Pharmacogenetics for the Individualization of Psychiatric Treatment

Arranz, Maria; Collier, David; Kerwin, Robert

doi:10.2165/00129785-200101010-00001

Cited by 34 publications

(15 citation statements)

References 93 publications

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“…[63][64][65][66] A drug with a higher average risk, for example, may be safe for those patients who inherited an ensemble of DNA markers with the most protective factors and the least risk factors. The ability to match a drug's genetic 'contour' with the DNA profile of an individual patient marks the beginning of high-resolution personalized pharmacotherapy for prevention of adverse drug reactions.…”

Section: Discussionmentioning

confidence: 99%

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

et al. 2007

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Atypical antipsychotics induce pre-diabetic symptoms in some but not all patients, characterized most notably by elevated weight. The side effect profiles of the various drugs in the class differ, however, raising the possibility of drug-specific mechanisms for similar side effects. We used physiogenomic analysis, an approach previously employed to study the genetics of drug and diet response, to discover and compare genetic associations with weight profiles observed in patients treated with olanzapine and risperidone as an approach to unraveling contrasting mechanistic features of both drugs. A total of 29 single nucleotide polymorphisms (SNPs) were selected from 13 candidate genes relevant to two potential pharmacological axes of psychotropic-related weight profiles, appetite peptides and peripheral lipid homeostasis. We applied physiogenomic analysis to a cross-section of 67 and 101 patients being treated with olanzapine and risperidone, respectively, and assessed genetic associations with the weight profiles. Weight profiles in patients treated with olanzapine were significantly associated with SNPs in the genes for apolipoprotein E, apolipoprotein A4 and scavenger receptor class B, member 1. Weight profiles in patients treated with risperidone were significantly associated with SNPs in the genes for leptin receptor, neuropeptide Y receptor Y5 and paraoxonase 1. These results are consistent with contrasting mechanisms for the weight profile of patients treated with these drugs. Genes associated with olanzapine weight profiles may be related to peripheral lipid homeostatic axes, whereas those associated with risperidone's may be related to brain appetite peptide regulation. Future physiogenomic studies will include neurotransmitter receptor SNPs and validation in independent samples.

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Section: Discussionmentioning

confidence: 99%

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

et al. 2007

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“…In fact, the therapeutic response of AD patients to conventional cholinesterase inhibitors is partially effective in only 10-20% of the cases, with side-effects, intolerance and non-compliance in more than 60% of the patients due to different reasons (e.g., efficacy, safety) [27,46]. Therefore, the individualization of therapy or pharmacological tailorization in AD and other CNS disorders is just a step forward of the longstanding goal of molecular pharmacogenomics [88][89][90] taking advantage from the information and procedures provided by the sequencing of the entire human genome [1].…”

Section: Pharmacogenomicsmentioning

confidence: 99%

Pharmacogenetic Aspects of Therapy with Cholinesterase Inhibitors: The Role of CYP2D6 in Alzheimers Disease Pharmacogenetics

Cacabelos¹,

Llovo²,

Fraile³

et al. 2007

CAR

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Recent studies demonstrate that the therapeutic response in Alzheimer's disease (AD) is genotype-specific. More than 200 genes are potentially associated with AD pathogenesis and neurodegeneration, and approximately 1,400 genes distributed across the human genome account for 20 to 95% of variability in drug disposition and pharmacodynamics. Cytochrome P450 enzymes encoded by genes of the CYP superfamily, such as CYP1A1 (15q22-q24), CYP2A6 (19q13.2), CYP2C8 (10q24), CYP2C9 (10q24), CYP2C19 (10q24.1-q24.3), CYP2D6 (22q13.1), CYP2E1 (10q24.3-qter), and CYP3A5 (7q22.1), acting as terminal oxidases in multicomponent electron transfer chains which are called P450-containing monooxygenase systems, metabolize more than 90% of drugs. Some of the enzymatic products of the CYP gene superfamily can share substrates, inhibitors and inducers whereas others are quite specific for their substrates and interacting drugs. Some cholinesterase inhibitors (tacrine, donepezil, galantamine) are metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. The distribution of CYP2D6 genotypes in the Spanish population is the following: (a) Extensive Metabolizers (EM)(51.61%): *1/*1, 47.10%; and *1/*10, 4.52%; (b) Intermediate Metabolizers (IM)(32.26%): *1/*3, 1.95%; *1/*4, 17.42%; *1/*5, 3.87%; *1/*6, 2.58%; *1/*7, 0.75%; *10/*10, 1.30%; *4/*10, 3.23%; *6/*10, 0.65%; and *7/*10, 0.65%; (b) Poor Metabolizers (PM)(9.03%): *4/*4, 8.37%; and *5/*5, 0.65%; and (c) Ultrarapid Metabolizers (UM)(7.10%): *1xN/*1, 4.52%; *1xN/*4, 1.95%; and CYP2D6 gene duplications, 0.65%. PMs and UMs also accumulate genotypes of risk associated with APOE-, PS-, ACE-, and PRNP-related genes. Approximately, 15% of the AD population may exhibit an abnormal metabolism of cholinesterase inhibitors; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of cholinesterase inhibitors to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including cholinesterase inhibitors (e.g., donepezil), the best responders are the CYP2D6-related EMs and IMs, and the worst responders are PMs and UMs. In addition, the presence of the APOE-4 allele in genetic clusters integrating CYP2D6 and APOE genotypes contributes to deteriorate the therapeutic outcome. From these data, it can be postulated that pharmacogenetic and pharmacogenomic factors are responsible for 75-85% of the therapeutic response in AD patients treated with conventional drugs.

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“…17,89,90 Dahl et al 91 evaluated the importance of genetic factors for the metabolism of clozapine and did not find significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between poor and extensive metabolizers of debrisoquine. Since clozapine is metabolized minimally by this enzyme, 92 more studies on clozapine metabolism would be helpful.…”

Section: Genetic Variants In Metabolizing Enzymes and Response To Trementioning

confidence: 99%

Pharmacogenetics in schizophrenia: a review of clozapine studies

Kohlrausch

2013

Rev. Bras. Psiquiatr.

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Objectives: Clozapine is quite effective to treat schizophrenia, but its use is complicated by several factors. Although many patients respond to antipsychotic therapy, about 50% of them exhibit inadequate response, and ineffective medication trials may entail weeks of unremitted illness, potential adverse drug reactions, and treatment nonadherence. This review of the literature sought to describe the main pharmacogenetic studies of clozapine and the genes that potentially influence response to treatment with this medication in schizophrenics. Methods: We searched the PubMed database for studies published in English in the last 20 years using keywords related to the topic. Results and Conclusions: Our search yielded 145 studies that met the search and selection criteria. Of these, 21 review articles were excluded. The 124 studies included for analysis showed controversial results. Therefore, efforts to identify key gene mechanisms that will be useful in predicting clozapine response and side effects have not been fully successful. Further studies with new analysis approaches and larger sample sizes are still required.

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Pharmacogenetics for the Individualization of Psychiatric Treatment

Cited by 34 publications

References 93 publications

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

Pharmacogenetic Aspects of Therapy with Cholinesterase Inhibitors: The Role of CYP2D6 in Alzheimers Disease Pharmacogenetics

Pharmacogenetics in schizophrenia: a review of clozapine studies

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