Search

In previous work we developed a pharmacogenetic predictor of antipsychotic (AP) induced extrapyramidal symptoms (EPS) based on four genes involved in mTOR regulation. The main objective is to improve this predictor by increasing its biological plausibility and replication. We re-sequence the four genes using next-generation sequencing. We predict functionality "in silico" of all identified SNPs and test it using gene reporter assays. Using functional SNPs, we develop a new predictor utilizing machine learning algorithms (Discovery Cohort, N = 131) and replicate it in two independent cohorts (Replication Cohort 1, N = 113; Replication Cohort 2, N = 113). After prioritization, four SNPs were used to develop the pharmacogenetic predictor of AP-induced EPS. The model constructed using the Naive Bayes algorithm achieved a 66% of accuracy in the Discovery Cohort, and similar performances in the replication cohorts. The result is an improved pharmacogenetic predictor of AP-induced EPS, which is more robust and generalizable than the original.

Risperidone (R) is the most prescribed antipsychotic drug for patients with a first episode of psychosis (FEP). In a naturalistic cohort of chronic psychiatric inpatients, we demonstrated that clinicians adjust R dosage by CYP2D6 activity, despite being blinded to the genotype, which we described as an "intuitive pharmacogenetic" process. The aim of the present study is to replicate our previous findings of intuitive pharmacogenetic in a cohort of FEP patients using CYP2D6 phenotype extrapolated from genotypes. 70 FEP patients, under baseline treatment with R monotherapy were genotyped using the iPLEX® ADME PGx multiplex panel and TaqMan® Genotyping and Copy Number Assays. Plasma concentrations of R and its metabolite, 9-hydroxyrisperidone (9-OH), were determined. The predictive properties of those variables associated with R dosage were tested using a multiple linear regression model as well as regression trees. Significant differences in the mean daily dosage of R among CYP2D6 phenotypes were observed (Kruskal-Wallis test p=0.02): PM (4.00±2.3mg/mL), IM (4.56±2.44), EM (6.22±4.0mg/day) and UM (10.20±4.91mg/day). However, non-significant differences were observed in the R/9-OH ratio or in the Concentration/Dose ratio. Regression tree provided better estimations of R dosage than the multiple linear regression model (MAE=0.958 and R 2 =0.871). We confirm the "intuitive pharmacogenetic" dosing of R according to the CYP2D6 phenotype in a FEP cohort. The results presented provides a rationale for the clinical use of CYP2D6 genotyping in personalized medicine., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Aim: To elucidate the relationship between CYP2D6 genotype and risperidone pharmacokinetics and extrapyramidal symptoms we propose the APSEP pharmacogenetic clinical trial., Materials & Methods: Twenty-five healthy subjects were included in this randomized, placebo-controlled, single dose (risperidone 2.5 mg) crossover and double-blind clinical trial. Subjects were selected according to their CYP2D6 genotype and classified as: poor metabolizers (n = 8), extensive metabolizers (n = 10) and ultrarapid metabolizers (n = 7)., Results & Conclusion: Our study demonstrates that CYP2D6 predicted 65% of the risperidone metabolism variability. Moreover, its ability to predict actigraphy records is similar to the predictive power of pharmacokinetic parameters (24%). Our results also highlight the need for the development of pharmacogenetic predictors that take into account the complexity of pharmacokinetic and pharmacodynamic relationships.

Objective: The effect of antipsychotics (APs) on negative symptoms is controversial. The present study assessed negative symptoms in healthy volunteers without any source of primary negative symptoms after single doses of haloperidol and risperidone., Methods: Twenty-five healthy subjects were included in this randomized, placebo-controlled, single-dose (haloperidol 5 mg and risperidone 2.5 mg) crossover and double-blind clinical trial. Negative symptoms were assessed by observer-rated scales and with a self-report scale. Possible confounding effects considered were extrapyramidal symptoms (EPS) and sedative effects. The occupation of striatal dopamine D2 receptors was also determined., Results: Risperidone induced a wide range of negative symptoms such as alogia, blunted affect, avolition/apathy, and attention impairment, whereas haloperidol only induced the avolition/apathy subdomain. Most of the effects of risperidone in healthy volunteers, with the exception of its effects on avolition/apathy, were attributable to AP-induced EPS. Haloperidol did not cause significant EPS after administration. No effect of sedation or psychomotor performance was observed on negative symptoms., Conclusions: Single doses of both haloperidol and risperidone induced nonmotor secondary negative symptoms in healthy volunteers. The clinical findings are especially relevant in view of the impact of negative symptoms on poor functioning. They may help to guide clinicians in their choice of APs (http://clinicaltrials.gov/ct2/show/NCT01259973)., (Copyright © 2013 John Wiley & Sons, Ltd.)

Risperidone is a potent antagonist of both dopamine and serotonin receptors. However, little is known about the underlying molecular mechanism by which risperidone acts. Although a number of genetic variants have been observed to correlate with treatment response there are no definitive predictors of response. We performed a genome-wide gene expression analysis (Human Genome U219 Array Plate) of a human neuroblastoma cell line (SK-N-SH) exposed to risperidone to identify molecular mechanisms involved in the cellular response to risperidone and thus identify candidate genes for pharmacogenetic studies. Our results revealed that cellular risperidone treatment is associated with a range of gene expression changes, which are time (6-48h) and dose related (0.1-10μM). We found that functional clusters of these changes correspond to Gene Ontology categories related to neural cell development functions, and synaptic structure and functions. We also identified Canonical Pathways related to these functional categories: neurogenesis and axon guidance; synaptic vesicle; and neurotransmitter signaling (dopamine, serotonin and glutamate). Finally, we identified candidate genes for pharmacogenetic studies related to the main risperidone secondary effects: motor disorders, cardiovascular disorders and metabolic disorders. Our results suggest that risperidone treatment affects the neurogenesis and neurotransmission of neuroblastoma cells, which is in agreement with the "initiation and adaptation" model to explain the mechanism of action of psychotropic drugs., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

The neurotoxicity of antipsychotic (AP) drugs seems to be linked with neurological side effects like extrapyramidal symptoms (EPS). On the other hand, neuroprotective effects can mitigate or slow the progressive degenerative structural changes in the brain leading to improved outcome of schizophrenia. First and second-generation antipsychotics may differ in their neurotoxic and neuroprotective properties. The aim of this study was to compare the neurotoxic/neuroprotective activity of haloperidol, a first-generation antipsychotic, and risperidone, a second-generation one, with paliperidone, a relatively new second-generation antipsychotic, in SK-N-SH cells. Haloperidol, risperidone and paliperidone (10, 50, 100 μM) were administered, either alone or in combination with dopamine (100 μM), to human neuroblastoma SK-N-SH. We examined the effects of the drugs on cell viability (measured by alamarBlue®), caspase-3 activity (measured by fluorimetric assay) and cell death (by measuring the externalization of phosphatidylserine). Haloperidol significantly decreased cell viability and increased caspase-3 activity and cell death. Risperidone and paliperidone did not affect cell viability or cell death. Both second-generation APs decreased caspase-3 activity, especially paliperidone. In cells treated with dopamine in combination with antipsychotics, only paliperidone (10 μM) induced a slight improvement in cell viability. While haloperidol potentiated the dopamine-induced increase in caspase-3 activity, risperidone and paliperidone reduced this effect. The results indicate that haloperidol induces apoptosis, whereas risperidone and paliperidone may afford protection against it. Of the APs tested, paliperidone always showed the strongest neuroprotective effect. The different antipsychotic effects on survival and cell death might be related to differences in their capacity to induce EPS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Previously one intronic DRD3 SNP, rs167771, was associated with risperidone-induced extrapyramidal side-effects (EPS). The aim of the present study was to search hitherto unidentified common functional variants or rare variants, in DRD3 associated with risperidone-induced EPS. 126 subjects treated with risperidone participated in this study. We sequenced the seven exons of DRD3. After sequencing we localized five dbSNPs and four new rare variants. None of the dSNPs or rare variants seems to be functional after bioinformatics analysis. Our results suggest that, rather than exonic regions, regulatory regions and introns could be related to the associations reported for DRD3 and the incidence of locomotor side-effects., (Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.)