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A Preliminary Finding of an Antipsychotic Effect With Only Transiently High Dopamine D₂ Receptor Occupancy

Shitij Kapur, MD, PhD, FRCPC; Robert Zipursky, MD, FRCPC; Corey Jones, BSc; C. S. Shammi, MD, FRCPC; Gary Remington, MD, PhD, FRCPC; Philip Seeman, MD, PhD

Arch Gen Psychiatry. 2000;57:553-559.

Background  Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2 (D₂) and serotonin type 2a (5-HT_2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile.

Methods  Twelve patients with schizophrenia were randomly assigned to doses of 150 to 600 mg/d (n=3, at 150, 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of treatment, D₂ and 5-HT_2a occupancy were measured using positron emission tomography (PET) imaging, 12 to 14 hours after the last dose. Clinical efficacy and adverse effect ratings were obtained at baseline, at the time of PET scanning, and at 12 weeks. Two additional patients were included to examine the effects of the drug 2 to 3 hours after last dose.

Results  Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and prolactin level elevation noted at baseline. It achieved these results with minimal (0%-27%) D₂ occupancy 12 hours after the last dose. Study of the additional subjects revealed that quetiapine does give rise to transiently high (58%-64%) D₂ occupancy 2 to 3 hours after a single dose that then decreases to minimal levels in 12 hours.

Conclusions  Quetiapine shows a transiently high D₂ occupancy, which decreases to very low levels by the end of the dosing interval. Quetiapine's low D₂ occupancy can explain its freedom from extrapyramidal symptoms and prolactin level elevation. The data suggest that transient D₂ occupancy may be sufficient for its antipsychotic effect. Future studies controlling for nonpharmacological effects as well as activities on other receptors will be necessary to confirm this suggestion.

From the Schizophrenia Program (Drs Kapur, Zipurksy, Jones, Shammi, and Remington) and PET Centre (Drs Kapur and Jones), the Clarke Division of the CAMH, Department of Psychiatry (Drs Kapur, Zipursky, Shammi, Remington, and Seeman), and the Department of Pharmacology, University of Toronto, Toronto, Ontario (Dr Seeman).

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