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Contribution of allelic variations to the phenotype of response to antidepressants and antipsychotics

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Abstract

Individualized medicine through molecular pharmacogenetics is one of the major future goals in clinical medicine. In psychopharmacology, pharmacogenetics became an expanding research component. Major research results were already attained: first, it is now feasible to predict a major proportion of the interindividual variation of plasma levels of most antidepressants and antipsychotics by using the DNA-sequence variation in genes for crucial CYP P450-enzymes as CYP2D6. Second, it is now possible to relate serious side effects (tardive dyskinesia, weight gain) of antipsychotics to specific genetic variants of genes for target proteins. Third, a long list of mainly functional variants in target protein genes was explored for their predictive power for the beneficial and adverse treatment outcome. Although specific results transferable into clinical practice were not yet obtained in this respect, the proof of principle could be demonstrated.

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References

  1. Arranz MJ, Munro J, Sham P, Kirov G, Murray RM, Collier DA, Kerwin RW (1998) Meta-analysis of studies on genetic variation in 5-Ht2A receptors and clozapine response. Schizophr Res 32(2):93–99

    Article  PubMed  CAS  Google Scholar 

  2. Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M, Lesch KP, Meyer JF, Sham P, Collier DA, Murray RM, Kerwin RW (2000) Pharmacogenetic prediction of clozapine response. Lancet 355(9215):1615–1616

    Article  PubMed  CAS  Google Scholar 

  3. Arranz MJ, de Leon J (2007) Pharmacogenetics and pharmacogenomics of schizophrenia: a rview of last decade of research. Mol Psychiatry 12(8):707–747

    Article  PubMed  CAS  Google Scholar 

  4. Basile VS, Ozdemir V, Masellis M, Meltzer HY, Lieberman JA, Potkin SG, Macciardi FM, Kennedy JL (2001), Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms: tardive dyskinesia in schizophrenia. Mol Psychiatry 6:230–234

    Article  PubMed  CAS  Google Scholar 

  5. Binder EB, Holsboer F (2006), Pharmacogenomics and antidepressant drugs. Ann Med 38:82–94

    Article  PubMed  CAS  Google Scholar 

  6. Brockmoller J, Kirchhainer J, Schmider J, Walter S, Sachse C, Muller-Oerlinghausen B et al (2002) The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther 72:438–452

    Article  PubMed  Google Scholar 

  7. Brosen K, Naranjo CA (2001) Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 11:275–283

    Article  PubMed  CAS  Google Scholar 

  8. Chou WH, Yan FX, Robbins-Weilert DK, Ryder TB, Liu WW, Perbost C, Fairchild M, de Leon J, Koch WH, Wedlung PJ (2003) Comparison of two CYP2D6 genotyping methods and assessment of genotype–phenotype relationships. Clin Chem 49(4):542–551

    Article  PubMed  CAS  Google Scholar 

  9. Collins FS (1999) Shattuck lecture—medical and societal consequences of the Human Genome Project. N Engl J Med 341(1):28–37

    Article  PubMed  CAS  Google Scholar 

  10. Cusin C, Serretti A, Zanardi R, Lattuada E, Rossini D, Lilli R, Lorenzi C, Smeraldi E (2002) Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. Int J Neuropsychopharmacol 5(1):27–35

    Article  PubMed  CAS  Google Scholar 

  11. Dahl ML (2002) Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet 41:453–470

    Article  PubMed  CAS  Google Scholar 

  12. de Leon J, Armstrong SC, Cozza KL (2006) Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics 47(1):75–85

    Article  PubMed  Google Scholar 

  13. Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB (2004) The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology 174(4):525–529

    Article  PubMed  CAS  Google Scholar 

  14. Emsley RA, Roberts MC, Rataemane S, Pretorius J, Oosthuizen PP, Turner J, Niehaus DJ, KeyterN, Stein DJ (2002) Ethnicity and treatment response in schizophrenia: a comparison of 3 ethnic groups. J Clin Psychiatry 63(1):9–14

    PubMed  Google Scholar 

  15. Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286(5439):487–491

    Article  PubMed  CAS  Google Scholar 

  16. Grasmäder K, Vewohlt PL, Kühn KU, Dragicevic A, von Widdern O, Zobel A, Hiemke C, Rietschel M, Maier W, Jaehde U, Rao ML (2004a) Population pharmacokinetic analysis of mirtazapine. Eur J Clin Pharmacol 60(7):473–480

    Article  PubMed  Google Scholar 

  17. Grasmäder K, Vewohlt PL, Rietschel M, Dragicevic A, Müller M, Hiemke C, Freymann N, Zobel A, Maier W, Rao ML (2004b) 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 60:329–336

    PubMed  Google Scholar 

  18. Hong CF, Lin CH, Yu YWY, Yang KH, Tsai SJ (2001) Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics 11:265–268

    Article  PubMed  CAS  Google Scholar 

  19. Hu X-Z, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815–826

    Article  PubMed  CAS  Google Scholar 

  20. Hu X-Z, Rush AJ, Charney D, Wilson AF, Sorant AJM, Papanicolaou GJ, Fava M, Trivedi MH, Wisniewski SR, Laje G, Paccock S, McMahon FJ, Manji H, Lipsky RH (2007) Association between a functional serotonin transporter promoter polymorphism and Citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry 64(7):783–792

    Article  PubMed  CAS  Google Scholar 

  21. Ingelman-Sundberg M (2004) Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trend Pharmacol Sci 25(4):193–200

    Article  CAS  Google Scholar 

  22. Ingelman-Sundberg M (2005) Genetic polymorphisms of cytochrome P450 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics 5(1):6–13

    Article  CAS  Google Scholar 

  23. Jonsson EG, Nothen MM, Grunhage F, Farde L, Nakashima Y, Propping P, Sedvall GC (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 4:290–296

    Article  PubMed  CAS  Google Scholar 

  24. Kirchhainer J, Nickchen K, Bauer M, Wong M-L, Licinio J, Roots I, Brockmöller J (2004) Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 9:442–473

    Article  Google Scholar 

  25. Kraft JB, Slager SL, McGrath PJ, Hamilton SP (2005) Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol Psychiatry 58(5):374–381

    Article  PubMed  CAS  Google Scholar 

  26. Lencz T, Robinson DG, Xu K, Ekholm J, Sevy S, Gunduz-Bruce H, Woerner MG, Kane JM, Goldman D, Malhotra AK (2006) DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry 163:529–531

    Article  PubMed  Google Scholar 

  27. Lerer B, Segman RH, Fangerau H, Daly AK, Basile VS, Cavallaro R, Aschauer HN, McCreadie RG, Ohlraun S, Ferrier N, Masellis M, Verga M, Scharfetter J, Rietschel M, Lovlie R, Levy UH, Meltzer HY, Kenney JL, Steen VM, Macciardi F (2002) Pharmacogenetics of tardive dyskinesia: comined analysis of 780 patients supports association with dopamine d3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology 27(1):105–119

    Article  PubMed  CAS  Google Scholar 

  28. Lundstrom K, Turpin MP (1996) Proposed schizophrenia-related gene polymorphis: expression of the Ser9Gly mutant human dopanie D3 receptor with the Semliki Forest virus system. Biochem Biophys Res Commun 225(3):1068–1072

    Article  PubMed  CAS  Google Scholar 

  29. Malhotra AK, Murphy GM Jr, Kennedy JL (2004) Pharmacogenetics of psychotropic drug response. Am J Psychiatry 161:780–796

    Article  PubMed  Google Scholar 

  30. McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJ, Papanicolaou GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H (2006) Variaton in the gene encoding te serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 78(5):804–814

    Article  PubMed  CAS  Google Scholar 

  31. Minov C, Baghai TC, Schüle C, Zwanzger P, Schwarz MJ, Zill P, Rupprecht R, Bondy B (2001) Serotonin-2A-receptor and transporter polymorphisms: lack of association in patients with major depression. Neurosci Lett 303(2):119–122

    Article  PubMed  CAS  Google Scholar 

  32. Murphy GM, Kremer C, Rodrigues HE, Schatzberg BA, Schatzberg AF (2003) Pharmocogenetics of antidepressant medication intolerance. Am J Psychiatry 160:1830–1835

    Article  PubMed  Google Scholar 

  33. Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP (2004) Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 9:879–889

    Article  PubMed  CAS  Google Scholar 

  34. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001) Potential role of pharmacogenomics in reducing adverse drug reactions, a systematic review. JAMA 286(18):2270–2279

    Article  PubMed  CAS  Google Scholar 

  35. Reynolds GP, Zhang ZJ, Zhang XB (2002) Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 359(9323):2086–2087

    Article  PubMed  CAS  Google Scholar 

  36. Reynolds GP, Yao Z, Zhang X, Sun J, Zhang Z (2005) Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. Eur Neuropsychopharmacol 15(2):143–151

    Article  PubMed  CAS  Google Scholar 

  37. Roden DM, George AL Jr (2002) The genetic basis of variability in drug responses. Nat Rev Drug Discov 1(1):37–44

    Article  PubMed  CAS  Google Scholar 

  38. Sato K, Yoshida K, Takahashi H, Ito K, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K, Otani K (2002) Association between -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene and fluvoxamine response in Japanese patients with major depressive disorder. Neuropsychobiology 46(3):136–140

    Article  PubMed  CAS  Google Scholar 

  39. Schumacher J, Schulze TG, Wienker TF, Rietschel M, Nothen MM (2000) Pharmacogenetics of the cloazapine response. Lancet 356(9228):506–507

    Article  PubMed  CAS  Google Scholar 

  40. Segman RH, Heresco-Ley U, Finkel B, Inbar R, Neeman T, Schlafman M, Dorevitch A, Yakir A, Lerner A, Goltser T, Shelevoy A, Lerer B (2000) Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility. Psychopharmacology 152(4):408–413

    Article  PubMed  CAS  Google Scholar 

  41. Segman RH, Heresco-Levy U, Finkel B., Goltser T, Shalem R, Schlafman M, Dorevitsch A, Yakir A, Greenberg D, Lerner A, Lerer B (2001) Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 6(2):225–229

    Article  PubMed  CAS  Google Scholar 

  42. Serretti A, Kato M, de Ronchi D, Kinoshita T (2007) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 12:247–257

    PubMed  CAS  Google Scholar 

  43. Sodhi MS, Arranz MJ, Curtis D, Ball DM, Sham P, Roberts GW, Price J, Collier DA, Kerwin RW (1995) Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport 7(1):169–172

    PubMed  CAS  Google Scholar 

  44. Tamminga WJ, Wemer J, Oosterhuis B, de Boer A, Vrackx S, Drenth BF et al. (2003) Polymorphic drug metabolism (CYP2D6) and utilisation of psychotropic drugs in hospitalised psychiatric patients: a retrospective study. Eur J Clin Pharmacol 59:57–64

    PubMed  CAS  Google Scholar 

  45. Tecott LH, Sun LM, Akana SF et al. (1995) Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 374:542–546

    Article  PubMed  CAS  Google Scholar 

  46. Wu S, Xing Q, Gao R, Li X, Gu N, Feng G, He L (2005) Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients. Neurosci Lett 376:1–4

    Article  PubMed  CAS  Google Scholar 

  47. Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama W, Nonaka K (2000) Identification of polymorphic loci in the promoter region of the serotonin 5HT2C receptor gene and their association with obesity and type II diabetes. Diabetologia 43:373–376

    Article  PubMed  CAS  Google Scholar 

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There is no conflict of interest. The authors assure that there is no association with a company whose product is named in the article or a company that markets a competitive product. The presentation of the topic is impartial and the representation of the contents is product neutral.

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  1. Klinik und Poliklinik für Psychiatrie und Psychotherapie, der Universität Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Wolfgang Maier (Prof. Dr.) & Astrid Zobel (PD Dr.)

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  1. Wolfgang Maier
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  2. Astrid Zobel
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Correspondence to Wolfgang Maier.

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Maier, W., Zobel, A. Contribution of allelic variations to the phenotype of response to antidepressants and antipsychotics. Eur Arch Psychiatry Clin Neurosc 258 (Suppl 1), 12–20 (2008). https://doi.org/10.1007/s00406-007-1004-z

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