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Clozapine pharmacogenetics

Clement C Zai, Arun K Tiwari, Gwyneth C Zai, Miriam S Maes, James L Kennedy
PURPOSE OF REVIEW: This review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects. RECENT FINDINGS: Antipsychotics prescribed to treat psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported...
March 9, 2018: Current Opinion in Psychiatry
Kevin J Li, Aaron P Greenstein, Lynn E Delisi
PURPOSE OF REVIEW: To examine the recent literature regarding sudden death in patients with schizophrenia and synthesize salient conclusions based on this evidence. RECENT FINDINGS: Sudden cardiac death (SCD) is the largest subset of sudden unexpected death (SUD), with up to 40% of SUD from cardiovascular causes. SCD has been associated with exposure to both first and second-generation antipsychotics. Clozapine [odds ratio (OR) 3.67, 95% confidence interval (CI) 1...
March 6, 2018: Current Opinion in Psychiatry
Sthitapranjya Pati, Ankit Sood, Sourish Mukhopadhyay, Vidita A Vaidya
The medial prefrontal cortex (mPFC) is implicated in anxiety-like behaviour. In rodent models, perturbations of mPFC neuronal activity through pharmacological manipulations, optogenetic activation of mPFC neurons or cell-type specific pharmacogenetic inhibition of somatostatin interneurons indicate conflicting effects on anxiety-like behaviour. In the present study we examined the effects of pharmacogenetic activation of Ca 2+/calmodulin-dependent protein kinase alpha (CamKII alpha)-positive excitatory neurons on anxiety-like behaviour...
March 2018: Journal of Biosciences
François R Girardin, Antoine Poncet, Arnaud Perrier, Nathalie Vernaz, Mark Pletscher, Caroline F Samer, Jeffrey A Lieberman, Jean Villard
Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA...
January 3, 2018: Pharmacogenomics Journal
Ai-Jun Li, Qing Wang, Sue Ritter
Catecholamine (CA) neurons in the ventrolateral medulla (VLM) contribute importantly to glucoregulation during glucose deficit. However, it is not known which CA neurons elicit different glucoregulatory responses or whether selective activation of CA neurons is sufficient to elicit these responses. Therefore, to selectively activate CA subpopulations, we injected male or female Th-Cre+ transgenic rats with the Cre-dependent DREADD construct, AAV2-DIO-hSyn-hM3D(Gq)-mCherry, at one of 4 rostrocaudal levels of the VLM: rostral C1 (C1r), middle C1 (C1m), the area of A1 and C1 overlap (A1/C1) or A1...
October 24, 2017: Endocrinology
Irina Piatkov, Dorgival Caetano, Yolinda Assur, Sue Lynn Lau, Trudi Jones, Steven C Boyages, Mark McLean
Clozapine (CZ) has superior efficacy to other antipsychotic agents in the treatment of schizophrenia and has been extensively used in clinical practice. ATP-binding cassette (ABC) transporter proteins are responsible for the distribution of various molecules as well as drugs across extracellular and intracellular membranes, including the blood-brain barrier. Genetic variations in these proteins can account for differences in treatment response. We investigated the influence of ABCB1 rs1045642 and ABCC1 rs212090 single-nucleotide polymorphisms (SNPs) on CZ serum level, clinical outcome, and changes in body mass index (BMI) in the first year of CZ treatment...
2017: Pharmacogenomics and Personalized Medicine
Maurizio Pompili, Gloria Giordano, Mario Luciano, Dorian A. Lamis, Valeria Del Vecchio, Gianluca Serafini, Gaia Sampogna, Denise Erbuto, Peter Falkai, Andrea Fiorillo
The objectives of this article are to describe current trends in the treatment of schizophrenia and the most interesting new approaches to optimizing outcome and fostering the development of new schizophrenia treatments. RESULTS: Increasing utilization of diverse types of atypical antipsychotic drugs (AAPDs), e.g. clozapine-type serotonin (5-HT)2A and weak dopamine (DA) D2 antagonist, amisulpride, a D2/D3/5-HT7 antagonist, and cariprazine, a D3 partial agonist with additional neurotransmitter targets, is occurring as their advantages in efficacy, especially for cognitive impairment and mood symptoms, and side effects is becoming appreciated...
August 3, 2017: CNS & Neurological Disorders Drug Targets
Herbert Y Meltzer
The objectives of this article are to describe current trends in the treatment of schizophrenia and the most interesting new approaches to optimizing outcome and fostering the development of new schizophrenia treatments. RESULTS: Increasing utilization of diverse types of atypical antipsychotic drugs (AAPDs), e.g. clozapine-type serotonin (5-HT)2A and weak dopamine (DA) D2 antagonist, amisulpride, a D2/D3/5-HT7 antagonist, and cariprazine, a D3 partial agonist with additional neurotransmitter targets, is occurring as their advantages in efficacy, especially for cognitive impairment and mood symptoms, and side effects is becoming appreciated...
July 28, 2017: CNS & Neurological Disorders Drug Targets
Irina Piatkov, Dorgival Caetano, Yolinda Assur, Sue Lynn Lau, Micheline Coelho, Trudi Jones, Tristan Nguyen, Steven Boyages, Mark McLean
OBJECTIVES: Clozapine (CZ) is the most effective drug for managing treatment-resistant schizophrenic disorders. Its use has been limited due to adverse effects, which include weight gain and new-onset diabetes, but the incidence of these varies between patients. METHODS: We investigated 187 Clozapine Clinic patients (of whom 137 consented for genotyping) for the presence of CYP2C19*17 and its association with CZ and norclozapine (NCZ) levels, and clinical outcomes...
July 18, 2017: World Journal of Biological Psychiatry
Frederick C Nucifora, Marina Mihaljevic, Brian J Lee, Akira Sawa
Schizophrenia is a devastating illness that affects up to 1% of the population; it is characterized by a combination of positive symptoms, negative symptoms, and cognitive impairment. Currently, treatment consists of one class of medications known as antipsychotics, which include typical (first-generation) and atypical (second-generation) agents. Unfortunately, antipsychotic medications have limited efficacy, with up to a third of patients lacking a full response. Clozapine, the first atypical antipsychotic developed, is the only medication shown to be superior to all other antipsychotics...
July 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
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
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