Farmakogenetika antidepresivov

Alessandro Serretti; Paolo Olgiati

Alessandro Serretti
Paolo Olgiati

Abstract

Izhodišča: Pri zdravljenju z antidepresivi velik problem predstavlja neodzivnost na zdravljenje, ki je ni mogoče vnaprej napovedati, pojavi pa se kar pri tretjini bolnikov. S farmakogenetskim pristopom so v zadnjih letih odkrili številne genetske polimofizme, ki so povezani z učinkovitostjo zdravljenja z antidepresivi in/ali z neželenimi učinki the zdravil. Prispevek prinaša pregled genetskih dejavnikov, ki lahko vplivajo na farmakodinamiko in farmakokinetiko antidepresivov. Med najpomembnejši polimorfizmi, ki vplivajo na farmakodinamiko in na kratkoročno učinkovitost zdravljenja z antidepresivi, so: polimorfizem (insercija/ delecija 44bp) v promoterju gena za serotoninski transporter SERTPR), ki vpliva na hitrost prepisovanja; polimorfizem A218C gena za triptofan hidroksilazo (TPH), polimorfizem T102C gena za serotoninski receptor 2A (5HT2A, polimorfizem C825T gena za beta3podenoto G proteina (Gbeta3), ko-šaperon, ki uravnava glukokortikoidni receptor (FKBP5) in polimorfizmi gena, ki uravnava cirkadiano aktivnost (Circadian Locomotor Output Cycles Kaput – CLOCK). Na famakokinetiko antidepresivov pa najpomembneje vplivajo citokromi P450, zlasti CYP2D6 preko katerega se presnavlja večina selektivnih zaviralcevi prevzema serotonina (SSRI). Na učinkovitost zdravljenja z antidepresivi pa vpliva tudi polimorfizem gena za pglikoprotein (MDR1 oz. ABCB1), ki transportira antidepresive preko hematoencefalne bariere.

Zaključki: Čeprav so farmakogenetske raziskave zdravljenja z antidepresivi še v začetni fazi, so rezultati obetavni in kažejo, da farmakogenetsko testiranje lahko pripomore k individualiziranemu in bolj racionalnemu zdravljenju z antidepresivi in k boljši kvaliteti življenja bolnikov.

Downloads

Download data is not yet available.

References

Moncrieff J, Kirsch I. Efficacy of antidepressants in adults. BMJ 2005; 331: 551–7.

Fava GA, Fabbri S, Sonino N. Residual symptoms in depression: an emerging therapeutic target. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1019–27.

Tranter R, O’Donovan C, Chandarana P, Kennedy S. Prevalence and outcome of partial remission in depression. J Psychiatry Neurosci 2002; 27: 241–7.

Quitkin F, McGrath P, Stewart J, Taylor B, DF. K. Can the effects of antidepressants be observed in the first two weeks of treatment? Neuropsychopharmacology 1996; 15: 390–4.

Goodnick PJ. Predictors of treatment response in mood disorders. Clinical practice. Washington: American Psychiatric Press; 1996.

Esposito K, Goodnick P. Predictors of response in depression. Psychiatr Clin North Am 2003; 26: 353–65.

Nierenberg AA. Predictors of response to antidepressants general principals and clinical implications. Psychiatr Clin North Am 2003; 26: 345–52.

Weinshilboum R. Inheritance and drug response. N Engl J Med 2003; 348: 529–37.

Roden D, George AJ. The genetic basis of variability in drug responses. Nat Rev Drug Discov 2002; 1: 37–44.

O’Reilly RL, Bogue L, Singh SM. Pharmacogenetic response to antidepressants in a multicase family with affective disorder. Biol Psychiatry 1994; 36: 467–71.

Pare CM, Rees L, Sainsbury MJ. Differentiation of two genetically specific types of depression by the response to anti-depressants. Lancet 1962; 2: 1340–3.

Orsini A. Antidepressant responses and segregation analyses in affective families. In: Racagni G, Smeraldi E, eds. Anxious Depression: assessment and treatment. New York: Raven Press; 1987.

Serretti A, Franchini L, Gasperini M, Rampoldi R, Smeraldi E. Mode of inheritance in mood disorders families according to fluvoxamine response. Acta Psychiatrica Scandinavica 1998; 98: 443–50.

Cramer JA, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv 1998; 49: 196–201.

Murphy G, Hollander S, Rodrigues H, Schatzberg A. Effects of the serotonin transporter promoter polymorphism on paroxetine and mirtazapine efficacy and side effects in geriatric major depression; In: Hospital TZH, ed Pharmacogenetics in psychiatry meeting. New York; 2003. vol 1.

Brown PO, Botstein D. Exploring the new world of the genome with DNA microarrays. Nat Genet 1999; 21: 33–7.

Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965; 122: 509–22.

Bondy M. Pathophysiology of depression and mechanisms of treatment. Dialogues in clinical neuroscience 2002; 4: 21–9.

Schwarz M, Ackenheil M. The role of substance P in depression: therapeutic implications. Dialogues in clinical neuroscience 2002; 4: 21–9.

Reul J, Holsboer F. Pathophysiology of depression and mechanisms of treatment. Dialogues in clinical neuroscience 2002; 4: 31–46.

Schiepers O, Wichers M, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29: 201–17.

Healy D, Waterhouse J. The circadian system and the therapeutics of the affective disorders. Pharmacol Ther 2005; 65: 241–63.

Booij L, Van der Does A, Riedel W. Monoamine depletion in psychiatric and healthy populations: review. Mol Psychiatry 2003; 8: 951–73.

Craig SP, Boularand S, Darmon MC, Mallet J, Craig IW. Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15.3-p14 by in situ hybridization. Cytogenetics & Cell Genetics 1991; 56: 157–9.

Nielsen DA, Jenkins GL, Stefanisko KM, Jefferson KK, Goldman D. Sequence, splice site and population frequency distribution analyses of the polymorphic human tryptophan hydroxylase intron 7. Brain Research. Molecular Brain Research 1997; 45: 145–8.

Jonsson EG, Goldman D, Spurlock G, Gustavsson JP, Nielsen DA, Linnoila M et al. Tryptophan hydroxylase and catechol-Omethyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers. European Archives of Psychiatry & Clinical Neuroscience 1997; 247: 297–302.

Rujescu D, Giegling I, Sato T, Hartmann A, Moller H. Genetic variations in tryptophan hydroxylase in suicidal behavior: analysis and meta-analysis. Biol Psychiatry 2003; 54: 465–73.

Bellivier F, Chaste P, Malafosse A. Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2004; 124: 87–91.

Serretti A, Zanardi R, Rossini D, Cusin C, Lilli R, Smeraldi E. Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity. Molecular Psychiatry 2001; 6: 586–92

Serretti A, Zanardi R, Cusin C, Rossini D, Lorenzi C, Smeraldi E. Tryptophan hydroxylase gene associated with paroxetine antidepressant activity. European Neuropsychopharmacology 2001; 11: 375–80.

Yoshida K, Naito S, Takahashi H, Sato K, Ito K, Kamata M et al. Monoamine oxidase: A gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1279–83.

Ham B, Lee M, Lee H, Kang R, Han C, Choi M, et al. No association between the tryptophan hydroxylase gene polymorphism and major depressive disorders and antidepressant response in a Korean population. Psychiatr Genet 2005; 15: 229–301.

Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003; 299: 76.

Malek Z, Dardente H, Pevet P, Raison S. Tissue-specific expression of tryptophan hydroxylase mRNAs in the rat midbrain: anatomical evidence and daily profiles. Eur J Neurosci 2005; 22: 895–901.

Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP. Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 2004.

Zill P, Buttner A, Eisenmenger W, Moller H, Ackenheil M, Bondy B. Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: A post-mortem study. J Psychiatr Res 2005: [Epub ahead of print].

Garriock H, Allen J, Delgado P, Nahaz Z, Kling M, Carpenter L et al. Lack of association of TPH2 exon XI polymorphisms with major depression and treatment resistance. Mol Psychiatry 2005; 10: 976–7.

Zhang X, Gainetdinov R, Beaulieu J-M, Sotnikova T, Burch L, Williams R, et al. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 2005; 45.

Holmes A, Murphy DL, Crawley JN. Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry 2003; 54: 953–9.

Holmes A, Yang RJ, Lesch KP, Crawley JN, Murphy DL. Mice lacking the serotonin transporter exhibit 5-HT(1A) receptormediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology 2003; 28: 2077–88.

Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, et al. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A 1993; 90: 2542–6.

Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, et al. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 1994; 95: 157–62.

Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, et al. Allelic variation of human serotonin trasporter gene expression. J Neurochem 1996; 66: 2621–4.

Smeraldi E, Zanardi R, Benedetti F, Dibella D, Perez J, Catalano M. Polymorphism Within the Promoter of the Serotonin Transporter Gene and Antidepressant Efficacy of Fluvoxamine. Molecular Psychiatry 1998; 3: 508–11.

Zanardi R, Benedetti F, DiBella D, Catalano M, Smeraldi E. Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of serotonin transporter gene. Journal of Clinical Psychopharmacology 2000; 20: 105–7.

Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, et al. Allelic Variation in the Serotonin Transporter Promoter Affects Onset of Paroxetine Treatment Response in Late-Life Depression. Neuropsychopharmacology 2000; 23: 587–90.

Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C, Lattuada E, et al. Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biological Psychiatry 2001; 50: 323–30.

Rausch JL, Johnson ME, Fei Y-J, Li JQ, Shendarkar N, Mac Hobby H, et al. Initial conditions of serotonin transporter kinetics and genotype: influence on ssri treatment trial outcome. Biological Psychiatry 2002; 51: 723–32.

Arias B, Catalan R, Gasto C, Gutierrez B, Fananas L. 5-HTTLPR polymorphism of the serotonin transporter gene predicts nonremission in major depression patients treated with citalopram in a 12-weeks follow up study. J Clin Psychopharmacol 2003; 23: 563–7.

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: 339–46.

Murphy GM, Jr., Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF. Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 2004; 61: 1163–9.

Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ. Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 2002; 7: 1115–9.

Lee MS, Lee HY, Lee HJ, Ryu SH. Serotonin transporter promoter gene polymorphism and long-term outcome of antidepressant treatment. Psychiatr Genet 2004; 14: 111–5.

Kato M, Ikenaga Y, Wakeno M, Okugawa G, Nobuhara K, Fukuda T, et al. Controlled clinical comparison of paroxetine and fluvoxamine considering the serotonin transporter promoter polymorphism. Int Clin Psychopharmacol 2005; 20: 151–6.

Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG, et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000; 11: 215–9.

Yoshida K, Ito K, Sato K, Takahashi H, Kamata M, Higuchi H, et al. Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 383–6.

Yoshida K, Takahashi H, Higuchi H, Kamata M, Ito K, Sato K, et al. Prediction of antidepressant response to milnacipran by norepinephrine transporter gene polymorphisms. Am J Psychiatry 2004; 161: 1575–80.

Perlis RH, Mischoulon D, Smoller JW, Wan YJ, Lamon-Fava S, Lin KM, et al. Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Biol Psychiatry 2003; 54: 879–83.

Takahashi H, Yoshida K, Ito K, Sato K, Kamata M, Higuchi H, et al. No association between the serotonergic polymorphisms and incidence of nausea induced by fluvoxamine treatment. Eur Neuropsychopharmacol 2002; 12: 477–81.

Mundo E, Walker M, Cate T, Macciardi F, Kennedy JL. The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder. Arch Gen Psychiatry 2001; 58: 539–44.

Masoliver E, Menoyo A, Perez V, Volpini V, Rio E, Perez J, et al. Serotonin transporter linked promoter (polymorphism) in the serotonin transporter gene may be associated with antidepressant-induced mania in bipolar disorder. Psychiatr Genet 2006; 16: 25–9.

Rousseva A, Henry C, Van Den Bulke D, Fournier G, Laplanche JL, Leboyer M, et al. Antidepressant-induced mania, rapid cycling and the serotonin transporter gene polymorphism. Pharmacogenomics J 2003; 3: 101–4.

Serretti A, Artioli P, Zanardi R, Lorenzi C, Rossini D, Cusin C, et al. Genetic features of antidepressant induced mania and hypomania in bipolar disorder. Psychopharmacology (Berl) 2004; 174: 504–11.

Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwin GM, et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 1996; 347: 731–3.

Gutierrez B, Pintor L, Gasto C, Rosa A, Bertranpetit J, Vieta E, et al. Variability in the serotonin transporter gene and increased risk for major depression with melancholia. Hum Gen 1998; 103: 319–22.

Ito K, Yoshida K, Sato K, Takahashi H, Kamata M, Higuchi H, et al. A variable number of tandem repeats in the serotonin transporter gene does not affect the antidepressant response to fluvoxamine. Psychiatry Res 2002; 111: 235–9.

Kraft J, Slager S, McGrath P, Hamilton S. Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol Psychiatry 2005; 58.