Innovations In Clinical Neuroscience

MAY-JUN 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 5 – 6 , M A Y – J U N E 2 0 1 7 ] 22 reactions—decarboxylation—with the participation of a myriad of complicated molecules including cofactors, hormones, enzymes, signaling molecules, and second messengers, collectively termed "CHESS" as shown in Figure 1. 4 Subsequently, the mechanism of transamination involves the breakdown or metabolism of neurotransmitters with the byproducts circulating via blood and cerebrospinal fluid (CSF). Both chemical reactions are significant in the role of SNPs and their respective phenotypes, such as poor metabolizers (PMs), extensive metabolizers (EMs), intermediate metabolizers (IMs), rapid (RMs), and ultra-rapid metabolizers (UMs), in the breakdown of neurotransmitters. The prevalence of SNPs can be quite variable, with inter-individual and inter- ethnic differences dictating the rate of metabolism of different P450 substrates. 5 For example, 10 to 15 percent of Caucasians are phenotypically intermediate metabolizers for CYP2D6, compared to the 6 to 8 percent who are poor metabolizers and 5 to 10 percent who are ultra-rapid metabolizers. 6 In the case of CYP2C19 phenotypes, 3 to 5 percent of Swedish, 20 percent of Japanese, and as high as 79 percent of the inhabitants on the island of Vanuatu in the Pacific Ocean are poor metabolizers. 7 SNPs, COGNITIVE FUNCTION, AND SUICIDES Recognition of an association between SNPs and cognition is relatively new, 8 although more studies are emerging that suggest this link might be a potential signal in the early detection and treatment of chronic neuropsychiatric conditions. 9 For example, in a study of 1,472 Swedish individuals of European ancestry, those with a CYP2C19 PM genotype had significantly lower levels of depressive symptoms than an EM cohort. 10 These authors concluded that additional studies are needed to establish the functional link between the P450 enzyme, CYP2C19 and depressive symptoms. On the other hand, from a pharmacogenomics standpoint, one can speculate that a lack of these enzymes (CYP2D6 and CYP2C19) could lead to adverse reactions and even fatality. Forensic autopsy studies, 11 however, have demonstrated the contrary. Correlation of deaths due to suicide (n=262), and fatal intoxication (n=242), as compared to natural causes (n=212) w as found to arise from the presence of two or more active CYP2D6 genes corresponding to the UM genotype, but was not demonstrated in PMs. Another group 12 explored the possible l ink between UMs, depressive episodes, and indications of suicidality in a cohort of 285 inpatients experiencing an episode of either unipolar or bipolar depression. These authors confirmed the study by Zackrisson et al [[[AUT: provide ref]]] that concluded there was no association between UM status and baseline Hamilton Depression Rating Scale (HAM-D) scores, but that duplication of the CYP2D6 genotype had a specific effect on suicidality. The logistic regression remained significant, even after inclusion of covariates that might affect the depression scores (gender, baseline score of HAM-D after exclusion of Item 3 for suicidality, number of previous depressive episodes, ethnic group, and study center). Depression or depressive symptoms, therefore, overall appear to be independent of the effect of SNP metabolism on suicides. This leads to the consideration of a possible association between SNPs and personality traits. The relationship between CYP2D6 metabolic capacity (hydroxylation) and personality traits was studied using the Karolinska Scale of Personality (KSP) in 253 university students and staff from Havana Hospital and Calixto Garcia Medical School in Cuba. 13 Debrisoquine hydroxylation capacity and CYP2D6 phenotypes (0, 1–2, and >2 alleles) were compared. A cluster of behaviors (e.g., anxiety, impulsivity) associated with personality features was related to the postulated reduction of serotonin in CYP2D6 PMs, further supporting the finding of increased risk of suicide attempts and completions linked to duplication and multiduplication of alleles (i.e., UMs, as more dependent on personality traits than on Axis I pathology. SUBSTRATES, METABOLITES, INHIBITORS, AND INDUCERS Biochemistry indicates that the two most common substrates, or enzymes (CYP2D6 and CYP2C19), are involved in FIGURE 1. Xxx

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