Signalling profile differences: paliperidone versus risperidone

Abstract

BACKGROUND AND PURPOSEPaliperidone is an active metabolite of the second-generation atypical antipsychotic, risperidone recently approved for the treatment of schizophrenia and schizoaffective disorder. Because paliperidone differs from risperidone by only a single hydroxyl group, questions have been raised as to whether there are significant differences in the effects elicited between these two drugs. EXPERIMENTAL APPROACHWe compared the relative efficacies of paliperidone versus risperidone to regulate several cellular signalling pathways coupled to four selected GPCR targets that are important for either therapeutic or adverse effects: human dopamine D2, human serotonin 2A receptor subtype (5-HT2A), human serotonin 2C receptor subtype and human histamine H1 receptors. KEY RESULTSWhereas the relative efficacies of paliperidone and risperidone were the same for some responses, significant differences were found for several receptor-signalling systems, with paliperidone having greater or less relative efficacy than risperidone depending upon the receptor-response pair. Interestingly, for 5-HT2A-mediated recruitment of β-arrestin, 5-HT2A-mediated sensitization of ERK, and dopamine D2-mediated sensitization of adenylyl cyclase signalling, both paliperidone and risperidone behaved as agonists. CONCLUSIONS AND IMPLICATIONSThese results suggest that the single hydroxyl group of paliperidone promotes receptor conformations that can differ from those of risperidone leading to differences in the spectrum of regulation of cellular signal transduction cascades. Such differences in signalling at the cellular level could lead to differences between paliperidone and risperidone in therapeutic efficacy or in the generation of adverse effects. AbbreviationsAA, arachidonic acid; APD, antipsychotic drug; G protein, guanine nucleotide-binding protein; 5-HT2A, serotonin 2A receptor subtype; 5-HT2C, serotonin 2C receptor subtype

Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

“…There is no available data describing psychotropic drug impact on lymphocytic ERK activation. In vitro and murine data describing antipsychotic ERK activation effects have included reports of risperidone-associated desensitization to ERK activation (Clarke et al, 2013), aripiprazole-associated suppression of ERK activation (Ishii et al, 2010), and quetiapine having no impact on ERK activation (Pereira et al, 2014). The alpha2-agonist literature regarding ERK activation is very limited with one report of the alpha2-agonist xylazine being associated with reduction in ERK activation in rat brain (Peng et al, 1998).…”

An update of safety of clinically used atypical antipsychotics

“…nM for paliperidone) [135]. Paliperidone has a D 2 receptor affinity approximately 3 times lower than risperidone, which may explain a lower incidence of EPS.…”

Paliperidone Metabolic Effects in Children and Adolescents: A Case Report

“…Almandil and Wong (1) emphasised the increasing concern regarding the appropriate use of atypical antipsychotics, as these drugs are likely to cause metabolic abnormalities, such as weight gain, obesity, hyperglycaemia and changes in blood lipid levels. One of the atypical antipsychotics, paliperidone, is the major active metabolite of risperidone (2). The main aim of this study is to present the use of paliperidone and its side effects in the treatment of adolescent patient with mental retardation and behavioural disorder.…”