Striatal and extrastriatal dopamine D2 receptor occupancy by paliperidone extended-release tablets: A PET study

Background and aims: Paliperidone is a novel antipsychotic drug in development for the treatment of schizophrenia. It shows almost the same pharmacological profile as risperidone of which it is the active metabolite with high affinity for dopamine D2 receptor and serotonin 5-HT2 receptor. Paliperidone ER is the extended-release (ER) formulation of paliperidone, which enables low peak to trough fluctuations and it was approved by FDA (USA) for the treatment of schizophrenia in mid December 2006. In this study, we evaluated the therapeutic dose range of paliperidone ER in the patients with schizophrenia using positron emission tomography (PET). The difference in dopamine D2 receptor occupancy by paliperidone ER between the striatal and extrastriatal regions was also investigated. Methods: Thirteen male patients (age range 22-40 yr; mean ± S.D., 29.4 ± 5.4 yr) who were diagnosed with schizophrenia according to the DSM-IV criteria participated in this study. They received no more than one oral antipsychotic drug prior to the entry. This study was conducted as a part of an open-label phase IIa trial of paliperidone ER in Japan (Sponsored by Janssen Pharmaceutical K.K.). Before the study initiation, a written informed consent (IC) was obtained from all patients participated. The paliperidone ER doses were 3 mg/day in 6 patients, 9 mg/day in 4 patients and 15 mg/day in 3 patients given once daily. The clinical symptoms were assessed with the positive and negative symptom scale (PANSS) at baseline (pre-dose) and at endpoint. The extrapyramidal symptoms were assessed by clinical observations. Two PET scans per patient were performed at least 2 weeks after the initiation of treatment with paliperidone ER on a same day with [11C]raclopride and [11C]FLB 457 for measurement of striatal and extrastriatal dopamine D2 receptor occupancy, respectively. This study was approved by the Ethics and Radiation Safety Committee of National Institute of Radiological Sciences, Chiba, Japan. Results: The dopamine D2 receptor occupancy in the striatum measured with [11C]raclopride was 54.2% to 85.5% and that in the temporal cortex measured with [11C]FLB 457 was 34.5% to 87.3%. ED50 in the striatum was 2.38 mg/day and 6.65 ng/ml and that in the temporal cortex was 2.84 mg/day and 7.73 ng/ml. There was no significant difference of dopamine D2 receptor occupancy between the striatum and the temporal cortex at any doses. Average PANSS scores of all patients were 62.9 ± 16.5 at baseline and 58.5 ± 16.8 at endpoint. Three patients, 2 patients in 15mg and 1 patient in 9mg, showed extrapyramidal symptoms during the course of the study. Conclusions: The data from this study suggests that about 5-10 mg of paliperidone ER has a comprehensive benefit-risk ratio. No significant difference of dopamine D2 receptor occupancy was observed between striatal and extrastriatal regions, indicating no regional selectivity of paliperidone.