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 ] 23 the hydroxylation step of the b iotransformation of precursor amino acids to neurotransmitters. However, the possibility of an additional role for CYP2D6 and CYP2C19 as catalysts through the process of O-demethylation i n the serotonin-melatonin cycle is evidenced by regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6. 1 4 The lack of CYP2D6 in PMs was postulated to be the probable cause of significant anxiety and fear in certain personalities specifically when compared to extensive metabolizers. If a lack of serotonin is associated with PMs in the serotonin- melatonin cycle, the possible explanation for the association of UMs with suicide would be excessive production of serotonin as opposed to rapid depletion of it by metabolism. It is clear from the above discussion that SNPs and their involvement in biochemical processes are not site- or reaction-specific (i.e., at hydroxylation or O-demethylation stages only), but might involve decarboxylation and transamination reactions as well. This might explain the rapid disappearance of neurotransmitters from reuptake sites and the lack of therapeutic response to psychotropic medications dispensed in otherwise acceptable therapeutic dose ranges in the 10 percent of Caucasians who represent PMs. Exogenous factors such as antidepressants, antipsychotics, and mood stabilizers further complicate the pre-existing SNP profile by acting as inhibitors and inducers of these P450 enzymes. In summary, the exact mechanisms or functionality of SNPs are mostly unknown, considering the complexity of pharmacokinetic, pharmacodynamic, inter-individual, and inter-ethnic challenges in assessment. However, broader implications of the involvement of SNPs in the diagnosis and treatment of conditions such as colon cancer and other cancers are encouraging. 15 TRANSLATIONAL BENEFITS AND RELEVANCE TO PSYCHIATRY Available statistical data reveal that 25 percent of the medications prescribed today are metabolized by CYP2D6 enzymes. 16 Approximately, 5 to 10 percent of the Caucasian population are p oor metabolizers of CYP2D6, 1 7 a nd 3 to 5 percent for CYP2C19 . Almost 98 percent of the CYP2D6 poor metabolizers can be identified and confirmed by genotyping alone and the n umber is higher for CYP2C19 PMs. 1 8 On the contrary, only 20 percent of ultra- rapid metabolizers can be identified by genotyping. Most importantly, CYP2D6 is a unique, non-inducible enzyme, giving it the advantage of being specific to drug metabolism; thus, phenotypic variability carries enormous diagnostic potential that could lead to better treatment outcomes. 19 And not surprisingly, combined high CYP2D6- CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances. 20 CONCLUSION Point of care testing (POC) with immediately available results becomes more important, especially in young adults in whom an escalation in the number and severity of self-destructive behaviors is increasingly associated with fatal outcomes. Other populations of concern would be the active duty military and veterans where suicides are also steadily rising and warrant close monitoring and predictive testing when available. At the very least, it behooves us as clinicians and scientists to further explore and clearly establish the relationship between SNPs and suicidal behaviors. DISCLAIMER The views expressed here are solely those of the authors and are not to be construed as official or representing those of the Department of the Army or the Department of Defense . REFERENCES 1. Ingelman-Sundberg M, Persson A, Jukic MM. 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. Pharmacogenomics. 2014;15(15):1841–1844. 2. Sankararaman S, Mallick S, Dannemann M, et al. The genomic landscape of Neanderthal ancestry in present-day humans. Nature. 2014;507(7492):354–357. 3. Ferugson CS, Tyndale RF. Cytochrome P450 enzymes in the brain: emerging evidence of biological significance. Trends Pharmacol Sci. 2011;32(12):708–714. 4. Yarlagadda A, Clayton AH. Blood brain barrier: the role of pyridoxine. Psychiatry (Edgmont). 2007;4(8):58–60. 5. Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007;116(3):496–5260. 6. Rebsamen MC, Desmueles J, Daali Y. The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenomics J. 2009;9(1):34–41. 7. Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002;41(12):913–958. 8. McClearn GE, Johansson B, Berg S, et al. Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science. 1997;276(5318):1560–1563. 9. Sim SC, Nordin L, Andersson TM, et al. Association between CYP2C19 polymorphism and depressive symptoms. American Journal of Medical Genetics. 2010;153B(6):1160–1166. 10. Sara CS, Linn N, Andersson TM, et al. 2010. Association between CYP2C19 polymorphism and depressive symptoms. Am J Med Genet. Part B153B:1160–1166. 11. Zackrisson AL, Lindblom B, Ahlner J. High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther. 2010;88(3):354–359. 12. Stingl JC, Vivaini R. CYP2D6 in the brain: impact on suicidality. Clin

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