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

• Published in: The American journal of psychiatry 2003-08, Vol.160 (8), p.1413-1420
• Main Authors: Bressan, Rodrigo A., Erlandsson, Kjell, Jones, Hugh M., Mulligan, Rachel, Flanagan, Robert J., Ell, Peter J., Pilowsky, Lyn S.
• Format: Article
• Language: English
• Subjects: Adult; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Benzamides - metabolism; Biological and medical sciences; Corpus Striatum - diagnostic imaging; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine D2 Receptor Antagonists; Female; Humans; Iodine Radioisotopes - metabolism; Limbic System - diagnostic imaging; Limbic System - drug effects; Limbic System - metabolism; Male; Medical sciences; Middle Aged; Neuropharmacology; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrrolidines - metabolism; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3; Schizophrenia - drug therapy; Schizophrenia - metabolism; Sulpiride - analogs & derivatives; Sulpiride - metabolism; Sulpiride - pharmacology; Sulpiride - therapeutic use; Temporal Lobe - diagnostic imaging; Temporal Lobe - drug effects; Temporal Lobe - metabolism; Thalamus - diagnostic imaging; Thalamus - drug effects; Thalamus - metabolism; Tomography, Emission-Computed, Single-Photon
• ISSN: 0002-953X; 1535-7228
• DOI: 10.1176/appi.ajp.160.8.1413

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-HT2A 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-HT2A receptor antagonism.