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:

Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis

Molecular Psychiatry volume 16, pages 960–972 (2011)Cite this article

Subjects

Abstract

Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Several studies report reduced peripheral (blood) levels of BDNF in schizophrenia, but findings are inconsistent. We undertook the first systematic review with meta-analysis of studies examining blood BDNF levels in schizophrenia compared with healthy controls, and examined potential effects of age, gender and medication. Included are individual studies of BDNF blood (serum or plasma) levels in schizophrenia (including schizoaffective disorder, or first episode psychosis), compared with age-matched healthy controls, obtained by electronic Medline and Embase searches, and hand searching. The decision to include or exclude studies, data extraction and quality assessment were completed by two independent reviewers. The initial search revealed 378 records, of which 342 were excluded on reading the Abstract, because they did not examine BDNF blood levels in schizophrenia compared with healthy controls. Of 36 papers screened in full, 17 were eligible for inclusion, but one was subsequently removed as an outlier. The remaining 16 studies provided moderate quality evidence of reduced blood BDNF levels in schizophrenia (Hedges g=−0.458, 95% confidence interval=−0.770 to −0.146, P<0.004, random effects model). Subgroup analyses reveal reduced BDNF in both drug-naïve and medicated patients, and in males and females with schizophrenia. Meta-regressions showed an association between reduced BDNF in schizophrenia and increasing age, but no effects of medication dosage. Overall, blood levels of BDNF are reduced in medicated and drug-naïve patients with schizophrenia; this evidence is of moderate quality, that is, precise but with considerable, unexplained heterogeneity across study results.

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H . BDNF function and intracellular signaling in neurons. Histol Histopathol 2010; 25: 237–258.

    CAS  PubMed  Google Scholar 

  2. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A et al. BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci USA 2008; 105: 2711–2716.

    Article  CAS  Google Scholar 

  3. Yamada K, Nabeshima T . Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 2003; 91: 267–270.

    Article  CAS  Google Scholar 

  4. Lipska BK, Lerman DN, Khaing ZZ, Weinberger DR . The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain. Eur J Neurosci 2003; 18: 3097–3104.

    Article  Google Scholar 

  5. van Haren NEM, Cahn W, Hulshoff Pol HE, Kahn RS . Schizophrenia as a progressive brain disease. Eur Psychiatry 2008; 23: 245–254.

    Article  CAS  Google Scholar 

  6. Toro CT, Hallak JE, Dunham JS, Leite JP, Sakamoto AC, Guarnieri R et al. The NR1 N-methyl-D-aspartate subunit and brain-derived neurotrophic factor in temporal lobe epilepsy hippocampus: a comparison of patients with and without coexisting psychiatric symptoms. Epilepsia 2007; 48: 2352–2356.

    CAS  PubMed  Google Scholar 

  7. Tanaka T, Saito H, Matsuki N . Inhibition of GABAA synaptic responses by brain-derived neurotrophic factor (BDNF) in rat hippocampus. J Neurosci 1997; 17: 2959–2966.

    Article  CAS  Google Scholar 

  8. Mattson MP . Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci 2008; 1144: 97–112.

    Article  CAS  Google Scholar 

  9. Durany N, Michel T, Zochling R, Boissl KW, Cruz-Sanchez FF, Riederer P et al. Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophrenia Res 2001; 52: 79–86.

    Article  CAS  Google Scholar 

  10. Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN et al. Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 2005; 25: 372.

    Article  CAS  Google Scholar 

  11. Mellios N, Huang HS, Baker SP, Galdzicka M, Ginns E, Akbarian S . Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 2009; 65: 1006–1014.

    Article  CAS  Google Scholar 

  12. Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE . Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2003; 8: 592–610.

    Article  CAS  Google Scholar 

  13. Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K et al. Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000; 5: 293–300.

    Article  CAS  Google Scholar 

  14. Wong J, Hyde TM, Cassano HL, Deep-Soboslay A, Kleinman JE, Shannon Weickert C . Promoter specific alterations of BNDF mRNA in schizophrenia. Neuroscience 2010; 169: 1071–1084.

    Article  CAS  Google Scholar 

  15. Huang EJ, Reichardt LF . Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001; 24: 677–736.

    Article  CAS  Google Scholar 

  16. Buckley PF, Pillai A, Evans D, Stirewalt E, Mahadik S . Brain derived neurotropic factor in first-episode psychosis. Schizophrenia Res 2007; 91: 1–5.

    Article  Google Scholar 

  17. Grillo RW, Ottoni GL, Leke R, Souza DO, Portela LV, Lara DR . Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics. J Psychiatric Res 2006; 41: 31–35.

    Article  Google Scholar 

  18. Ikeda Y, Yahata N, Ito I, Nagano M, Toyota T, Yoshikawa T et al. Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia. Schizophrenia Res 2008; 101: 58–66.

    Article  Google Scholar 

  19. Jindal RD, Pillai AK, Mahadik SP, Eklund K, Montrose DM, Keshavan MS . Decreased BDNF in patients with antipsychotic naïve first episode schizophrenia. Schizophrenia Res 2010; 119: 47–51.

    Article  Google Scholar 

  20. Jockers-Scherubl MC, Danker-Hopfe H, Mahlberg R, Selig F, Rentzsch J, Schurer F et al. Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. Neurosci Lett 2004; 371: 79–83.

    Article  Google Scholar 

  21. Lee BH, Kim YK . Increased plasma brain-derived neurotropic factor, not nerve growth factor-beta, in schizophrenia patients with better response to risperidone treatment. Neuropsychobiology 2009; 59: 51–58.

    Article  CAS  Google Scholar 

  22. Mackin P, Gallagher P, Watson S, Young A, Ferrier IN . Changes in brain-derived neurotrophic factor following treatment with mifepristone in bipolar disorder and schizophrenia. Australian and New Zealand J Psychiatry 2007; 41: 321–326.

    Article  Google Scholar 

  23. Pirildar S, Gonul AS, Taneli F, Akdeniz F . Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 709–713.

    Article  CAS  Google Scholar 

  24. Shimizu E, Hashimoto K, Watanabe H, Komatsu N, Okamura N, Koike K et al. Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia are indistinguishable from controls. Neurosci Lett 2003; 351: 111–114.

    Article  CAS  Google Scholar 

  25. Toyooka K, Asama K, Watanabe Y, Muratake T, Takahashi M, Someya T et al. Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. Psychiatry Res 2002; 110: 249–257.

    Article  CAS  Google Scholar 

  26. Vinogradov S, Fisher M, Holland C, Shelly W, Wolkowitz O, Mellon SH . Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? Biol Psychiatry 2009; 66: 549–553.

    Article  CAS  Google Scholar 

  27. Xiu MH, Hui L, Dang YF, Hou TD, Zhang CX, Zheng YL et al. Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry Clin Neurosci 2009; 33: 1508–1512.

    Article  CAS  Google Scholar 

  28. Yoshimura R, Hori H, Sugita A, Ueda N, Kakihara S, Umene W et al. Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-hydroxypnenylglycol (MHPG) levels, but did not alter plasma brain-derived neurotrophic factor (BDNF) levels in schizophrenic patients. Prog Neuropsychopharmacol Biol psychiatry 2007; 31: 1072–1077.

    Article  CAS  Google Scholar 

  29. Reis HJ, Nicolato R, Barbosa IG, Teixeira do Prado PH, Romano-Silva MA, Teixeira AL . Increased serum levels of brain-derived neurotrophic factor in chronic institutionalized patients with schizophrenia. Neurosci Lett 2008; 439: 157–159.

    Article  CAS  Google Scholar 

  30. Gama CS, Andreazza AC, Kunz M, Berk M, Belmonte-de-Abreu PS, Kapczinski F . Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder. Neurosci Lett 2007; 420: 45–48.

    Article  CAS  Google Scholar 

  31. Katoh-Semba R, Wakako R, Komori T, Shigemi H, Miyazaki N, Ito H et al. Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls. Int J Dev Neurosci 2007; 25: 367–372.

    Article  CAS  Google Scholar 

  32. Brozek J, Oxman A, Schünemann H . GRADEpro. Version 32 for Windows 2008. Computer program.

  33. Grade WG . Grading quality of evidence and strength of recommendations. Br Med J 2004; 328: 1490.

    Article  Google Scholar 

  34. Borenstein M, Hedges L, Higgins J, Rothstein H . Comprehensive Meta-Analysis. Version 2 Biostat: Engelwood, NJ, 2005.

    Google Scholar 

  35. Higgins J, Green S . Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration 2008. Version 501 2008.

    Book  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Chen DC, Wang J, Wang B, Yang SC, Zhang CX, Zheng YL et al. Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes. Psychopharmacology 2009; 207: 375–380.

    Article  CAS  Google Scholar 

  38. Tan LY, Zhou DF, Zhang XY . Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements. Schizophrenia Res 2005; 74: 263–270.

    Article  Google Scholar 

  39. Tan YL, Zhou DF, Zhang XY . Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements. Neurosci Lett 2005; 382: 27–32.

    Article  CAS  Google Scholar 

  40. Yun LT, Dong FZ, Lian YC, Yi ZZ, Xiang YZ . Decreased BDNF in serum of patients with chronic schizophrenia on long-term treatment with antipsychotics. Neurosci Lett 2005; 382: 27–32.

    Article  Google Scholar 

  41. Zhang XY, Zhou DF, Wu GY, Cao LY, Tan YL, Haile CN et al. BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology 2008; 33: 2200–2205.

    Article  CAS  Google Scholar 

  42. Zhang XY, Tan YL, Zhou DF, Cao LY, Wu GY, Xu Q et al. Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics. J Psychiatric Res 2007; 41: 997–1004.

    Article  Google Scholar 

  43. Guimaraes LR, Jacka FN, Gama CS, Berk M, Leitao-Azevedo CL, Belmonte de Abreu MG et al. Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1595–1598.

    Article  CAS  Google Scholar 

  44. Hedges S, El-Mallakh RS, Carvey PM, Suddath RL, Wyatt RL . Dopamine-responsive neurotrophic factor in schizophrenia. Schizophrenia Res 1995; 18: 83–84.

    Article  CAS  Google Scholar 

  45. Hori H, Yoshimura R, Yamada Y, Ikenouchi A, Mitoma M, Ida Y et al. Effects of olanzapine on plasma levels of catecholamine metabolites, cytokines, and brain-derived neurotrophic factor in schizophrenic patients. Inter Clin Psychopharmacol 2007; 22: 21–27.

    Article  Google Scholar 

  46. Huang TL, Hung YY . Lorazepam reduces the serum brain-derived neurotrophic factor level in schizophrenia patients with catatonia. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 158–159.

    Article  CAS  Google Scholar 

  47. Lee JG, Shin BS, Lee YC, Park SW, Kim YH . Clinical effectiveness of the Kampo medicine kamishoyosan for adjunctive treatment of tardive dyskinesia in patients with schizophrenia: a 16-week open trial. Psychiatry Clin Neurosci 2007; 61: 509–514.

    Article  Google Scholar 

  48. Gama CS, Berk M, Andreazza AC, Kapczinski F, Belmonte-de-Abreu P . Serum levels of brain-derived neurotrophic factor and thiobarbituric acid reactive substances in chronically medicated schizophrenic patients: a positive correlation. Revista Brasileira de Psiquiatria 2008; 34: 337–340.

    Article  Google Scholar 

  49. Cannon TD, Yolken R, Buka S, Torrey EF . Decreased neurotrophic response to birth hypoxia in the etiology of schizophrenia. Biol Psychiatry 2008; 64: 797–802.

    Article  CAS  Google Scholar 

  50. Palomino A, Vallejo-Illarramendi A, Gonzalez-Pinto A, Aldama A, Gonzalez-Gomez C, Mosquera F et al. Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients. Schizophrenia Res 2006; 86: 321–322.

    Article  Google Scholar 

  51. Huang TL, Lee CT . Associations between serum brain-derived neurotrophic factor levels and clinical phenotypes in schizophrenia patients. J Psychiatric Res 2006; 40: 664–668.

    Article  Google Scholar 

  52. Rizos EN, Rontos I, Laskos E, Arsenis G, Michalopoulou PG, Vasilopoulos D et al. Investigation of serum BDNF levels in drug-naive patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1308–1311.

    Article  CAS  Google Scholar 

  53. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR . Introduction to Meta-Analysis. John Wiley & Sons, Ltd.: West Sussex, UK, 2009.

    Book  Google Scholar 

  54. Chlan-Fourney J, Ashe P, Nylen K, Juorio AV, Li XM . Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 2002; 954: 11–20.

    Article  CAS  Google Scholar 

  55. 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 Neuropsychopharmcol 2008; 11: 1169–1180.

    Article  CAS  Google Scholar 

  56. Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW . Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 2000; 101: 305–312.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  58. Ozan E, Okur H, Eker C, Eker OD, Gonul 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  Google Scholar 

  59. Tseng M, Alda M, Xu L, Sun X, Wang J-F, Grof P et al. BDNF protein levels are decreased in transformed lymphoblasts from lithium-responsive patients with bipolar disorder. J Psychiatry Neurosci 2008; 33: 449–453.

    PubMed  PubMed Central  Google Scholar 

  60. Zuccato C, Cattaneo E . Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 2009; 5: 311–322.

    Article  CAS  Google Scholar 

  61. Peng S, Wuu J, Mufson EJ, Fahnestock M . Precursor form of brainderived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem 2005; 93: 1412–1421.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  63. Kendler KS, Neale MC . Endophenotype: a conceptual analysis. Mol Psychiatry 2010; 15: 789–797.

    Article  Google Scholar 

Download references

Acknowledgements

This project was supported by research funding from the Australian National Health and Medical Research Council (NHMRC: Project Grant 630471), the Australian Research Council (Future Fellowship: FT0991511) and the Schizophrenia Research Institute, using an infrastructure grant from the NSW Department of Health. We acknowledge Amy Sparks for assistance with production of the paper, and the following authors for the provision of raw data for inclusion in the meta-analysis: Peter Buckley, Clarissa Gama, Alex Genevsky, Ana Maria González-Pinto, TL, Huang, Yumiko Ikeda, Flávio Kapczinski, Yong-Ku Kim, Diogo Rizzato Lara, Carlos Matute, E Rizos, Eiji Shimizu, Amaia Ugarte Ugarte, Sophia Vinogradov, Reiji Yoshimura and Xiang Yang Zhang.

Author information

Authors and Affiliations

  1. School of Psychiatry, University of New South Wales, Randwick, NSW, Australia

    M J Green, S L Matheson, A Shepherd, C S Weickert & V J Carr

  2. Schizophrenia Research Institute, Darlinghurst, NSW, Australia

    M J Green, S L Matheson, A Shepherd, C S Weickert & V J Carr

  3. UNSW Research Unit for Schizophrenia Epidemiology, O'Brien Centre at St Vincent's Hospital, Darlinghurst, NSW, Australia

    M J Green & V J Carr

  4. Neuroscience Research Australia, Randwick, NSW, Australia

    C S Weickert

Authors
  1. M J Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S L Matheson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Shepherd
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C S Weickert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V J Carr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M J Green.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Green, M., Matheson, S., Shepherd, A. et al. Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 16, 960–972 (2011). https://doi.org/10.1038/mp.2010.88

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2010.88

Keywords

This article is cited by

Search

Advanced search

Quick links