Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response -: A double-blind PET study in schizophrenia

Blockade of dopamine D-2 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 D-2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D-2 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 D-2 occupancy levels across subjects. Clinical response, side effects, striatal ([C-11]-raclopride-positron emission tomography (PET)), and extrastriatal ([C-11]- FLB 457-PET) D-2 receptors were evaluated after treatment. The measured D-2 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 D-2 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 D-2 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 D-2 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 D-2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.