Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications

Rationale To examine the D₂ occupancy of two commonly used antipsychotic medications and relate this to the D₂ occupancy by endogenous dopamine in schizophrenia.Objectives The aim of this study is to compare the occupancy of striatal D₂ receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D₂ occupancy by dopamine as a result of these treatments.Methods Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [¹²³I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V₃) after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]–1. D₂ receptor occupancy was calculated by comparing V₃ measured in treated patients to an age-corrected V₃ value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1–(V₃ treated/V₃ drug free).Results V₃ was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23±0.06 versus 0.34±0.08, P=0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69±8% versus 55±11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D₂ receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D₂ receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D₂ receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D₂ receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required.Conclusions These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D₂ receptors to levels slightly lower than those found in unmedicated healthy subjects.