Pharmacogenetics of Antidepressants: from Genetic Findings to Predictive Strategies
https://doi.org/10.29413/ABS.2019-4.2.5
Abstract
The constantly growing contribution of depressive disorders to the global disease statistics calls for a growth of treatment effectiveness and optimization. Antidepressants are the most frequently prescribed medicines for depressive disorders. However, development of a standardized pharmacotherapeutic approach is burdened by the genomic heterogeneity, lack of reliable predictive biomarkers and variability of the medicines metabolism aggravated by multiple side effects of antidepressants. According to modern assessments up to 20 % of the genes expressed in our brain are involved in the pathogenesis of depression. Large-scale genetic and genomic research has found a number of potentially prognostic genes. It has also been proven that the effectiveness and tolerability of antidepressants directly depend on the variable activity of the enzymes that metabolize medicines. Almost all modern antidepressants are metabolized by the cytochrome P450 family enzymes. The most promising direction of research today is the GWAS (Genome-Wide Association Study) method that is aimed to link genomic variations with phenotypical manifestations. In this type of research genomes of depressive patients with different phenotypes are compared to the genomes of the control group containing same age, sex and other parameters healthy people. Notably, regardless of the large cohorts of patients analyzed, none of the GWA studies conducted so far can reliably reproduce the results of other analogous studies. The explicit heterogeneity of the genes associated with the depression pathogenesis and their pleiotropic effects are strongly influenced by environmental factors. This may explain the difficulty of obtaining clear and reproducible results. However, despite any negative circumstances, the active multidirectional research conducted today, raises the hope of clinicians and their patients to get a whole number of schedules how to achieve remission faster and with guaranteed results
About the Authors
L. K. Khokhlov
Yaroslavl State Medical University
Russian Federation
Russian Federation
Leonid K. Khokhlov – Dr. Sc. (Med.), Professor, Professor of the Department of Psychiatry
ul. Revolyutsionnaya 5, Yaroslavl 150000
N. E. Lukyanov
Yaroslavl State Medical University
Russian Federation
Russian Federation
Nikolay E. Lukyanov – Student
ul. Revolyutsionnaya 5, Yaroslavl 150000
References
1. WHO. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organization; 2017.
2. Mosolov SN. The clinical use of modern antidepressants. Saint Petersburg: MIA; 1995. (In Russ.)
3. Fabbri C, Serretti A. Clinical application of antidepressant pharmacogenetics: Considerations for the design of future studies. Neurosci Lett. 2018; pii: S0304-3940(18)30423-3. doi: 10.1016/j.neulet.2018.06.020
4. Outhred T, Das P, Dobson-Stone C, Felmingham KL, Bryant RA, Nathan PJ, et al. The impact of 5-HTTLPR on acute serotonin transporter blockade by escitalopram on emotion processing: Preliminary findings from a randomised, crossover fMRI study. Australian & New Zealand Journal of Psychiatry. 2014; 48(12): 1115-1125. doi: 10.1177/0004867414533837
5. Outhred T, Das P, Dobson-Stone C, Felmingham KL, Bryant RA, Nathan PJ, et al. Impact of 5-HTTLPR on SSRI serotonin transporter blockade during emotion regulation: A preliminary fMRI study. Journal of Affective Disorders. 2016; 196, 11-19. doi: 10.1016/j.jad.2016.02.019
6. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem. 1994; 40(2): 288-295.
7. Fava M, Kendler KS. Major depressive disorder. Neuron. 2000; 28(2): 335-341.
8. Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, et al. Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study. Biol Psychiatry. 2007; 62(4): 327-331. doi: 10.1016/j.biopsych.2006.09.022
9. Porcelli S, Fabbri C, Serretti A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) Pharmacogenetics and Imaging – Pharmacogenetics of Antidepressants association with antidepressant efficacy. Eur Neuropsychopharmacol. 2012; 22(4): 239-258. doi: 10.1016/j.euroneuro.2011.10.003
10. Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry. 2010; 15(5): 473-500. doi: 10.1038/mp.2008.116
11. Staeker J, Leucht S, Laika B, Steimer W. Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients. Genet Test Mol Biomarkers. 2014; 18(1): 20-31. doi: 10.1089/gtmb.2013.0217
12. Rotberg B, Kronenberg S, Carmel M, Frisch A, Brent D, Zalsman G, et al. Additive effects of 5-HTTLPR (serotonin transporter) and tryptophan hydroxylase 2 G-703T gene polymorphisms on the clinical response to citalopram among children and adolescents with depression and anxiety disorders. J Child Adolesc Psychopharmacol. 2013; 23(2): 117-122. doi: 10.1089/cap.2012.0020
13. Yamada K, Nabeshima T. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci. 2003; 91(4): 267-270.
14. Akimoto H, Oshima S, Sugiyama T, Negishi A, Nemoto T, Kobayashi D. Changes in brain metabolites related to stress resilience: Metabolomic analysis of the hippocampus in a rat model of depression. Behav Brain Res. 2018; 359: 342-352. doi: 10.1016/j.bbr.2018.11.017
15. Covington HE, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, et al. Antidepressant actions of histone deacetylase inhibitors. J Neurosci. 29(37): 11451-11460. doi: 10.1523/JNEUROSCI.1758-09.2009
16. Roth TL, Lubin FD, Sodhi M, Kleinman JE. Epigenetic mechanisms in schizophrenia. Biochim Biophys Acta. 2009; 1790(9): 869-877. doi: 10.1016/j.bbagen.2009.06.009
17. Arancio O, Chao MV. Neurotrophins, synaptic plasticity and dementia. Current Opinion in Neurobiology. 2007; 17(3): 325-330. doi: 10.1016/j.conb.2007.03.013
18. Bjorkholm C, Monteggia LM. BDNF – a key transducer of antidepressant effects. Neuropharmacology. 2016; 102: 72-79. doi: 10.1016/j.neuropharm.2015.10.034
19. Niitsu T, Fabbri C, Bentini F, Serretti A. Pharmacogenetics in major depression: a comprehensive meta-analysis. Progr Neuropsychopharmacol Biol Psychiatry. 2013; 1(45): 183-194. doi: 10.1016/j.pnpbp.2013.05.011
20. Yan T, Wang L, Kuang W, Xu J, Li S, Chen J, et al. Brain-derived neurotrophic factor Val66Met polymorphism association with antidepressant efficacy: a systematic review and meta-analysis. Asia-Pacific Psychiatry. 2014; 6(3): 241-251. doi: 10.1111/appy.12148
21. Murphy GM Jr, Sarginson JE, Ryan HS, O’Hara R, Schatzberg AF, Lazzeroni LC. BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression. Pharmacogenet Genom. 2013; 23(6): 301-313. doi: 10.1097/FPC.0b013e328360b175
22. Grad I, Picard D. The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol. 2007; 275(1-2): 2-12. doi: 10.1016/j.mce.2007.05.018
23. Willour VL, Chen H, Toolan J, Belmonte P, Cutler DJ, Goes FS, et al. Family-based association of FKBP5 in bipolar disorder. Mol Psychiatry. 2009; 14(3): 261-268. doi: 10.1038/sj.mp.4002141
24. Mandelli L, Serretti A. Gene environment interaction studies in depression and suicidal behavior: An update. Neurosci Biobehav Rev. 2013; 37(10-1): 2375-2397. doi: 10.1016/j.neubiorev.2013.07.011
25. Chang HS, Won E, Lee HY, Ham BJ, Lee MS. Association analysis for corticotropin releasing hormone polymorphisms with the risk of major depressive disorder and the response to antidepressants. Behav Brain Res. 2015; 292: 116-124. doi: 10.1016/j.bbr.2015.06.005
26. Keers R, Bonvicini C, Scassellati C, Uher R, Placentino A, Giovannini C, et al. Variation in GNB3 predicts response and adverse reactions to antidepressants. J Psychopharmacol. 2011; 25(7): 867-874. doi: 10.1177/0269881110376683
27. Lin E, Chen PS, Chang HH, Gean PW, Tsai HC, Yang YK, et al. Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorder. Progr Neuropsychopharmacol Biol Psychiatry. 2009; 33(7): 1167-1172. doi: 10.1016/j.pnpbp.2009.06.015
28. Lee HJ, Cha JH, Ham BJ, Han CS, Kim YK, Lee SH, et al. Association between a G-protein beta 3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders. Pharmacogenomics J. 2004; 4(1): 29-33. doi: 10.1038/sj.tpj.6500217
29. Serretti A, Lorenzi C, Cusin C, Zanardi R, Lattuada E, Rossini D, et al. SSRIs antidepressant activity is influenced by G beta 3 variants. Eur Neuropsychopharmacol. 2003; 13(2): 117-122. doi: 10.1016/S0924-977X(02)00154-2
30. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R, et al. Association of a human G-protein beta 3 subunit variant with hypertension. Nat Genet. 1998; 18(1): 45-48. doi: 10.1038/ng0198-45
31. Hu Q, Zhang SY, Liu F, Zhang XJ, Cui GC, Yu EQ, et al. Influence of GNB3 C825T polymorphism on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis. J Affect Disord. 2015; 172: 103-109. doi: 10.1016/j.jad.2014.09.039
32. Kato M, Wakeno M, Okugawa G, Fukuda T, Takekita Y, Hosoi Y, et al. Antidepressant response and intolerance to SSRI is not influenced by G-protein beta3 subunit gene C825T polymorphism in Japanese major depressive patients. Progr Neuro-psychopharmacol Biol Psychiatry. 2008; 32(4): 1041-1044. doi: 10.1016/j.pnpbp.2008.01.019
33. Joyce PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR, et al. Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline. Int J Neuropsychopharmacol. 2003; 6(4): 339-346. doi:10.1017/S1461145703003663
34. Spronk D, Arns M, Barnett KJ, Cooper NJ, Gordon E. An investigation of EEG, genetic and cognitive markers of treatment response to antidepressant medication in patients with major depressive disorder: a pilot study. J Affect Disord. 2011; 128(1-2): 41-48. doi: 10.1016/j.jad.2010.06.021
35. Arias B, Serretti A, Lorenzi C, Gasto C, Catalan R, Fananas L. Analysis of COMT gene (Val 158 Met polymorphism) in the clinical response to SSRIs in depressive patients of European origin. J Affect Disord. 2006; 90(2-3): 251-256. doi:10.1016/j.jad.2005.11.008
36. Chiesa A, Lia L, Alberti S, Lee SJ, Han C, Patkar AA, et al. Lack of influence of rs4680 (COMT) and rs6276 (DRD2) on diagnosis and clinical outcomes in patients with major depression. Int J Psychiatry Clin Pract. 2014; 18(2): 97-102. doi: 10.3109/13651501.2014.894073
37. Kocabas NA, Faghel C, Barreto M, Kasper S, Linotte S, Mendlewicz J, et al. The impact of catechol-O-methyltransferase SNPs and haplotypes on treatment response phenotypes in major depressive disorder: a case-control association study. Int Clin Psychopharmacol. 2010; 25(4): 218-227. doi: 10.1097/YIC.0b013e328338b884
38. Wang Y, Liu X, Yu Y, Han Y, Wei J, Collier D, et al. The role of single nucleotide polymorphism of D2 dopamine receptor gene on major depressive disorder and response to antidepressant treatment. Psychiatry Res. 2012; 200(2-3): 1047-1050. doi: 10.1016/j.psychres.2012.06.024
39. Jha MK, Trivedi MH. Pharmacogenomics and Biomarkers of Depression. In: Handb Exp Pharmacol. Berlin, Heidelberg: Springer; 2018: 1-13. doi: 10.1007/164_2018_171
40. Calati R, Crisafulli C, Balestri M, Serretti A, Spina E, Calabro M, et al. Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients. Progr Neuropsychopharmacol Biol Psychiatry. 2013; 44: 271-278. doi: 10.1016/j.pnpbp.2013.03.005
41. Powell TR, Schalkwyk LC, Heffernan AL, Breen G, Lawrence T, Price T, et al. Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response. Eur Neuropsychopharmacol. 2013; 23(9): 1105-1114. doi: 10.1016/j.euroneuro.2012.09.009
42. Baune BT, Dannlowski U, Domschke K, Janssen DG, Jordan MA, Ohrmann P, et al. The interleukin 1 beta (IL1B) gene is associated with failure to achieve remission and impaired emotion processing in major depression. Biol Psychiatry. 2010; 67(6): 543-549. doi: 10.1016/j.biopsych.2009.11.004
43. Crisafulli C, Fabbri C, Porcelli S, Drago A, Spina E, DeRonchi D, et al. Pharmacogenetics of antidepressants. Front Pharmacol. 2011; 2: 6. doi: 10.3389/fphar.2011.00006
44. Altar CA., Hornberger J, Shewade A, Cruz V, Garrison J, Mrazek D. Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. Int Rev Psychiatry. 2013; 25(5): 509-533. doi: 10.3109/09540261.2013.825579
45. Muller DJ, Kekin I, Kao AC, Brandl EJ. Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: update and report from a pharmacogenetic service clinic. Int Rev Psychiatry. 2013; 25(5): 554-571. doi: 10.3109/09540261.2013.83894
46. Gex-Fabry M, Eap CB, Oneda B, Gervasoni N, Aubry JM, Bondolfi G, et al. CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther Drug Monit. 2008; 30(4): 474-482. doi: 10.1097/FTD.0b013e31817d6f5d
47. Mrazek DA, Biernacka JM, O’Kane DJ, Black JL, Cunningham JM, Drews MS, et al. CYP2C19 variation and citalopram response. Pharmacogenet Genomics. 2011; 21(1): 1-9.
48. Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA. Applications of CYP450 Testing in the Clinical Setting. Mol Diagn Ther. 2013; 17(3): 165-184. doi: 10.1007/s40291-013-0028-5
49. Tsai MH, Lin KM, Hsiao MC, Shen WW, Lu ML, Tang HS, et al. Genetic polymorphisms of cytochrome P450 enzymes influence me-tabolism of the antidepressant escitalopram and treatment response. Pharmacogenomics. 2010; 11(4): 537-546. doi: 10.2217/pgs.09.168
50. Ji Y, Schaid DJ, Desta Z, Kubo M, Batzler AJ, Snyder K, et al. Citalopram and escitalopram plasma drug and metaboliteconcentrations: genome-wide associations. Br J Clin Pharmacol. 2014; 78(2): 373-383. doi: 10.1111/bcp.12348
51. Hodgson K, Tansey K, Dernovsek MZ, Hauser J, Henigsberg N, Maier W, et al. Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol. 2014; 28(2): 133-141. doi: 10.1177/0269881113512041
52. Probst-Schendzielorz K, Viviani R, Stingl JC. Effect of cytochrome P450 polymorphism on the action and metabolism of selective serotonin reuptake inhibitors. Expert Opin Drug Metab Toxicol. 2015; 11(8): 1219-1232. doi: 10.1517/17425255.2015.1052791
53. Altar CA, Hornberger J, Shewade A, Cruz V, Garrison J, Mrazek D. Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. Int Rev Psychiatry. 2013; 25(5): 509-533. doi: 10.3109/09540261.2013.825579
54. Muller DJ, Kekin I, Kao AC, Brandl EJ. Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: update and report from a pharmacogenetic service clinic. Int Rev Psychiatry. 2013; 25(5): 554-571. doi: 10.3109/09540261.2013.838944
55. Chou WH, Yan FX, de Leon J, Barnhill J, Rogers T, Cronin M, et al. Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness. J Clin Psychopharmacol. 2000; 20(2): 246-251.
56. Bijl MJ, Visser LE, Hofman A, Vulto AG, van Gelder T, Stricker BH, et al. Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants. Br J Clin Pharmacol. 2008; 65(4): 558-564. doi: 10.1111/j.1365-2125.2007.03052.x
57. Brandl EJ, Tiwari AK, Zhou X, Deluce J, Kennedy JL, Muller DJ, et al. Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder. Pharmacogenomics J. 2014; 14(2): 176-181. doi: 10.1038/tpj.2013.12
58. Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur Neuropsychopharmacol. 2008; 18(3): 157-169. doi: 10.1016/j.euroneuro.2007.06.003
59. O’Brien FE, Dinan TG, Griffin BT, Cryan JF. Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol. 2012; 165(2): 289-312. doi: 10.1111/j.1476-5381.2011.01557.x
60. Breitenstein B, Bruckl TM, Ising M, Muller-Myhsok B, Holsboer F, Czamara D. ABCB1 gene variants and antidepressant treatment outcome: a meta-analysis. Am J Med Genet Part B Neuropsychiatr Genet. 2015; 168(4): 274-283. doi: 10.1002/ajmg.b.32309
61. Breitenstein B, Scheuer S, Pfister H, Uhr M, Lucae S, Holsboer F, et al. The clinical application of ABCB1 genotyping in antidepressant treatment: a pilot study. CNS Spectr. 2014; 19(2): 165-175. doi: 10.1017/S1092852913000436
62. García-González J, Tansey KE, Hauser J, Henigsberg N, Maier W, Mors O, et al. Pharmacogenetics of antidepressant response: A polygenic approach. Prog. Neuropsychopharmacol. Biol Psychiatry. 2017; 75: 128-134. doi: 10.1016/j.pnpbp.2017.01.011
63. Bousman CA, Forbes M, Jayaram M, Eyre H, Reynolds CF, Berk M, et al. Antidepressant prescribing in the precision medicine era: a prescriber’s primer on pharmacogenetic tools. BMC Psychiatry. 2017; 17(1): 60. doi: 10.1186/s12888-017-1230-5
64. Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017; 102(1): 37-44. doi: 10.1002/cpt.597
65. Quaranta S, Dupouey J, Colle R, Verstuyft C. Pharmacogenetics of antidepressant drugs: State of the art and clinical implementation – recommendations from the French National Network of Pharmacogenetics. Therapie. 2017; 72(2): 311-318. doi: 10.1016/j.therap.2016.09.018
66. Serretti A. The Present and Future of Precision Medicine in Psychiatry: Focus on Clinical Psychopharmacology of Antidepressants. Clin Psychopharmacol Neurosci. 2018; 16(1): 1-6. doi: 10.9758/cpn.2018.16.1.1
67. Zeier Z, Carpenter LL, Kalin NH, Rodriguez CI, McDonald WM, Widge AS, et al. Clinical Implementation of Pharmacogenetic Decision Support Tools for Antidepressant Drug Prescribing. Am J Psychiatry. 2018; 175(9): 873-886. doi: 10.1176/appi.ajp.2018.17111282
68. Abbott R, Chang DD, Eyre HA, Bousman CA, Merrill DA, Lavretsky H. Pharmacogenetic Decision Support Tools: A New Paradigm for Late-Life Depression? Am J Geriatr Psychiatry. 2018; 26(2): 125-133. doi: 10.1016/j.jagp.2017.05.012
69. Flint J, Kendler KS. The genetics of major depression. Neuron. 2014; 81(5): 1214. doi: 10.1016/j.neuron.2014.02.033
70. Dunn EC, Brown RC, Dai Y, Rosand J, Nugent NR, Amstadter AB, et al. Genetic Determinants of Depression: Recent Findings and Future Directions. Harvard Review of Psychiatry. 2015; 23(1): 1-18. doi: 10.1097/HRP.0000000000000054
71. Kohli MA, Lucae S, Saemann PG, Schmidt MV, Demirkan A, Hek K, et al. The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression. Neuron. 2011; 70(2): 252-265. doi: 10.1016/j.neuron.2011.04.005
72. Levinson DF, Mostafavi S, Milaneschi Y, Rivera M, Ripke S, Wray NR, et al. Genetic studies of major depressive disorder: why are there no genome-wide association study findings and what can we do about it? Biol Psychiatry. 2014; 76(7): 510-512. doi: 10.1016/j.biopsych.2014.07.029
73. Gonda X, Petschner P, Eszlari N, Baksa D, Edes A, Antal P, et al. Genetic variants in major depressive disorder: From pathophysiology to therapy. Pharmacol Ther. 2018; 194: 22-43. doi: 10.1016/j.pharmthera.2018.09.002
74. Sullivan PF, de Geus EJ, Willemsen G, James MR, Smit JH, Zandbelt T, et al. Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol Psychiatry. 2009; 14(4): 359-375. doi: 10.1038/mp.2008.125
75. Mbarek H, Milaneschi Y, Hottenga JJ, Ligthart L, de Geus EJC, Ehli EA, et al. Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder. Twin Research and Human Genetics. 2017; 20(4): 267-270. doi: 10.1017/thg.2017.30
76. Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR, et al. Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Mol Psychiatry. 2012; 17(1): 36-48. DOI: 10.1038/mp.2010.109
77. Hyde CL, Nagle MW, Tian C, Chen X, Paciga SA, Wendland JR, et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nature Genetics. 2016; 48(9): 1031-1036. doi: 10.1038/ng.3623
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For citations:
Khokhlov L.K., Lukyanov N.E. Pharmacogenetics of Antidepressants: from Genetic Findings to Predictive Strategies. Acta Biomedica Scientifica. 2019;4(2):33-43. (In Russ.) https://doi.org/10.29413/ABS.2019-4.2.5
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