Occupancy of dopamine D sub(2) receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications

Rationale: To examine the D sub(2) occupancy of two commonly used antipsychotic medications and relate this to the D sub(2) occupancy by endogenous dopamine in schizophrenia. Objectives: The aim of this study is to compare the occupancy of striatal D sub(2) receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D sub(2) 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 [ super(123)I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V sub(3) double prime ) after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]-1. D sub(2) receptor occupancy was calculated by comparing V sub(3) double prime measured in treated patients to an age-corrected V sub(3) double prime value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1-(V sub(3) double prime treated/V sub(3) double prime drug free). Results: V sub(3) double prime was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23 plus or minus 0.06 versus 0.34 plus or minus 0.08, P=0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69 plus or minus 8% versus 55 plus or minus 11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D sub(2) 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 D sub(2) receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D sub(2) receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D sub(2) 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 D sub(2) receptors to levels slightly lower than those found in unmedicated healthy subjects.