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Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time

Molecular Psychiatry volume 20, pages 602–608 (2015)Cite this article

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Abstract

One of the leading neurobiological hypotheses on depression states that decreased expression of brain-derived neurotrophic factor (BDNF) contributes to depression. This is supported by consistent findings of low serum BDNF levels in depressed patients compared with non-depressed controls. Whereas it has been generally assumed that this is a state characteristic of depression, strong inferences about state or trait effects require a longitudinal study design. To investigate the longitudinal association between serum BDNF and depression, we measured serum BDNF, (current and past) depression status, use of antidepressants, and all potential covariates at baseline and after 2 years in 1751 individuals, consisting of patients with an incident (n=153), remitted (n=420) and persistent depression (n=310) and non-depressed controls (n=868). We analyzed change/differences in serum BDNF across these four groups with analyses of covariance adjusted for covariates and baseline BDNF value, together with the effects of starting and stopping antidepressant treatment. Our analyses revealed a significant difference for the depression course groups (P=0.007). Compared with non-depressed controls, persistently depressed and remitted patients had a steeper decrease of BDNF levels over time (−1.33 (P=0.001) and −0.97 ng ml−1 (P=0.011), respectively), whereas BDNF reductions in patients with incident depression were similar to those in healthy controls. Initiation or discontinuation of antidepressants was not associated with BDNF change (P=0.72). These findings suggest that BDNF not only contributes to depression, but that depression in turn may also contribute to low BDNF.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Penninx BW, Nolen WA, Lamers F, Zitman FG, Smit JH, Spinhoven P et al. Two-year course of depressive and anxiety disorders: results from the Netherlands Study of Depression and Anxiety (NESDA). J Affect Disord 2011; 133: 76–85.

    Article  PubMed  Google Scholar 

  3. Vos T, Haby MM, Barendregt JJ, Kruijshaar M, Corry J, Andrews G . The burden of major depression avoidable by longer-term treatment strategies. Arch Gen Psychiatry 2004; 61: 1097–1103.

    Article  PubMed  Google Scholar 

  4. Kendler KS, Thornton LM, Gardner CO . Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am J Psychiatry 2001; 158: 582–586.

    Article  CAS  PubMed  Google Scholar 

  5. Robinson OJ, Sahakian BJ . Recurrence in major depressive disorder: a neurocognitive perspective. Psychol Med 2008; 38: 315–318.

    Article  CAS  PubMed  Google Scholar 

  6. Booij SH, Bouma EM, de Jonge P, Ormel J, Oldehinkel AJ . Chronicity of depressive problems and the cortisol response to psychosocial stress in adolescents: the TRAILS study. Psychoneuroendocrinology 2013; 38: 659–666.

    Article  CAS  PubMed  Google Scholar 

  7. Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM . Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484). Mol Psychiatry 2013; 19: 791–800.

    Article  PubMed  Google Scholar 

  8. Molendijk ML, Bus BA, Spinhoven P, Penninx BW, Kenis G, Prickaerts J et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry 2011; 11: 1088–1095.

    Article  Google Scholar 

  9. Yoshimura R, Hori H, Sugita-Ikenouchi A, Umene-Nakano W, Katsuki A, Nakamura J . Serum brain-derived neurotrophic factor levels at 6 months after remission are not associated with subsequent depressive episodes. J Clin Psychopharmacol 2013; 33: 142–143.

    Article  PubMed  Google Scholar 

  10. Penninx BW, Beekman AT, Smit JH, Zitman FG, Nolen WA, Spinhoven P et al. The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods. Int J Methods Psychiatr Res 2008; 17: 121–140.

    PubMed  PubMed Central  Google Scholar 

  11. Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH . The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26: 477–486.

    Article  CAS  PubMed  Google Scholar 

  12. Lyketsos CG, Nestadt G, Cwi J, Heithoff K, Eaton WW . The Life Chart Interview - a standardized method to describe the course of psychopathology. Int J Method Psych 1994; 4: 143–155.

    Google Scholar 

  13. Levine DW, Kripke DF, Kaplan RM, Lewis MA, Naughton MJ, Bowen DJ et al. Reliability and validity of the Women's Health Initiative Insomnia Rating Scale. Psychol Assess 2003; 15: 137–148.

    Article  PubMed  Google Scholar 

  14. de Graaf R, Bijl RV, Ten Have M, Beekman AT, Vollebergh WA . Pathways to comorbidity: the transition of pure mood, anxiety and substance use disorders into comorbid conditions in a longitudinal population-based study. J Affect Disord 2004; 82: 461–467.

    Article  PubMed  Google Scholar 

  15. Brugha T, Bebbington P, Tennant C, Hurry J . The List of Threatening Experiences: a subset of 12 life event categories with considerable long-term contextual threat. Psychol Med 1985; 15: 189–194.

    Article  CAS  PubMed  Google Scholar 

  16. Brugha TS, Cragg D . The List of Threatening Experiences: the reliability and validity of a brief life events questionnaire. Acta Psychiat Scand 1990; 82: 77–81.

    Article  CAS  PubMed  Google Scholar 

  17. Bus BA, Molendijk ML, Penninx BJ, Buitelaar JK, Kenis G, Prickaerts J et al. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 2011; 36: 228–239.

    Article  CAS  PubMed  Google Scholar 

  18. Bus BA, Tendolkar I, Franke B, de GJ, Heijer MD, Buitelaar JK et al. Serum brain-derived neurotrophic factor: Determinants and relationship with depressive symptoms in a community population of middle-aged and elderly people. World J Biol Psychiatry 2012; 13: 39–47.

    Article  PubMed  Google Scholar 

  19. Babor TF, Kranzler HR, Lauerman RJ . Early detection of harmful alcohol consumption: comparison of clinical, laboratory, and self-report screening procedures. Addict Behav 1989; 14: 139–157.

    Article  CAS  PubMed  Google Scholar 

  20. Rothman KJ . No adjustments are needed for multiple comparisons. Epidemiology 1990; 1: 43–46.

    Article  CAS  PubMed  Google Scholar 

  21. Bland JM, Altman DG . Multiple significance tests: the Bonferroni method. BMJ 1995; 310: 170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. McKinnon MC, Yucel K, Nazarov A, MacQueen GM . A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. J Psychiatry Neurosci 2009; 34: 41–54.

    PubMed  PubMed Central  Google Scholar 

  23. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM . Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997; 56: 131–137.

    Article  CAS  PubMed  Google Scholar 

  24. Schmidt HD, Duman RS . Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 2010; 35: 2378–2391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dreimuller N, Schlicht KF, Wagner S, Peetz D, Borysenko L, Hiemke C et al. Early reactions of brain-derived neurotrophic factor in plasma (pBDNF) and outcome to acute antidepressant treatment in patients with Major Depression. Neuropharmacology 2012; 62: 264–269.

    Article  PubMed  Google Scholar 

  26. Tadic A, Wagner S, Schlicht KF, Peetz D, Borysenko L, Dreimuller N et al. The early non-increase of serum BDNF predicts failure of antidepressant treatment in patients with major depression: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 415–420.

    Article  CAS  PubMed  Google Scholar 

  27. 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  PubMed  PubMed Central  Google Scholar 

  28. Molendijk ML, Bus BA, Spinhoven P, Penninx BW, Prickaerts J, Oude Voshaar RC et al. Gender specific associations of serum levels of brain-derived neurotrophic factor in anxiety. World J Biol Psychiatry 2012; 13: 535–543.

    Article  PubMed  Google Scholar 

  29. Pies R . Are antidepressants effective in the acute and long-term treatment of depression? Sic et Non. Innov Clin Neurosci 2012; 9: 31–40.

    PubMed  PubMed Central  Google Scholar 

  30. Ziegenhorn AA, Schulte-Herbruggen O, Danker-Hopfe H, Malbranc M, Hartung HD, Anders D et al. Serum neurotrophins—a study on the time course and influencing factors in a large old age sample. Neurobiol Aging 2007; 28: 1436–1445.

    Article  CAS  PubMed  Google Scholar 

  31. Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P et al. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging 2005; 26: 115–123.

    Article  CAS  PubMed  Google Scholar 

  32. Karege F, Bondolfi G, Gervasoni N, Schwald M, Aubry JM, Bertschy G . Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry 2005; 57: 1068–1072.

    Article  CAS  PubMed  Google Scholar 

  33. Lederbogen F, Horer E, Hellweg R, Heuser I, Deuschle M . Platelet counts in depressed patients treated with amitriptyline or paroxetine. Eur Psychiatry 2003; 18: 89–91.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The BDNF measurements were financed by a Clinical Fellowship from the NWO (Netherlands Organisation for Scientific Research; project number 90700231) awarded to Richard C. Oude Voshaar, MD, PhD and a VIDI-grant from the NWO (grant nr. 016.085.353) awarded to Bernet M. Elzinga, PhD.

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Authors and Affiliations

  1. Department of Psychiatry, Nijmegen Centre for Evidence Based Practice (NCEBP) Radboud University Medical Centre, Nijmegen, The Netherlands,

    B A A Bus, I Tendolkar & R C O Voshaar

  2. Clinical, Health and Neuropsychology Unit, Leiden University, Leiden, the Netherlands and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands,

    M L Molendijk & B M Elzinga

  3. Faculty of Medicine and LVR Clinic for Psychiatry and Psychotherapy, University of Duisburg-Essen, Germany

    I Tendolkar

  4. Donders Institute for Brain Cognition and Behaviour, Centre for Neuroscience, Nijmegen, The Netherlands

    I Tendolkar

  5. Department of Psychiatry and EMGO Institute, VU University Medical Center, Amsterdam, The Netherlands,

    B W J H Penninx

  6. Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands,

    B W J H Penninx

  7. Department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands,

    B W J H Penninx & R C O Voshaar

  8. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands,

    J Prickaerts

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  1. B A A Bus
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Corresponding author

Correspondence to B A A Bus.

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Bus, B., Molendijk, M., Tendolkar, I. et al. Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time. Mol Psychiatry 20, 602–608 (2015). https://doi.org/10.1038/mp.2014.83

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