In today's modern society, it seems to be more and more challenging to cope with life stresses. The effect of psychological stress on emotional and physical health can be devastating, and increased stress is associated with increased rates of heart attack, hypertension, obesity, addiction, anxiety and depression. This review focuses on the possibility of an influence of psychological stress on the metabolism of selected antidepressants (TCAs, SSRIs, SNRIs, SARIs, NDRIs a MMAs) and anxiolytics (benzodiazepines and azapirone), as patients treated with antidepressants and/or anxiolytics can still suffer from psychological stress. Emphasis is placed on the drug metabolism mediated by the enzymes of Phase I, typically cytochromes P450 (CYPs), which are the major enzymes involved in drug metabolism, as the majority of psychoactive substances are metabolized by numerous CYPs (such as CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2A6, CYP2D6, CYP3A4). As the data on the effect of stress on human enzymes are extremely rare, modulation of the efficacy and even regulation of the biotransformation pathways of drugs by psychological stress can be expected to play a significant role, as there is increasing evidence that stress can alter drug metabolism, hence there is a risk of less effective drug metabolism and increased side effects.

Department of Medical Chemistry and Biochemistry Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Pharmacology Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Zobrazit více v PubMed

Manwell A, Barbic SP, Roberts K, Durisko Z, Lee C, Ware E, McKenzie K. What is mental health? Evidence towards a new definition from a mixed methods multidisciplinary international survey. BMJ Open 2015;5:e007079. PubMed DOI

Fink G. Stress: Concepts, Definition and History. Reference Module in Nueroscience and Biobehavioral Psychology, Elsevier 2017. DOI

Stanwell-Smith R. Mad, bad and dangerous to know? History and mental health. Perspect Public Health 2019;139:110. PubMed DOI

Skolnick P. Antidepressants for the new millennium. Eur J Pharmacol 1999;375:31-40. PubMed DOI

Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorders. Dialogues Clin Neurosci 2017;19:93-107. DOI

Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-21. PubMed DOI

Guengerich FP. Cytochrome p450 and chemical toxicology. Chem Res Toxicol 2008;21:70-83. PubMed DOI

Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138:103- 41. PubMed DOI

Konstandi M, Johnson EO, Lang MA. Consequences of psychophysiological stress on cytochrome P450-catalyzed drug metabolism. Neurosci Biobehav Rev 2014;45:149-67. PubMed DOI

Zemanova N, Anzenbacher P, Zapletalova I, Jourova L, Hermanova P, Hudcovic T, Kozakova H, Vodicka M, Pacha J, Anzenbacherova E. The role of the microbiome and psychosocial stress in the expression and activity of drug metabolizing enzymes in mice. Sci Rep 2020;10:8529. PubMed DOI

Yang L, Zhao Y, Wang Y, Liu L, Zhang X, Li B, Cui R. The Effects of Psychological Stress on Depression. Curr Neuropharmacol 2015;13:494-504. PubMed DOI

Godoy LD, Rossignoli MT, Delfino-Pereira P, Garcia-Cairasco N, de Lima Umeoka EH. A Comprehensive Overview on Stress Neurobiology: Basic Concepts and Clinical Implications. Front Behav Neurosci 2018;12:127. PubMed DOI

Epel ES, Crosswell AD, Mayer SE, Prather AA, Slavich GM, Puterman E, Mendes WB. More than a feeling: A unified view of stress measurement for population science. Front Neuroendocrinol 2018;49:146-69. PubMed DOI

Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA 2007;298:1685-87. PubMed DOI

Ray A, Gulati K, Rai N. Stress, Anxiety, and Immunomodulation: A Pharmacological Analysis. Vitam Horm 2017;103:1-25. PubMed DOI

Schneiderman N, Ironson G, Siegel SD. Stress and health: psychological, behavioral, and biological determinants. Annu Rev Clin Psychol 2005;1:607-28. PubMed DOI

Dalle E, Mabandla MV. Early Life Stress, Depression And Parkinson's Disease: A New Approach. Mol Brain 2018;11:18. PubMed DOI

Humer E, Pieh C, Probst T. Metabolomic Biomarkers in Anxiety Disorders. Int J Mol Sci 2020;21(13):4784. doi: 10.3390/ijms21134784 PubMed DOI

Grundmann M, Kacirova I, Urinovska R. Therapeutic monitoring of psychoactive drugs - antidepressants: a review. Biomed Pap Med Fac Univ Palacky Olomouc 2015;159:35-43. PubMed DOI

Nash J, Nutt D. Antidepressants. Psychiatry 2004;3:22-26. DOI

Taylor C, Fricker AD, Devi LA, Gomes I. Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways. Cell Signal 2005;17:549-57. PubMed DOI

Racagni G, Popoli M. Cellular and molecular mechanisms in the long-term action of antidepressants. Dialogues Clin Neurosci 2008;10:385-400. DOI

Taylor C, Nutt D. Anxiolytics. Psychiatry 2004;3:17-21. DOI

Rushmore TH, Kong AN. Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Curr Drug Metab 2002;3:481-90. PubMed DOI

Casarett LJ, Doull J, Klaassen, CD. Casarett and Doull's toxicology: the basic science of poisons. 7th ed. New York: McGraw-Hill;2008.

Croom E. Metabolism of xenobiotics of human environments. Prog Mol Biol Transl Sci 2012;112:31-88. PubMed DOI

Guengerich FP. Mechanisms of Cytochrome P450-Catalyzed Oxidations. ACS Catal 2018;8:10964-76. PubMed DOI

Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc 2010;154:103-16. PubMed DOI

Meyer UA. Pharmacogenetics - five decades of therapeutic lessons from genetic diversity. Nat Rev Genet 2004;5:669-76. PubMed DOI

Ingelman-Sundberg M, Gomez A. The past, present and future of pharmacoepigenomics. Pharmacogenomics 2010;11:625-27. PubMed DOI

Zhang Y, Klein K, Sugathan A, Nassery N, Dombkowski A, Zanger, UM, Waxman, DJ. Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease. PLoS One 2011;6:e23506. PubMed DOI

Aitken AE, Richardson TA, Morgan ET. Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol 2006;46:123-49. PubMed DOI

Konstandi M. Psychophysiological stress: a significant parameter in drug pharmacokinetics. Expert Opin Drug Metab Toxicol 2013;9:1317-34. PubMed DOI

Chrousos GP. Stress, chronic inflammation, and emotional and physical well-being: Concurrent effects and chronic sequelae. J. Allergy Clin Immunol 2000;106:275-91. PubMed DOI

Daskalopoulos EP, Malliou F, Rentesi G, Marselos M, Lang MA, Konstandi M. Stress is a critical player in CYP3A, CYP2C, and CYP2D regulation: role of adrenergic receptor signaling pathways. Am J Physiol Endocrinol Metab 2012;303:E40-54. PubMed DOI

Flint MS, Hood BL, Sun M, Stewart NA, Jones-Laughner J, Conrads TP. Proteomic analysis of the murine liver in response to a combined exposure to psychological stress and 7,12-dimethylbenz(a)anthracene. J Proteome Res 2010;9:509-20. PubMed DOI

Stancil SL, Pearce RE, Tyndale RF, Kearns GL, Vyhlidal CA, Leeder JS, Abdel-Rahman S. Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults. Br J Clin Pharmacol 2019;85(5):960-69. PubMed DOI

Zanger UM, Klein K. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet 2013;4:24. PubMed DOI

Konstandi M, Johnson E, Lang MA, Camus-Radon AM, Marselos M. Stress modulates the enzymatic inducibility by benzo[alpha]pyrene in the rat liver. Pharmacol Res 2000;42:205-11. PubMed DOI

Goldstein JA, Chen Y. The transcriptional regulation of the human CYP2C genes. Curr Drug Metab 2009;10(6):567-78. doi: 10.2174/138920009789375397 PubMed DOI

Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes (Basel) 2020;11(11):1295. doi: 10.3390/genes11111295 PubMed DOI

Ban TA. Pharmacotherapy of mental illness-a historical analysis. Prog Neuropsychopharmacol Biol Psychiatry 2001;25:709-27. PubMed DOI

Dean L. Imipramine Therapy and CYP2D6 and CYP2C19 Genotype. 2017 Mar 23. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425164/

Ayano G. Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 1A2 Enzyme and Relevant Drug Interactions: Review of Articles. Austin J Pharmacol Ther 2016;4(2):1085. DOI

Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Muller DJ, Gaedigk A, Stingl JC. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013;93:402-08. PubMed DOI

Nielsen KK, Flinois JP, Beaune P, Brosen K. The biotransformation of clomipramine in vitro, identification of the cytochrome P450s responsible for the separate metabolic pathways. J Pharmacol Exp Ther 1996;277:1659-64. PubMed

Baumann P. Clinical pharmacokinetics of citalopram and other selective serotonergic reuptake inhibitors (SSRI). Int Clin Psychopharmacol 1992;6S5:13-20. DOI

Culpepper L. Escitalopram: A New SSRI for the Treatment of Depression in Primary Care. Prim Care Companion J Clin Psychiatry 2002;4:209-14. PubMed DOI

Sangkuhl K, Klein TE, Altman RB. PharmGKB summary: citalopram pharmacokinetics pathway. Pharmacogenet Genomics 2011;21:769-72. PubMed DOI

Spigset O, Axelsson S, Norstrom A, Hagg S, Dahlqvist R. The major fluvoxamine metabolite in urine is formed by CYP2D6. Eur J Clin Pharmacol 2001;57:653-58. PubMed DOI

Margolis JM, O'Donnell JP, Mankowski DC, Ekins S, Obach RS. (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes. Drug Metab Dispos 2000;28:1187-91.

Kowalska M, Nowaczyk J, Fijalkowski L, Nowaczyk A. Paroxetine-Overview of the Molecular Mechanisms of Action. Int J Mol Sci 2021;22(4):1662. doi: 10.3390/ijms22041662 PubMed DOI

Obach RS, Cox LM, Tremaine LM. Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos 2005;33:262-70. PubMed DOI

Sangkuhl K, Stingl JC, Turpeinen M, Altman RB, Klein TE. PharmGKB summary: venlafaxine pathway. Pharmacogenet Genomics 2014;24:62-72. PubMed DOI

Dean L. Venlafaxine Therapy and CYP2D6 Genotype. 2015 Jul 27 [updated 2020 Jun 29]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012. PMID: 28520361

Lantz RJ, Gillespie TA, Rash TJ, Kuo F, Skinner M, Kuan HY, Knadler MP. Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. Drug Metab Dispos 2003;31:1142-50. PubMed DOI

Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry 1999;60:4-13.

Rotzinger S, Fang J, Baker GB. Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources. Drug Metab Dispos 1998;26:572-75.

Protti M, Mandrioli R, Marasca C, Cavalli A, Serretti A, Mercolini L. New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others. Med Res Rev 2020;40:1794-832. PubMed DOI

Demyttenaere K, Jaspers, L. Review: Bupropion and SSRI-induced side effects. J Psychopharmacol 2008;22:792-804. PubMed DOI

Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations. Clin Ther 2005;27:1685-95. PubMed DOI

Roddy E. ABC of smoking cessation. Bupropion and other drugs in non-nicotine therapy. Cas Lek Cesk 2004;143:863-65. PubMed

Chen G, Hojer AM, Areberg J, Nomikos G. Vortioxetine: Clinical Pharmacokinetics and Drug Interactions. Clin Pharmacokinet 2018;57:673-86. PubMed DOI

Cruz MP. Vilazodone HCl (Viibryd): A Serotonin Partial Agonist and Reuptake Inhibitor For the Treatment of Major Depressive Disorder. PT (Pharmacy and Therapeutics) 2012;37:28-31.

Dean L. Diazepam Therapy and CYP2C19 Genotype. 2018 Dec 10 [Updated 2020 Oct 15]. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK379740/.

Chouinard G, Lefko-Singh K, Teboul E. Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem. Cell Mol Neurobiol 1999;19:533-52. PubMed DOI

Olkkola KT, Ahonen J. Midazolam and other benzodiazepines. Handb Exp Pharmacol 2008;(182):335-60. doi: 10.1007/978-3-540-74806-9_16 PubMed DOI

Allqvist A, Miura J, Bertilsson L, Mirghani RA. Inhibition of CYP3A4 and CYP3A5 catalyzed metabolism of alprazolam and quinine by ketoconazole as racemate and four different enantiomers. Eur J Clin Pharmacol 2007;63:173-79. PubMed DOI

Morishita S. Clonazepam as a therapeutic adjunct to improve the management of depression: a brief review. Hum Psychopharmacol 2009;24:191-98. PubMed DOI

Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M, Menus A, Bitter I, Monostory K. Optimization of Clonazepam Therapy Adjusted to Patient's CYP3A Status and NAT2 Genotype. Int J Neuropsychopharmacol 2016;19(12):pyw083. doi: 0.1093/ijnp/pyw083 PubMed DOI

Zhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R, Vachharajani N, Mitroka J. Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes. Drug Metab Dispos 2005;33:500-07. PubMed DOI

Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 2007;151:737-48. PubMed DOI

Kalgutkar AS, Vaz AD, Lame ME, Henne KR, Soglia J, Zhao SX, Abramov YA, Lombardo F, Collin C, Hendsch ZS, Hop CE. Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab Dispos 2005;33:243-53. PubMed DOI

Coles R, Kharasch ED. Stereoselective metabolism of bupropion by cytochrome P4502B6 (CYP2B6) and human liver microsomes. Pharm Res 2008;25:1405-11. PubMed DOI

Molanaei H, Stenvinkel P, Qureshi AR, Carrero JJ, Heimburger O, Lindholm B, Diczfalusy U, Odar-Cederlof I, Bertilsson L. Metabolism of alprazolam (a marker of CYP3A4) in hemodialysis patients with persistent inflammation. Eur J Clin Pharmacol 2012;68:571-77. PubMed DOI