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Clozapine pharmacogenetics

Huan-Xin Sun, Dian-Ru Wang, Chen-Bo Ye, Zhen-Zhen Hu, Chen-Yao Wang, Zhi-Li Huang, Su-Rong Yang
The ventral tegmental area (VTA) is crucial for brain functions, such as voluntary movement and cognition; however, the role of VTA in sleep-wake regulation when directly activated or inhibited remains unknown. In this study, we investigated the effects of activation or inhibition of VTA neurons on sleep-wake behavior using the pharmacogenetic "designer receptors exclusively activated by designer drugs (DREADD)" approach. Immunohistochemistry staining was performed to confirm the microinjection sites, and combined with electrophysiological experiments, to determine whether the VTA neurons were activated or inhibited...
2017: Sleep and Biological Rhythms
Danielle L Taylor, Arun K Tiwari, Jeffrey A Lieberman, Steven G Potkin, Herbert Y Meltzer, Joanne Knight, Gary Remington, Daniel J Müller, James L Kennedy
Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. GRM2 (rs4067 and rs2518461), SLC1A2 (rs4354668, rs4534557, and rs2901534), SLC6A9 (rs12037805, rs1978195, and rs16831558), GRIA1 (rs2195450), and GAD1 (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy...
February 2017: Molecular Neuropsychiatry
Kamini Vasudev, Yun-Hee Choi, Ross Norman, Richard B Kim, Ute I Schwarz
OBJECTIVE: Atypical antipychotics are linked to a higher incidence of metabolic side effects, including weight gain, dyslipidemia, and diabetes. In this study, we examined the prevalence and potential genetic predictors of metabolic side effects in 60 adult patients on clozapine. METHOD: Genetic variants of relevance to clozapine metabolism, clearance, and response were assessed through targeted genotyping of cytochrome P450 enzymes CYP1A2 and CYP2C19, the efflux transporter ABCB1, the serotonin receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR)...
February 2017: Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie
Trehani M Fonseka, Daniel J Müller, Sidney H Kennedy
Antipsychotic medications (APs), particularly second-generation APs, are associated with significant weight gain in schizophrenia patients. Recent evidence suggests that the immune system may contribute to antipsychotic-induced weight gain (AIWG) via AP-mediated alterations of cytokine levels. Antipsychotics with a high propensity for weight gain, such as clozapine and olanzapine, influence the expression of immune genes, and induce changes in serum cytokine levels to ultimately down-regulate neuroinflammation...
May 2016: Molecular Neuropsychiatry
Federico Manuel Daray, Demián Rodante, Laura G Carosella, María Elena Silva, Melina Martínez, María V Fernández Busch, Diego F Faccone, Rodolfo P Rothlin, Paulo C Maffía
Introduction: The HTR2C gene is an important candidate in pharmacogenetic studies of antipsychotic-induced weight gain (AIWG). However, inconsistent results have been obtained. The present study investigated the association between -759C>T, functional polymorphism of the HTR2C receptor, and AIWG. Methods: A prospective cohort of 48 female inpatients with schizophrenia and related illness treated according to normal clinical practice with second generation antipsychotics (SGAs) risperidone, clozapine, quetiapine, and olanzapine were evaluated...
January 2017: Pharmacopsychiatry
Yang Liu, Ying Huang, Tiemin Liu, Hua Wu, Huxing Cui, Laurent Gautron
Although Agouti-related peptide (AgRP) neurons play a key role in the regulation of food intake, their contribution to the anorexia caused by proinflammatory insults has yet to be identified. Using a combination of neuroanatomical and pharmacogenetics experiments, this study sought to investigate the importance of AgRP neurons and downstream targets in the anorexia caused by the peripheral administration of a moderate dose of lipopolysaccharide (LPS) (100 μg/kg, ip). First, in the C57/Bl6 mouse, we demonstrated that LPS induced c-fos in select AgRP-innervated brain sites involved in feeding but not in any arcuate proopiomelanocortin neurons...
June 2016: Endocrinology
Florence Gressier, Stefano Porcelli, Raffaella Calati, Alessandro Serretti
Clozapine (CLZ) is the prototype atypical antipsychotic and it has many advantages over other antipsychotic drugs. Several data suggest that both CLZ response and induced weight gain are strongly determined by genetic variability. However, results remain mainly inconclusive. We aim to review the literature data about pharmacogenetics studies on CLZ efficacy, focusing on pharmacodynamic genes. Further, we performed meta-analyses on response when at least three studies for each polymorphism were available. Sensitivity analyses were conducted on Caucasian population when feasible...
February 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Chenglin Miao, Qichen Cao, Hiroshi T Ito, Homare Yamahachi, Menno P Witter, May-Britt Moser, Edvard I Moser
Hippocampal place cells undergo remapping when the environment is changed. The mechanism of hippocampal remapping remains elusive but spatially modulated cells in the medial entorhinal cortex (MEC) have been identified as a possible contributor. Using pharmacogenetic and optogenetic approaches, we tested the role of MEC cells by examining in mice whether partial inactivation in MEC shifts hippocampal activity to a different subset of place cells with different receptive fields. The pharmacologically selective designer Gi-protein-coupled muscarinic receptor hM4D or the light-responsive microbial proton pump archaerhodopsin (ArchT) was expressed in MEC, and place cells were recorded after application of the inert ligand clozapine-N-oxide (CNO) or light at appropriate wavelengths...
November 4, 2015: Neuron
Venuja Sriretnakumar, Eric Huang, Daniel J Müller
INTRODUCTION: Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients' genetics, paving the way toward individualized treatment...
2015: Expert Opinion on Drug Metabolism & Toxicology
John Lally, James H MacCabe
INTRODUCTION: Antipsychotic medications are mainstays in the treatment of schizophrenia and a range of other psychotic disorders. SOURCES OF DATA: Recent meta-analyses of antipsychotic efficacy and tolerability have been included in this review, along with key papers on antipsychotic use in schizophrenia and other psychotic illnesses. AREAS OF AGREEMENT: The heterogeneity in terms of individuals' response to antipsychotic treatment and the current inability to predict response leads to a trial-and-error strategy with treatment choice...
June 2015: British Medical Bulletin
M Verbelen, D A Collier, D Cohen, J H MacCabe, C M Lewis
Clozapine is the only evidence-based therapy for treatment-resistant schizophrenia, but it induces agranulocytosis, a rare but potentially fatal haematological adverse reaction, in less than 1% of users. To improve safety, the drug is subject to mandatory haematological monitoring throughout the course of treatment, which is burdensome for the patient and one of the main reasons clozapine is underused. Therefore, a pharmacogenetic test is clinically useful if it identifies a group of patients for whom the agranulocytosis risk is low enough to alleviate monitoring requirements...
October 2015: Pharmacogenomics Journal
Joanna Oi-Yue Yau, Gavan P McNally
Pavlovian conditioning involves encoding the predictive relationship between a conditioned stimulus (CS) and an unconditioned stimulus, so that synaptic plasticity and learning is instructed by prediction error. Here we used pharmacogenetic techniques to show a causal relation between activity of rat dorsomedial prefrontal cortex (dmPFC) neurons and fear prediction error. We expressed the excitatory hM3Dq designer receptor exclusively activated by a designer drug (DREADD) in dmPFC and isolated actions of prediction error by using an associative blocking design...
January 7, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Veeramanikandan Rajagopal, Lakshmikirupa Sundaresan, Anto P Rajkumar, Chithra Chittybabu, Anju Kuruvilla, Alok Srivastava, Poonkuzhali Balasubramanian, Kuruthukulangara S Jacob, Molly Jacob
The use of clozapine, an effective antipsychotic drug used in treatment-resistant schizophrenia, is associated with adverse effects. Sialorrhea is one such effect, which can be distressing for many patients. Studies on the pharmacogenetics of the adverse effects of clozapine are limited. The aim of the present study was to determine whether clozapine-induced sialorrhea is associated with a 120 base-pairs (bp) tandem duplication polymorphism in the dopamine receptor subtype D4 (DRD4) gene. Ninety-five patients, mean age 35...
December 2014: Psychiatric Genetics
J-M Batail, B Langrée, G Robert, S Bleher, M-C Verdier, E Bellissant, B Millet, D Drapier
Schizophrenia is a chronic illness with a progressive course that can be marked by resistance to antipsychotic treatment. This can make therapeutic support challenging for the practitioner, with results that are partial and unsatisfactory. In the literature, treatment with high-dose olanzapine (>20mg/day) appears to be a good alternative to clozapine, the gold standard for treatment-resistant schizophrenia. In the present observational prospective study, we studied the clinical and biological profiles of patients treated with olanzapine doses up to 100mg/day...
November 2014: Schizophrenia Research
Trehani M Fonseka, Margaret A Richter, Daniel J Müller
Second generation antipsychotics (SGAs) have been implicated in the de novo emergence and exacerbation of obsessive-compulsive symptoms (OCS) in patients with schizophrenia. Among SGAs, clozapine, olanzapine, and risperidone are the most prominent agents associated with these sequelae, according to case reports. Comorbid OCS can impede recovery by compromising treatment benefits, medication compliance, and clinical prognoses. Previous reviews of SGA-induced OCS have predominantly focused on descriptive case reports, with limited attention paid toward experimental findings...
November 2014: Current Psychiatry Reports
Ayumu Inutsuka, Azusa Inui, Sawako Tabuchi, Tomomi Tsunematsu, Michael Lazarus, Akihiro Yamanaka
Orexin neurons in the hypothalamus regulate energy homeostasis by coordinating various physiological responses. Past studies have shown the role of the orexin peptide itself; however, orexin neurons contain not only orexin but also other neurotransmitters such as glutamate and dynorphin. In this study, we examined the physiological role of orexin neurons in feeding behavior and metabolism by pharmacogenetic activation and chronic ablation. We generated novel orexin-Cre mice and utilized Cre-dependent adeno-associated virus vectors to express Gq-coupled modified GPCR, hM3Dq or diphtheria toxin fragment A in orexin neurons...
October 2014: Neuropharmacology
Maria Teresa Dell'Anno, Massimiliano Caiazzo, Damiana Leo, Elena Dvoretskova, Lucian Medrihan, Gaia Colasante, Serena Giannelli, Ilda Theka, Giovanni Russo, Liudmila Mus, Gianni Pezzoli, Raul R Gainetdinov, Fabio Benfenati, Stefano Taverna, Alexander Dityatev, Vania Broccoli
Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson's disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene-independent stable phenotype in culture and in animal models...
July 2014: Journal of Clinical Investigation
Mark D Brennan
This review considers pharmacogenetics of the so called 'second-generation' antipsychotics. Findings for polymorphisms replicating in more than one study are emphasized and compared and contrasted with larger-scale candidate gene studies and genome-wide association study analyses. Variants in three types of genes are discussed: pharmacokinetic genes associated with drug metabolism and disposition, pharmacodynamic genes encoding drug targets, and pharmacotypic genes impacting disease presentation and subtype...
April 2014: Pharmacogenomics
Aaron Jenkins, José A Apud, Fengyu Zhang, Heather Decot, Daniel R Weinberger, Amanda J Law
Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia...
August 2014: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Luis Abel Quinones, Maria Alejandra Lavanderos, Juan Pablo Cayun, Elena Garcia-Martin, Jose Augusto Agundez, Dante Daniel Caceres, Angela Margarita Roco, Jorge E Morales, Luisa Herrera, Gonzalo Encina, Carlos Alberto Isaza, Maria Ana Redal, Laura Larovere, Nestor Walter Soria, Javier Eslava-Schmalbach, Gilberto Castaneda-Hernandez, Andres Lopez-Cortes, Luiz Alexandre Magno, Marisol Lopez, Miguel Angel Chiurillo, Idania Rodeiro, Dinorah Castro de Guerra, Enrique Teran, Francisco Estevez-Carrizo, Ismael Lares-Assef
Pharmacogenetics and Pharmacogenomics areas are currently emerging fields focused to manage pharmacotherapy that may prevent undertreatment while avoiding associated drug toxicity in patients. Large international differences in the awareness and in the use of pharmacogenomic testing are presumed, but not well assessed to date. In the present study we review the awareness of Latin American scientific community about pharmacogenomic testing and the perceived barriers for their clinical application. In order to that, we have compiled information from 9 countries of the region using a structured survey which is compared with surveys previously performed in USA and Spain...
February 2014: Current Drug Metabolism
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