Impact of cytochrome P450 genes on suicide attempt and risk

Abstract

Dear Editor, Recently, we read with interest the article entitled ‘‘The impact of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide attempt and suicide risk—a European multicentre study on treatment-resistant major depressive disorder’’ published online in this journal [1]. The main conclusion of this study is that ‘‘the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts.’’ However, we would like to highlight some aspects of the methodology and results sections that were not discussed as limitations of the present article, which may partially explain these conflicting findings and change such conclusion. In the abstract section, the aim of the present study was clearly stated ‘‘to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/ or a personal history of suicide attempts,’’ in the light of some associations between cytochrome P450 metabolizer status and suicidality [2–5]. However, the main variables under study, the ‘‘metabolizer status’’ based on CYP450 genotyping and the suicidal phenotypes of ‘‘risk’’ and ‘‘attempt,’’ were vaguely and/or inaccurately defined in Methods, which might have led to misclassification of individuals into the different categories. Furthermore, the results section seems confusing. Most importantly, Table 2 did not show the observed frequencies of the patients with suicidal ‘‘risk’’ and ‘‘attempt’’ in each ‘‘metabolizer status’’ group for the studied genes (CYP1A2, CYP2C9, CYP2C19, CYP2D6). It just showed the number and percentage of individuals per metabolic profiles, which was variable for each gene. Regarding the definition of the P450 ‘‘metabolizer status’’ phenotypes, we will just focus on CYP2D6 since it has been the only gene associated with suicide ‘‘risk’’ and personal history of suicide ‘‘attempts’’ to date [2–5]. In particular, this relationship has been found with CYP2D6 ultrarapid metabolizers (UMs or individuals with more than two active genes) [2, 3, 5], who may present discontinuation [6] or drug therapeutic failure when taking substrates of this enzyme to prevent suicide. However, the study of Hofer et al. [1] used a convenience sample previously studied [7] that grouped under the label of CYP2D6 ‘‘UMs’’ or ‘‘ultrametabolizers’’ as originally called [7] all individuals presenting a mutation in the CYP2D6*XN allele. In other words, they classified as UMs not only those individuals carrying duplicate active alleles but also those with duplicate non-active or reduced function CYP2D6 genes. Despite this fact had already been acknowledged as a limitation by Serretti et al. [7], Hofer et al. [1] did not and considered all those carrying ‘‘the mutation in the CYP2D6*XN allele’’ as UMs. In our opinion, this is inaccurate and authors must consider both classifying as UMs only those subjects carrying more than two CYP2D6 functional gene copies and discussing that this fact does not predict an ultrarapid metabolism in all subjects [8]. Secondly, with regard to the definition of the phenotypes of suicide ‘‘risk’’ and personal history of ‘‘attempts’’, authors acknowledged as a limitation the use of the MINI and HAM-D instead of using questionnaires to assess the severity of the suicide intent as recently reported in association with CYP2D6 active genes [4]. However, the E. M. Penas-Lledo M. E. G. Naranjo A. LLerena CICAB Clinical Research Center, Extremadura University Hospital Medical School and CIBERSAM, Badajoz, Spain