Is regionally selective D-2/D-3 dopamine occupancy sufficient for atypical antipsychotic effect? - An in vivo quantitative [I-123]epidepride SPET study of amisulpride-treated patients

TY - JOUR

T1 - Is regionally selective D-2/D-3 dopamine occupancy sufficient for atypical antipsychotic effect? - An in vivo quantitative [I-123]epidepride SPET study of amisulpride-treated patients

AU - Bressan, R A

AU - Erlandsson, K

AU - Jones, H M

AU - Mulligan, R

AU - Flanagan, R J

AU - Ell, P J

AU - Pilowsky, L S

PY - 2003

Y1 - 2003

N2 - 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 D-2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D-2-like receptors with modest striatal D-2 receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D-2/D-3 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" D-2/D-3 receptor blockade in vivo. Method: Five hours of dynamic single photon emission tomography data were acquired after injection of [I-123]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 D-2/D-3 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 D-2/D-3 receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D-2 receptor occupancy and preferential occupancy of limbic cortical dopamine D-2/D-3 receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT2A receptor antagonism.

AB - 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 D-2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D-2-like receptors with modest striatal D-2 receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D-2/D-3 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" D-2/D-3 receptor blockade in vivo. Method: Five hours of dynamic single photon emission tomography data were acquired after injection of [I-123]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 D-2/D-3 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 D-2/D-3 receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D-2 receptor occupancy and preferential occupancy of limbic cortical dopamine D-2/D-3 receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT2A receptor antagonism.

M3 - Conference paper

SN - 1535-7228

VL - 160

SP - 1413

EP - 1420

JO - The American Journal of Psychiatry

JF - The American Journal of Psychiatry

IS - 8

T2 - Summer Meeting of the British-Association-for-Psychopharmacology

Y2 - 1 January 2003

ER -