THE D-2 DOPAMINE-RECEPTOR OCCUPANCY OF RISPERIDONE AND ITS RELATIONSHIP TO EXTRAPYRAMIDAL SYMPTOMS - A PET STUDY

Risperidone is a recently introduced neuroleptic distinguished by a decreased incidence of extrapyramidal side effects (EPS). The mechanism of its low EPS is unclear. Since it has been shown that EPS is related to the level of D-2 receptor occupancy, we studied nine patients receiving 2-6 mg/day of risperidone using [C-11]-raclopride PET scans in order to determine the in vivo D-2 receptor binding characteristics of risperidone. The mean level of receptor occupancy was 66% at 2 mg; 73% at 4 mg; and 79% at 6 mg. Three patients, those with the highest receptor occupancies, exhibited mild EPS, though none required anitparkinsonian medications. Our results suggest that at doses of 4-6 mg the in vivo D-2 receptor occupancy of risperidone is similar to that of typical neuroleptics and higher than that of clozapine. This would suggest that the EPS benefits of risperidone cannot be explained by a low D-2 binding but may be related to its high 5-HT2 affinity. However, the emergence of EPS at higher levels of D-2 receptor occupancy, in this study and in previous clinical trials, would suggest that risperidone's high 5-HT2 affinity provides only a relative protection from EPS. And once the D-2 occupancy exceeds a certain threshold this 'relative' 5-HT2-mediated protection from EPS may be lost.