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Influence of CYP2D6 and CYP2C19 Gene Variants on Antidepressant

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Influence of CYP2D6 and CYP2C19 Gene Variants on Antidepressant The Pharmacogenomics Journal (2014) 14, 176–181 & 2014 Macmillan Publishers Limited All rights reserved 1470-269X/14 www.nature.com/tpj ORIGINAL ARTICLE Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder EJ Brandl1,2, AK Tiwari1,2, X Zhou2,3, J Deluce2,3, JL Kennedy1,2,DJMu¨ ller1,2,4 and MA Richter1,2,3,4 Numerous studies have reported on pharmacogenetics of antidepressant response in depression. In contrast, little is known of response predictors in obsessive-compulsive disorder (OCD), a disorder with among the lowest proportion of responders to medication (40–60%). Our study is the largest investigation to date (N ¼ 184) of treatment response and side effects to antidepressants in OCD based on metabolizer status for CYP2D6 and CYP2C19. We observed significantly more failed medication trials in CYP2D6 non-extensive compared with extensive metabolizers (P ¼ 0.007). CYP2D6 metabolizer status was associated with side effects to venlafaxine (P ¼ 0.022). There were nonsignificant trends for association of CYP2D6 metabolizer status with response to fluoxetine (P ¼ 0.056) and of CYP2C19 metabolizer status with response to sertraline (P ¼ 0.064). Our study is the first to indicate that CYP genes may have a role in antidepressant response in OCD. More research is required for a future clinical application of genetic testing, which could lead to improved treatment outcomes. The Pharmacogenomics Journal (2014) 14, 176–181; doi:10.1038/tpj.2013.12; published online 2 April 2013 Keywords: obsessive-compulsive disorder (OCD); pharmacogenetics; CYP2D6; CYP2C19; treatment response INTRODUCTION OCD is widely accepted as having strong genetic influence, with Obsessive-compulsive disorder (OCD) occurs in approximately two replicated findings reported for the glutamate transporter gene percent of the population1 and is characterized by a broad variety SLC1A1 and several serotonergic, dopaminergic and other 11 of obsessions and/or compulsions causing significant distress for candidate genes. There is growing interest in looking beyond the patient. Treatment options generally viewed as first-line susceptibility loci in psychiatry; for example, in major depression treatment include psychotherapy (cognitive behavioral therapy), disorder there is increasing evidence for impact of genetic factors and selective serotonin reuptake inhibitors.2 Although showing a on treatment response to antidepressants. Among the numerous similar success rate, the tricyclic antidepressant clomipramine has pharmacogenetic candidate genes implicated in treatment been associated with higher rates of adverse events during the response in depression studies are HTR2A, encoding serotonin treatment,3 and thus is usually regarded as a second line 2A receptors, the serotonin transporter gene SLC6A4, the gene alternative. Other strategies include antidepressants with encoding brain-derived neurotrophic factor, BDNF, TPH1 and TPH2, 12–15 different mechanisms of action, such as venlafaxine, mirtazapine encoding tryptophan hydroxylase 1 and 2 respectively. In or second-generation antipsychotics. Despite this broad variety of OCD, a very small number of pharmacogenetic studies have been available pharmacological options, only 40–60% of patients performed. Promising findings have been obtained in several show a sufficient treatment response.4,5 In OCD, higher dosages genes implicated in depression including HTR2A, SLC6A4, BDNF and longer treatment duration are required6 as compared with and COMT, encoding catechol-o-methyltransferase, the enzyme depressive disorders to achieve optimal response. There is no responsible for breaking down catecholamines. However, these standardized definition of response and remission in OCD, few studies have been underpowered and have delivered 16 although various groups have proposed reductions in the inconsistent results, supporting the need for further research. scores on the Yale-Brown Obsessive-Compulsive Scale or the Major candidates of interest for pharmacogenetic research are Clinical Global Impression-Improvement Scale (CGI-I).7 Similarly, no the genes encoding enzymes participating in the metabolism of reliable factors to predict treatment response have been identified antidepressants. These are primarily in the cytochrome (CYP) P450 as yet. Among the clinical and demographic factors reported to be family, and include CYP1A2, CYP2C19, CYP2D6 and CYP3A4. associated with a poorer response to selective serotonin reuptake CYP2D6 is involved in the metabolism of most antidepressants, inhibitor treatment are: long duration of untreated illness, severity, and is primarily responsible for breakdown of amitriptyline, onset in childhood and specific predominant symptoms such as venlafaxine, fluoxetine and paroxetine among others. This enzyme hoarding and symmetry.7 Besides these clinical factors, functional also contributes to the metabolism of other antidepressants such neuroimaging studies have demonstrated that normalization of as citalopram, duloxetine and mirtazapine. CYP2C19 mainly the observed increased activity in the cortico-striato-thalamo- metabolizes the antidepressants citalopram, escitalopram and cortical circuit of OCD patients is associated with successful amitriptyline17 and contributes to the metabolism of sertraline.18 treatment.8–10 CYP enzymes are highly variable in their activity, which is 1Department of Neuroscience, Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 2Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada and 3Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Correspondence: Dr MA Richter, Department of Psychiatry, Sunnybrook Health Sciences Centre, FG42, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. E-mail: [email protected] 4Co-senior authorship. Received 11 September 2012; revised 29 January 2013; accepted 4 February 2013; published online 2 April 2013 CYP genes and antidepressant response EJ Brandl et al 177 influenced by genetic variation, as well as by environmental factors ‘marked’ or ‘severe side effects’ were assigned to our ‘significant side and medication intake. Numerous allele variants, deletions effects’ group. As with analysis of response, we also investigated overall and duplications have been identified in CYP2D6, located on tolerance to medications in individuals who recalled multiple medication chromosome 22, and lead to reduced, absent or increased enzyme trials, grouping them depending on whether they reported significant side X activity (for an overview, see http://www.cypalleles.ki.se/cyp2d6.htm). effects to 50% oro50% of drugs tried. All patients gave their written informed consent. The procedures were in Individuals are typically classified as ultrarapid metabolizer (UM) with accordance with the institutional ethics guidelines and the declaration more than two active alleles, extensive metabolizer (EM) with one or of Helsinki. two active alleles, intermediate metabolizer (IM) with one or two alleles with reduced activity or poor metabolizer (PM) when no active Genotyping alleles are present. A similar classification can be undertaken for the CYP2C19 enzyme, encoded by the CYP2C19 gene, which is located Genomic DNA was purified from whole blood samples using a standard nonenzymatic method (described previously in Lahiri and Nurnberger32). on chromosome 10. Genotyping for CYP2D6*3 (rs35742686), *4 (rs3892097), *10 (rs1065852), The influence of impaired or elevated CYP2D619–25 and 26,27 *17 (rs28371706), *41 (rs28371725) and CYP2C19*2 (rs4244285), *3 CYP2C19 activity on plasma levels of different antidepressants (rs4986893) and *17 (rs12248560) was performed using predesigned has been demonstrated repeatedly. Therefore, an impact on treat- TaqMan SNP genotyping assays by Applied Biosystems, Foster City, CA, ment response to antidepressants seems highly likely. However, the USA. Copy number variants including the deletion (*5) and multiplications influence of CYP2D6 and CYP2C19 gene variation on treatment of CYP2D6 were determined using the copy number variant assay and response in OCD has not been extensively investigated. One study28 CopyCaller Version 1.0 (Applied Biosystems). Two independent researchers reported no association between the presence of four different confirmed the genotype calling and 5% of the sample was regenotyped alleles with reduced CYP2D6 activity with treatment response to with 100% concordance. Subjects for whom genotype status could not be called were excluded from the analyses. paroxetine or venlafaxine. In contrast, in a pilot study by our 29 Prediction of CYP2D6 PM, IM, EM or UM metabolizer status followed group, we found evidence for a worse treatment response in criteria based on the expected enzyme activity of the alleles, with *1 being patients with non-extensive (reduced or enhanced) CYP2D6 activity. fully active, *3,*4 and *5 leading to no enzyme activity and *10, *17 and To extend our previous pilot study and to further investigate the *41 leading to reduced activity. For CYP2C19, the predicted enzyme influence of predicted CYP2D6 and CYP2C19 metabolizer status on antidepressant response to in OCD, we have now performed an association study in a larger sample of OCD patients. Table 1. Basic demographic and clinical data of the study population (N ¼ 184) given as N or mean þ / À s.d. Gender (male: female) 71:113 MATERIALS AND METHODS Subjects Ethnicity European
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