¹²³I]Epidepride SPET Study of Amisulpride-Treated Patients

OBJECTIVE: Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D₂ and serotonin 5-HT_2A receptors or 2) selective action at limbic cortical dopamine D₂-like receptors with modest striatal D₂ receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D₂/D₃ dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors’ goal was to evaluate whether treatment with amisulpride results in "limbic selective" D₂/D₃ receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [¹²³I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a healthy volunteer comparison group (N=6). RESULTS: Eight amisulpride-treated patients (mean dose=406 mg/day) showed moderate levels of D₂/D₃ receptor occupancy in the striatum (56%), and significantly higher levels were seen in the thalamus (78%) and temporal cortex (82%). CONCLUSIONS: Treatment with amisulpride results in a similar pattern of limbic cortical over striatal D₂/D₃ receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D₂ receptor occupancy and preferential occupancy of limbic cortical dopamine D₂/D₃ receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT_2A receptor antagonism.

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