1. ¹Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, ON, Canada
2. ²PET Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada
3. ³Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

Correspondence: Dr S Kapur, Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, 33 Russell Street, Toronto, ON, Canada M5S 2S1. Tel: +1 416 979 6890; Fax: +1 416 260 4206; E-mail: shitij_kapur@camh.net

Received 29 June 2006; Revised 6 September 2006; Accepted 11 September 2006; Published online 1 November 2006.

Abstract

Blockade of dopamine D₂ receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D₂ receptors may be more critical to antipsychotic response than the striatal dopamine D₂ receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D₂ occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D₂ occupancy levels across subjects. Clinical response, side effects, striatal ([¹¹C]-raclopride-positron emission tomography (PET)), and extrastriatal ([¹¹C]-FLB 457-PET) D₂ receptors were evaluated after treatment. The measured D₂ occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D₂ occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D₂ occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D₂ blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D₂ blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.