Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

Abstract

Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [ 18 F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.

Pharmacogenomics and Efficacy of Risperidone Long‐Term Treatment in Thai Autistic Children and Adolescents

“…However, the results did not show a statistically significant difference due to small sample size. Although risperidone and its metabolite showed some difference in pharmacokinetics and pharmacodynamics properties , the response was not significantly different . Active moiety concentration, the sum of RIS and 9‐OH RIS, plays a major role in efficacy of risperidone.…”

A systematic microdialysis study of dopamine transmission in the accumbens shell/core and prefrontal cortex after acute antipsychotics

“…Less lipophilic drugs like amisulpride and sulpiride, which slowly enter the brain (Mauri et al 1996;Rosenzweig et al 2002), or like risperidone, which is rapidly converted into the less liposoluble 9-hydroxy metabolite, paliperidone (Mannens et al 1993;Muly et al 2012), given in appropriate doses, increase DA preferentially in shell because the absence of the initial overshoot allows titration of the drug to doses that preferentially activate DA in the shell, an area with higher responsivity of DA transmission compared to the core due to a lower level of DA transporter (Calipari et al 2012;Wu et al 2001). However, once NAc shell DA has reached its maximal stimulation, higher doses would further increase DA in the core, with loss of preferential shell DA activation.…”

Behavioral Mechanisms That Depend on Dopamine and Serotonin in Caenorhabditis elegans Interact With the Antipsychotics Risperidone and Aripiprazole

“… 32 Our results show that both risperidone and aripiprazole reduced the capability of the N2 wild type to react to gentle touch ( Figure 1 ). These antipsychotics are antagonists 33 and partial agonists 34 of the human DRD2 dopamine receptor, respectively. Caenorhabditis elegans has 2 orthologues, DOP-2 and DOP-3, for the DRD2 receptor.…”