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:

Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484)

Molecular Psychiatry volume 19, pages 791–800 (2014)Cite this article

Subjects

Abstract

Meta-analyses, published in 2008–2010, have confirmed abnormally low serum brain-derived neurotrophic factor (BDNF) concentrations in depressed patients and normalization of this by antidepressant treatment. These findings are believed to reflect peripheral manifestations of the neurotrophin hypothesis, which states that depression is secondary to an altered expression of BDNF in the brain. Since the publication of these meta-analyses, the field has seen a huge increase in studies on these topics. This motivated us to update the evidence on the aforementioned associations and, in addition, to compile the data on serum BDNF concentrations in relation to the symptom severity of depression. Using a manifold of data as compared with earlier meta-analyses, we find low serum BDNF concentrations in 2384 antidepressant-free depressed patients relative to 2982 healthy controls and to 1249 antidepressant-treated depressed patients (Cohen’s d=−0.71 and −0.56, P-values <0.0000001). When publication bias is accounted for, these effect-sizes become substantially smaller (d=−0.47 and −0.34, respectively, P-values<0.0001). We detect between-study heterogeneity in outcomes for which only year of publication and sample size are significant moderators, with more recent papers and larger samples sizes in general being associated with smaller between-group differences. Finally, the aggregated data negate consistent associations between serum BDNF concentrations and the symptom severity of depression. Our findings corroborate the claim that altered serum BDNF concentrations are peripheral manifestations of depression. However, here we highlight that the evidence for this claim is slimmer as was initially thought and amidst a lot of noise.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Duman RS, Heninger GR, Nestler EJ . A molecular and cellular theory of depression. Arch Gen Psychiatry 1997; 54: 597–606.

    Article  CAS  PubMed  Google Scholar 

  2. Park H, Poo M-M . Neurotrophin regulation of neuronal circuit development and function. Nat Rev Neurosci 2013; 14: 7–23.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Taliaz D, Stall N, Dar DE, Zangen A . Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry 2010; 15: 80–92.

    Article  CAS  PubMed  Google Scholar 

  5. Thompson Ray M, Weickert CS, Wyatt E, Webster MJ . Decreased BDNF, trkB-TK+ and GAD mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J Psychiatry Neurosci 2011; 36: 195–203.

    Article  PubMed  Google Scholar 

  6. Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM . Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 2002; 109: 143–148.

    Article  CAS  PubMed  Google Scholar 

  7. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C et al. Alternations of serum concentrations of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003; 54: 70–75.

    Article  CAS  PubMed  Google Scholar 

  8. Brunoni AR, Lopes M, Fregni F . A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008; 11: 1169–1180.

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Bocchio-Chiavetto L, Bagnardi V, Zanardini R, Molteni R, Nielsen MG, Placentino A et al. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. W J Biol Psychiatry 2010; 11: 763–773.

    Article  Google Scholar 

  11. Basterzi AD, Yazici K, Aslan E, Delialioglu N, Tasdelen B, Acar ST et al. Effects of fluoxetine and venlafaxine on serum brain-derived neurotrophic factor concentrations in depressed patients. Prog Neuro-Psychopharmacol Biol Psychiatry 2009; 33: 281–285.

    Article  CAS  Google Scholar 

  12. Elfving B, Buttenschøn HN, Foldager L, Poulsen PHP, Andersen JH, Grynderup MB et al. Depression, the val66met polymorphism, age, and gender influence the serum BDNF level. J Psychiatric Res 2012; 46: 1118–1125.

    Article  Google Scholar 

  13. Moher D, Liberati A, Tetzlaff J, Altman DG . Preferred reporting items for systematic reviews and meta-analyses: the prisma statement. Ann Intern Med 2009; 151: 264–269.

    Article  PubMed  Google Scholar 

  14. Wells GA, Shea B, O’Connel D . The Newcastle-Ottawa Scale (NOS) for assessing the quality non-randomised studies in meta-analyses. Ottawa Healthcare Institute. http://www.ohri.ca, accessed 7 February 2013.

  15. The Cochrane Collaboration Handbook http://www.cochrane.org/, accessed 29 June 2013.

  16. Borenstein M, Hedges LV, Higgins JPT . Introduction to Meta-Analyses. Wiley: Chicester, NH, USA, 2009.

    Book  Google Scholar 

  17. Cohen J . Statistical Power Analysis for the Behavioral Sciences. Lawrence Erlbaum Associates: Hillsdale, NJ, USA, 1988.

    Google Scholar 

  18. Mosteller F, Colditz GA . Understanding research synthesis (meta-analysis). Annu Rev Public Health 1996; 17: 1–23.

    Article  CAS  PubMed  Google Scholar 

  19. Higgins JPT, Thompson SG . Quantifying heterogeneity in meta-analysis. Statist Med 2002; 21: 1539–155.

    Article  Google Scholar 

  20. Hamilton M . A rating scale for depression. J Neurol Neurosug Psychiatry 1960; 23: 56–62.

    Article  CAS  Google Scholar 

  21. 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 

  22. Egger M, Davey Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Duval S, Tweedie RL . A nonparametric ‘trim and fill’ method of accounting for publication bias in meta-analysis. J Am Stat Soc 2000; 95: 89–98.

    Google Scholar 

  24. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L . Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity. Statist Med 2007; 26: 4544–4562.

    Article  Google Scholar 

  25. Faul F, Erdfelder E, Buchner A, Lang AG . Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Beh Res Methods 2009; 41: 1149–1160.

    Article  Google Scholar 

  26. Gervasoni N, Aubry JM, Bondolfi G, Osiek C, Schwald M, Bertschy G et al. Partial normalization of serum brain-derived neurotrophic factor in remitted patients after a major depressive episode. Neuropsychobiol 2005; 51: 234–238.

    Article  CAS  Google Scholar 

  27. Gönül AS, Kitis O, Eker MC, Eker OD, Ozan E, Coburn K . Association of the brain-derived neurotrophic factor val66met polymorphism with hippocampus volumes in drug-free depressed patients. W J Biol Psychiatry 2011; 12: 110–118.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Aydemir C, Yalcin ES, Aksaray S, Kisa C, Yildirim SG, Uzbay T et al. Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1256–1260.

    Article  CAS  PubMed  Google Scholar 

  30. Zanardini R, Gazzoli A, Ventriglia M, Perez J, Bignotti S, Rossini PM et al. Effect of repetitive transcranial magnetic stimulation on serum brain-derived neurotrophic factor in drug resistant depressed patients. J Affect Disord 2006; 91: 83–86.

    Article  CAS  PubMed  Google Scholar 

  31. Lommatzsch M, Hornych K, Zingler C, Schuff-Werner P, Hoppner J, Virchow JC et al. Maternal serum concentrations of BDNF and depression in the perinatal period. Psychoendocrinol 2006; 31: 388–394.

    Article  CAS  Google Scholar 

  32. Bocchi-Chiavetto L, Zanardini R, Bortolomasi M, Abate M, Segala M, Giacopuzzi M et al. Electroconvulsive therapy (ECT) increases serum brain-derived neurotrophic factor in drug resistant depressed patients. Eur Neuropsychopharmacol 2006; 16: 56–59.

    Article  Google Scholar 

  33. Lang UE, Bajbouj M, Gallinat J, Hellweg R . Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetetive transcranial magnetic stimulation. Psychopharmacol 2006; 187: 56–59.

    Article  CAS  Google Scholar 

  34. Aydemir O, Deveci A, Taskin OE, Taneli F, Esen-Danaci A . Serum brain-derived neurotrophic factor level in dysthymia: a comparative study with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1023–1026.

    Article  CAS  PubMed  Google Scholar 

  35. Yoshimura R, Mitoma M, Sugita A, Hori H, Okamoto T, Umene W et al. Effects of paroxetine or milnacipran on serum brain-derived neurotrophic factor in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1034–1037.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. Hellweg R, Ziegenhorn A, Heuser I, Deuschle M . Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment. Pharmacopsychiatry 2008; 41: 66–71.

    Article  CAS  PubMed  Google Scholar 

  38. Okamoto T, Yoshimura R, Ikenouchi-Sugita A, Hori H, Umene-Nakano W, Inoue Y et al. Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanilic acid and brain-derived neurotrophic factor in refractory depressed patients: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1185–1190.

    Article  CAS  PubMed  Google Scholar 

  39. Stanek K, Gunstad J, Leahey T, Glickman E, Alexander T, Spitznagel MB et al. Serum brain-derived neurotrophic factor is associated with reduced appetite in healthy older adults. J Health Aging 2008; 12: 183–185.

    Article  CAS  Google Scholar 

  40. Huang TL, Lee CT, Liu YL . Serum brain-derived neurotrophic factor levels in patients with major depression: effects of antidepressants. J Psychiatr Res 2008; 42: 521–525.

    Article  PubMed  Google Scholar 

  41. Piccinni A, Marazziti D, Catena M, Domenici L, Del Debbio A, Bianchi C et al. Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatment. J Affect Disord 2008; 105: 279–283.

    Article  CAS  PubMed  Google Scholar 

  42. Matrisciano F, Bonaccorso S, Ricciardi A, Scaccianoce S, Panaccione I, Wang L et al. Changes in BDNF serum concentrations in patients with major depression disorder (MDD) after 6 months treatment with sertraline, ecitalopram, or venlafaxine. J Psych Res 2009; 43: 247–254.

    Article  Google Scholar 

  43. Gorgulu Y, Caliyurt O . Rapid antidepressant effect of sleep deprivation therapy correlates with serum BDNF changes in major depression. Brain Res Bull 2009; 80: 158–162.

    Article  CAS  PubMed  Google Scholar 

  44. Grønli O, Stensland GØ, Wynn R, Olstad R . Neurotrophic factors in serum following ECT: a pilot study. World J Biol Psychiatry 2009; 10: 295–301.

    Article  PubMed  Google Scholar 

  45. Umene-Nakano W, Yoshimura R, Ikenouchi-Sugita A, Hori H, Hayashi K, Ueda N et al. Serum levels of brain-derived neurotrophic factor in comorbidity of depression and alcohol dependence. Hum Psychopharmacol Clin Exp 2009; 24: 409–413.

    Article  CAS  Google Scholar 

  46. Fernandes B, Gama CS, Massuda R, Torres M, Camargo D, Kunz M et al. Serum brain-derived neurotrophic factor is not associated with response to electroconvulsive therapy: a pilot in drug resistant depressed patients. Neurosci Lett 2009; 453: 195–198.

    Article  CAS  PubMed  Google Scholar 

  47. Lee JG, Shin BS, You YS, Kim JE, Yoon SW, Jeon DW et al. Decreased serum brain-derived neurotrophic factor levels in elderly Korean with dementia. Psychiatry Invest 2009; 6: 299–305.

    Article  CAS  Google Scholar 

  48. Ozan E, Okur H, Eker C, Eker DE, Gönül AS, Akarsu N . The effect of depression, BDNF gene val66met polymorphism and gender on serum BDNF levels. Brain Res Bull 2010; 81: 61–65.

    Article  CAS  PubMed  Google Scholar 

  49. Diniz BS, Teixeira AL, Talib LL, Mendoca VA, Gattaz WF, Forlenza OV . Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression. W J Biol Psychiatry 2010; 11: 550–555.

    Article  Google Scholar 

  50. Eker C, Kitis O, Taneli F, Eker DE, Ozan E, Yucel K et al. Correlation of serum BDNF levels with hippocampal volumes in first episode, medication-free depressed patients. Eur Arch Psychiatry Clin Neurosci 2010; 260: 527–533.

    Article  PubMed  Google Scholar 

  51. Hu Y, Yu X, Yang F, Si T, Wang W, Tan Y et al. The brain-derived neurotrophic factor is associated with the therapeutic efficacy of modified electroconvulsive therapy in Chinese patient with depression. J ECT 2010; 26: 121–125.

    Article  CAS  PubMed  Google Scholar 

  52. Zhou Z, Lu T, Xu G, Yue X, Zhu W, Ma M et al. Decreased serum brain-derived neurotrophic factor (BDNF) is associated with post-stroke depression but not with BDNF gene val66met polymorphism. Clin Chem Lab Med 2011; 49: 185–189.

    CAS  PubMed  Google Scholar 

  53. Su SC, Sun MT, Wen MJ, Lin CJ, Chen YC, Hung YJ . Brain-derived neurotrophic factor, adiponectin, and proinflammatory markers in various subtypes of depression in young men. Int J Psychiatry Med 2011; 42: 211–226.

    Article  PubMed  Google Scholar 

  54. Rojas PS, Fritsch R, Rojas RA, Jara P, Fiedler JL . Serum brain-derived neurotrophic factor and glucocorticoid receptor levels in lymphocytes as markers of antidepressant response in major depressive patients: a pilot study. Psychiatry Res 2011; 189: 239–245.

    Article  CAS  PubMed  Google Scholar 

  55. Gorgulu Y, Caliyurt O . Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression. Brain Res Bull 2009; 80: 158–162.

    Article  CAS  PubMed  Google Scholar 

  56. Yoshimura R, Kishi T, Suzuki A, Umene-Nakano W, Ikenouchi-Sugita A, Hori H et al. The brain-derived neurotrophic factor (BDNF) polymorphism val66met is associated with neither serum BDNF level nor response to selective serotonin reuptake inhibitors in depressed Japanese patients. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1022–1025.

    Article  CAS  PubMed  Google Scholar 

  57. Wolkowitz OM, Wolf J, Shelly W, Rosser R, Burke HM, Lerner GK et al. Serum BDNF levels before treatment predict SSRI response in depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 15: 1623–1630.

    Article  CAS  Google Scholar 

  58. Kobayakawa M, Inagaki M, Fujimori M, Hamazaki K, Hamazaki T, Akechi T et al. Serum brain-derived neurotrophic factor and antidepressant-naive major depression after lung cancer diagnosis. Jpn J Clin Oncol 2011; 4: 1233–1237.

    Article  Google Scholar 

  59. Terracciano A, Lobina M, Piras MG, Cannas A, Meirelles O, Mulas A et al. Lower serum BDNF associated with higher neuroticism and depressive symptoms. Psychosom Med 2011; 74: 638–642.

    Article  CAS  Google Scholar 

  60. Molendijk ML, Bus BAA, Spinhoven P, Penninx BJWH, Kenis G, Prickaerts J et al. Serum concentrations of brain-derived neurotrophic factor in major depressive disorder: state and trait issues, clinical features, and pharmacological treatment. Mol Psychiatry 2011; 16: 1088–1095.

    Article  CAS  PubMed  Google Scholar 

  61. Toups MSP, Greer TL, Kurian BT, Grannemann BD, Carmody TJ, Huebinger R et al. Effects of serum brain-derived neurotrophic factor on exercise augmentation treatment of depression. J Psychiatric Res 2011; 45: 1301–1306.

    Article  Google Scholar 

  62. Satomura E, Baba H, Nakano Y, Maeshima H, Suzuki T, Arai H . Correlations between brain-derived neurotrophic factor and clinical symptoms inmedicated patients with major depression. J Affect Disord 2011; 135: 332–335.

    Article  CAS  PubMed  Google Scholar 

  63. Sözeri-Varma G, Enli Y, Toker-Uğurlu T, Alaçam H, Kalkan-Oğuzhanoğlu N . Decreased serum BDNF levels in major depressive patients. Neurol Psychiatry Brain Res 2011; 17: 84–88.

    Article  Google Scholar 

  64. Bus BAA, Tendolkar I, Franke B, de Graaf J, Den Heijer M, 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. W J Biol Psychiatry 2012; 13: 39–47.

    Article  Google Scholar 

  65. Gedge L, Beaudoin A, Lazowski L, Toit R, Jokic R, Milev R . Effects of electro-convulsive therapy and repetetive transcranial magnetic stimulation on serum brain-derived neurotrophic factor levels in patients with depression. Front Psychiatry 2012; 3: 1–8.

    Article  Google Scholar 

  66. Gazal M, Motta LS, Wiener CD, Fernandes JC, Quevedo LA, Jansen K et al. Brain-derived neurotrophic factor in post-partum depressive mothers. Neurochem Res 2012; 37: 583–587.

    Article  CAS  PubMed  Google Scholar 

  67. Birkenhäger TK, Geldermans S, Van den Broek WW, van Beveren N, Fekkes D . Serum brain-derived neurotrophic factor level in relation to illness severity and episode duration in patients with major depression. J Psychiatr Res 2012; 46: 285–289.

    Article  PubMed  Google Scholar 

  68. Deuschle M, Gilles M, Scharnholz B, Lederbogen F, Lang U, Hellweg R . Changes of serum concentrations of brain-derived neurotrophic factor (BDNF) during treatment with venlafaxine and mirtazapine: role of medication and response to treatment. Pharmacopsychiatry 2013; 46: 54–58.

    CAS  PubMed  Google Scholar 

  69. Harvey BH, Hamer M, Louw R, van der Westhuizen FH, Malan L . Metabolic and glutathione redox markers associated with brain-derived neurotrophic factor in depressed African men and women: evidence for counter-regulation. Neuropsychobiol 2012; 67: 33–40.

    Article  CAS  Google Scholar 

  70. Oral E, Canpolat S, Yildirim S, Gulec M, Aliyev E, Aydin N. et al. Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder. Brain Res Bull 2012; 88: 454–459.

    Article  CAS  PubMed  Google Scholar 

  71. Karlović D, Serretti A, Jevtović S, Vrkić N, Šeric V, Peleš AM . Diagnostic accuracy of serum brain derived neurotrophic factor concentration in antidepressant naïve patients with first major depression episode. J Psychiatric Res 2012; 47: 162–167.

    Article  Google Scholar 

  72. Jeon HJ, Kang E-S, Lee EH, Jeong E-H, Jeon JR, Mischoulon D et al. Childhood trauma and platelet brain-derived neurotrophic factor (BDNF) after a three month follow-up in patients with major depressive disorder. J Psychiatric Res 2012; 46: 966–972.

    Article  Google Scholar 

  73. Yoshida T, Ishikawa M, Niitsu T, Nakazato M, Watanabe H, Shiraishi T et al. Decreased serum levels of mature brain-derived neurotrophic factor, but not Its precursor proBDNF, in patients with major depressive disorder. PLoS ONE 2012; 7: e42676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gazal M, Motta LS, Wiener CD, Fernandes JC, Quevedo LA, Jansen K et al. Brain-derived neurotrophic factor in post-partum depressive mothers. Neurochem Res 2012; 37: 583–587.

    Article  CAS  PubMed  Google Scholar 

  75. Oral E, Canpolat S, Yildirim S, Gulec M, Aliyev E, Aydin N . Cognitive functions and serum brain derived neurotrophic factor in patients with major depressive disorder. Brain Res Bull 2012; 88: 454–459.

    Article  CAS  PubMed  Google Scholar 

  76. Papakostas GI, Shelton RC, Kinrys G, Henry ME, Bakow BR, Lipkin SH et al. Assessment of multi-assay, serum-based biological diagnostic test for major depressive disorder: a pilot and replication study. Mol Psychiatry 2013; 18: 332–339.

    Article  CAS  PubMed  Google Scholar 

  77. Gonul AS, Akdeniz F, Taneli F, Donat O, Eker Ç, Vahip S . Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 2005; 255: 381–386.

    Article  PubMed  Google Scholar 

  78. Sasaki T, Niitsu T, Hashimoto T, Kanahara N, Shiina A, Hasegawa T et al. Decreased levels of between brain-derived neurotrophic factor in male pediatric patients with depression. Open Clin Chem J 2011; 4: 28–33.

    Article  CAS  Google Scholar 

  79. Bus BAA, Molendijk ML, Penninx BJWH, Buitelaar JK, Kenis G, Prickaerts J et al. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinol 2011; 36: 228–239.

    Article  CAS  Google Scholar 

  80. Giese M, Unternaher E, Huttig H, Beck J, Brand S, Calabrese P et al. BDNF: an indicator of insomnia? Mol Psychiatry, advance online publication, 12 February 2013 doi:10.1038/mp.2013.10.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  81. Molendijk ML, Haffmans JPM, Bus BAA, Spinhoven P, Penninx BWJH, Prickaerts J et al. BDNF concentrations show strong seasonal variation and correlations with the amount of ambient sunlight. PLoS One 2012; 7: e48046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Elzinga BM, Molendijk ML, Oude Voshaar RC, Bus AA, Prickaerts J, Spinhoven P et al. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF val66met. Psychopharmacol 2011; 214: 319–328.

    Article  CAS  Google Scholar 

  83. Rush AJ . The varied clinical presentations of major depressive disorders. J Clin Psychiatry 2007; 68: S4–S10.

    Article  Google Scholar 

  84. Sterne JAC, Davey Smith G . Sifting the evidence – what’s wrong with significance tests? BMJ 2001; 322: 226–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dickersin K . The existence of publication bias and risk factors for its occurrence. JAMA 1990; 263: 1385–1359.

    Article  CAS  PubMed  Google Scholar 

  86. Munafo MR, Flint J . Meta-analysis of genetic association studies. Trends Gen 2004; 20: 439–444.

    Article  CAS  Google Scholar 

  87. Ioannidis JPA . Why most published research findings are false. PLoS MED 2005; 2: e124, 89.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Kapur S, Phillips AG, Insel TR . Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol Psychiatry 2012; 17: 1174–1179.

    Article  CAS  PubMed  Google Scholar 

  89. Schmidt HD, Shelton RC, Duman RS . Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacol 2011; 36: 2375–2394.

    Article  CAS  Google Scholar 

  90. Groves JO . Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry 2007; 12: 1079–1088.

    Article  CAS  PubMed  Google Scholar 

  91. Gass P, Hellweg R . Peripheral brain-derived neurotrophic factor (BDNF) levels as a biomarker for affective disorders. Int J Neuropsychopharmacol 2010; 13: 1–4.

    Article  CAS  PubMed  Google Scholar 

  92. Green MJ, Matheson SL, Sheperd A, Weickert CS, Carr VJ . Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 2011; 16: 960–972.

    Article  CAS  PubMed  Google Scholar 

  93. Fernandes BS, Gama CS, Cereser KM, Yatham LN, Fries GR, Colpo G et al. Brain-derived neurotrophic factor as a state marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatric Res 2011; 45: 995–1004.

    Article  Google Scholar 

  94. Monteleone P, Fabrazzo M, Martiadis V, Serritella C, Pannuto M, Maj M . Circulating brain-derived neurotrophic factor is decreased in women with anorexia and bulimia nervosa but not in women with binge eating disorder: relationships to co-morbid depression, psychopathology and hormonal variables. Psychol Med 2005; 35: 897–905.

    Article  PubMed  Google Scholar 

  95. Molendijk ML, Bus BAA, Spinhoven P, Penninx BWJH, Prickaerts J, Oude Voshaar RC et al. Gender specific associations of serum BDNF concentrations in anxiety. W J Biol Psychiatry 2012; 13: 535–543.

    Article  Google Scholar 

  96. Penninx BWJH, Milaneschi Y, Lamers F, Vogelzangs N . Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Med 2013; 11: 129.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Dawood T, Anderson J, Barton D, Lambert E, Esler M, Hotchkin E et al. Reduced overflow of BDNF from the brain is linked with suicide risk in depressive illness. Mol Psychiatry 2007; 12: 981–983.

    Article  CAS  PubMed  Google Scholar 

  98. Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M et al. Blood BDNF concentrations reflect brain-tissue BDNF concentrations across species. Int J Neuropsychopharmacol 2011; 14: 347–353.

    Article  CAS  PubMed  Google Scholar 

  99. Cassiman D, Denef C, Desmet VJ, Roskams T . Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology 2001; 33: 148–158.

    Article  CAS  PubMed  Google Scholar 

  100. Karege F, Schwald M, Cisse M . Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci Lett 2002; 328: 261–264.

    Article  CAS  PubMed  Google Scholar 

  101. Sanderson S, Tatt ID, Higgings JPT . Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007; 36: 666–676.

    Article  PubMed  Google Scholar 

  102. aan het Rot M, Zarate CA, Charney DS, Mathew SJ . Ketamine for depression: where do wego from here? Biol Psychiatry 2012; 72: 537–547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Machado-Vieira R, Yuan P, Brutsche N, Diaz-Granados N, Luckenbaugh D, Manji HK et al. Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-D- aspartate antagonist. J Clin Psychiatry 2009; 70: 1662–1666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lang UE, Bajbouj M, Gallinat J, Hellweg R . Brain-derived neurotrophic factor serumconcentrations in depressive patients during vagus nerve stimulation and repetetive transcranial magnetic stimulation. Psychopharmacol 2006; 187: 56–59.

    Article  CAS  Google Scholar 

  105. Yoshida T, Ishikawa M, Masaomi I, Hashimoto K . Serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in healthy subjects. Open ClinChem 2012; 5: 7–12.

    CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank the five reviewers for their helpful comments on our manuscript, the authors who on request kindly provided us with data, and Jeroen Claessen (MSc) for a textual review of an early version of the manuscript. This project is financed with NWO VIDI-grant (Dutch Governmental Scientific Organization, grant number: 016.085.353) awarded to Bernet Elzinga and a KNAW grant (Dutch Governmental Scientific Organization, grant: Programma Akademie Assistent).

Author information

Authors and Affiliations

  1. Clinical, Health and Neuropsychology Unit, Leiden University, Leiden, The Netherlands

    M L Molendijk, P Spinhoven, M Polak & B M Elzinga

  2. Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands

    M L Molendijk, P Spinhoven & B M Elzinga

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

    P Spinhoven & B W J H Penninx

  4. Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    B A A Bus

  5. Department of Psychiatry, EMGO Institute and Neuroscience Campus Amsterdam VU, Amsterdam, The Netherlands

    B W J H Penninx

  6. University Center for Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    B W J H Penninx

Authors
  1. M L Molendijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Spinhoven
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Polak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B A A Bus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B W J H Penninx
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B M Elzinga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M L Molendijk.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Author contributions

All authors participated in interpreting the study outcomes and manuscript redaction and approved the final version of the paper. BE, BP, PS and MM designed the study. BB and MM performed the literature search. MP and MM extracted the data and performed quality assessments. MM conducted the statistical analyses and wrote the paper.

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Molendijk, M., Spinhoven, P., Polak, M. et al. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484). Mol Psychiatry 19, 791–800 (2014). https://doi.org/10.1038/mp.2013.105

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2013.105

Keywords

This article is cited by

Search

Advanced search

Quick links