Chapter 3
Genetics of Treatment-resistant Depression
Chiara Fabbri,
Stefano Porcelli,
Alessandro Serretti,
Chiara Fabbri
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorStefano Porcelli
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorAlessandro Serretti
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorChiara Fabbri,
Stefano Porcelli,
Alessandro Serretti,
Chiara Fabbri
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorStefano Porcelli
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorAlessandro Serretti
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorSiegfried Kasper MD,
Stuart Montgomery MD,
Siegfried Kasper MD
Professor and Chair, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna Austria
Search for more papers by this authorStuart Montgomery MD
Emeritus Professor of Psychiatry Professor of Psychiatry (retired), Imperial College of Science, Technology and Medicine, University of London, London UK
Search for more papers by this authorBook Author(s):Siegfried Kasper MD,
Stuart Montgomery MD,
Siegfried Kasper MD
Professor and Chair, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna Austria
Search for more papers by this authorStuart Montgomery MD
Emeritus Professor of Psychiatry Professor of Psychiatry (retired), Imperial College of Science, Technology and Medicine, University of London, London UK
Search for more papers by this authorSummary
Gene variants influence the clinical outcomes of antidepressant treatments, explaining 50% of the variance. In particular, treatment-resistant depression (TRD) is a cause of considerable societal burden and would greatly benefit from the identification of genetic predictors. The most promising genes for association with TRD are SLC6A4, 5-HTR1A, COMT, BDNF and CREB1, but further work is needed in order to translate findings into clinical recommendations. Indeed, the complex nature of major depression and antidepressant response make the picture complex to dissect. Nonetheless, hopefully in a few years, genetic prediction of TRD could become a widespread clinical reality.
References
- Aklillu, E., Karlsson, S., Zachrisson, O. O. et al. (2009) Association of MAOA gene functional promoter polymorphism with CSF dopamine turnover and atypical depression. Pharmacogen. Gen., 19(4), 267–275.
- Albert, P. R. & Francois, B. L. (2010) Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy. Front. Neurosci., 4, 35.
- Anttila, S., Huuhka, K., Huuhka, M. et al. (2007a) Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J. Neural. Transm., 114(8), 1065–1068.
- Anttila, S., Huuhka, K., Huuhka, M. et al. (2007b) Interaction between TPH1 and GNB3 genotypes and electroconvulsive therapy in major depression. J. Neural. Transm., 114(4), 461–468.
- Anttila, S., Huuhka, K., Huuhka, M. et al. (2008) Catechol-O-methyltransferase (COMT) polymorphisms predict treatment response in electroconvulsive therapy. Pharmacogen. J., 8(2), 113–116.
- Anttila, S., Viikki, M., Huuhka, K. et al. (2009) TPH2 polymorphisms may modify clinical picture in treatment-resistant depression. Neurosci. Lett., 464(1), 43–46.
- Baffa, A., Hohoff, C., Baune, B. T. et al. (2010) Norepinephrine and serotonin transporter genes: impact on treatment response in depression. Neuropsychobiol., 62(2), 121–131.
- Blendy, J. A. (2006) The role of CREB in depression and antidepressant treatment. Biol. Psychiatry, 59(12), 1144–1150.
- Bocchio-Chiavetto, L., Miniussi, C., Zanardini, R. et al. (2008) 5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression. Neurosci. Lett., 437(2), 130–134.
- Bonvicini, C., Minelli, A., Scassellati, C. et al. (2010) Serotonin transporter gene polymorphisms and treatment-resistant depression. Prog. Neuropsychopharmacol. Biol. Psychiatry, 34(6), 934–939.
- Brent, D., Melhem, N., Ferrell, R. et al. (2010) Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study. Am. J. Psychiatry, 167(2), 190–197.
- Buckholtz, J. W., Meyer-Lindenberg, A., Honea, R. A. et al. (2007) Allelic variation in RGS4 impacts functional and structural connectivity in the human brain. J. Neurosci., 27(7), 1584–1593.
- Chessell, I. P., Hatcher, J. P., Bountra, C. et al. (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain, 114(3), 386–396.
- Del Bo, R., Scarlato, M., Ghezzi, S. et al. (2005) Vascular endothelial growth factor gene variability is associated with increased risk for AD. Ann. Neurology, 57(3), 373–380.
- Dhaenen, H. (2001) Imaging the serotonergic system in depression. Eur. Arch. Psychiatry Clin. Neurosci., 251(Suppl 2), II76–80.
- Domschke, K., Zavorotnyy, M., Diemer, J. et al. (2010) COMT val158met influence on electroconvulsive therapy response in major depression. Am. J. Med. Genet. B. Neuropsychiatr. Genet., 153B(1), 286–290.
- Drago, A., Crisafulli, C., Sidoti, A. et al. (2011) The molecular interaction between the glutamatergic, noradrenergic, dopaminergic and serotoninergic systems informs a detailed genetic perspective on depressive phenotypes. Prog. Neurobiol., 94(4), 418–460.
- Dwivedi, Y., Rao, J. S., Rizavi, H. S. et al. (2003) Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects. Arch. Gen. Psychiatry, 60(3), 273–282.
- Egan, M. F., Kojima, M., Callicott, J. H. et al. (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112(2), 257–269.
- Falkenberg, V. R., Gurbaxani, B. M., Unger, E. R. et al. (2011) Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. Neuromolec. Med., 13(1), 66–76.
- Garriock, H. A., Allen, J. J., Delgado, P. et al. (2005) Lack of association of TPH2 exon XI polymorphisms with major depression and treatment resistance. Mol. Psychiatry, 10(11), 976–977.
- Gold, S. J., Heifets, B. D., Pudiak, C. M. et al. (2002) Regulation of regulators of G protein signaling mRNA expression in rat brain by acute and chronic electroconvulsive seizures. J. Neurochem., 82(4), 828–838.
- Heurteaux, C., Lucas, G., Guy, N. et al. (2006) Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat. Neurosci., 9(9), 1134–1141.
- Huuhka, M., Anttila, S., Leinonen, E. et al. (2005) The apolipoprotein E polymorphism is not associated with response to electroconvulsive therapy in major depressive disorder. J. ECT, 21(1), 7–11.
- Huuhka, K., Anttila, S., Huuhka, M. et al. (2007) Brain-derived neurotrophic factor (BDNF) polymorphisms G196A and C270T are not associated with response to electroconvulsive therapy in major depressive disorder. Eur. Arch. Psychiatry Clin. Neurosci., 257(1), 31–35.
- Huuhka, K., Anttila, S., Huuhka, M. et al. (2008a) Dopamine 2 receptor C957T and catechol-o-methyltransferase Val158Met polymorphisms are associated with treatment response in electroconvulsive therapy. Neurosci. Lett., 448(1), 79–83.
- Huuhka, K., Kampman, O., Anttila, S. et al. (2008b) RGS4 polymorphism and response to electroconvulsive therapy in major depressive disorder. Neurosci. Lett., 437(1), 25–28.
- Jacobs, B. L., van Praag, H. & Gage, F. H. (2000) Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol. Psychiatry, 5(3), 262–269.
- Kato, M. & Serretti, A. (2010) Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol. Psychiatry, 15(5), 473–500.
- Kishida, I., Aklillu, E., Kawanishi, C. et al. (2007) Monoamine metabolites level in CSF is related to the 5-HTT gene polymorphism in treatment-resistant depression. Neuropsychopharmacol., 32(10), 2143–2151.
- Kocabas, N. A., Antonijevic, I., Faghel, C. et al. (2011) Brain-derived neurotrophic factor gene polymorphisms: influence on treatment response phenotypes of major depressive disorder. Int. Clin. Psychopharmacol., 26(1), 1–10.
- Kocabas, N. A., Faghel, C., Barreto, M. et al. (2010) 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., 25(4), 218–227.
- Kocabas, N. A., Antonijevic, I., Faghel, C. et al. (2011) Dysbindin gene (DTNBP1) in major depressive disorder (MDD) patients: lack of association with clinical phenotypes. World J. Biol. Psychiatry, 11(8), 985–990.
- Levin, G. M., Bowles, T. M., Ehret, M. J. et al. (2007) Assessment of human serotonin 1A receptor polymorphisms and SSRI responsiveness. Mol. Diagn. Ther., 11(3), 155–160.
- Lin, P. I., Vance, J. M., Pericak-Vance, M. A. et al. (2007) No gene is an island: the flip-flop phenomenon. Am. J. Hum. Gen., 80(3), 531–538.
- Maier, W. & Zobel, A. (2008) Contribution of allelic variations to the phenotype of response to antidepressants and antipsychotics. Eur. Arch. Psychiatry Clin. Neurosci., 258(Suppl. 1), 12–20.
- Malaguti, A., Rossini, D., Lucca, A. et al. (2011) Role of COMT, 5-HT(1A), and SERT genetic polymorphisms on antidepressant response to Transcranial Magnetic Stimulation. Depression & Anxiety, 28(7), 568–573.
- Mamdani, F., Lopez, J., Berlim, M. et al. (2011) Transcriptomic and epigenetic correlates of antidepressant response. XIXth World Congress of Psychiatric Genetics: Genes to Biology, Washington, DC, USA.
- Mandelli, L., Mazza, M., Martinotti, G. et al. (2010) Further evidence supporting the influence of brain-derived neurotrophic factor on the outcome of bipolar depression: independent effect of brain-derived neurotrophic factor and harm avoidance. J. Psychopharmacol., 24(12), 1747–1754.
- Manji, H. K., Quiroz, J. A., Sporn, J. et al. (2003) Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol. Psychiatry, 53(8), 707–742.
- Minelli, A., Zanardini, R., Abate, M. et al. (2011) Vascular Endothelial Growth Factor (VEGF) serum concentration during electroconvulsive therapy (ECT) in treatment resistant depressed patients. Prog. Neuropsychopharmacol. Biol. Psychiatry, 35(5), 1322–1325.
- Noro, M., Antonijevic, I., Forray, C. et al. (2010) 5HT1A and 5HT2A receptor genes in treatment response phenotypes in major depressive disorder. Int. Clin. Psychopharmacol., 25(4), 228–231.
- O'Brien, F. E., Dinan, T. G., Griffin, B. T. et al. (2011) Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. Brit. J. Pharmacol., doi:10.1111/j.1476-5381.2011.01557.x.
- Paik, S., Tang, G., Shak, S. et al. (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J. Clin. Oncol., 24(23), 3726–3734.
- Perlis, R. H., Moorjani, P., Fagerness, J. et al. (2008) Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(∗)D study. Neuropsychopharmacol., 33(12), 2810–2819.
- Porcelli, S., Drago, A., Fabbri, C. et al. (2011a) Mechanisms of antidepressant action: an integrated dopaminergic perspective. Prog. Neuropsychopharmacol. Biol. Psychiatry, 35(7), 1532–1543.
- Porcelli, S., Drago, A., Fabbri, C. et al. (2011b) Pharmacogenetics of antidepressant response. J. Psychiatry Neurosci., 36(2), 87–113.
- Porcelli, S., Fabbri, C., Drago, A. et al. (2011c) Genetics and antidepressants: where we are. Clin. Neuropsych., 8(2), 99–150.
- Porcelli, S., Fabbri, C., Spina, E. et al. (2011d) Genetic polymorphisms of cytochrome P450 enzymes and antidepressant metabolism. Exp. Op. Drug Metab. Toxicol., 7(9), 1101–1115.
- Psychiatric GWAS Consortium Steering Committee (2009) A framework for interpreting genome-wide association studies of psychiatric disorders. Mol. Psychiatry, 14(1), 10–17.
- Reimherr, F., Amsterdam, J., Dunner, D. et al. (2010) Genetic polymorphisms in the treatment of depression: speculations from an augmentation study using atomoxetine. Psy. Res., 175(1–2), 67–73.
- Richardson-Jones, J. W., Craige, C. P., Guiard, B. P. et al. (2010) 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron, 65(1), 40–52.
- Roberts, R., Wells, G. A., Stewart, A. F. et al. (2010) The genome-wide association study – a new era for common polygenic disorders. J. Cardio. Trans. Res., 3(3), 173–182.
- Rosenhagen, M. C. & Uhr, M. (2010) Single nucleotide polymorphism in the drug transporter gene ABCB1 in treatment-resistant depression: clinical practice. J. Clin. Psychopharmacol., 30(2), 209–211.
- Sapolsky, R. M. (2000) The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol. Psychiatry, 48(8), 755–765.
- Scharinger, C., Rabl, U., Pezawas, L. et al. (2011) The genetic blueprint of major depressive disorder: contributions of imaging genetics studies. World J. Biol. Psychiatry, 2, 474–488.
- Schosser, A., Calati, R., Serretti, A. et al. (2011) The impact of COMT gene polymorphisms on suicidality in treatment resistant major depressive disorder – a European Multicenter Study. Eur. Neuropsychopharmacol, 25(4), 218–227.
- Segi-Nishida, E. (2011) Exploration of new molecular mechanisms for antidepressant actions of electroconvulsive seizure. Biol. Pharmaceut. Bull., 34(7), 939–944.
- Serretti, A., Franchini, L., Gasperini, M. et al. (1998) Mode of inheritance in mood disorders families according to fluvoxamine response. Acta Psychiatr. Scand., 98(6), 443–450.
- Serretti, A., Kato, M. & Kennedy, J. L. (2008) Pharmacogenetic studies in depression: a proposal for methodologic guidelines. Pharmacogen. J., 8(2), 90–100.
- Serretti, A., Chiesa, A., Calati, R. et al. (2011a) A preliminary investigation of the influence of CREB1 gene on treatment resistance in major depression. J. Affect. Disord., 128(1–2), 56–63.
- Serretti, A., Chiesa, A., Calati, R. et al. (2011b) No influence of PTGS2 polymorphisms on response and remission to antidepressants in major depression. Psy. Res., 188(1), 166–169.
- Serretti, A., Olgiati, P., Bajo, E. et al. (2011c) A model to incorporate genetic testing (5-HTTLPR) in pharmacological treatment of major depressive disorders. World J. Biol. Psychiatry, 12(7), 501–515.
- Shih, J. C., Chen, K. & Ridd, M. J. (1999) Role of MAO A and B in neurotransmitter metabolism and behavior. Polish J. Pharmacol., 51(1), 25–29.
- Slodkowska, E. A. & Ross, J. S. (2009) MammaPrint 70-gene signature: another milestone in personalized medical care for breast cancer patients. Exp. Rev. Mol. Diagnost., 9(5), 417–422.
- Steffensen, K. D., Waldstrom, M., Brandslund, I. et al. (2010) The relationship of VEGF polymorphisms with serum VEGF levels and progression-free survival in patients with epithelial ovarian cancer. Gyn. Oncol., 117(1), 109–116.
- Stewart, J. A., Kampman, O., Huuhka, M. et al. (2009) ACE polymorphism and response to electroconvulsive therapy in major depression. Neurosci. Lett., 458(3), 122–125.
- Sullivan, P. F. (2007) Spurious genetic associations. Biol. Psychiatry, 61(10), 1121–1126.
- Sullivan, P. F., Neale, M. C. & Kendler, K. S. (2000) Genetic epidemiology of major depression: review and meta-analysis. Am. J. Psychiatry, 157(10), 1552–1562.
- Trivedi, M. H., Rush, A. J., Wisniewski, S. R. et al. (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR∗D: implications for clinical practice. Am. J. Psychiatry, 163(1), 28–40.
- Tsuang, M. S. F. (1990) The Genetics of Mood Disorders. Johns Hopkins University Press, Baltimore, MD, USA.
- Uhr, M., Tontsch, A., Namendorf, C. et al. (2008) Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron, 57(2), 203–209.
- Viikki, M., Anttila, S., Kampman, O. et al. (2010a) Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression. Neurosci. Lett., 477(3), 105–108.
- Viikki, M., Kampman, O., Illi, A. et al. (2010b) TPH1 218A/C polymorphism is associated with major depressive disorder and its treatment response. Neurosci. Lett., 468(1), 80–84.
- Viikki, M., Kampman, O., Anttila, S. et al. (2011a) P2RX7 polymorphisms Gln460Arg and His155Tyr are not associated with major depressive disorder or remission after SSRI or ECT. Neurosci. Lett., 493(3), 127–130.
- Viikki, M., Huuhka, K., Leinonen, E. et al. (2011b) Interaction between two HTR2A polymorphisms and gender is associated with treatment response in MDD. Neurosci. Lett., 501(1), 20–24.
- Warner-Schmidt, J. L. & Duman, R. S. (2008) VEGF as a potential target for therapeutic intervention in depression. Curr. Opin. Pharmacol., 8(1), 14–19.
- Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447(7145), 661–678.
- Wilkie, M. J., Smith, D., Reid, I. C. et al. (2007) A splice site polymorphism in the G-protein beta subunit influences antidepressant efficacy in depression. Pharmacogen. Gen., 17(3), 207–215.
- Xu, B., Roos, J. L., Dexheimer, P. et al. (2011) Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat. Gen., 43(9), 864–868.
- Yu, H. & Chen, Z. Y. (2011) The role of BDNF in depression on the basis of its location in the neural circuitry. Acta Pharmacol. Sinica, 32(1), 3–11.
- Zanardi, R., Magri, L., Rossini, D. et al. (2007) Role of serotonergic gene polymorphisms on response to transcranial magnetic stimulation in depression. Eur. Neuropsychopharmacol., 17(10), 651–657.
- Zarate, C. Jr, Machado-Vieira, R., Henter, I. et al. (2010) Glutamatergic modulators: the future of treating mood disorders? Harvard Rev . Psychiatry, 18(5), 293–303.
- Zhang, X., Gainetdinov, R. R., Beaulieu, J. M. et al. (2005) Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron, 45(1), 11–16.
