Elsevier

Journal of Affective Disorders

Volume 174, 15 March 2015, Pages 432-440
Journal of Affective Disorders

Review
BDNF as a biomarker for successful treatment of mood disorders: A systematic & quantitative meta-analysis

https://doi.org/10.1016/j.jad.2014.11.044Get rights and content

Abstract

Background

Peripheral brain-derived neurotrophic factor (BDNF) is decreased in acute major depressive disorder (MDD) and bipolar disorder (BD) and recovered after treatment. Here we validated on a meta-analytical level whether BDNF restores differentially according to treatment response and whose measurements could be used as a biomarker, plasma or serum.

Methods

Using strict inclusion criteria, we compared BDNF in healthy controls and patients with MDD (38 studies, n=6619), and BD (17 studies, n=1447). Pre- and post-treatment BDNF levels were meta-analyzed according to treatment response in patients from 21 MDD studies (n=735) and 7 BD studies (n=88). Serum and plasma subgroups were analyzed, publication bias was assessed and heterogeneity was investigated.

Results

Serum and plasma BDNF were decreased in acute MDD and BD, and did not differ in euthymia in comparison with control subjects. Antidepressive treatment increased serum BDNF levels in MDD in responders (Cohen׳s d (d)=1.27, p=4.4E-07) and remitters (d=0.89, p=0.01), significantly more than in non-responders (d=0.11, p=0.69). For plasma BDNF in MDD and for BD, the evidence was insufficient for a meta-analysis. Although no significant difference was found between serum and plasma ES, variance of plasma ES was higher.

Limitations

Between-study heterogeneity was explained only partially; signs of publication bias in serum studies.

Conclusion

Serum BDNF might be regarded as a biomarker for the successful treatment of MDD. Serum measurements seem more reliable than plasma ones. Further research should focus on defining optimal time points for BDNF measurements and increase evidence for the usage of BDNF as a predictive biomarker in BD.

Introduction

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family. For over 30 years, research on BDNF has been fruitful in many fields, from basic to clinical. Through dendritic arborization and synaptic consolidation, BDNF mediates neuronal plasticity, migration, and survival in both the central and peripheral nervous system (Bramham and Messaoudi, 2005, Greenberg et al., 2009). It is secreted by neurons and peripheral cells such as leukocytes (Edling et al., 2004), endothelial cells (Nakahashi et al., 2000), and platelets (Yamamoto and Gurney, 1990), and passes the blood–brain barrier (Pan et al., 1998).

BDNF is involved in a wide range of neuropsychiatric and neurodegenerative diseases (Autry and Monteggia, 2012). A number of individual studies and later meta-analyses have demonstrated decreased BDNF levels in mood disorders (Bocchio-Chiavetto et al., 2010, Brunoni et al., 2008, Fernandes et al., 2014, Fernandes et al., 2011, Lin, 2009, Molendijk et al., 2012, Sen et al., 2008). The neurotrophin theory of mood disorders arose in 2006 (Duman and Monteggia, 2006); but the initial excitement has recently changed into a more balanced discussion (Groves, 2007, Molendijk et al., 2013). Major depressive disorder (MDD) and bipolar disorder (BD) are prevalent and disabling mood disorders (retrieved from 30.01.2014 from http://www.nimh.nih.gov/,, World Health Organization, 2008). Despite progress in pharmacotherapy, roughly half of MDD patients do not respond to the first antidepressant treatment (Dierckx et al., 2012, Undurraga and Baldessarini, 2012). Response rates for the second and third antidepressant remain even lower in patients who do not respond to the first prescription (Murrough and Charney, 2012). In non-responders, a clinical decision to switch medication is usually made during the second to fourth week of treatment (Bauer et al., 2007, Suehs B et al., 2008). Waiting several weeks until the treatment response or medication switch is burdensome for patients and leads to therapy dropout (Nakajima et al., 2010). In order to reduce this time window, BDNF was suggested as an early marker for treatment response (Tadic et al., 2011).

Today, it is well established that BDNF is decreased in mood disorders. Discussions remain only about the degree of reduction (Bocchio-Chiavetto et al., 2010, Brunoni et al., 2008, Molendijk et al., 2013). On a meta-analytical level it was also shown that BDNF increases with clinical improvement (Brunoni et al., 2008); but the treatment response was not taken into account. However, individual studies have shown differential BDNF restoration in responders and non-responders (Deuschle et al., 2013, Yoshimura et al., 2010a).

Although the relevance of BDNF for mood disorders is obvious, the source of measured BDNF is diverse. BDNF levels can be measured in whole blood, plasma, serum, or blood cells. Plasma and serum BDNF levels show at least a 100-fold difference (Radka et al., 1996, Rosenfeld et al., 1995) and may result from different processes. Plasma levels might be responsible for the immediate delivery of BDNF to the nervous system, while serum levels reflect the platelet pool of this protein, which can be released upon activation (Tamura et al., 2012). Changes in serum BDNF levels were addressed in a recent meta-analysis by Molendijk et al. (2014), while combined serum and plasma levels in their meta-analysis. Both reported decreased BDNF in acute mood episodes.

In the current meta-analysis, we aimed to elucidate three questions: i) Is there any difference between changes in plasma BDNF and in serum BDNF levels in mood disorders? (ii) Are there state-dependent differences in plasma and serum BDNF levels as suggested by other serum plasticity markers (Schroeter et al., 2008; Schroeter and Steiner, 2009)? iii) Does BDNF restore differentially depending on the treatment response? If so, this would help to establish BDNF as a predictive biomarker for successful antidepressive treatment.

We hypothesized that both plasma and serum BDNF levels are decreased compared with healthy control subjects in acute mood episodes and are not different from control subjects during the euthymic state of MDD and BD. In longitudinal studies we hypothesized that both serum and plasma levels increase only in responders to treatment of MDD and BD.

Section snippets

Literature search and inclusion criteria

Two independent reviewers (MP, KST) conducted a literature search through the electronic databases PubMed, ISI Web of Science, and PsycINFO. Keywords ‘BDNF’ or ‘brain-derived neurotrophic factor’ were combined with either ‘depression’, ‘major depression’, or ‘bipolar’, ‘mania’, ‘euthymia’, and ‘remission’ (last search-27.08.2013). We screened titles, abstracts, and full texts, when appropriate, according to predefined inclusion criteria: (i) original peer-reviewed article, (ii) adult patients

Results of the systematic literature search

The PRISMA flow diagram summarizes the identification of the relevant studies (Fig. 1). Our inclusion criteria were satisfied by 48 studies with MDD patients and 19 studies involving BD patients (Supplementary Tables 3–6). In sum, the studies taken into account by the meta-analyses included a large group of 3365 and 758 patients with MDD and BD, respectively.

Thirty-eight studies were included in our cross-sectional MDD meta-analysis and 19 in our cross-sectional BD meta-analysis (Supplementary

Discussion

In the current meta-analysis we confirmed the previous findings of reduced BDNF levels in acute, but not in euthymic, mood episodes (Bocchio-Chiavetto et al., 2010, Brunoni et al., 2008, Fernandes et al., 2014, Fernandes et al., 2011, Lin, 2009, Molendijk et al., 2012, Sen et al., 2008). This was true for both MDD and BD, with no significant differences among their ES. Serum and plasma ES were not different in the cross-sectional studies, but the CI for plasma studies was always wider, and thus

Conflict of interest

The authors declare no conflict of interest.

Role of funding source

This study has been supported by the International Max Planck Research School on Neuroscience of Communication (IMPRS NeuroCom; MP), by LIFE—Leipzig Research Center for Civilization Diseases at the University of Leipzig - funded by the European Union, European Regional Development Fund and by the Free State of Saxony within the framework of the excellence initiative (PS & MLS), by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and

Acknowledgments

We would like to thank all the authors who replied to our enquiries regarding additional data, the library of Max Planck institute for their assistance in the literature retrieval, and Elizabeth Kelly for proofreading the manuscript.

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