Article

A PET Study Evaluating Dopamine D 2 Receptor Occupancy for Long-Acting Injectable Risperidone

Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada
American Journal of Psychiatry (Impact Factor: 12.3). 04/2006; 163(3):396-401. DOI: 10.1176/appi.ajp.163.3.396
Source: PubMed

ABSTRACT

Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks.
After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone.
Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy.
All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

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    • "Therefore, an atypical antipsychotic long-acting injection (LAI) into the muscle from which a sustainable and stable therapeutic effect can be expected for a certain period is a priority[5]. LAI is designed to be dissolved and to decompose at the muscle injection site and disseminated into the general circulation for several weeks[6]. In order to achieve the maximum effect of the drug, it is important to precisely inject LAI into the muscle. "

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    • "If the total dosages were too low to achieve optimal receptor occupancy, or if the elimination half-life of the oral drugs was too short to maintain optimal occupancy, RLAI therapy may not be sufficient to control disease symptoms. In Japan, the maximum dose of RLAI is limited to 50 mg/2-week, which is estimated to produce an occupancy range of 65.4 to 74.4% (Remington et al., 2006), corresponding to the optimal range for patients with a first schizophrenic episode (Kapur et al., 2000). Further studies are needed to clarify the accuracy of this data and its validity for subsequent episodes. "
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    • "In this study, a median plasma paliperidone concentration of above 7.5 ng/mL, which is associated with a central D2-receptor occupancy of approximately 60% [28], was reached within 2 to 4 days after the first dose. This is within the range (60-80%) associated with antipsychotic efficacy [29-33]. This also confirms that the 150 mg eq. "
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