Decreased Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF), but Not Its Precursor proBDNF, in Patients with Major Depressive Disorder

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Abstract

Background

Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD.

Methodology/Principal Findings

Sixty-nine patients with MDD and 78 age- and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients.

Conclusions/Significance

These findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.

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Most cited references 16

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A molecular and cellular theory of depression.

R S Duman, G Heninger, E J Nestler (1997)

Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.

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Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

Eiji Shimizu, Kenji Hashimoto, Naoe Okamura … (2003)

Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD). We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method. We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p =.002). There was a significant negative correlation (r = -.350, z = -2.003, p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment. Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients.

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Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment

M. L. Molendijk, B A A Bus, Ph. Spinhoven … (2010)

Recent evidence supports ‘the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally. We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (⩾6 months) and 382 healthy controls. We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St John's wort (P=0.03). Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 3 August 2012

Volume: 7

Issue: 8

Electronic Location Identifier: e42676

Affiliations

[1 ]Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan

[2 ]Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan

[3 ]Research Center for Child Mental Development, Chiba University Graduate School of Medicine, Chiba, Japan

Rikagaku Kenkyūsho Brain Science Institute, Japan

Author notes

* E-mail: hashimoto@ 123456faculty.chiba-u.jp

Competing Interests: Kenji Hashimoto is a member of Editorial Board of PLoS ONE. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. The other authors have declared that no competing interests exist.

Performed the experiments: TY KH. Analyzed the data: TY KH. Contributed reagents/materials/analysis tools: TY MI TN MN HW TS AS TH NK TH ME AK MI. Wrote the paper: TY KH.

Article

Publisher ID: PONE-D-12-16776

DOI: 10.1371/journal.pone.0042676

PMC ID: 3411809

PubMed ID: 22880079

SO-VID: cb8ae2dd-cae2-49cb-b2af-186c87055b9b

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 12 June 2012

Date accepted : 10 July 2012

Page count

Pages: 6

Funding

This study was supported by a grant (to KH) from Comprehensive Research on Disability, Health and Welfare, Health and Labor Sciences Research Grants, Japan, and a grant (to TY) from Japan Foundation for Neuroscience and Mental Health, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Decreased Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF), but Not Its Precursor proBDNF, in Patients with Major Depressive Disorder

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Methodology/Principal Findings

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Most cited references 16

A molecular and cellular theory of depression.

Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment

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