Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-11T08:58:42.648Z Has data issue: false hasContentIssue false
  • English
  • Français

Pharmacogenomic study of side-effects for antidepressant treatment options in STAR*D

Published online by Cambridge University Press:  01 November 2011

S. L. Clark ,
D. E. Adkins ,
K. Aberg ,
J. M. Hettema ,
J. L. McClay ,
R. P. Souza  and
E. J. C. G. van den Oord
S. L. Clark*
Affiliation:
Center for Biomarker Research and Personalized Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
D. E. Adkins
Affiliation:
Center for Biomarker Research and Personalized Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
K. Aberg
Affiliation:
Center for Biomarker Research and Personalized Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
J. M. Hettema
Affiliation:
Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
J. L. McClay
Affiliation:
Center for Biomarker Research and Personalized Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
R. P. Souza
Affiliation:
Laboratory of Neurosciences, Universidade Do Extremo Sul Catarinense, Criciuma, SC, Brazil
E. J. C. G. van den Oord
Affiliation:
Center for Biomarker Research and Personalized Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
*
*Address for correspondence: Dr S. L. Clark, Center for Biomarker Research and Personalized Medicine, School of Pharmacy, McGuire Hall, Room 216A, P.O. Box 980533, Richmond, VA 23298-0581, USA. (Email: slclark2@vcu.edu)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Understanding individual differences in susceptibility to antidepressant therapy side-effects is essential to optimize the treatment of depression.

Method

We performed genome-wide association studies (GWAS) to search for genetic variation affecting the susceptibility to side-effects. The analysis sample consisted of 1439 depression patients, successfully genotyped for 421K single nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Outcomes included four indicators of side-effects: general side-effect burden, sexual side-effects, dizziness and vision/hearing-related side-effects. Our criterion for genome-wide significance was a prespecified threshold ensuring that, on average, only 10% of the significant findings are false discoveries.

Results

Thirty-four SNPs satisfied this criterion. The top finding indicated that 10 SNPs in SACM1L mediated the effects of bupropion on sexual side-effects (p=4.98×10−7, q=0.023). Suggestive findings were also found for SNPs in MAGI2, DTWD1, WDFY4 and CHL1.

Conclusions

Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that could mediate adverse effects of antidepressant medication.

Keywords

Depressiongenome-wide association studypharmacogenomicsside-effectssingle nucleotide polymorphismsSTAR*D
Type
Original Articles
Information
Psychological Medicine , Volume 42 , Issue 6 , June 2012 , pp. 1151 - 1162
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aberg, K, Adkins, DE, Bukszar, J, Webb, BT, Caroff, SN, Miller, DD, Sebat, J, Stroup, S, Fanous, AH, Vladimirov, VI, McClay, JL, Lieberman, JA, Sullivan, PF, van den Oord, EJ (2010 a). Genomewide association study of movement-related adverse antipsychotic effects. Biological Psychiatry 67, 279–282.CrossRefGoogle ScholarPubMed
Aberg, K, Adkins, DE, Liu, Y, McClay, JL, Bukszar, J, Jia, P, Zhao, Z, Perkins, D, Stroup, TS, Lieberman, JA, Sullivan, PF, van den Oord, EJ (2010 b). Genome-wide association study of antipsychotic-induced QTc interval prolongation. Pharmacogenomics Journal. Published online: 5 October 2010. doi:10.1038/tpj.2010.76.Google ScholarPubMed
Adkins, DE, Aberg, K, McClay, JL, Bukszar, J, Zhao, Z, Jia, P, Stroup, TS, Perkins, D, McEvoy, JP, Lieberman, JA, Sullivan, PF, van den Oord, EJ (2011). Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Molecular Psychiatry 16, 321–332.CrossRefGoogle ScholarPubMed
Adkins, DE, Aberg, K, McClay, JL, Hettema, JM, Kornstein, SG, Bukszar, J, van den Oord, EJ (2010). A genomewide association study of citalopram response in major depressive disorder – a psychometric approach. Biological Psychiatry 68, e25–e27.CrossRefGoogle ScholarPubMed
Altshuler, D, Daly, MJ, Lander, ES (2008). Genetic mapping in human disease. Science 322, 881–888.CrossRefGoogle ScholarPubMed
Ayala, ME (2009). Brain serotonin, psychoactive drugs, and effects on reproduction. Central Nervous System Agents in Medicinal Chemistry 9, 258–276.CrossRefGoogle ScholarPubMed
Barbee, JG (1998). Mixed symptoms and syndromes of anxiety and depression: diagnostic, prognostic, and etiologic issues. Annals of Clinical Psychiatry 10, 15–29.CrossRefGoogle ScholarPubMed
Barrett, JC, Fry, B, Maller, J, Daly, MJ (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265.CrossRefGoogle ScholarPubMed
Beecham, GW, Martin, ER, Li, YJ, Slifer, MA, Gilbert, JR, Haines, JL, Pericak-Vance, MA (2009). Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. American Journal of Human Genetics 84, 35–43.CrossRefGoogle ScholarPubMed
Benjamini, Y, Hochberg, Y (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological) 57, 289–300.CrossRefGoogle Scholar
Berger, MF, Lawrence, MS, Demichelis, F, Drier, Y, Cibulskis, K, Sivachenko, AY, Sboner, A, Esgueva, R, Pflueger, D, Sougnez, C, Onofrio, R, Carter, SL, Park, K, Habegger, L, Ambrogio, L, Fennell, T, Parkin, M, Saksena, G, Voet, D, Ramos, AH, Pugh, TJ, Wilkinson, J, Fisher, S, Winckler, W, Mahan, S, Ardlie, K, Baldwin, J, Simons, JW, Kitabayashi, N, Macdonald, TY, Kantoff, PW, Chin, L, Gabriel, SB, Gerstein, MB, Golub, TR, Meyerson, M, Tewari, A, Lander, ES, Getz, G, Rubin, MA, Garraway, LA (2011). The genomic complexity of primary human prostate cancer. Nature 470, 214–220.CrossRefGoogle ScholarPubMed
Black, MA (2004). A note on the adaptive control of false discovery rates. Journal of the Royal Statistical Society. Series B 66, 297–304.CrossRefGoogle Scholar
Blagoveshchenskaya, A, Cheong, FY, Rohde, HM, Glover, G, Knodler, A, Nicolson, T, Boehmelt, G, Mayinger, P (2008). Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1. Journal of Cell Biology 180, 803–812.CrossRefGoogle ScholarPubMed
Bollen, KA (1989). Structural Equations with Latent Variables. Wiley: New York.CrossRefGoogle Scholar
Brown, BW, Russell, K (1997). Methods correcting for multiple testing: operating characteristics. Statistics in Medicine 16, 2511–2528.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
Bull, SA, Hu, XH, Hunkeler, EM, Lee, JY, Ming, EE, Markson, LE, Fireman, B (2002 a). Discontinuation of use and switching of antidepressants: influence of patient-physician communication. Journal of the American Medical Association 288, 1403–1409.CrossRefGoogle ScholarPubMed
Bull, SA, Hunkeler, EM, Lee, JY, Rowland, CR, Williamson, TE, Schwab, JR, Hurt, SW (2002 b). Discontinuing or switching selective serotonin-reuptake inhibitors. Annals of Pharmacotherapy 36, 578–584.CrossRefGoogle ScholarPubMed
Byun, E, Caillier, SJ, Montalban, X, Villoslada, P, Fernandez, O, Brassat, D, Comabella, M, Wang, J, Barcellos, LF, Baranzini, SE, Oksenberg, JR (2008). Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. Archives of Neurology 65, 337–344.CrossRefGoogle ScholarPubMed
Chen, QY, Chen, Q, Feng, GY, Lindpaintner, K, Chen, Y, Sun, X, Chen, Z, Gao, Z, Tang, J, He, L (2005). Case-control association study of the close homologue of L1 (CHL1) gene and schizophrenia in the Chinese population. Schizophrenia Research 73, 269–274.CrossRefGoogle ScholarPubMed
Clayton, AH, Warnock, JK, Kornstein, SG, Pinkerton, R, Sheldon-Keller, A, McGarvey, EL (2004). A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. Journal of Clinical Psychiatry 65, 62–67.CrossRefGoogle ScholarPubMed
Corona, G, Maggi, M (2010). The role of testosterone in erectile dysfunction. Nature Reviews. Urology 7, 46–56.CrossRefGoogle ScholarPubMed
Demyttenaere, K, Albert, A, Mesters, P, Dewe, W, De Bruyckere, K, Sangeleer, M (2005). What happens with adverse events during 6 months of treatment with selective serotonin reuptake inhibitors? Journal of Clinical Psychiatry 66, 859–863.CrossRefGoogle ScholarPubMed
Demyttenaere, K, Jaspers, L (2008). Review: bupropion and SSRI-induced side effects. Journal of Psychopharmacology 22, 792–804.CrossRefGoogle ScholarPubMed
Deng, F, Price, MG, Davis, CF, Mori, M, Burgess, DL (2006). Stargazin and other transmembrane AMPA receptor regulating proteins interact with synaptic scaffolding protein MAGI-2 in brain. Journal of Neuroscience 26, 7875–7884.CrossRefGoogle ScholarPubMed
Franchini, L, Serretti, A, Gasperini, M, Smeraldi, E (1998). Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. Journal of Psychiatric Research 32, 255–259.CrossRefGoogle ScholarPubMed
Frost, J, Sandvik, P, Spigset, O (2010). Sexual dysfunction induced by antidepressants [in Norwegian]. Tidsskrift for den Norske laegeforening 130, 1930–1931.CrossRefGoogle ScholarPubMed
Garriock, HA, Kraft, JB, Shyn, SI, Peters, EJ, Yokoyama, JS, Jenkins, GD, Reinalda, MS, Slager, SL, McGrath, PJ, Hamilton, SP (2010). A genomewide association study of citalopram response in major depressive disorder. Biological Psychiatry 67, 133–138.CrossRefGoogle ScholarPubMed
Goldstein, H (1995). Multilevel Statistical Models. Arnold: London.Google Scholar
Harvey, KV, Balon, R (1995). Augmentation with buspirone: a review. Annals of Clinical Psychiatry 7, 143–147.CrossRefGoogle ScholarPubMed
International HapMap Consortium (2005). A haplotype map of the human genome. Nature 437, 1299–1320.CrossRefGoogle Scholar
Kato, M, Serretti, A (2010). Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Molecular Psychiatry 15, 473–500.CrossRefGoogle ScholarPubMed
Kirchheiner, J, Nickchen, K, Bauer, M, Wong, ML, Licinio, J, Roots, I, Brockmoller, J (2004). Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Molecular Psychiatry 9, 442–473.CrossRefGoogle Scholar
Lavedan, C, Licamele, L, Volpi, S, Hamilton, J, Heaton, C, Mack, K, Lannan, R, Thompson, A, Wolfgang, CD, Polymeropoulos, MH (2009). Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Molecular Psychiatry 14, 804–819.CrossRefGoogle Scholar
Lei, SF, Yang, TL, Tan, LJ, Chen, XD, Guo, Y, Guo, YF, Zhang, L, Liu, XG, Yan, H, Pan, F, Zhang, ZX, Peng, YM, Zhou, Q, He, LN, Zhu, XZ, Cheng, J, Liu, YZ, Papasian, CJ, Deng, HW (2009). Genome-wide association scan for stature in Chinese: evidence for ethnic specific loci. Human Genetics 125, 1–9.CrossRefGoogle ScholarPubMed
Link, E, Parish, S, Armitage, J, Bowman, L, Heath, S, Matsuda, F, Gut, I, Lathrop, M, Collins, R (2008). SLCO1B1 variants and statin-induced myopathy – a genomewide study. New England Journal of Medicine 359, 789–799.Google ScholarPubMed
Liu, C, Batliwalla, F, Li, W, Lee, A, Roubenoff, R, Beckman, E, Khalili, H, Damle, A, Kern, M, Furie, R, Dupuis, J, Plenge, RM, Coenen, MJ, Behrens, TW, Carulli, JP, Gregersen, PK (2008 a). Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Molecular Medicine 14, 575–581.CrossRefGoogle ScholarPubMed
Liu, Y, Boukhelifa, M, Tribble, E, Morin-Kensicki, E, Uetrecht, A, Bear, JE, Bankaitis, VA (2008 b). The Sac1 phosphoinositide phosphatase regulates Golgi membrane morphology and mitotic spindle organization in mammals. Molecular Biology of the Cell 19, 3080–3096.CrossRefGoogle ScholarPubMed
Liu, YZ, Guo, YF, Wang, L, Tan, LJ, Liu, XG, Pei, YF, Yan, H, Xiong, DH, Deng, FY, Yu, N, Zhang, YP, Zhang, L, Lei, SF, Chen, XD, Liu, HB, Zhu, XZ, Levy, S, Papasian, CJ, Drees, BM, Hamilton, JJ, Recker, RR, Deng, HW (2009). Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. PLoS Genetics 5, e1000420.CrossRefGoogle ScholarPubMed
Loehlin, JC (2004). Latent Variable Models: An Introduction to Factor, Path, and Structural Equation Analysis. Lawrence Erlbaum Associates: Mahwah, NJ.CrossRefGoogle Scholar
Maddox, JC, Levi, M, Thompson, C (1994). The compliance with antidepressants in general practice. Journal of Psychopharmacology 8, 48–53.CrossRefGoogle ScholarPubMed
Malhotra, AK, Murphy, Jr. GM, Kennedy, JL (2004). Pharmacogenetics of psychotropic drug response. American Journal of Psychiatry 161, 780–796.CrossRefGoogle ScholarPubMed
McClay, JL, Adkins, DE, Aberg, K, Bukszar, J, Khachane, AN, Keefe, RS, Perkins, DO, McEvoy, JP, Stroup, TS, Vann, RE, Beardsley, PM, Lieberman, JA, Sullivan, PF, van den Oord, EJ (2011 a). Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. Neuropsychopharmacology 36, 616–626.CrossRefGoogle ScholarPubMed
McClay, JL, Adkins, DE, Aberg, K, Stroup, S, Perkins, DO, Vladimirov, VI, Lieberman, JA, Sullivan, PF, van den Oord, EJ (2011 b). Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics. Molecular Psychiatry 16, 76–85.CrossRefGoogle ScholarPubMed
Mitchell, AJ (2006). High medication discontinuation rates in psychiatry: how often is it understandable? Journal of Clinical Psychopharmacology 26, 109–112.CrossRefGoogle ScholarPubMed
Modell, JG, May, RS, Katholi, CR (2000). Effect of bupropion-SR on orgasmic dysfunction in nondepressed subjects: a pilot study. Journal of Sex and Marital Therapy 26, 231–240.Google ScholarPubMed
Morag, A, Pasmanik-Chor, M, Oron-Karni, V, Rehavi, M, Stingl, JC, Gurwitz, D (2011). Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. Pharmacogenomics 12, 171–184.CrossRefGoogle ScholarPubMed
Muthén, LK, Muthén, BO (1998–2010). MPlus User's Guide. Muthén & Muthén: Los Angeles, CA.Google Scholar
Nunnally, JC, Bernstein, IH (1994). Psychometric Theory. McGraw-Hill: New York.Google Scholar
Oreilly, RL, Bogue, L, Singh, SM (1994). Pharmacogentic response to antidepressants in a multicase family with affective disorder. Biological Psychiatry 36, 467–471.CrossRefGoogle Scholar
Papakostas, GI, Fava, M (2009). Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. European Neuropsychopharmacology 19, 34–40.CrossRefGoogle ScholarPubMed
Pare, CMB, Mack, JW (1971). Differentiation of two genetically specific types of depression by response to antidepressant drugs. Journal of Medical Genetics 8, 306–309.CrossRefGoogle ScholarPubMed
Pinheiro, JC, Bates, DM (2000). Mixed-Effects Models in S and S-Plus. Springer: New York, NY.CrossRefGoogle Scholar
Pollack, MH, Reiter, S, Hammerness, P (1992). Genitourinary and sexual adverse effects of psychotropic medication. International Journal of Psychiatry in Medicine 22, 305–327.CrossRefGoogle ScholarPubMed
Porcelli, S, Drago, A, Fabbri, C, Gibiino, S, Calati, R, Serretti, A (2011). Pharmacogenetics of antidepressant response. Journal of Psychiatry and Neuroscience 36, 87–113.CrossRefGoogle ScholarPubMed
Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MA, Bender, D, Maller, J, Sklar, P, De Bakker, PI, Daly, MJ, Sham, PC (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics 81, 559–575.CrossRefGoogle ScholarPubMed
Regier, DA, Rae, DS, Narrow, WE, Kaelber, CT, Schatzberg, AF (1998). Prevalence of anxiety disorders and their comorbidity with mood and addictive disorders. British Journal of Psychiatry (Suppl.) 34, 24–28.CrossRefGoogle Scholar
Rohde, HM, Cheong, FY, Konrad, G, Paiha, K, Mayinger, P, Boehmelt, G (2003). The human phosphatidylinositol phosphatase SAC1 interacts with the coatomer I complex. Journal of Biological Chemistry 278, 52689–52699.CrossRefGoogle ScholarPubMed
Rush, AJ, Fava, M, Wisniewski, SR, Lavori, PW, Trivedi, MH, Sackeim, HA, Thase, ME, Nierenberg, AA, Quitkin, FM, Kashner, TM, Kupfer, DJ, Rosenbaum, JF, Alpert, J, Stewart, JW, McGrath, PJ, Biggs, MM, Shores-Wilson, K, Lebowitz, BD, Ritz, L, Niederehe, G (2004). Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Controlled Clinical Trials 25, 119–142.CrossRefGoogle Scholar
Safarinejad, MR (2010). The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a double-blind placebo-controlled and randomized study. British Journal of Urology International 106, 840–847.CrossRefGoogle ScholarPubMed
Sakurai, K, Migita, O, Toru, M, Arinami, T (2002). An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. Molecular Psychiatry 7, 412–415.CrossRefGoogle ScholarPubMed
Searle, SR, Casella, G, McCulloch, CE (1992). Variance Components. Wiley: New York.CrossRefGoogle Scholar
Segraves, RT (1989). Effects of psychotropic drugs on human erection and ejaculation. Archives of General Psychiatry 46, 275–284.CrossRefGoogle ScholarPubMed
Serretti, A, Chiesa, A (2009). Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. Journal of Clinical Psychopharmacology 29, 259–266.CrossRefGoogle ScholarPubMed
Souery, D, Oswald, P, Massat, I, Bailer, U, Bollen, J, Demyttenaere, K, Kasper, S, Lecrubier, Y, Montgomery, S, Serretti, A, Zohar, J, Mendlewicz, J (2007). Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. Journal of Clinical Psychiatry 68, 1062–1670.CrossRefGoogle ScholarPubMed
Storey, J (2003). The positive false discovery rate: a Bayesian interpretation and the q-value. Annals of Statistics 31, 2013–2035.CrossRefGoogle Scholar
Storey, JD, Tibshirani, R (2003). Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences USA 100, 9440–9445.CrossRefGoogle ScholarPubMed
Uhl, GR, Liu, QR, Drgon, T, Johnson, C, Walther, D, Rose, JE, David, SP, Niaura, R, Lerman, C (2008). Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Archives of General Psychiatry 65, 683–693.CrossRefGoogle ScholarPubMed
van den Oord, EJ, Adkins, DE, McClay, J, Lieberman, J, Sullivan, PF (2009). A systematic method for estimating individual responses to treatment with antipsychotics in CATIE. Schizophrenia Research 107, 13–21.CrossRefGoogle ScholarPubMed
Wisniewski, SR, Rush, AJ, Balasubramani, GK, Trivedi, MH, Nierenberg, AA (2006). Self-rated global measure of the frequency, intensity, and burden of side effects. Journal of Psychiatric Practice 12, 71–79.CrossRefGoogle ScholarPubMed
Wright, GJ, Leslie, JD, Ariza-McNaughton, L, Lewis, J (2004). Delta proteins and MAGI proteins: an interaction of Notch ligands with intracellular scaffolding molecules and its significance for zebrafish development. Development 131, 5659–5669.CrossRefGoogle ScholarPubMed
Zobel, A, Maier, W (2010). Pharmacogenetics of antidepressive treatment. European Archives of Psychiatry and Clinical Neuroscience 260, 407–417.CrossRefGoogle ScholarPubMed
Supplementary material: File

Clark Supplementary Material

Clark Supplementary Material

Download Clark Supplementary Material(File)
File 102.9 KB