Pharmacogenetics of Antidepressants: Is There a Magic Bullet for Treating Depression?

抗憂鬱劑的藥物基因學：治療憂鬱症的仙丹妙藥是否存在？

李敏秀(Min-Soo Lee)

抗憂鬱劑 ； 單胺 ； 藥物基因學 ； 全基因體關聯性研究 (GWAS) ； antidepressants ； monoamines ； pharmacogenetics ； Genome-wide Association Studies (GWAS)

台灣精神醫學

30卷2期（2016 / 06 / 01）

79 - 90+ii

英文

憂鬱症是現今社會最常見的精神疾患之一。已有許多精神醫學領域的研究者投身於憂鬱症病因的研究，但臨床上對於抗憂鬱劑治療反應的個體差異問題仍持續存在。為了更順利地進入本文主題，筆者將會先介紹單胺假說、血清素在造成臨床憂鬱症的角色、以及抗憂鬱劑的問世（簡短描述三環抗憂鬱劑、選擇性血清素回收抑制劑，及其他新型抗憂鬱劑），接下來再介紹藥物基因學的概念與候選基因(candidate genes)。 筆者認為，基因因素被視為對藥物反應有獨立的影響，並舉四個基因研究為例：血清素轉運體 (5-HTT/SLC6A4) 與血清素受體2A (HTR2A)、G 蛋白β3 次單元 (GNB3)、腦源性神經滋養因子 (BDNF)、及色胺酸水解酶(TPH)。值得注意的是，其中有些候選基因研究的結果是不一致的。2009 年起，全基因體關聯性研究 (Genome-wide Association Studies, GWAS) 提供了更進一步的基礎以瞭解抗憂鬱劑及憂鬱症治療的藥物基因學機轉，但更多的研究及技術的發展仍是需要的。

Depression is one of the most common mental disorders nowadays. Many researchers in psychiatry have investigated the cause of depression. Unfortunately, the problem of individual differences in response to antidepressant treatment still lingers in the clinical fi eld. For setting up the stage for the main topics in the later part of this overview, I start introducing the topics of monoamine hypothesis, the rôle of serotonin in causing clinical depression, as well as advents of antidepressants (briefl y describing tricyclic antidepressants, the arrival of selective serotoninreuptake inhibitor, and novel antidepressants). Then, I introduce the concept of pharmacogenetics, the candidate genes. Afterwards, I consider that genetic factors are recognized to have an independent effect on drug responses. To demonstrate, I highlight fi ve gene studies-serotonin transporter (5-HTT/SLC6A4), serotonin receptor 2A (HTR2A), G-protein β3 subunit (GNB3), brain-derived neurotrophic factor (BDNF), and tryptophan hydroxylase (TPH). But some of candidate gene studies have been conducted, but results were not consistent. Since 2009, Genomewide Association Studies (GWAS) has provided further grounds for understanding the pharmacogenetic mechanisms of antidepressants and depression treatment. Further research and technological development are still needed.

1. López-Muñoz, F,Shen, WW,Álamo, C,Cacabelos, R(2014).Serendipitous discovery of first two antidepressants.Taiwanese Journal of Psychiatry,28,67-70.
   連結：
2. Anguelova, M,Benkelfat, C,Turecki, G(2003).A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders.Mol Psychiatry,8,574-591.
3. Arias, B,Fabbri, C,Gressier, F(2012).TPH1, MAOA, serotonin receptor 2A and 2C genes in citalopram response: possible effect in melancholic and psychotic depression.Neuropsychobiology,67,41-47.
4. Bellivier, F,Leboyer, M,Courtet, P(1998).Association between the tryptophan hydroxylase gene and manicdepressive illness.Arch Gen Psychiatry,55,33-37.
5. Berger, M,Gray, JA,Roth, BL(2009).The expanded biology of serotonin.Ann Rev Med,60,355-366.
6. Boadle-Biber, MC(1993).Regulation of serotonin synthesis.Prog Biophysic Mol Biol,60,1-15.
7. Bymaster, FP,Zhang, W,Carter, PA(2002).Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex.Psychopharmacology,160,353-361.
8. Carlsson, A,Lindqvist, M,Magnusson, T(1957).3, 4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists.Nature,180,1200.
9. Chang, HS,Lee, HY,Ham, BJ(2012).Association between brain-derived neurotrophic factor V66M and treatment responses to escitalopram in patients with major depressive disorder.Asia Pac Psychiatry,4,241-249.
10. Chen, L,Lawlor, DA,Lewis, SJ(2008).Genetic association study of BDNF in depression: Finding from two cohort studies and a meta-analysis.Am J Med Genet Part B Neuropsychiatr Genet,147,814-821.
11. Choi, MJ,Kang, RH,Lim, SW,Oh, KS,Lee, MS(2006).Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder.Brain Res,1118,176-182.
12. Cooper, JR,Melcer, I(1961).The enzymic oxidation of tryptophan to 5-hydroxytryptophan in the biosynthesis of serotonin.J Pharmacol Eexper Ther,132,265-268.
13. Fabbri, C,Di, Girolamo, G,Serretti, A(2013).Pharmacogenetics of antidepressant drugs: an update after almost 20 years of research.Am J Med Genet Part B Neuropsychiatr Genet,162,487-520.
14. Fabbri, C,Marsano, A,Albani, D(2014).PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway.Pharmacogenom J,14,463-472.
15. Fabbri, C,Serretti, A(2015).Pharmacogenetics of major depressive disorder: top genes and pathways toward clinical applications.Curr Psychiatry Rep,17,1-11.
16. Fernandes, B,Berk, M,Turck, C,Steiner, J,Goncalves, C(2014).Decreased peripheral brain-derived neurotrophic factor levels are a biomarker of disease activity in major psychiatric disorders: a comparative metaanalysis.Mol Psychiatry,19,750-751.
17. Franchini, L,Serretti, A,Gasperini, M,Smeraldi, E(1998).Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees.J Psychiatr Res,32,255-259.
18. Freis, ED(1954).Mental depression in hypertensive patients treated for long periods with large doses of reserpine.N Engl J Med,251,1006-1008.
19. Gao, J,Pan, Z,Jiao, Z(2012).TPH2 gene polymorphisms and major depression–a meta-analysis.PloS One,7,e36721.
20. Garriock, HA,Kraft, JB,Shyn, SI(2010).A genomewide association study of citalopram response in major depressive disorder.Biol Psychiatry,67,133-138.
21. Gizatullin, R,Zaboli, G,Jonsson, EG,Asberg, M,Leopardi, R(2006).Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression.Biol Psychiatry,59,295-300.
22. Gizatullin, R,Zaboli, G,Jönsson, EG,Åsberg, M,Leopardi, R(2008).The tryptophan hydroxylase (TPH) 2 gene unlike TPH-1 exhibits no association with stress-induced depression.J Affect Disord,107,175-179.
23. Ham, BJ,Lee, BC,Paik, JW(2007).Association between the tryptophan hydroxylase-1 gene A218C polymorphism and citalopram antidepressant response in a Korean population.Prog NeuroPsychopharmacol Biol Psychiatry,31,104-107.
24. Ham, BJ,Lee, MS,Lee, HJ(2005).No association between the tryptophan hydroxylase gene polymorphism and major depressive disorders and antidepressant response in a Korean population.Psychiatr Genet,15,299-301.
25. Hasin, DS,Goodwin, RD,Stinson, FS,Grant, BF(2005).Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions.Arch Gen Psychiatry,62,1097-1106.
26. Heils, A,Teufel, A,Petri, S(1996).Allelic variation of human serotonin transporter gene expression.J Neurochem,66,2621-2624.
27. Hong, C,Chen, T,Yu, YW,Tsai, S(2006).Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder.Pharmacogenomics J,6,27-33.
28. Horstmann, S,Lucae, S,Menke, A(2010).Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment.Neuropsychopharmacology,35,727-740.
29. Hrdina, PD(ed.),Singhal, RL(ed.)(1981).Neuroendocrine Regulation and Altered Behaviour.Berlin:Springer-Verlag.
30. Hu, Q,Zhang, S-Y,Liu, F(2015).Influence of GNB3 C825T polymorphism on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis.J Affect Disord,172,103-109.
31. Huapaya, L,Ananth, J(1980).Is there a relation between depression and hypertension?.Rev Neuropsiquiatr,43,97-105.
32. Insel, TR,Charney, DS(2003).Research on major depression: strategies and priorities.JAMA,289,3167-3168.
33. Ising, M,Lucae, S,Binder, EB(2009).A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression.Arch Gen Psychiatry,66,966-975.
34. Joffe, RT,Sokolov, ST(2000).Thyroid hormone treatment of primary unipolar depression: a review.Int J Neuropsychopharmacol,3,143-147.
35. Joyce, PR,Mulder, RT,Luty, SE(2003).Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein β3 subunit as predictors of response to fluoxetine and nortriptyline.Int J Neuropsychopharmacol,6,339-346.
36. Kang, R,Chang, H,Wong, M(2010).Brain-derived neurotrophic factor gene polymorphisms and mirtazapine responses in Koreans with major depression.J Psychopharmacol,24,1755-1763.
37. Kang, RH,Hahn, SW,Choi, MJ,Lee, MS(2007).Relationship between G-protein beta-3 subunit C825T polymorphism and mirtazapine responses in Korean patients with major depression.Neuropsychobiology,56,1-5.
38. Kapur, S,Remington, G(1996).Serotonin-dopamine interaction and its relevance to schizophrenia.Am J Psychiatry,153,466-476.
39. Kato, M,Wakeno, M,Okugawa, G(2008).Antidepressant response and intolerance to SSRI is not influenced by G-protein β3 subunit gene C825T polymorphism in Japanese major depressive patients.Prog Neuro-Psychopharmacol Biol Psychiatry,32,1041-1044.
40. Kato, M,Wakeno, M,Okugawa, G(2007).No association of TPH1 218A/C polymorphism with treatment response and intolerance to SSRIs in Japanese patients with major depression.Neuropsychobiology,56,167-171.
41. Keers, R,Bonvicini, C,Scassellati, C(2011).Variation in GNB3 predicts response and adverse reactions to antidepressants.J Psychopharmacol,25,867-874.
42. Kessler, RC,Berglund, P,Demler, O(2003).The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R).JAMA,289,3095-3105.
43. Kessler, RC,McGonagle, KA,Zhao, S(1994).Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey.Arch Gen Psychiatry,51,8-19.
44. King, M(2009).King M: Serotonin: The Medical Biochemistry Page. Indiapolis, Indiana: Indiana University School of Medicine, 2009..
45. Kishi, T,Yoshimura, R,Kitajima, T(2010).HTR2A is associated with SSRI response in major depressive disorder in a Japanese cohort.Neuromol Med,12,237-242.
46. Lee, HJ,Cha, J,Ham, BJ(2004).Association between a G-protein β3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders.Pharmacogenom J,4,29-33.
47. Lin, E,Chen, PS,Chang, HH(2009).Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorder.Prog Neuro-Psychopharmacol Biol Psychiatry,33,1167-1172.
48. López-Muñoz, F,Álamo, C,Juckel, G,Assion, HJ(2007).Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. part I: monoamine oxidase inhibitors.J Clin Psychopharmacol,27,555-559.
49. McMahon, FJ,Buervenich, S,Charney, D(2006).Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment.Am J Hum Genet,78,804-814.
50. Nemeroff, CB(1998).The neurobiology of depression.Sci Am,278,42-49.
51. O’Reilly, RL,Bogue, L,Singh, SM(1994).Pharmacogenetic response to antidepressants in a multicase family with affective disorder.Biol Psychiatry,36,467-471.
52. Olié, JP,Kasper, S(2007).Efficacy of agomelatine, a MT 1/MT 2 receptor agonist with 5-HT 2C antagonistic properties, in major depressive disorder.Int J Neuropsychopharmacol,10,661-673.
53. Oquendo, MA,Ellis, SP,Greenwald, S,Malone, KM,Weissman, MM,Mann, JJ(2001).Ethnic and sex differences in suicide rates relative to major depression in the United States.Am J Psychiatry,158,1652-1658.
54. Pare, C,Rees, L,Sainsbury, M(1962).Differentiation of two genetically specific types of depression by the response to anti-depressants.Lancet,280,1340-1343.
55. Perlis, RH,Fijal, B,Adams, DH,Sutton, VK,Trivedi, MH,Houston, JP(2009).Variation in catechol-O-methyltransferase is associated with duloxetine response in a clinical trial for major depressive disorder.Biol Psychiatry,65,785-791.
56. Peters, EJ,Slager, SL,Jenkins, GD(2009).Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response.Pharmacogenet Genom,19,1-10.
57. Philip, NS,Carpenter, LL,Tyrka, AR,Price, LH(2010).Pharmacologic approaches to treatment resistant depression: a re-examination for the modern era.Exp Opin Pharmacother,11,709-722.
58. Polyakova, M,Stuke, K,Schuemberg, K,Mueller, K,Schoenknecht, P,Schroeter, ML(2015).BDNF as a biomarker for successful treatment of mood disorders: a systematic and quantitative meta-analysis.J Affect Disord,174,432-440.
59. Porcelli, S,Fabbri, C,Serretti, A(2012).Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy.Eur Neuropsychopharmacol,22,239-258.
60. Robins, LN,Regier, DA(1991).Psychiatric Disorders in America: The Epidemiologic Catchment Area Study.New York:Free Press.
61. Schneier, FR,Liebowitz, MR,Davies, SO(1990).Fluoxetine in panic disorder.J Clin Psychopharmacol,10,119-121.
62. Serretti, A,Kato, M,De Ronchi, D,Kinoshita, T(2007).Metaanalysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients.Mol Psychiatry,12,247-257.
63. Serretti, A,Zanardi, R,Rossini, D,Cusin, C,Lilli, R,Smeraldi, E(2001).Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity.Mol Psychiatry,6,586-592.
64. Shah, NS(ed.),Donald, AG(ed.)(1984).Psychoneuroendocrine Dysfunction.Berlin:Springer-Verlag.
65. Shore, PA,Silver, SL,Brodie, BB(1955).Interaction of reserpine, serotonin, and lysergic acid diethylamide in brain.Science,122,284-285.
66. Sulser, F(1987).Serotonin-norepinephrine receptor interactions in the brain: implications for the pharmacology and pathophysiology of affective disorders.J Clin Psychiatry,48(Supp),12-18.
67. Tollefson, GD,Rampey, AH,Potvin, JH(1994).A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder.Arch Gen Psychiatry,51,559-567.
68. Tsai, SJ,Cheng, CY,Yu, YW,Chen, TJ,Hong, CJ(2003).Association study of a brain-derived neurotrophic factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response.Am J Med Genet Part B Neuropsychiatr Genet,123b,19-22.
69. Uher, R,Perroud, N,Ng, MY(2010).Genome-wide pharmacogenetics of antidepressant response in the GENDEP project.Am J Psychiatry,167,555-564.
70. Van Den Bogaert, A,Sleegers, K,De Zutter, S(2006).Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population.Arch Gen Psychiatry,63,1103-1110.
71. Verhagen, M,van der Meij, A,van Deurzen, PA(2010).Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity.Mol Psychiatry,15,260-271.
72. Walther, DJ,Bader, M(2003).A unique central tryptophan hydroxylase isoform.Biochem Pharmacol,66,1673-1680.
73. Wang, HC,Yeh, TL,Chang, HH(2011).TPH1 is associated with major depressive disorder but not with SSRI/SNRI response in Taiwanese patients.Psychopharmacology,213,773-779.
74. Wilkie, MJ,Smith, D,Reid, IC(2007).A splice site polymorphism in the G-protein β subunit influences antidepressant efficacy in depression.Pharmacogenet Genom,17,207-215.
75. Wong, DT,Bymaster, FP,Engleman, EA(1995).Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication.Life Sci,57,411-441.
76. Yan, T,Wang, L,Kuang, W(2014).Brain-derived neurotrophic factor Val66Met polymorphism association with antidepressant efficacy: a systematic review and meta-analysis.Asia Pac Psychiatry,6,241-251.
77. Yin, L,Zhang, Y,Zhang, X,Yu, T,He, G,Sun, X(2015).TPH, SLC6A2, SLC6A3, DRD2 and DRD4 polymorphisms and neuroendocrine factors predict SSRIs treatment outcome in the Chinese population with major depression.Pharmacopsychiatry,48,95-103.
78. Yoshida, K,Naito, S,Takahashi, H(2002).Monoamine oxidase: a gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder.Prog Neuro-Psychopharmacol Biol Psychiatry,26,1279-1283.
79. Zill, P,Baghai, T,Zwanzger, P(2004).SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression.Mol Psychiatry,9,1030-1036.
80. Zill, P,Baghai, TC,Zwanzger, P(2000).Evidence for an association between a G-protein β3-gene variant with depression and response to antidepressant treatment.Neuroreport,11,1893-1897.

1. 陳嘉祥(2016)。Psychiatric Practice in the Era of Precision Medicine。臺灣精神醫學，30(3)，158-168+i。