Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: Multilocus interaction in the mTOR pathway

Mas, Sergi; Gassó, Patricia; Ritter, Marie A; Malagelada, Cristina; Bernardo, Miquel; Lafuente, Amàlia

doi:10.1016/j.euroneuro.2014.11.011

Cited by 33 publications

(22 citation statements)

References 36 publications

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“…For each drug, the pharmacogenomics interpretative report (Additional file 1: Figure S3) highlights gene-drug interactions and provides drug-specific treatment recommendations as per FDA-approved drug labeling [13], published pharmacogenetic guidelines [11, 12, 28] and selected clinical studies [29–35]. For example, in a patient carrying the CYP2D6*4/*4 diplotype (predicted as a poor metabolizer phenotype), the antidepressant amitriptyline will be highlighted in yellow and the following recommendation will be associated to the drug: “Consider an alternative drug not metabolized by this pathway.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial

et al. 2017

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BackgroundA 12-week, double-blind, parallel, multi-center randomized controlled trial in 316 adult patients with major depressive disorder (MDD) was conducted to evaluate the effectiveness of pharmacogenetic (PGx) testing for drug therapy guidance.MethodsPatients with a CGI-S ≥ 4 and requiring antidepressant medication de novo or changes in their medication regime were recruited at 18 Spanish public hospitals, genotyped with a commercial PGx panel (Neuropharmagen®), and randomized to PGx-guided treatment (n = 155) or treatment as usual (TAU, control group, n = 161), using a computer-generated random list that locked or unlocked psychiatrist access to the results of the PGx panel depending on group allocation. The primary endpoint was the proportion of patients achieving a sustained response (Patient Global Impression of Improvement, PGI-I ≤ 2) within the 12-week follow-up. Patients and interviewers collecting the PGI-I ratings were blinded to group allocation. Between-group differences were evaluated using χ2-test or t-test, as per data type.ResultsTwo hundred eighty patients were available for analysis at the end of the 12-week follow-up (PGx n = 136, TAU n = 144). A difference in sustained response within the study period (primary outcome) was not observed (38.5% vs 34.4%, p = 0.4735; OR = 1.19 [95%CI 0.74-1.92]), but the PGx-guided treatment group had a higher responder rate compared to TAU at 12 weeks (47.8% vs 36.1%, p = 0.0476; OR = 1.62 [95%CI 1.00-2.61]), and this difference increased after removing subjects in the PGx-guided group when clinicians explicitly reported not to follow the test recommendations (51.3% vs 36.1%, p = 0.0135; OR = 1.86 [95%CI 1.13-3.05]). Effects were more consistent in patients with 1–3 failed drug trials. In subjects reporting side effects burden at baseline, odds of achieving a better tolerability (Frequency, Intensity and Burden of Side Effects Rating Burden subscore ≤2) were higher in the PGx-guided group than in controls at 6 weeks and maintained at 12 weeks (68.5% vs 51.4%, p = 0.0260; OR = 2.06 [95%CI 1.09-3.89]).ConclusionsPGx-guided treatment resulted in significant improvement of MDD patient’s response at 12 weeks, dependent on the number of previously failed medication trials, but not on sustained response during the study period. Burden of side effects was also significantly reduced.Trial registrationEuropean Clinical Trials Database 2013-002228-18, registration date September 16, 2013; ClinicalTrials.gov NCT02529462, retrospectively registered: August 19, 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-017-1412-1) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial

et al. 2017

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“…Previous work from our lab, using genome-wide gene expression analysis, revealed a connection between the development of EPS and the mTOR pathway in mice striatum and in peripheral blood of naïve patients suffering a first episode of psychosis [9][10][11]. Recently, various authors have implicated the mTOR signaling pathway in the modulation exerted by AP drugs such as thioridazine [12,13], olanzapine [14], haloperidol [15,16] and risperidone [17], among others.…”

Section: Introductionmentioning

confidence: 99%

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

García-Cerro¹,

Mas²,

Gortat³

et al. 2018

Neuropsychiatry

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Objective: Acute extrapyramidal symptoms (EPS) are frequent and serious adverse reactions to antipsychotic (AP) drugs. Although the proposed mechanism is an excessive blockade of dopamine D2 receptors in the striatopallidal pathway of the striatum, previous studies implicated the mTOR pathway in the susceptibility to EPS. The objective of the present study is to analyze the mTOR-mediated response to risperidone in subpopulations of striatal neurons and its relationship to risperidone-induced motor side effects. Methods:Two mouse strains (A/J and DBA/2J) with different susceptibility to developing EPS were treated with risperidone 1 mg/kg for three consecutive days. Here we monitored, by double labeling immunohistochemistry, ribosomal protein S6 (rpS6) phosphorylation (Ser235/236 and Ser244/247 sites), a marker of mTOR signaling, in the striatonigral pathway (D1-medium spiny neurons (MSNs)), the striatopallidal pathway (D2-MSNs) and striatal cholinergic interneurons. Results:We found that EPS-resistant DBA/2J mice show higher baseline levels of phosphoactivated rpS6 protein in striatal MSNs, compared with EPS-prone A/J mice. Moreover, risperidone differentially targeted rpS6 phosphorylation in direct and indirect pathway neurons in a strain-specific manner: a significant decrease in the phosphorylation of rpS6 at Ser235/236 and Ser240/244 in DRD1-MSNs EPS-resistant DBA/2J mice after; and a significant increase of phospho-Ser235/236-rpS6 in the striatopallidal pathway of the EPS-prone A/J mice in response to risperidone. Conclusions:Our results reveal the vital role of genetic background in the response to risperidone, and point to the mTOR pathway as an important factor in EPS susceptibility.

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“…TSC2 строго регулируется с помощью RTP801 (ген DDIT4), который, в свою очередь, зависит от активности Parkin (ген PARK2) и FCHSD1. Поскольку активность mTOR зависит от AKT, регулятор активности AKT DISC1, связанный с шизофренией, также был включен в путь (Mas et al, 2014).…”

Section: взаимодействие дофаминового сигналлинга и путей регуляции Mtorunclassified

“…TSC2 is heavily regulated by RTP801 (gene name DDIT4) which in turns depends on Parkin (gene name PARK2) and FCHSD1 activity. DISC1, a regulator of AKT activity related to schizophrenia, has been included in the pathway (Mas et al, 2014).…”

Section: взаимодействие дофаминового сигналлинга и путей регуляции Mtormentioning

confidence: 99%

Перспективы моделирования лекарственноиндуцированных гиперкинезов на Drosophila melanogaster

2019

Letters to Vavilov Journal of Genetics and Breeding

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1 Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук, Новосибирск, Россия 2 Новосибирский национальный исследовательский государственный университет, Новосибирск, Россия Aннотация. В обзоре рассмотрены перспективы моделирования лекарственно-индуцированных гиперкинезов на животных, в частности, на Drosophila melanogaster. Представлены данные по известным на настоящий момент моделям расстройств аутистического спектра на дрозофиле. Приведены сведения о связанности и эволюционной консервативности сигнальных путей дофамина и mTOR, задействованных в этих моделях. Обсуждается гипотеза о том, что нарушения в сигнальном пути mTOR повышают вероятность возникновения лекарственных гиперкинезов, а также возможность поиска вариантов фармакологической коррекции лекарственно-индуцированных гиперкинезов с использованием в качестве модельных животных D. melanogaster.Kлючевые слова: Drosophila melanogaster; дофаминовые рецепторы; сигнальный путь mTOR; расстройства аутистического спектра; L-ДОФА-индуцированные дискинезии; тардивная дискинезия; фармакологическая коррекция.Благодарности. Работа поддержана государственным бюджетным проектом № 0324-2019-0041. Обзор / ReviewПисьма в Вавиловский журнал генетики и селекции. 2019;5(1):6-12 Введение В последние десятилетия резко возросло использование нейролептиков для коррекции нейропсихических расстройств, особенно среди детей и подростков. Одним из самых часто встречающихся побочных эффектов приема длительных курсов нейролептиков являются медикаментозно индуцированные ги- Prospects for the simulation of drug-induced hyperkinesis on Drosophila melanogasterAbstract. The review analyses the prospects of studying drug-induced hyperkinesis in animal models, Drosophila melanogaster in particular. The data on currently known Drosophila models of autism spectrum disorders and the data on connectivity and evolutionary conservatism of dopamine and mTOR signaling pathways are presented. The hypothesis on the probability of drug-induced hyperkinesis occurrence being increased by the disturbance in mTOR signaling pathway is discussed as well as the possibility of searching for pharmacological correction options with the use of D. melanogaster as a model.

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Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: Multilocus interaction in the mTOR pathway

Cited by 33 publications

References 36 publications

Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial

Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

Перспективы моделирования лекарственноиндуцированных гиперкинезов на Drosophila melanogaster

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