An association study of debrisoquine hydroxylase (CYP2D6) polymorphisms in schizophrenia

Dawson, Elisabeth; Powell, J.; Nöthen, M. M.; Crocq, Marc‐Antoine; Lanczik, M.; Körner, Judith; Rietschel, Marcella; Os, Jim van; Wright, Pádraig; Gill, Michael

doi:10.1097/00041444-199400440-00005

Cited by 21 publications

(7 citation statements)

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“…A lower frequency of PMs than expected has been observed in schizophrenia inpatients , which is in agreement with previous studies . Other studies did not find these differences . However, these studies should be interpreted with caution since they only analyzed two or three defective CYP2D6 variant alleles ( *3 , *4 , and/or *10 ) as causing PM status, and/or used a diverse control group.…”

Section: Cyp2d6 and Vulnerability To Psychopathology: Studies In Patisupporting

confidence: 90%

CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics‐guided clinical trials

Peñas-Lledó¹,

LLerena

2014

Brit J Clinical Pharma

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Individual and population differences in polymorphic cytochrome P450 enzyme function have been known for decades. The biological significance of these differences has now been deciphered with regard to drug metabolism, action and toxicity as well as disposition of endogenous substrates, including neuroactive compounds. While the cytochrome P450 enzymes occur abundantly in the liver, they are expressed in most tissues of the body, albeit in varying amounts, including the brain. The latter location of cytochrome P450s is highly pertinent for susceptibility to neuropsychiatric diseases, not to mention local drug metabolism at the site of psychotropic drug action in the brain. In the current era of personality medicine with companion theranostics (i.e. the fusion of therapeutics with diagnostics), this article underscores that such versatile biological roles of cytochrome P450s offer multiple points of entry for personalized medicine and rational therapeutics. We focus our discussion on CYP2D6, one of the most intensively researched drug and endogenous compound metabolism pathways, with a view to relevance for, and optimization of, pharmacogenomic-guided clinical trials. Working on the premise that CYP2D6 is related to human behaviour and certain personality traits such as serotonin and dopamine system function, we further suggest that the motivation of healthy volunteers to participate in clinical trials may in part be influenced by an under-or over-representation of certain CYP2D6 metabolic groups. CYP2D6 genetic polymorphisms and neuroactive endogenous compound metabolismAmong cytochrome P450s, CYP2D6 is one of the most intensively researched and clinically important enzymes involved in the metabolism of a large number of widely used central nervous system (CNS) drugs. CYP2D6 is highly polymorphic. Multiple allelic variants of the CYP2D6 gene have been identified, which are associated with an absent or increased enzyme activity in individuals who are respectively so called poor (PMs) and extensive metabolizers (EMs), including in the latter group a subgroup of ultrarapid metabolizers (UMs). This polymorphic enzyme is involved in the metabolism of many drugs of relevance to psychiatry, neurology and addiction medicine such as antidepressants, antipsychotics and opioids [1, 2]. Moreover, CYP2D6 has also been shown to contribute to endogenous metabolism of neuroactive substrates, which can explain the associations hitherto observed with human behaviour and disease susceptibility (e.g., personality, neurocognition and neuropsychiatric disorders) [3, 4] CYP2D6 was identified in both animal and human brain tissues in the late 1980s [5]. More than a decade later, dextromethorphan to dextrorphan metabolism was demonstrated in human brain microsomes [6]. CYPD6 has been described in neurons in the human cerebral cortex, hippocampus and cerebellum [7], basal ganglia and midbrain [8, 9]. Other studies have provided additional evidence of CYP2D6 expression in these brain regions and the thalamus [10] as well as in glial cel...

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Section: Cyp2d6 and Vulnerability To Psychopathology: Studies In Patisupporting

confidence: 90%

CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics‐guided clinical trials

Peñas-Lledó¹,

LLerena

2014

Brit J Clinical Pharma

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“…Vallada et al [26] reported no evidence for linkage between the CYP2D6 locus on chromosome 22 and schizophrenia in 23 multiply affected families. Dawson et al [27] report no evidence for alleles association between the A and B alleles of CYP2D6 and schizophrenia using a sample of 200 unrelated affected individuals, since alleles frequencies did not deviate significantly from those observed in control populations. This indicates that there is no hidden stratification of allele frequencies in schizophrenic populations which might alter our conclusions.…”

Section: Discussionmentioning

confidence: 93%

Cytochrome P4502D6 genotype does not determine response to clozapine.

Arranz

Dawson

et al. 1995

Brit J Clinical Pharma

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“…Although one study showed a lower frequency of PMs in schizophrenic patients than in healthy subjects [11], previous studies of CYP2D6 found no association with schizophrenia [23][24][25][26][27]. Moreover, the meta-analysis provided by the Schizophrenia Research Forum reported no significant association between the main PM alleles, CYP2D6*3 and *4, and schizophrenia (OR = 0.95, 95% CI = 0.78-1.15; OR = 1.17, 95% CI = 0.61-2.…”

Section: Discussionmentioning

confidence: 99%

Lack of association between schizophrenia and polymorphisms in dopamine metabolism and transport genes

Álvarez

Mas

Gassó

et al. 2010

Fundamemntal Clinical Pharma

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We investigated the relationship between several functional polymorphisms in genes coding for dopamine metabolism and transport enzymes (MAO-A VNTR; MAO-A 941T>G; DAT VNTR; DAT -67A/T; CYP2D6*3; CYP2D6*4; CYP2D6*5; CYP2D6*6) and the frequency of schizophrenia. Participants in the study were 242 subjects diagnosed with schizophrenia and related disorders and 290 hospital-based controls. Genomic DNA was isolated from whole blood and genotyped by several methods. However, there was no association between schizophrenia and the alleles, genotypes or diplotypes that were studied or their interactions. Polymorphisms in genes coding for dopamine metabolism and transport enzymes did not predispose to or protect from schizophrenia and related disorders.

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An association study of debrisoquine hydroxylase (CYP2D6) polymorphisms in schizophrenia

Cited by 21 publications

References 0 publications

CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics‐guided clinical trials

CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics‐guided clinical trials

Cytochrome P4502D6 genotype does not determine response to clozapine.

Lack of association between schizophrenia and polymorphisms in dopamine metabolism and transport genes

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