Pharmacogenomics in Psychiatry: Implications for Practice

Moore, Thea R.; Hill, Angela M.; Panguluri, Siva K.

doi:10.2174/1872208309666140904113615

Cited by 19 publications

(10 citation statements)

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“…Sex was not found to be a risk factor in our sample, although some studies indicate a higher risk among women. 7,38 Recent reviews point that the cause of agranulocytosis is not dose related or correlated with a certain ethnic group, 39 although some earlier studies suggested increased or lower risk in certain populations (higher in Scandinavians, Ashkenazic Jews, lower in Chinese). 40 No relation with clozapine dose was found in the present study, and to our knowledge, special susceptibility for CAA does not exist for Turkish patients.…”

Section: Discussionmentioning

confidence: 99%

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

Yağcıoğlu

Yoca

Ayhan

et al. 2016

Journal of Clinical Psychopharmacology

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Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.

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Section: Discussionmentioning

confidence: 99%

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

Yağcıoğlu

Yoca

Ayhan

et al. 2016

Journal of Clinical Psychopharmacology

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“…[12][13][14] With regards to TRS and SRS genetic components, variability in cytochrome P450 (CYP) enzyme activities have been described as significant in influencing CLZ bioavailability. [15][16][17] CYP3A4 and CYP1A2 are primarily responsible for the formation of N-desmethylclozapine, 18,19 with CYP2C19 playing a role and CYP2C9 and 2D6 playing more modest roles. 20 In light of these functions, our group previously observed CYP1A2*1F polymorphism associations with SRS, 9 thereby shedding some light on the relevance of CYP-genetic polymorphisms in CLZ responses.…”

Section: Introductionmentioning

confidence: 99%

<p>The CYP2C192 and CYP2C1917 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>

Rodrigues-Silva¹,

Semedo²,

Neri³

et al. 2020

NDT

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Introduction: Clozapine (CLZ) is the gold standard drug for treatment-refractory schizophrenia (TRS). However, approximately 30% of patients partially respond to CLZ, defining this subset with super refractory schizophrenia (SRS). Alterations in enzyme activity may affect CLZ responses; the CYP3A4, CYP1A2 and CYP2C19 genes are primarily responsible for CLZ metabolism. Objective: The aim of this study was to assess if CYP2C19 variants were associated with TRS or SRS. Methods: CYP2C19*2 loss-of-function and CYP2C19*17 gain-of-function polymorphism genotype testing were performed in 108 individuals undergoing pharmacological treatment for TRS or SRS. DNA was extracted and polymorphisms were analyzed by polymerase chain reaction (PCR) and sequencing. Results: CYP2C19*17 had positive correlations with SRS and lower Brief Psychiatric Rating Scale (BPRS) scores for TRS. In addition, CYP2C19*2 was associated with lower CLZ dosages for TRS. Conclusion: These results show that CYP2C19*2 and CYP2C19*17 polymorphisms influence CLZ responses during schizophrenia treatment.

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“…Clinical, demographic and genetic specific profiles could contribute in different ratios to significant interpatient variability noticed in both therapeutic efficacy and adverse drug reactions (ADR) (Moore, Hill & Panguluri, 2014;Tauser 2012). "Antipsychotic Trials of Intervention Effectiveness" (CATIE) estimates that over 70% of chronic schizophrenia patients stopped the antipsychotics because of sub-optimal efficacy or safety and treatment-resistant schizophrenia (TRS) affects ~30% of patients (Eum, Lee, & Bishop, 2016).…”

Section: Pharmacogenomics: the Promise Of Personalized Psychotropic Tmentioning

confidence: 99%

Pharmacogenomics in Psychiatric Disorders

Taușer

2020

BRAIN

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The broad arsenal of psychotropic medications is characterised by significant interindividual variability in clinical response and adverse effects, stringent monitoring requirements, potential drug-drug interactions, difficult long-term adherence and high costs. Pharmacogenomics investigates the correlation between genetic polymorphisms and responsiveness to drugs and could provide a valuable guide to fulfill the promise of personalized therapy in the context of the genomic medicine era, by tailoring treatment based on the patient's specific genetic markers. The present paper overviews the current advances in the clinical applications of pharmacogenomics to individualized psychotropic therapy. Material and methods. The relevant recent pharmacogenomics literature is selected and analysed in order to illustrate the impact on the clinical outcomes and quality of life in psychiatric patients of the genetic variants in the neurotransmitter receptors (dopamine and serotonin), metabolic pathways of drugs (cytochrome CYP450 2D6 and 2C19) and the human leukocyte antigen system. The paper focuses on some of the major psychotropic drug classes, such as: antipsychotics, antidepressants and mood stabilizers. Validation of statistically significant pharmacogenomics relationships has enabled the development and market approval of some predictive tests which are already integrated into some psychotropic drugs label. Results and discussions. Predictive pharmacogenomics tests have changed the classical approach of prescription "trial-and error" and "one dose fits all patients" towards personalized therapy. In addition, in new therapeutic candidates' clinical development, pharmacogenomics practically guides the clinical studies design, by substantially reducing the failure rates, costs and exposure risks of non-responders patients to new drugs. Current translation barriers of predictive pharmacogenomic tests from bench to clinical practice are also discussed. Conclusion. The paper emphasizes the current progress and future prospects in the field of pharmacogenomics as a guide to personalized therapy of psychiatric disorders, by: a) pretreatment selection of the right drug, prescribed in its optimized dose, to the right patient, according to one's specific genetic biomarkers; b) by improved clinical trials design based on genetic stratification of patients' population into responders versus nonresponders, especially in the costly phases III and IV.

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Pharmacogenomics in Psychiatry: Implications for Practice

Cited by 19 publications

References 14 publications

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

<p>The CYP2C192 and CYP2C1917 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>

Pharmacogenomics in Psychiatric Disorders

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Pharmacogenomics in Psychiatry: Implications for Practice

Cited by 19 publications

References 14 publications

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

<p>The CYP2C19*2 and CYP2C19*17 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>

Pharmacogenomics in Psychiatric Disorders

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<p>The CYP2C192 and CYP2C1917 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia</p>