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:

BDNF Val66Met genotype and 6-month remission rates in late-life depression

The Pharmacogenomics Journal volume 11, pages 146–154 (2011)Cite this article

Subjects

Abstract

Although not observed in younger adult cohorts, in older individuals the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with major depressive disorder (MDD) risk. It is further associated with subjective social support and magnetic resonance imaging (MRI) hyperintense lesions, clinical features independently related to MDD. We examined the relationship between this polymorphism and antidepressant remission rates in an elderly sample with MDD, while also testing for mediation effects of social support and hyperintensities. A total of 229 elderly Caucasian subjects with MDD completed baseline assessments, 1.5 T MRI, and BDNF genotyping. They received antidepressant medication under a structured treatment algorithm and were evaluated for remission at 3 and 6 months. At the 3-month evaluation, BDNF Val66Met genotype was not associated with remission (Wald's χ2=2.51, P=0.1131). When not controlling for multiple comparisons, Met66 allele carriers were more likely to be remitted at 6 months (χ2=4.32, P=0.0377) with an odds ratio of 1.82 (95% CI: 1.04, 3.22). This effect persisted after controlling for lesion volume and social support, neither of which mediated this relationship. Thus in this exploratory analysis, the Met66 allele may be associated with increased odds of remission in older subjects, but also with increased time to remission as there was no 3-month effect.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Manji HK, Drevets WC, Charney DS . The cellular neurobiology of depression. Nat Med 2001; 7: 541–547.

    Article  CAS  Google Scholar 

  2. Duman RS, Monteggia LM . A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006; 59: 1116–1127.

    Article  CAS  Google Scholar 

  3. Escobar ML, Figueroa-Guzman Y, Gomez-Palacio-Schjetnan A . In vivo insular cortex LTP induced by brain-derived neurotrophic factor. Brain Res 2003; 991: 274–279.

    Article  CAS  Google Scholar 

  4. Nagappan G, Lu B . Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications. Trends Neurosci 2005; 28: 464–471.

    Article  CAS  Google Scholar 

  5. Poo MM . Neurotrophins as synaptic modulators. Nat Rev Neurosci 2001; 2: 24–32.

    Article  CAS  Google Scholar 

  6. Sen S, Duman R, Sanacora G . Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 2008; 64: 527–532.

    Article  CAS  Google Scholar 

  7. Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM . Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 2003; 54: 703–709.

    Article  CAS  Google Scholar 

  8. Nibuya M, Morinobu S, Duman RS . Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995; 15: 7539–7547.

    Article  CAS  Google Scholar 

  9. Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M . Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev 2006; 58: 115–1134.

    Article  CAS  Google Scholar 

  10. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    Article  CAS  Google Scholar 

  11. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 2004; 24: 4401–4411.

    Article  CAS  Google Scholar 

  12. Chen L, Lawlor DA, Lewis SJ, Yuan W, Abdollahi MR, Timpson NJ et al. Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 814–821.

    Article  CAS  Google Scholar 

  13. Verhagen M, van der Meij A, van Deurzen PA, Janzing JG, Arias-Vasquez A, Buitelaar JK et al. Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatry. E-pub ahead of print 15 October 2008.

  14. Hwang JP, Tsai SJ, Hong CJ, Yang CH, Lirng JF, Yang YM . The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with geriatric depression. Neurobiol Aging 2006; 27: 1834–1837.

    Article  CAS  Google Scholar 

  15. Taylor WD, Zuchner S, McQuoid DR, Steffens DC, Speer MC, Krishnan KR . Allelic differences in the BDNF val66met polymorphism in late-life depression. Am J Geriatr Psychiatry 2007; 15: 850–857.

    Article  Google Scholar 

  16. Taylor WD, Zuchner S, McQuoid DR, Payne ME, MacFall JR, Steffens DC et al. The BDNF Val66Met polymorphism and cerebral white matter hyperintensities in late-life depression. Am J Geriatr Psychiatry 2008; 16: 263–271.

    Article  Google Scholar 

  17. Taylor WD, Zuchner S, McQuoid DR, Steffens DC, Blazer DG, Krishnan KR . Social support in older individuals: the role of the BDNF Val66Met polymorphism. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1205–1212.

    Article  Google Scholar 

  18. Choi MJ, Kang RH, Lim SW, Oh KS, Lee MS . Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res 2006; 1118: 176–182.

    Article  CAS  Google Scholar 

  19. Yoshida K, Higuchi H, Kamata M, Takahasi H, Inoue K, Suzuki T et al. The G196A polymorphism of the brain-derived neurotrophic factor gene and the antidepressant effect of milnacipran and fluvoxamine. J Psychopharm 2007; 21: 650–656.

    Article  CAS  Google Scholar 

  20. Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ . Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet 2003; 123: 19–22.

    Article  Google Scholar 

  21. Kang RH, Chang HS, Wong ML, Choi MJ, Park JY, Lee HY et al. Brain-derived neurotrophic factor gene polymorphisms and mirtazapine responses in Koreans with major depression. J Psychopharm. E-pub ahead of print 3 June 2009.

  22. Robins LN, Helzer JE, Croughan J, Ratcliff KS . National Institute of Mental Health Diagnostic Interview Schedule. Its history, characteristics, and validity. Arch Gen Psychiatry 1981; 38: 381–389.

    Article  CAS  Google Scholar 

  23. Montgomery SA, Asberg M . A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.

    Article  CAS  Google Scholar 

  24. Steffens DC, Hays JC, Krishnan KRR . Disability in geriatric depression. Am J Geriatr Psychiatry 1999; 7: 34–40.

    Article  CAS  Google Scholar 

  25. Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 1992; 41: 237–248.

    Article  CAS  Google Scholar 

  26. Landerman R, George LK, Campbell RT, Blazer DG . Alternative models of the stress buffering hypothesis. Am J Comm Psychol 1989; 17: 626–642.

    Article  Google Scholar 

  27. George LK, Blazer DG, Hughes DC, Fowler N . Social support and the outcome of major depression. Br J Psychiatry 1989; 154: 478–485.

    Article  CAS  Google Scholar 

  28. Folstein MF, Folstein SE, McHugh PR . Mini-mental state’ a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.

    Article  CAS  Google Scholar 

  29. Steffens DC, McQuoid DR, Krishnan KRR . The Duke Somatic Treatment Algorithm for Geriatric Depression (STAGED) approach. Psychopharmacol Bull 2002; 36: 58–68.

    PubMed  Google Scholar 

  30. Taylor WD, MacFall JR, Payne ME, McQuoid DR, Steffens DC, Provenzale JM et al. Greater MRI lesion volumes in elderly depressed subjects than in control subjects. Psychiatry Res 2005; 139: 1–7.

    Article  Google Scholar 

  31. Payne ME, Fetzer DL, MacFall JR, Provenzale JM, Byrum CE, Krishnan KRR . Development of a semi-automated method for quantification of MRI gray and white matter lesions in geriatric subjects. Psychiatry Res 2002; 115: 63–77.

    Article  Google Scholar 

  32. Rimmler J, McDowell JG, Slotterback BD, Haynes CS, Menold MM, Rogala A et al. Development of a data coordinating center (DCC): Data quality control for complex disease studies. Am J Hum Genet (Suppl). 1998; 63: A240.

    Google Scholar 

  33. Zimmerman M, Posternak MA, Chelminski I . Defining remission on the Montgomery–Asberg Depression Rating Scale. J Clin Psychiatry 2004; 65: 163–168.

    Article  Google Scholar 

  34. Holmbeck GN . Toward terminological, conceptual, and statistical clarity in the study of mediators and moderators: examples from the child-clinical and pediatric psychology literatures. J Consult Clin Psychol 1997; 65: 599–610.

    Article  CAS  Google Scholar 

  35. Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS et al. Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry 2008; 13: 709–716.

    Article  CAS  Google Scholar 

  36. Trivedi MH, Rush AJ, Wisniewski S, 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  Google Scholar 

  37. Garza AA, Ha TG, Garcia C, Chen MJ, Russo-Neustadt AA . Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain. Pharmacol Biochem Behav 2004; 77: 209–220.

    Article  CAS  Google Scholar 

  38. Matrisciano F, Bonaccorso S, Ricciardi A, Scaccianoce S, Panaccione I, Wang L et al. Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine. J Psychiatr Res 2008; 43: 247–254.

    Article  Google Scholar 

  39. Licinio J, Dong C, Wong ML . Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry 2009; 66: 488–497.

    Article  CAS  Google Scholar 

  40. Cohen A, Houck PR, Szanto K, Dew MA, Gilman SE, Reynolds 3rd CF . Social inequalities in response to antidepressant treatment in older adults. Arch Gen Psychiatry 2006; 63: 50–56.

    Article  Google Scholar 

  41. Alexopoulos GS, Kiosses DN, Heo M, Murphy CF, Shanmugham B, Gunning-Dixon F . Executive dysfunction and the course of geriatric depression. Biol Psychiatry 2005; 58: 204–210.

    Article  Google Scholar 

  42. Erickson KI, Kim JS, Suever BL, Voss MW, Francis BM, Kramer AF . Genetic contributions to age-related decline in executive function: a 10-year longitudinal study of COMT and BDNF polymorphisms. Front Hum Neurosci 2008; 2: 11.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by NIMH Grants R01 MH054846-14, R01 MH078216-03, and P50 MH60451-09. We thank Martha Payne and Denise Messer for MR analysis methods and image processing.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    W D Taylor, D R McQuoid, J Bridgers, R R Krishnan & D C Steffens

  2. Neuropsychiatric Imaging Research Laboratory, Duke University Medical Center, Durham, NC, USA

    W D Taylor, J R MacFall, R R Krishnan & D C Steffens

  3. Department of Medicine, Duke Center for Human Genetics, Duke University Medical Center, Durham, NC, USA

    A Ashley-Koch

  4. Department of Radiology, Duke University Medical Center, Durham, NC, USA

    J R MacFall

  5. Duke–NUS Graduate Medical School, Singapore

    R R Krishnan

Authors
  1. W D Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D R McQuoid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Ashley-Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J R MacFall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Bridgers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R R Krishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D C Steffens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W D Taylor.

Ethics declarations

Competing interests

Dr Taylor, Dr Ashely-Koch and Dr MacFall, and Mr McQuoid and Ms Bridgers have no conflicts to report. Dr Steffens reports receiving consultancy fees from TransForm Pharmaceuticals Inc. and speaking fees from Forest Pharmaceuticals and Wyeth Pharmaceuticals. Dr Krishnan has received consultancy fees from CeNeRx, Corcept, GlaxoSmithKline, Johnson & Johnson, Merck, Roche and Sonexa. He has ownership interest in Orexigen, CeNeRx and Sonexa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taylor, W., McQuoid, D., Ashley-Koch, A. et al. BDNF Val66Met genotype and 6-month remission rates in late-life depression. Pharmacogenomics J 11, 146–154 (2011). https://doi.org/10.1038/tpj.2010.12

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2010.12

Keywords

This article is cited by

Search

Advanced search

Quick links