Advertisement

Longitudinal multi-level biomarker analysis of BDNF in major depression and bipolar disorder

  • 240 Accesses

Abstract

Preliminary evidence suggests that BDNF (brain derived neurotrophic factor) rs6265 genetic polymorphism, BDNF gene promotor methylation and BDNF serum levels might play an important role in the pathogenesis of affective disorders. As studies testing the BDNF system across molecular levels are sparse, this study aimed at investigating the BDNF val66met genotype, BDNF DNA methylation changes and peripheral BDNF serum levels in acute and remitted phases of MDD (major depressive disorder) and BD (bipolar disorder) and healthy controls. We found a significant difference of methylation levels at CpG site 1-1-1 and 3-1-1 between MDD and healthy controls (p < 0.003) with MDD patients showing significantly higher methylation levels. CpG 5-2-1 revealed a statistically significant difference between MDD and healthy controls and MDD and BD (p = 0.00003). Similar to the results of the methylation analysis a significant difference between MDD and healthy controls was found in BDNF serum levels (p = 0.002) with significantly lower BDNF serum levels in MDD compared to healthy controls. A difference between the samples from admission and discharge from hospital of both BDNF gene methylation and serum levels could not be detected in the present study and no influence of the BDNF val66met genotype on neither methylation nor BDNF serum level.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Andrade L, Caraveo-Anduaga JJ, Berglund P et al (2003) The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res 12(1):3–21

  2. 2.

    Merikangas KR, Jin R, He J-P et al (2011) Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 68(3):241–251

  3. 3.

    Subbarao A, Rhee SH, Young SE et al (2008) Common genetic and environmental influences on major depressive disorder and conduct disorder. J Abnorm Child Psychol 36(3):433–444

  4. 4.

    Lesch KP (2004) Gene-environment interaction and the genetics of depression. J Psychiatry Neurosci 29(3):174–184

  5. 5.

    John CM, Eisenberg M, Development, Diagnostic Co et al (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95

  6. 6.

    Berk M, Kapczinski F, Andreazza AC et al (2011) Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 35(3):804–817

  7. 7.

    Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 63(1):71–124

  8. 8.

    Egan MF, Kojima M, Callicott JH et al (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112(2):257–269

  9. 9.

    Lang UE, Hellweg R, Sander T et al (2009) The Met allele of the BDNF Val66Met polymorphism is associated with increased BDNF serum concentrations. Mol Psychiatry 14(2):120–122

  10. 10.

    Sklar P, Gabriel SB, McInnis MG et al (2002) Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus: Brain-derived neutrophic factor. Mol Psychiatry 7(6):579–593

  11. 11.

    Geller B, Badner JA, Tillman R et al (2004) Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 161(9):1698–1700

  12. 12.

    Carlberg L, Scheibelreiter J, Hassler MR et al (2014) Brain-derived neurotrophic factor (BDNF)-epigenetic regulation in unipolar and bipolar affective disorder. J Affect Disord 168:399–406

  13. 13.

    Dell’Osso B, D’Addario C, Carlotta Palazzo M et al (2014) Epigenetic modulation of BDNF gene: differences in DNA methylation between unipolar and bipolar patients. J Affect Disord 166:330–333

  14. 14.

    Tadić A, Müller-Engling L, Schlicht KF et al (2014) Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. Mol Psychiatry 19(3):281–283

  15. 15.

    Monteleone P, Serritella C, Martiadis V et al (2008) Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. Bipolar Disord 10(1):95–100

  16. 16.

    Fernandes BS, Gama CS, Kauer-Sant‘Anna M et al (2009) Serum brain-derived neurotrophic factor in bipolar and unipolar depression: a potential adjunctive tool for differential diagnosis. J Psychiatr Res 43(15):1200–1204

  17. 17.

    Kreinin A, Lisson S, Nesher E et al (2015) Blood BDNF level is gender specific in severe depression. PLoS One 10(5):e0127643

  18. 18.

    Fernandes BS, Gama CS, Cereser KM et al (2011) Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res 45(8):995–1004

  19. 19.

    Fernandes BS, Molendijk ML, Kohler CA et al (2015) Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med 13:289

  20. 20.

    Piccinni A, Veltri A, Costanzo D et al (2015) Decreased plasma levels of brain-derived neurotrophic factor (BDNF) during mixed episodes of bipolar disorder. J Affect Disord 171:167–170

  21. 21.

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

  22. 22.

    Young RC, Biggs JT, Ziegler VE et al (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429–435

  23. 23.

    Sheehan DV, Lecrubier Y, Sheehan KH et al (1998) The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33 (quiz 34–57)

  24. 24.

    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from nucleated cells. Nucleic Acids Res 16(3):1215

  25. 25.

    He C, Holme J, Anthony J (2014) SNP genotyping: the KASP assay. In: Fleury D, Whitford R (eds) Crop breeding. Methods in molecular biology (methods and protocols), vol 1145. Humana Press, New York, NY, pp 75–86. https://doi.org/10.1007/978-1-4939-0446-4_7

  26. 26.

    D’Addario C, Dell’Osso B, Galimberti D et al (2013) Epigenetic modulation of BDNF gene in patients with major depressive disorder. Biol Psychiatry 73(2):e6–e7

  27. 27.

    Faul F, Erdfelder E, Lang A-G et al (2007) G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39(2):175–191

  28. 28.

    Tramontina J, Frey BN, Andreazza AC et al (2007) Val66met polymorphism and serum brain-derived neurotrophic factor levels in bipolar disorder. Mol Psychiatry 12(3):230–231

  29. 29.

    Neves-Pereira M, Cheung JK, Pasdar A et al (2005) BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 10(2):208–212

  30. 30.

    Kang H-J, Kim J-M, Bae K-Y et al (2015) Longitudinal associations between BDNF promoter methylation and late-life depression. Neurobiol Aging 36(4):1764.e1–1764.e7

  31. 31.

    Januar V, Ancelin M-L, Ritchie K et al (2015) BDNF promoter methylation and genetic variation in late-life depression. Transl Psychiatry 5:e619

  32. 32.

    D’Addario C, Dell’Osso B, Palazzo MC et al (2012) Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology 37(7):1647–1655

  33. 33.

    Fuchikami M, Morinobu S, Segawa M et al (2011) DNA methylation profiles of the brain-derived neurotrophic factor (BDNF) gene as a potent diagnostic biomarker in major depression. PLoS One 6(8):e23881

  34. 34.

    Roy B, Shelton RC, Dwivedi Y (2017) DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation. J Psychiatr Res 89:115–124

  35. 35.

    Nuernberg GL, Aguiar B, Bristot G et al (2016) Brain-derived neurotrophic factor increase during treatment in severe mental illness inpatients. Transl Psychiatry 6(12):e985

  36. 36.

    Polyakova M, Stuke K, Schuemberg K et al (2015) BDNF as a biomarker for successful treatment of mood disorders. A systematic and quantitative meta-analysis. J Affect Disord 174:432–440

  37. 37.

    Kleimann A, Kotsiari A, Sperling W et al (2015) BDNF serum levels and promoter methylation of BDNF exon I, IV and VI in depressed patients receiving electroconvulsive therapy. Journal of neural transmission 122(6):925–928 (Vienna, Austria: 1996)

  38. 38.

    Kim J-M, Stewart R, Kang H-J et al (2013) A longitudinal study of BDNF promoter methylation and genotype with poststroke depression. J Affect Disord 149(1–3):93–99

  39. 39.

    Schuster R, Kleimann A, Rehme M-K et al (2017) Elevated methylation and decreased serum concentrations of BDNF in patients in levomethadone compared to diamorphine maintenance treatment. Eur Arch Psychiatry Clin Neurosci 267(1):33–40

  40. 40.

    Bocchio-Chiavetto L, Bagnardi V, Zanardini R et al (2010) Serum and plasma BDNF levels in major depression: A replication study and meta-analyses. World J Biol Psychiatry 11(6):763–773

  41. 41.

    Wolkowitz OM, Wolf J, Shelly W et al (2011) Serum BDNF levels before treatment predict SSRI response in depression. Prog Neuropsychopharmacol Biol Psychiatry 35(7):1623–1630

  42. 42.

    Başterzi AD, Yazici K, Aslan E et al (2009) Effects of fluoxetine and venlafaxine on serum brain derived neurotrophic factor levels in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 33(2):281–285

  43. 43.

    Lee H-Y, Kim Y-K (2008) Plasma brain-derived neurotrophic factor as a peripheral marker for the action mechanism of antidepressants. Neuropsychobiology 57(4):194–199

  44. 44.

    Shimizu E, Hashimoto K, Okamura N et al (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54(1):70–75

  45. 45.

    Gonul AS, Akdeniz F, Taneli F et al (2005) Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 255(6):381–386

  46. 46.

    Cedar H, Bergman Y (2012) Programming of DNA methylation patterns. Annu Rev Biochem 81:97–117

  47. 47.

    Stenz L, Zewdie S, Laforge-Escarra T et al (2015) BDNF promoter I methylation correlates between post-mortem human peripheral and brain tissues. Neurosci Res 91:1–7

Download references

Acknowledgements

We thank Joyce Auer, Sabine Stanzel and Theresia Töpner for their excellent technical support and we thank all the patients and controls for participating in this study.

Author information

Correspondence to Sarah Kittel-Schneider.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare regarding the present study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 12 kb)

Supplementary material 2 (DOCX 13 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schröter, K., Brum, M., Brunkhorst-Kanaan, N. et al. Longitudinal multi-level biomarker analysis of BDNF in major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci (2019). https://doi.org/10.1007/s00406-019-01007-y

Download citation

Keywords

  • BDNF
  • Bipolar disorder
  • Major depression
  • Fluid biomarker
  • Risk gene