THE INFLUENCE OF PHARMACOGENETICS IN THE CLINICAL USE OF ANTIDEPRESSANTS

Yıl 2022, Cilt: 23 Sayı: 4, 475 - 480, 17.10.2022

Özlem Çevlik Mert Kaşkal

https://doi.org/10.18229/kocatepetip.892349

Öz

The interest on personalized medicine encourages researches on pharmacogenetics. The promotion of new analytical combinations in extensive drug development and also with the progression in the technologies for human gene cloning resulted in a great interest for pharmacogenetics. In last years the development on genetical sciences also influenced pharmacogenetics. Personalized medicine also includes areas such as stratified medicine and precision medicine and these terms are closely related with pharmacogenetics. Moderate response rates and the difference in drug effect on individuals focus pharmacogenetics on psychopharmacology area and antidepressants. It is considered that genetic factors may contribute %50 of antidepressant drug response. Additionally the genetical properties of the patient may effect the pharmacokinetics and pharmacodynamics of the antidepressants therefore the change in the effect and an increase in the side effects may be seen. The genes which codes serotonin transporter, 5-HTTLPR and SLC6A4 are commonly investigated and they are thought to be the main reasons of the difference in antidepressant drug responses. Also the difference in the activities of CYP 2D6 and CYP 2C19 may change the pharmacokinetics of the antidepressants and therefore the stable concentration of antidepressant leves in the plasma. These variations in the factors contributing to the drug levels may lead to a difference in the response rates of antidepressants. In this review, we focused on the pharmacogenetics of different classes of antidepressant drugs such as selective serotonine reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants and mono-amine oxidase inhibitors. We have compiled pharmacogenetic studies on antidepressants and effect of genetic variations on the drug responses.

Anahtar Kelimeler

Antidepressant, Pharmacogenetics, Psychopharmacology

FARMAKOGENETİĞİN ANTİDEPRESANLARIN KLİNİK KULLANIMI ÜZERİNE ETKİSİ

Öz

Kişiselleştirilmiş tıbba olan ilgi, farmakogenetik üzerine olan araştırmaları da teşvik etmektedir. İlaç geliştirmede yeni analitik metodların ortaya çıkması ve aynı zamanda insan genom teknolojisinde görülen olumlu gelişmeler araştırmacıların farmakogenetiğe olan ilgisini artırmıştır. Son yıllarda genetik biliminde olan bu tür gelişmeler farmakogenetik bilimine olumlu yönde katkı yapmıştır. Kişileştirilmiş tıp terimi aynı zamanda hedefe yönelik ilaç tedavisi ve kişinin genetiğine göre özel tedavi verme kavramlarını gündeme getirmiştir. İlaç tedavisinde görülen değişik yanıt oranları ve genetik farklılıkların ilaç tedavi başarı oranlarını etkilemesi farmakogenetik çalışmaları, psikofarmakoloji ve antidepresanlar üzerine odaklamıştır. Genetik faktörlerin antidepresan ilaç yanıtına yaklaşık %50 kadar katkısı olabileceği düşünülmektedir. Bunlara ek olarak kişinin genetik faktörleri, antidepresanların farmakokinetik ve farmakodinamik özelliklerini etkileyerek ilacın etki oranlarını değiştirebilir aynı zamanda ilacın kandaki konsantrasyon değişimine bağlı görülebilecek istenmeyen etki sıklığında artışa da sebep olabilmektedir. Serotonin taşıyıcılarını kodlayan genler olan, 5-HTTLPR ve SLC6A4 isimli genler yaygın olarak araştırılmakta ve antidepresan ilaç yanıtında temel farklılıkların bu genlerdeki değişimlerin olduğu sanılmaktadır. Ayrıca CYP 2D6 ve CYP 2C19’un aktivitelerindeki farklılıkların antidepresanların karaciğerdeki yıkım hızını, farmakokinetik özelliklerini etkileyebilmekte ve plazmadaki antidepresan kontsantrasyonlarını değiştirebilmektedir. Tüm bu faktörlerde olabilecek değişiklikler antidepresan tedavisine olan yanıtları değiştirebilmekte ve genetik farklılıklara bağlı doz ayarlaması yapılması gündeme gelmektedir. Bu derlemede, seçici serotonin geri alım inhibitörleri, serotonin-nöradrenalin geri alım inhibitörleri, trisiklik antidepresanlar ve mono-amin oksidaz inhibitörleri gibi farklı antidepresan gruplarının farmakogenetik özelliklerine odaklandık. Genetik varyasyonların, antidepresanların farmakokinetik ve farmakodinamik özellikleri üzerine olan etkilerini ve bu etkilerin antidepresanların kliniğine olan yansımalarını derledik.

Anahtar Kelimeler

Antidepresanlar, Farmakogenetik, Psikofarmakoloji

Kaynakça

• 1. Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Bio technol Bio Eng. 2017;3(5) 437-8.
• 2. Sistare FD, DeGeorge JJ: Preclinical predictors of clinical safety: Opportunities for improvement. Clin Pharmacol Ther. 2007;82(2):210.
• 3. Roden DM, McLeod HL, Relling MV, et al. Pharmacogenomics. Lancet. 2019;394(10197):521-32.
• 4. Stingl J, Viviani R. Polymorphism in CYP2D6 and CYP2C19, members of the cytochrome P450 mixed-function oxidase system, in the metabolism of psychotropic drugs. J Intern Med. 2015;277(2):167-77.
• 5. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009;48(12):761-804.
• 6. Drago A, Ronchi DD, Serretti A. 5-HT1A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Int J Neuropsychopharmacol. 2008;11(5):701-21.
• 7. Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015;98(2):127-34.
• 8. Kishi T, Yoshimura R, Kitajima T, et al. HT2RA is associated with SSRI response in major depressive disorder in a Japanese cohort. Neuromolecular Med. 2009;12(3):237–42.
• 9. Eleanor Murphy and Francis J. McMahon. Pharmacogenetics of Antidepressants, Mood Stabilizers, and Antipsychotics in Diverse Human Populations. Discov Med. 2013; 16(87):113–22.
• 10. Porcelli S, Fabbri C, Serretti A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. European Neuropsychopharmacology, 2012;(22):239–58.
• 11. Rausch JL, Johnson ME, Fei YJ, et al. Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry. 2002;51(9):723-32.
• 12. Ruhé HG, Ooteman W, Booij J, et al. Serotonin transporter gene promoter polymorphisms modify the association between paroxetine serotonin transporter occupancy and clinical response in major depressive disorder. Pharmacogenet Genomics. 2009;19(1):67-76.
• 13. Taylor MJ, Sen S, Bhagwagar Z. Antidepressant response and the serotonin transporter gene-linked polymorphic region. Biol Psychiatry. 2010;68(6):536-43.
• 14. Reimherr F, Amsterdam J, Dunner D, et al. Genetic polymorphisms in the treatment of depression:speculations from an augmentation study using atomoxetine. Psychiatry Res. 2010;175:67–73.
• 15. Parsey RV, Olvet DM, Oquendo MA, et al. Higher 5-HT1A receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study. Neuropsychopharmacology. 2006;31(8):1745-9.
• 16. Scutt G, Overall A, Scott R, et al. Does the 5-HT1A rs6295 polymorphism influence the safety and efficacy of citalopram therapy in the oldest old? Ther Adv Drug Saf. 2018;9(7):355-66.
• 17. Lim SW, Shiue YL, Ho CH, et al. Anxiety and Depression in Patients with Traumatic Spinal Cord Injury: A Nationwide Population-Based Cohort Study. J Depress Anxiety. 2017;12:1-4.
• 18. Dong ZQ, Li XR, He L, He G, Yu T, Sun XL. 5-HTR1A and 5-HTR2A genetic polymorphisms and SSRI antidepressant response in depressive Chinese patients. Neuropsychiatr Dis Treat. 2016;12:1623-29.
• 19. McMahon FJ, Buervenich S, Charney D et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006;78(5):804-14.
• 20. Norton N, Owen MJ. HTR2A: association and expression studies in neuropsychiatric genetics. Ann Med. 2005;37(2):121–9.
• 21. Illi A, Setälä-Soikkeli E, Viikki M, et al. 5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression. Neuroreport. 2009;20(12):1125-8.
• 22. Renoux C, Lix LM, Patenaude V, et al. Serotonin-Norepinephrine Reuptake Inhibitors and the Risk of AKI: A Cohort Study of EightAdministrative Databases and Meta-Analysis. Clin J Am SocNephrol. 2015;10(10):1716-22.
• 23. Song SY, Ko YB, Kim H, et al. Effect of serotonin-norepinephrine reuptake inhibitors for patients with chemotherapy-induced painful peripheral neuropathy: A meta-analysis. Medicine (Baltimore). 2020;99:1-9.
• 24. Suwała J, Machowska M, Wiela-Hojeńska A. Venlafaxine pharmacogenetics: a comprehensive review. Pharmacogenomics. 2019;20(11):829-45.
• 25. JJ Swen, M Nijenhuis, A de Boer et al. Pharmacogenetics: From Bench to Byte- An Update of guidelines.2011;89(5),662-73.
• 26. Serretti, A., Calati, R., Massat, I et al. CytochromeP450 CYP1A2, CYP2C9, CYP2C19and CYP2D6 genes are not associatedwith response and remission ina sample of depressive patients. Int.Clin. Psychopharmacol. 2009;(24): 250–6.
• 27. Grasmäder K, Verwohlt PL, Rietschel M et al. Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur J Clin Pharmacol. 2004;60(5):329-36.
• 28. Min, W, Li T, Ma X, et al. Monoamine transporter gene polymorphisms affect susceptibility to depression and predict antidepressant response. Psychopharmacology (Berl.) 2009;(205):409–17.
• 29. Knadler MP, Lobo E, Chappell J, Bergstrom R. Duloxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet. 2011;50(5):281- 94.
• 30. Chan C, Yeo KP, Pan AX, et al. Duloxetine pharmacokinetics are similar in Japanese and Caucasian subjects. Br J Clin Pharmacol 2007;63(3):310-4.
• 31. Zastrozhin M, Petukhov A, Pankratenko E, et al. Impact of Polymorphism of CYP2D6 on Equilibrium Concentration of Duloxetine in Patients Suffering from Major Depressive Disorder. Psychopharmacol Bull. 2020; 23;50(3):47-57.
• 32. Strawn JR, Geracioti L, Rajdev N, et al. Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review. Expert Opin Pharmacother. 2018;19(10):1057-70.
• 33. Rubin EH, Biggs JT, Preskorn SH. Nortriptyline pharmacokinetics and plasma levels: implications for clinical practice. J Clin Psychiatry. 1985;46(10):418-24.
• 34. Shimoda K, Someya T, Yokono A, et al. The impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients. J Clin Psychopharmacol. 2002;22:371–8.
• 35. Bertilsson L, Mellstrom B, Sjokvist F et al. Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications. Lancet. 1981;(1):560-1.
• 36. Hicks JK, Sangkuhl K, Swen JJ, 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.
• 37. Shulman KI, Herrmann N, Walker SE. Current Place of Monoamine Oxidase Inhibitors in the Treatment of Depression. CNS Drugs.2013;27(10):789–97.
• 38. Bonnet U. Moclobemide: therapeutic use and clinical studies. CNS Drug Rev. 2003;9(1):97-140.
• 39. Cacabelos R, Torrellas C, Carrera I. Opportunities in pharmacogenomics in the treatment of Alzheimer’s disease. Future Neurology. 2015;10:(3): 229-52.
• 40. Kraft J, Slager S, McGrath P, Hamilton S. Sequence analysisof the serotonin transporter and associations with antidepressant response. Biol. Psychiatry.2005; (58):374–81.
• 41. Smeraldi E, Serretti A, Artioli P, et al. Serotonin transporter gene-linked polymorphic region: possible pharmacogenetic implications of rare variants. Psychiatr. Genet. 2006;(16):153–8.