Occupancy of dopamine D1, D2 and serotonin2A receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol

Rationale Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine D-2, D-1 and 5-HT2A receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol's interaction with 5-HT2A and/or D-1 receptors. Objectives To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 +/- 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 +/- 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 +/- 5.5 mg/day). Materials and methods Each patient underwent two PET scans with 3-N-[C-11]methylspiperone (target: frontal 5-HT2A), [C-11]SCH23390 (striatal D-1) or [C-11]raclopride (striatal D-2). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls. Results D-2-RO under FLX was between 50% and 70%, indicating an ED50 of about 0.7 ng/ml serum. 5-HT2A and D-1-RO was 20 +/- 10% and 20 +/- 5% (mean, SEM). Under HAL, D-1-RO was 14 +/- 6% and under RIS not significantly different from zero. Conclusions We were able to demonstrate a moderate 5-HT2A and D-1 occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation. Therefore, if flupentixol's efficacy on negative symptoms is based on its interaction with 5-HT2A and/or D-1 receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest that mechanisms other than D-1 or 5-HT2A antagonism may contribute to flupentixol's efficacy on negative symptoms.