Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genome-wide association studies of placebo and duloxetine response in major depressive disorder

Abstract

We investigated variants associated with treatment response in depressed patients treated with either the antidepressant duloxetine or placebo using a genome-wide approach. Our sample (N=391) included individuals aged 18–75 years, diagnosed with major depressive disorder and treated with either duloxetine or placebo for up to 8 weeks. We conducted genome-wide associations for treatment response as operationalized by percentage change in Montgomery–Åsberg Depression Rating Scale score from baseline, as well as mixed models analyses across five time points. In the placebo-treated subsample (N=205), we observed a genome-wide association with rs76767803 (β=0.69, P=1.25 × 10−8) upstream of STAC1. STAC1 rs76767803 was also associated with response using mixed model analysis (χ2=3.95; P=0.001). In the duloxetine-treated subsample (N=186), we observed suggestive associations with ZNF385D (rs4261893; β=−0.46, P=1.55 × 10−5), NCAM1 (rs2303377; β=0.45, P=1.76 × 10−5) and MLL5 (rs117986340; β=0.91, P=3.04 × 10−5). Our findings suggest that a variant upstream of STAC1 is associated with placebo response, which might have implications for treatment optimization, clinical trial design and drug development.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Rivera M, McGuffin P . The successful search for genetic loci associated with depression. Genome Med 2015; 7: 92.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lam RW, Kennedy SH . Evidence-based strategies for achieving and sustaining full remission in depression: focus on metaanalyses. Can J Psychiatry 2004; 49 (3 Suppl 1): 17S–26S.

    PubMed  Google Scholar 

  3. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–40.

    Article  PubMed  Google Scholar 

  4. Thase ME, Entsuah AR, Rudolph RL . Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001; 178: 234–241.

    Article  CAS  PubMed  Google Scholar 

  5. Sullivan PF, Neale MC, Kendler KS . Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000; 157: 1552–1562.

    Article  CAS  PubMed  Google Scholar 

  6. Tansey KE, Guipponi M, Hu X, Domenici E, Lewis G, Malafosse A et al. Contribution of common genetic variants to antidepressant response. Biol Psychiatry 2013; 73: 679–682.

    Article  CAS  PubMed  Google Scholar 

  7. Gvozdic K, Brandl EJ, Taylor DL, Muller DJ . Genetics and personalized medicine in antidepressant treatment. Curr Pharm Des 2012; 18: 5853–5878.

    Article  CAS  PubMed  Google Scholar 

  8. Dell'osso B, Camuri G, Dobrea C, Buoli M, Serati M, Altamura AC . Duloxetine in affective disorders: a naturalistic study on psychiatric and medical comorbidity, use in association and tolerability across different age groups. Clin Pract Epidemiol Ment Health 2012; 8: 120–125.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Perlis RH, Fijal B, Adams DH, Sutton VK, Trivedi MH, Houston JP . Variation in catechol-O-methyltransferase is associated with duloxetine response in a clinical trial for major depressive disorder. Biol Psychiatry 2009; 65: 785–791.

    Article  CAS  PubMed  Google Scholar 

  10. Atake K, Yoshimura R, Hori H, Katsuki A, Nakamura J . Catechol-O-methyltransferase Val158Met genotype and the clinical responses to duloxetine treatment or plasma levels of 3-methoxy-4-hydroxyphenylglycol and homovanillic acid in Japanese patients with major depressive disorder. Neuropsychiatr Dis Treat 2015; 11: 967–974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Houston JP, Kohler J, Ostbye KM, Heinloth A, Perlis RH . Association of catechol-O-methyltransferase variants with duloxetine response in major depressive disorder. Psychiatry Res 2011; 189: 475–477.

    Article  CAS  PubMed  Google Scholar 

  12. Houston JP, Zou W, Aris V, Fijal B, Chen P, Heinloth AN et al. Evaluation of genetic models for response in a randomized clinical trial of duloxetine in major depressive disorder. Psychiatry Res 2012; 200: 63–65.

    Article  CAS  PubMed  Google Scholar 

  13. Maciukiewicz M, Marshe VS, Tiwari AK, Fonseka TM, Freeman N, Rotzinger S et al. Genetic variation in IL-1beta, IL-2, IL-6, TSPO and BDNF and response to duloxetine or placebo treatment in major depressive disorder. Pharmacogenomics 2015; 16: 1919–1929.

    Article  CAS  PubMed  Google Scholar 

  14. Perlis RH, Fijal B, Dharia S, Heinloth AN, Houston JP . Failure to replicate genetic associations with antidepressant treatment response in duloxetine-treated patients. Biol Psychiatry 2010; 67: 1110–1113.

    Article  CAS  PubMed  Google Scholar 

  15. Perlis RH, Fijal B, Dharia S, Houston JP . Pharmacogenetic investigation of response to duloxetine treatment in generalized anxiety disorder. Pharmacogenomics J 2013; 13: 280–285.

    Article  CAS  PubMed  Google Scholar 

  16. Garcia-Gonzalez J, Tansey KE, Hauser J, Henigsberg N, Maier W, Mors O et al. Pharmacogenetics of antidepressant response: a polygenic approach. Prog Neuropsychopharmacol Biol Psychiatry 2017; 75: 128–134.

    Article  CAS  PubMed  Google Scholar 

  17. Rief W, Nestoriuc Y, Weiss S, Welzel E, Barsky AJ, Hofmann SG . Meta-analysis of the placebo response in antidepressant trials. J Affect Disord 2009; 118: 1–8.

    Article  CAS  PubMed  Google Scholar 

  18. Leuchter AF, McCracken JT, Hunter AM, Cook IA, Alpert JE . Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. J Clin Psychopharmacol 2009; 29: 372–377.

    Article  CAS  PubMed  Google Scholar 

  19. Tiwari AK, Zai CC, Sajeev G, Arenovich T, Muller DJ, Kennedy JL . Analysis of 34 candidate genes in bupropion and placebo remission. Int J Neuropsychopharmacol 2013; 16: 771–781.

    Article  CAS  PubMed  Google Scholar 

  20. Hall KT, Loscalzo J, Kaptchuk TJ . Genetics and the placebo effect: the placebome. Trends Mol Med 2015; 21: 285–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. H. Lundbeck A/S. A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled, Duloxetine-Referenced, Fixed-Dose Study Evaluating the Efficacy and Safety of Three Dosages of [Vortioxetine] Lu aa21004, in Acute Treatment of Major Depressive Disorder. ClinicalTrials.gov. National Library of Medicine (US): Bethesda, MD, 2000.

  22. H. Lundbeck A/S. A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled, Active-Referenced, Dose-Finding Study of Lu aa24530 in Major Depressive Disorder. ClinicalTrials.gov. National Library of Medicine (US): Bethesda, MD, 2000.

  23. H. Lundbeck A/S. A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled, Duloxetine-Referenced, Fixed-Dose Study Evaluating the Efficacy and Safety of Lu AA21004 (15 and 20 mg/day) in the Acute Treatment of Adult Patients with Major Depressive Disorder. ClinicalTrials.gov. National Library of Medicine (US): Bethesda, MD, 2000.

  24. Lam RW, Milev R, Rotzinger S, Andreazza AC, Blier P, Brenner C et al. Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort. BMC Psychiatry 2016; 16: 105.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ward LD, Kellis M . HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 2012; 40: D930–934.

    Article  CAS  PubMed  Google Scholar 

  26. Dong S, Walker MF, Carriero NJ, DiCola M, Willsey AJ, Ye AY et al. De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Cell Rep 2014; 9: 16–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shen E, Shulha H, Weng Z, Akbarian S . Regulation of histone H3K4 methylation in brain development and disease. Philos Trans R Soc Lond B Biol Sci 2014; 369: 20130514.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wedzony K, Chocyk A, Mackowiak M . Potential roles of NCAM/PSA-NCAM proteins in depression and the mechanism of action of antidepressant drugs. Pharmacol Rep 2013; 65: 1471–1478.

    Article  CAS  PubMed  Google Scholar 

  29. Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14: 764–773, 739.

    Article  CAS  PubMed  Google Scholar 

  30. Xu C, Aragam N, Li X, Villla EC, Wang L, Briones D et al. BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies. PLoS ONE 2013; 8: e51674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Eicher JD, Powers NR, Miller LL, Akshoomoff N, Amaral DG, Bloss CS et al. Genome-wide association study of shared components of reading disability and language impairment. Genes Brain Behav 2013; 12: 792–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hotaling JM, Waggott DR, Goldberg J, Jarvik G, Paterson AD, Cleary PA et al. Pilot genome-wide association search identifies potential loci for risk of erectile dysfunction in type 1 diabetes using the DCCT/EDIC study cohort. J Urol 2012; 188: 514–520.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ostensson M, Monten C, Bacelis J, Gudjonsdottir AH, Adamovic S, Ek J et al. A possible mechanism behind autoimmune disorders discovered by genome-wide linkage and association analysis in celiac disease. PLoS ONE 2013; 8: e70174.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Trabzuni D, Ryten M, Walker R, Smith C, Imran S, Ramasamy A et al. Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies. J Neurochem 2011; 119: 275–282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Suzuki H, Kawai J, Taga C, Yaoi T, Hara A, Hirose K et al. Stac, a novel neuron-specific protein with cysteine-rich and SH3 domains. Biochem Biophys Res Commun 1996; 229: 902–909.

    Article  CAS  PubMed  Google Scholar 

  36. Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 2012; 489: 391–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schneider KK, Schote AB, Meyer J, Markett S, Reuter M, Frings C . Individual response speed is modulated by variants of the gene encoding the alpha 4 sub-unit of the nicotinic acetylcholine receptor (CHRNA4). Behav Brain Res 2015; 284: 11–18.

    Article  CAS  PubMed  Google Scholar 

  38. Chaijale NN, Snyder K, Arner J, Curtis AL, Valentino RJ . Repeated social stress increases reward salience and impairs encoding of prediction by rat locus coeruleus neurons. Neuropsychopharmacology 2015; 40: 513–523.

    Article  PubMed  Google Scholar 

  39. Dayan CM, Panicker V . Novel insights into thyroid hormones from the study of common genetic variation. Nat Rev Endocrinol 2009; 5: 211–218.

    Article  CAS  PubMed  Google Scholar 

  40. Wu EL, Chien IC, Lin CH, Chou YJ, Chou P . Increased risk of hypothyroidism and hyperthyroidism in patients with major depressive disorder: a population-based study. J Psychosom Res 2013; 74: 233–237.

    Article  PubMed  Google Scholar 

  41. Ittermann T, Volzke H, Baumeister SE, Appel K, Grabe HJ . Diagnosed thyroid disorders are associated with depression and anxiety. Soc Psychiatry Psychiatr Epidemiol 2015; 50: 1417–1425.

    Article  PubMed  Google Scholar 

  42. Pecina M, Martinez-Jauand M, Hodgkinson C, Stohler CS, Goldman D, Zubieta JK . FAAH selectively influences placebo effects. Mol Psychiatry 2014; 19: 385–391.

    Article  CAS  PubMed  Google Scholar 

  43. Pecina M, Martinez-Jauand M, Love T, Heffernan J, Montoya P, Hodgkinson C et al. Valence-specific effects of BDNF Val66Met polymorphism on dopaminergic stress and reward processing in humans. J Neurosci 2014; 34: 5874–5881.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bhathena A, Wang Y, Kraft JB, Idler KB, Abel SJ, Holley-Shanks RR et al. Association of dopamine-related genetic loci to dopamine D3 receptor antagonist ABT-925 clinical response. Transl Psychiatry 2013; 3: e245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Furmark T, Appel L, Henningsson S, Ahs F, Faria V, Linnman C et al. A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J Neurosci 2008; 28: 13066–13074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Brandl EJ, Tiwari AK, Zai CC, Nurmi EL, Chowdhury NI, Arenovich T et al. Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample. Pharmacogenomics J 2016; 16: 352–356.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was conducted with the support of the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. This study was part of a Canadian Biomarker Integration Network in Depression (CAN-BIND) project. The authors wish to acknowledge the CAN-BIND team listed here: www.canbind.ca/our-team. MM is supported by a CIHR postdoctoral fellowship; VSM is supported by an OMHF doctoral studentship and a trainee fellowship from the CIHR-STAGE program, and DJM is supported by the Joanne Murphy Professorship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D J Müller.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maciukiewicz, M., Marshe, V., Tiwari, A. et al. Genome-wide association studies of placebo and duloxetine response in major depressive disorder. Pharmacogenomics J 18, 406–412 (2018). https://doi.org/10.1038/tpj.2017.29

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2017.29

This article is cited by

Search

Quick links