A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances

Abstract

This study examined, for the first time, whether a high CYP2D6-CYP2C19 metabolic capacity combination increases the likelihood of suicidal intent severity in a large study cohort. Survivors of a suicide attempt (n=587; 86.8% women) were genotyped for CYP2C19 (*2, *17) and CYP2D6 (*3, *4, *4xN, *5, *6, *10, wtxN) genetic variation and evaluated with the Beck Suicide Intent Scale (SIS). Patients with a high CYP2D6-CYP2C19 metabolic capacity showed an increased risk for a severe suicide attempt (P<0.01) as measured by the SIS-objective circumstance subscale (odds ratio (OR)=1.37; 95% confidence interval (CI)=1.05-1.78; P=0.02) after adjusting for confounders (gender, age, level of studies, marital status, mental disorders, tobacco use, family history of suicide, personal history of attempts and violence of the attempt). Importantly, the risk was greater in those without a family history of suicide (OR=1.82; CI=1.19-2.77; P=0.002). Further research is warranted to evaluate whether the observed relationship is mediated by the role of CYP2D6 and CYP2C19 involvement in the endogenous physiology or drug metabolism or both.

Polymorphic Expression of Cyp2C19 and Cyp2D6 in the Developing and Adult Human Brain Causing Variability in Cognition, Risk for Depression and Suicide: The Search for the Endogenous Substrates

“…A recent study by Llerena and collaborators examining suicide risk among subjects having both high CYP2D6 and CYP2C19 expression is interesting [24]. Thus, patients with a high CYP2D6-CYP2C19 metabolic capacity showed an increased risk for a severe suicide attempt as measured future science group Expression of CYP2C19 & CYP2D6 in the developing & adult human brain: variability in cognition, risk for depression & suicide Editorial by the SIS-objective circumstance subscale, particularly in absence of a family history of suicide.…”

A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants

“…Taken together, these findings suggest that the role of CYP2C19 on depressive symptoms appears to be complex and might be different according to specific ADs, also in light of the fact that combinations of variants located in genes coding for different CYP enzymes, such as CYP2D6 (Penas-Lledo et al, 2015), might also be relevant to explain part of the variability in AD therapy outcome.…”

“…In contrast with these results, a recent study found that patients undergoing treatment with escitalopram carrying the CYP2C19*17 allele were more likely to switch to another antidepressant within one year of follow‐up (Jukic, Haslemo, Molden, & Ingelman‐Sundberg, ). Taken together, these findings suggest that the role of CYP2C19 on depressive symptoms appears to be complex and might be different according to specific ADs, also in light of the fact that combinations of variants located in genes coding for different CYP enzymes, such as CYP2D6 (Penas‐Lledo et al, ), might also be relevant to explain part of the variability in AD therapy outcome.…”

CYP2D6 Genetic Polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas

“…Moreover, since drugs and plants are metabolized by a myriad of different enzymes that are encoded by their respective genes, substrate specificity and drug dosage seem to be only two of many factors [22] contributing to a drug response measured by quantitative variables such as degree of efficacy or number/severity of side effects. In support of that, despite the evidence about the relationship of CYP2D6 and drug response [6], the combined use of parallel alternate metabolic CYP pathways [23] that can compensate in the case of CYP2D6 PMs to individualize treatments with certain CYP2D6 sub- strates is, as yet, very limited, as is use of other genes such as those encoding drug receptors also involved in response [24]. Finally, individualized therapy to increase drug safety in different populations will also largely benefit from collecting and interrogating large genomics datasets in order to identify biological mechanisms associated with observed outcomes [25].…”