Elsevier

Journal of Affective Disorders

Volume 183, 1 September 2015, Pages 287-294
Journal of Affective Disorders

Research report
Neurotrophic factors in depression in response to treatment

https://doi.org/10.1016/j.jad.2015.05.027Get rights and content

Highlights

  • Baseline serum levels did not predict the improvement in depression scores after treatment.

  • No baseline or longitudinal correlation between depression scores and serum levels was observed.

  • No significant association between treatment response and serum levels of BDNF or VEGF was found.

  • We found a significant decrease of serum BDNF and VEGF levels during antidepressant treatment.

  • A positive correlation between serum BDNF and VEGF levels was observed.

Abstract

Background

Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGF) have been suggested to play a role in the pathophysiology of depression. The neurotrophic model of depression hypothesises that the serum level of e.g. BDNF is decreased during depression and increased in response to treatment. The aim of the present study was to investigate BDNF and VEGF as potential predictors of response to antidepressant treatment.

Methods

We investigated the longitudinal associations between depression scores and serum levels of these neurotrophic factors during antidepressant treatment in 90 individuals with depression of at least moderate severity. Serum levels were measured at baseline and after 8 and 12 weeks of treatment with nortriptyline or escitalopram.

Results

No baseline or longitudinal correlations between depression scores and serum levels of BDNF and VEGF were found, and the baseline serum levels did not predict the MADRS depression score after 12 weeks of treatment or the improvement in depression scores. Interestingly, we observed a significant baseline and longitudinal correlation between serum levels of BDNF and VEGF. The two classes of antidepressant treatment did not affect the results differently.

Limitations

Information on potential factors influencing the serum levels is missing.

Conclusion

Our results do not support the neurotrophic model of depression, since a significant decrease in serum BDNF and VEGF levels after 12 weeks of antidepressant treatment was observed. Our study encourages future studies with large sample sizes, more observations and a longer follow-up period.

Introduction

Depression may involve neurodegeneration and aberrant neuronal network function (Duman, 2002, Kubera et al., 2011). As neurotrophic factors are critical regulators of the formation and plasticity of neuronal networks, these factors are recognised as important for a deeper understanding of depression. The neurotrophic hypothesis suggests that mood disorders are associated with a dysfunction of neuronal networks under the influence of neurotrophic factors. A neurotrophic model of depression implicates a stress-induced decline in neurotrophins and in the atrophy in limbic structures which ultimately results in mood disorders that may be reversed or blocked by antidepressants (Duman and Monteggia, 2006).

One of the most extensively investigated targets with respect to neuroplasticity is brain-derived neurotrophic factor (BDNF). BDNF is an important member of the neurotrophin family, abundant in the brain and the periphery and has been suggested to play a pathophysiological role in depression. The first paper to report differences in serum BDNF levels between depressed individuals and healthy controls was published more than 12 years ago (Karege et al., 2002). Since then, a large number of papers have been published as reviewed in a recent meta-analysis (Molendijk et al., 2014). Most papers have shown decreased serum levels in un-medicated depressed individuals compared to healthy controls (Molendijk et al., 2014). Serum BDNF levels of un-medicated depressed patients have been reported to increase to the levels of healthy controls after antidepressant treatment (Shimizu et al., 2003, Aydemir et al., 2005). No significant differences in BDNF concentrations among antidepressant treated depressed individuals and healthy controls were observed in the above-mentioned meta-analysis (Molendijk et al., 2014). A functional single nucleotide polymorphism (SNP) within BDNF (rs6265/Val66Met) has been investigated in numerous genetic studies of depression. Some studies have likewise investigated the association between rs6265 and serum BDNF levels in addition to the association between rs6265 and depression scores (Duncan et al., 2009, Lang et al., 2009, Verhagen et al., 2010, Yoshimura et al., 2011, Elfving et al., 2012). In general, the findings from these studies are varied and await further research.

Vascular endothelial growth factor A (VEGF) was originally described as an angiogenic mitogen in 1989 (Leung et al., 1989). More recently, pleiotrophic effects of VEGF in the central nervous system (CNS) have been shown as reviewed by Nowacka and Obuchowicz (2012). VEGF exhibits neurotrophic and neuroprotective effects in the CNS and in the peripheral nervous system, and has also been shown to stimulate neurogenesis (Jin et al., 2002). The relationship between VEGF and depression is therefore of interest.

The first clinical study of VEGF in depressed individuals was published in 2007 and showed a significant increase of mRNA VEGF levels in depressed individuals compared to control individuals (Iga et al., 2007). Since then, more than 12 studies have been published, most of which are included in a recent review by Clark-Raymond and Halaris (2013). The studies have been conflicting as some found a higher VEGF level in depressed subjects versus controls (Kahl et al., 2009, Lee and Kim, 2012, Elfving et al., 2014) and some found no significant differences (Dome et al., 2009, Ventriglia et al., 2009, Kotan et al., 2012). Clinical evidence on the effect of antidepressants on VEGF levels is insufficient and inconclusive. However, most published studies found no significant differences in VEGF mRNA, plasma or serum levels in response to treatment (Iga et al., 2007, Ventriglia et al., 2009, Halmai et al., 2013, Fornaro et al., 2013).

Recently the presence of a mutual interaction between VEGF and BDNF at an intracellular level has been suggested (Fournier and Duman, 2012). The localisation of receptors for BDNF and VEGF on neuroblasts has raised the possibility that these neurotrophic factors could work both independently and/or cooperatively to influence specific stages of neurogenesis (Fournier and Duman, 2012).

Most previous studies investigating the longitudinal changes in BDNF and VEGF levels have focused on response to treatment and included less than 40 individuals. We measured depression scores in addition to serum levels of BDNF and VEGF at baseline and after 8 and 12 weeks of antidepressant treatment in 90 depressive individuals from the Danish contribution to the Genome-Based Therapeutic Drugs for Depression (GENDEP) project.

Section snippets

Study sample

The GENDEP trial was a 12-week open label part-randomised study of depression with two active pharmacological treatment arms. The study was conducted in nine European academic psychiatry centres from July 2004 to June 2008. It was designed to establish clinical and genetic determinants of therapeutic response to two antidepressants. Subjects were allocated to either escitalopram, a selective inhibitor of the serotonin transporter, or nortriptyline, a tricyclic antidepressant inhibiting the

Sample characteristics

The 90 Danish individuals included in the present study consist of 26 males and 64 females with an average age of 37.6 years (SD=10.8). Forty-nine individuals were allocated to nortriptyline at baseline and 41 to escitalopram. Fifty individuals (56%) were drug naïve at study entry. Most individuals were at their first or second depressive episode. The median (lower–upper quartiles) for serum BDNF levels were 21,723 (15,847–26,384) pg/ml at baseline, 15,822 (9929–20,266) pg/ml at T1, and 15,722

Discussion

In summary, we observed a significant decrease in serum BDNF and VEGF levels after 12 weeks of antidepressant treatment, and we also observed a significant correlation between BDNF and VEGF at baseline and at later time points. However, no correlations between depression scores and serum levels of BDNF and VEGF were observed and the baseline serum levels did not predict the MADRS depression score after 12 weeks of treatment.

Conclusion

In conclusion, serum levels of BDNF or VEGF are not predictors of depression severity, and our results does not support the neurotrophic model of depression. Nevertheless, the results suggest a role of circulating serum BDNF and VEGF in depression and a possible interaction between these neurotrophic factors. Future studies with large sample sizes and a longer follow-up period and more observations are however warranted.

Role of funding source

The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract ref.: LSHB-CT-2003-503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

We would like to thank Helle Buch, Anne Stamp, Lisbeth Jorgensen and Erik Larsen for their contributions.

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