Skip to main content Accessibility help
×
Home
  • Print publication year: 2013
  • Online publication date: May 2013

29 - Pharmacogenetics and mood disorders

from Section 5 - The promise of biomarkers and response prediction

Summary

This chapter reviews some of the key considerations of pharmacogenetics in the treatment of mood disorders. There have been a number of small studies aimed at finding genetic markers of antidepressant treatment outcome. If the serotonin transporter (SLC6A4) is the most studied gene in psychiatry, a functional polymorphism in its promoter region (known as the linked polymorphic region (LPR)), is the most studied genetic marker. Variation in brain-derived neurotrophic factor (BDNF) has been thought to play a role in the etiology of affective disorders and the mediation of antidepressant treatment response. Genome-wide association studies (GWAS) are a relatively new kind of genetic study that take advantage of large numbers of highly informative genetic markers, spread across each chromosome. Adverse events occur with all pharmacological treatments. Two groups of antidepressant-associated adverse events have been studied in large samples: treatment-emergent suicidal ideation (TESI) and sexual dysfunction (SD).

Related content

Powered by UNSILO

References

Anttila, S., Huuhka, K., Huuhka, M.et al. (2007). Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. Journal of Neural Transmission, 114, 1065–1068.
Berg, A.O., Piper, M., Armstrong, K.et al. (2007). Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors. Genetics in Medicine, 9, 819–825.
Binder, E.B., Salyakina, D., Lichtner, P.et al. (2004). Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature Genetics, 36, 1319–1325.
Black, J.L., III, O’Kane, D.J., and Mrazek, D.A. (2007). The impact of CYP allelic variation on antidepressant metabolism: A review. Expert Opinion on Drug Metabolism and Toxicology, 3, 21–31.
Brandish, P.E., Su, M., Holder, D.J.et al. (2005). Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex. Neuron, 45, 861–872.
Brennand, K.J., Simone, A., Jou, J.et al. (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature, 473, 221–225.
Cabanero, M., Laje, G., Tera-Wadleigh, S., and McMahon, F.J. (2009). Association study of phosphodiesterase genes in the Sequenced Treatment Alternatives to Relieve Depression sample. Pharmacogenetics and Genomics, 19, 235–238.
Choi, M.J., Kang, R.H., Lim, S.W., Oh, K.S., and Lee, M.S. (2006). Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Research, 1118, 176–182.
Chung, W.H., Hung, S.I., Hong, H.S.et al. (2004). Medical genetics: A marker for Stevens–Johnson syndrome. Nature, 428, 486.
Domschke, K., Lawford, B., Laje, G.et al. (2009). Brain-derived neurotrophic factor (BDNF) gene: No major impact on antidepressant treatment response. International Journal of Neuropsychopharmacology, 13, 93–101.
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, 257–269.
FDA (2005). Antidepressant Use in Children, Adolescents and Adults [online] Avalabel. http://www.fda.gov/cder/drug/antidepressants/default.htm (accessed March 2012).
Ferrell, P.B., Jr. and McLeod, H.L. (2008). Carbamazepine, HLA-B*1502 and risk of Stevens–Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics, 9, 1543–1546.
Fournier, J.C., DeRubeis, R.J., Hollon, S.D.et al. (2010). Antidepressant drug effects and depression severity: A patient-level meta-analysis. Journal of the American Medical Association, 303, 47–53.
Garriock, H.A., Kraft, J.B., Shyn, S.I.et al. (2010). A genomewide association study of citalopram response in major depressive disorder. Biological Psychiatry, 67, 133–138.
Grof, P., Duffy, A., Cavazzoni, P.et al. (2002). Is response to prophylactic lithium a familial trait?The Journal of Clinical Psychiatry, 63, 942–947.
Gupta, A., Schulze, T.G., Nagarajan, V.et al. (2011). Interaction networks of lithium and valproate molecular targets reveal a striking enrichment of apoptosis functional clusters and neurotrophin signaling. Pharmacogenomics Journal, 12, 328–341.
Horstmann, S., Lucae, S., Menke, A.et al. (2010). Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology, 35, 727–740.
Hu, X.Z., Rush, A.J., Charney, D.et al. (2007). Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Archives of General Psychiatry, 64, 783–792.
Huezo-Diaz, P., Perroud, N., Spencer, E.et al. (2011). CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP. Journal of Psychopharmacology, 26, 398–407.
Ioannidis, J.P., Trikalinos, T.A., Ntzani, E.E., and Contopoulos-Ioannidis, D.G. (2003). Genetic associations in large versus small studies: An empirical assessment. Lancet, 361, 567–571.
Ising, M., Lucae, S., Binder, E.B.et al. (2009). A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Archives of General Psychiatry, 66, 966–975.
Khan, A., Detke, M., Khan, S.R., and Mallinckrodt, C. (2003). Placebo response and antidepressant clinical trial outcome. Journal of Nervous and Mental Disease, 191, 211–218.
Kirchheiner, J., Lorch, R., Lebedeva, E.et al. (2008). Genetic variants in FKBP5 affecting response to antidepressant drug treatment. Pharmacogenomics, 9, 841–846.
Kishi, T., Fukuo, Y., Yoshimura, R.et al. (2010). Pharmacogenetic study of serotonin 6 receptor gene with antidepressant response in major depressive disorder in the Japanese population. Human Psychopharmacology, 25, 481–486.
Kraft, J.B., Peters, E.J., Slager, S.L.et al. (2007). Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biological Psychiatry, 61, 734–742.
Laje, G., Paddock, S., Manji, H.et al. (2007). Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. American Journal of Psychiatry, 164, 1530–1538.
Laje, G., Allen, A.S., Akula, N.et al. (2009). Genome-wide association study of suicidal ideation emerging during citalopram treatment of depressed outpatients. Pharmacogenetics and Genomics, 19, 666–674.
Lekman, M., Laje, G., Charney, D.et al. (2008). The FKBP5-gene in depression and treatment response: An association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) cohort. Biological Psychiatry, 63, 1103–1110.
Lin, K.M., Chiu, Y.F., Tsai, I.J.et al. (2011). ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment. Pharmacogenetics and Genomics, 21, 163–170.
Lohoff, F.W., Aquino, T.D., Narasimhan, S.et al. (2011). Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder. Pharmacogenomics Journal, e-pub ahead of print, doi: 10.1038/tpj.2011.47.
Lucae, S., Ising, M., Horstmann, S.et al. (2010). HTR2A gene variation is involved in antidepressant treatment response. European Neuropsychopharmacology, 20, 65–68.
Lupski, J.R., Belmont, J.W., Boerwinkle, E., and Gibbs, R.A. (2011). Clan genomics and the complex architecture of human disease. Cell, 147, 32–43.
McCarthy, M.J., Leckband, S.G., and Kelsoe, J.R. (2010). Pharmacogenetics of lithium response in bipolar disorder. Pharmacogenomics, 11, 1439–1465.
McCormack, M., Alfirevic, A., Bourgeois, S.et al. (2011). HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. New England Journal of Medicine, 364, 1134–1143.
McMahon, F.J., Buervenich, S., Charney, D.et al. (2006). Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. American Journal of Human Genetics, 78, 804–814.
Menke, A., Lucae, S., Kloiber, S.et al. (2008). Genetic markers within glutamate receptors associated with antidepressant treatment-emergent suicidal ideation. American Journal of Psychiatry, 165, 917–918.
Menke, A., Domschke, K., Czamara, D.et al. (2012). Genome-wide association study of antidepressant treatment-emergent suicidal ideation. Neuropsychopharmacology, 37, 797–807.
Mrazek, D.A., Rush, A.J., Biernacka, J.M.et al. (2008). SLC6A4 variation and citalopram response. American Journal of Medical Genetics, B: 150B, 341–351.
Mrazek, D.A., Biernacka, J.M., O’Kane, D.J.et al. (2011). CYP2C19 variation and citalopram response. Pharmacogenetics and Genomics, 21, 1–9.
Murphy, G.M., Jr., Hollander, S.B., Rodrigues, H.E., Kremer, C., and Schatzberg, A.F. (2004). Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Archives of General Psychiatry, 61, 1163–1169.
Nair, A. and Vaidya, V.A. (2006). Cyclic AMP response element binding protein and brain-derived neurotrophic factor: Molecules that modulate our mood?Journal of Bioscience, 31, 423–434.
Paddock, S., Laje, G., Charney, D.et al. (2007). Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. American Journal of Psychiatry, 164, 1181–1188.
Perlis, R.H., Fijal, B., Dharia, S., Heinloth, A.N., and Houston, J.P. (2010). Failure to replicate genetic associations with antidepressant treatment response in duloxetine-treated patients. Biological Psychiatry, 67, 1110–1113.
Perlis, R. H., Purcell, S., Fava, M.et al. (2007). Association between treatment-emergent suicidal ideation with citalopram and polymorphisms near cyclic adenosine monophosphate response element binding protein in the STAR*D study. Archives of General Psychiatry, 64, 689–697.
Perlis, R.H., Dennehy, E.B., Miklowitz, D.J.et al. (2009a). Retrospective age at onset of bipolar disorder and outcome during two-year follow-up: Results from the STEP-BD study. Bipolar Disorders, 11, 391–400.
Perlis, R.H., Laje, G., Smoller, J.W.et al. (2009b). Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients. Neuropsychopharmacology, 34, 1819–1828.
Perroud, N., Aitchison, K.J., Uher, R.et al. (2009). Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project. Neuropsychopharmacology, 34, 2517–2528.
Perroud, N., Uher, R., Ng, M.Y.et al. (2012). Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project. Pharmacogenomics Journal, 12, 68–77.
Peters, E.J., Slager, S.L., Kraft, J.B.et al. (2008). Pharmacokinetic genes do not influence response or tolerance to citalopram in the STAR*D sample. PLoS One, 3, e1872.
Popkie, A.P., Zeidner, L.C., Albrecht, A.M.et al. (2010). Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. Journal of Biological Chemistry, 285, 41337–41347.
Rasmussen, H.B. and Werge, T.M. (2007). Novel procedure for genotyping of the human serotonin transporter gene-linked polymorphic region (5-HTTLPR) – a region with a high level of allele diversity. Psychiatric Genetics, 17, 287–291.
Saarelainen, T., Hendolin, P., Lucas, G.et al. (2003). Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. Journal of Neuroscience, 23, 349–357.
Sarginson, J.E., Lazzeroni, L.C., Ryan, H.S.et al. (2010). ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression. Pharmacogenetics and Genomics, 20, 467–475.
Schulze, T.G., Alda, M., Adli, M.et al. (2010). The International Consortium on Lithium Genetics (ConLiGen): An initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment. Neuropsychobiology, 62, 72–78.
Serretti, A., Kato, M., and Kennedy, J.L. (2008). Pharmacogenetic studies in depression: A proposal for methodologic guidelines. Pharmacogenomics Journal, 8, 90–100.
Serretti, A., Kato, M., De, R.D., and Kinoshita, T. (2007). Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Molecular Psychiatry, 12, 247–257.
Smith, D.J., Evans, R., and Craddock, N. (2010). Predicting response to lithium in bipolar disorder: A critical review of pharmacogenetic studies. Journal of Mental Health, 19, 142–156. Original Article: Willeie, M.J.V., Smith, G., Day, R.K. et al. (2009). Polymorphisms in the SLC6A4 and HTRZA genes influence treatment outcome following antidepresssant therapy. The Pharmacogenetics Journal, 9, 61–70.
Squassina, A., Piccardi, P., Del Zompo, M.et al. (2010). NRG1 and BDNF genes in schizophrenia: An association study in an Italian case-control sample. Psychiatry Research, 176, 82–84.
Taylor, M.J., Sen, S., and Bhagwagar, Z. (2010). Antidepressant response and the serotonin transporter gene-linked polymorphic region. Biological Psychiatry, 68, 536–543.
Teranishi, K.S., Slager, S.L., Garriock, H.et al. (2007). Variants in PDE11A and PDE1A are not associated with citalopram response. Molecular Psychiatry, 12, 1061–1063.
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. American Journal of Psychiatry, 163, 28–40.
Uhr, M., Tontsch, A., Namendorf, C.et al. (2008). Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron, 57, 203–209.
Uher, R., Huezo-Diaz, P., Perroud, N.et al. (2009). Genetic predictors of response to antidepressants in the GENDEP project. Pharmacogenomics Journal, 9, 225–233.
Uher, R., Perroud, N., Ng, M.Y.et al. (2010). Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. American Journal of Psychiatry, 167, 555–564.
Ventriglia, M., Bocchio Chiavetto, L., Benussi, L.et al. (2002). Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Molecular Psychiatry, 7, 136–137.
Wadelius, M., Chen, L.Y., Downes, K.et al. (2005). Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics Journal, 5, 262–270.
Winner, J.G., Goebert, D., Matsu, C., and Mrazek, D.A. (2010). Training in psychiatric genomics during residency: A new challenge. Academic Psychiatry, 34, 115–118.
Wong, M.L., Whelan, F., Deloukas, P.et al. (2006). Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. Proceedings of the National Academy of Sciences USA, 103, 15124–15129.
Yu, Z., Ono, C., Sora, I., and Tomita, H. (2011). Effect of chronic lithium treatment on gene expression profile in mouse microglia and brain dendritic cells. Japanese Journal of Psychopharmacology, 31, 101–102.