title: CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics-guided clinical trials.
abstract: Individual and population differences in polymorphic cytochrome P450 enzyme function have been known for decades. The biological significance of these differences has now been deciphered with regard to drug metabolism, action and toxicity as well as disposition of endogenous substrates, including neuroactive compounds. While the cytochrome P450 enzymes occur abundantly in the liver, they are expressed in most tissues of the body, albeit in varying amounts, including the brain. The latter location of cytochrome P450s is highly pertinent for susceptibility to neuropsychiatric diseases, not to mention local drug metabolism at the site of psychotropic drug action in the brain. In the current era of personality medicine with companion theranostics (i.e. the fusion of therapeutics with diagnostics), this article underscores that such versatile biological roles of cytochrome P450s offer multiple points of entry for personalized medicine and rational therapeutics. We focus our discussion on CYP2D6, one of the most intensively researched drug and endogenous compound metabolism pathways, with a view to relevance for, and optimization of, pharmacogenomic-guided clinical trials. Working on the premise that CYP2D6 is related to human behaviour and certain personality traits such as serotonin and dopamine system function, we further suggest that the motivation of healthy volunteers to participate in clinical trials may in part be influenced by an under- or over-representation of certain CYP2D6 metabolic groups.
authors.affiliation: CICAB Clinical Research Centre, Extremadura University Hospital and Medical School, Badajoz.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Peñas-Lledó
authors.forename: Adrián
authors.initials: A
authors.lastname: Llerena
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods*; D003071:Cognition; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D064368:Healthy Volunteers / Q000523:psychology; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy / Q000235:genetics*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010551:Personality / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D011619:Psychotropic Drugs / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D018377:Neurotransmitter Agents; D011619:Psychotropic Drugs; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; clinical trials; endogenous compound metabolism; personality traits; pharmacogenetics; psychopathology
references.citation: Endocrinology. 2001 Sep;142(9):3901-8
references.pmid: 11517168
references.citation: Biochem Biophys Res Commun. 1998 Aug 28;249(3):838-43
references.pmid: 9731223
references.citation: Pharmacogenomics J. 2007 Dec;7(6):408-10
references.pmid: 17325735
references.citation: Biochem Soc Trans. 1997 Nov;25(4):S577
references.pmid: 9450005
references.citation: Arch Gen Psychiatry. 1991 Nov;48(11):1022-5
references.pmid: 1747017
references.citation: Clin Pharmacol Ther. 2002 Oct;72(4):438-52
references.pmid: 12386646
references.citation: Acta Psychiatr Scand. 1997 Nov;96(5):325-8
references.pmid: 9395148
references.citation: Curr Drug Targets. 2004 Aug;5(6):573-9
references.pmid: 15270204
references.citation: Am J Psychiatry. 1958 Aug;115(2):129-33
references.pmid: 13559508
references.citation: Clin Pharmacol Ther. 2010 Sep;88(3):354-9
references.pmid: 19907421
references.citation: Br J Clin Pharmacol. 2004 Jun;57(6):785-9
references.pmid: 15151524
references.citation: J Pers Disord. 2014 Dec;28(6):873-83
references.pmid: 25437930
references.citation: Br J Clin Pharmacol. 2007 Jul;64(1):96-9
references.pmid: 17324244
references.citation: J Appl Psychol. 1997 Feb;82(1):30-43
references.pmid: 9119797
references.citation: Pharmacogenomics J. 2013 Feb;13(1):1-11
references.pmid: 23089672
references.citation: Acta Psychiatr Scand. 1993 Jan;87(1):23-8
references.pmid: 8424321
references.citation: Psychiatr Genet. 1994 Winter;4(4):215-8
references.pmid: 7712118
references.citation: Am J Med Genet. 1996 Apr 9;67(2):236-7
references.pmid: 8723057
references.citation: Xenobiotica. 1997 Jan;27(1):111-25
references.pmid: 9041683
references.citation: Pharmacogenomics. 2006 Dec;7(8):1199-210
references.pmid: 17184207
references.citation: Eur J Clin Pharmacol. 2008 Jun;64(6):575-82
references.pmid: 18320183
references.citation: Neuropharmacology. 2008 Dec;55(7):1147-55
references.pmid: 18687346
references.citation: Mol Psychiatry. 2011 Jul;16(7):691-2
references.pmid: 21321564
references.citation: Science. 1954 Sep 3;120(3114):359-61
references.pmid: 13186861
references.citation: Pharmacogenomics. 2008 Jul;9(7):833-40
references.pmid: 18597648
references.citation: Pharmacogenet Genomics. 2005 Aug;15(8):579-87
references.pmid: 16007002
references.citation: Lancet. 1989 Jun 17;1(8651):1398
references.pmid: 2567421
references.citation: Drug Metab Dispos. 2009 Jul;37(7):1528-38
references.pmid: 19359404
references.citation: Psychiatr Genet. 1998 Spring;8(1):25-8
references.pmid: 9564684
references.citation: Am J Med Genet. 1995 Feb 27;60(1):85-7
references.pmid: 7485241
references.citation: Clin Pharmacol Ther. 2011 Mar;89(3):352-3
references.pmid: 21248727
references.citation: Psychiatr Genet. 2001 Sep;11(3):153-5
references.pmid: 11702057
references.citation: Biochem Biophys Res Commun. 1987 Nov 13;148(3):1144-50
references.pmid: 3500719
references.citation: J Pharmacol Exp Ther. 2008 Nov;327(2):538-45
references.pmid: 18698000
references.citation: Neuroimage. 2012 Feb 1;59(3):2818-23
references.pmid: 21835244
references.citation: Psychiatry Res. 2005 Jul 15;136(1):69-78
references.pmid: 16023733
references.citation: Arch Gen Psychiatry. 1990 Oct;47(10):980
references.pmid: 2222138
references.citation: Psychiatr Genet. 2003 Jun;13(2):111-3
references.pmid: 12782969
references.citation: Pharmacogenomics. 2009 Jan;10(1):17-28
references.pmid: 19102711
references.citation: Eur J Pharmacol. 2010 Jan 25;626(2-3):171-8
references.pmid: 19818757
references.citation: Pharmacogenomics. 2009 Apr;10(4):685-99
references.pmid: 19374522
references.citation: Am J Psychiatry. 1989 Aug;146(8):1052-5
references.pmid: 2750979
references.citation: Eur Arch Psychiatry Clin Neurosci. 2013 Aug;263(5):385-91
references.pmid: 23081704
references.citation: Ther Drug Monit. 2001 Dec;23(6):616-20
references.pmid: 11802093
references.citation: Eur Arch Psychiatry Clin Neurosci. 2013 Dec;263(8):703-4
references.pmid: 23504002
references.citation: Exp Clin Psychopharmacol. 2007 Dec;15(6):539-45
references.pmid: 18179306
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2004 May 15;127B(1):90-3
references.pmid: 15108188
references.citation: J Pharmacol Exp Ther. 2003 Apr;305(1):315-22
references.pmid: 12649384
references.citation: Pharmacogenomics. 2009 Jul;10(7):1111-20
references.pmid: 19604084
references.citation: Pharmacogenomics. 2007 Nov;8(11):1597-608
references.pmid: 18034624
references.citation: Pharmacogenet Genomics. 2007 Nov;17(11):989-93
references.pmid: 18075468
references.citation: Pharmacogenetics. 2003 Mar;13(3):173-81
references.pmid: 12618595
references.citation: Nat Rev Drug Discov. 2013 Feb;12(2):103-15
references.pmid: 23370249
references.citation: Drug Metab Rev. 2004 May;36(2):243-77
references.pmid: 15237854
references.citation: Mol Psychiatry. 2013 Jan;18(1):8-9
references.pmid: 22733128
references.citation: Mol Psychiatry. 2011 Mar;16(3):237, 333-41
references.pmid: 20368706
references.citation: Pharmacogenomics. 2012 Jan;13(2):179-84
references.pmid: 22141351
references.citation: J Clin Psychopharmacol. 2006 Aug;26(4):440-2
references.pmid: 16855473
references.citation: Nord J Psychiatry. 2004;58(1):61-4
references.pmid: 14985156
references.citation: Pharmacogenomics. 2009 Apr;10(4):541-7
references.pmid: 19374513
references.citation: Curr Drug Targets. 2006 Dec;7(12):1671-80
references.pmid: 17168842
references.citation: Pharmacogenetics. 2001 Apr;11(3):237-45
references.pmid: 11337939
references.citation: J Psychiatry Neurosci. 2002 Nov;27(6):406-15
references.pmid: 12491573
references.citation: Clin Pharmacol Ther. 2010 Sep;88(3):304-5
references.pmid: 20725080
references.citation: Pharmacogenomics J. 2012 Apr;12(2):173-5
references.pmid: 20877302
references.citation: Arch Gen Psychiatry. 1983 Oct;40(10):1152-3
references.pmid: 6625866
references.citation: Endocrinology. 2004 Feb;145(2):699-705
references.pmid: 14563706
references.citation: Fundam Clin Pharmacol. 2007 Aug;21(4):451-3
references.pmid: 17635185
references.citation: Pharmacogenet Genomics. 2007 May;17(5):339-47
references.pmid: 17429316
references.citation: Lancet. 1989 Mar 11;1(8637):555
references.pmid: 2564084