ReviewPeripheral vascular endothelial growth factor as a novel depression biomarker: A meta-analysis
Introduction
The neurotrophic hypothesis, initially postulated by Duman et al. (1997), characterizes major depressive disorder (MDD) as related to aberrant neuroplastic pathways in brain areas subserving emotional and cognitive processing. According to this framework, exposure to chronic unremitting stress results in a down-regulation of brain-derived neurotrophic factor (BDNF) signaling mechanisms, which would impair neurogenesis and resilience (Taliaz et al., 2011). Furthermore, the neurotrophic hypothesis also predicts that the amelioration of depressive symptoms afforded by antidepressants is a result of a relative increase in hippocampal BDNF expression and activity (Duman and Monteggia, 2006). At least five previously published meta-analyses have shown that peripheral BDNF levels were consistently lower in MDD patients when compared to healthy controls, while antidepressant therapy and non-pharmacological treatments such as electroconvulsive therapy (ECT) increased low circulating BDNF levels (Bocchio-Chiavetto et al., 2010, Brunoni et al., 2014, Brunoni et al., 2008, Sen et al., 2008). Conversely, peripheral BDNF levels did not appear to change following treatment with non-invasive brain stimulation interventions (Brunoni et al., 2015). Nevertheless, a recent extensive meta-analysis indicated that the difference in serum BDNF levels between individuals with MDD and healthy controls is slimmer than once thought (Molendijk et al., 2014).
The initial neurotrophic hypothesis has been updated with evidence pointing to the additional involvement of vascular endothelial growth factor (VEGF) in the neurobiology of MDD (Nowacka and Obuchowicz, 2012). VEGF is a well-known cellular mitogen widely expressed in neurons, which participates in pathophysiological processes related to angiogenesis, such as cancer (Smith et al., 2014) and cardiovascular diseases (De Winter and Klomp, 2010). Moreover, during the past decade, accumulating evidence has suggested a role for VEGF in the pathophysiology of MDD as well as in the mechanism of antidepressant drug action (Fournier and Duman, 2012). For instance, experiments using the chronic unpredictable stress (CUS) and the novelty suppressed feeding (NSF) models for depression have shown that diverse antidepressant drugs as well as electroshock increase the expression of VEGF in the hippocampus of rodents (Warner-Schmidt and Duman, 2007). In addition, antagonism to VEGF type 2 receptors – VEGFR2 – abolishes antidepressant-like behavioral effects in preclinical models for depression (Greene et al., 2009, Warner-Schmidt and Duman, 2007). In individuals with MDD, two studies found no increase in VEGF levels after treatment with antidepressants (Iga et al., 2007, Ventriglia et al., 2009), while a previous report evidenced increments in circulation VEGF after ECT treatment (Minelli et al., 2011). Thus, the effects of antidepressant drug treatment and non-pharmacological intervention on peripheral levels of VEGF remain inconclusive (Clark-Raymond and Halaris, 2013). Furthermore, in the hippocampus, neurogenesis is closely related to angiogenesis (Palmer et al., 2000), and VEGF stimulates adult neurogenesis in the subgranular and subventricular zones, with important implications for the pathophysiology and treatment of MDD (Jin et al., 2002).
Notwithstanding compelling preclinical evidences implicating VEGF as a key mediator involved in MDD pathophysiology, individual clinical studies have provided mixed results, with some studies reporting higher peripheral levels of VEGF in patients with MDD compared to healthy controls (Elfving et al., 2014 Takebayashi et al., 2010), whereas other investigations had found unaltered levels (Ventriglia et al., 2009). These divergent results are likely due to heterogeneous samples, assay techniques, and treatment regiments (Clark-Raymond and Halaris, 2013). For example, Elfving and colleagues (Elfving et al., 2014) investigated a large sample of individuals with MDD (n = 155) and healthy controls (n = 280), and found higher serum VEGF levels among individuals with depression. However, these authors have also shown that body mass index (BMI) predicted higher VEGF serum levels.
In the present study we aimed to perform a meta-analysis of studies comparing peripheral VEGF levels among persons with MDD versus healthy controls. Additional aims of this study were to determine the degree of heterogeneity and to investigate the potential influence of some moderators, such as BMI and smoking, might have on circulating VEGF levels. This will help to clarify the role of VEFG in MDD.
Section snippets
Methods
The protocol for this systematic review and meta-analysis followed recommended guidelines of the Preferred Reported Items for Systematic Reviews and Meta-analyses (PRISMA) statement (Moher et al., 2009). Two of the authors (AFC and CAK) independently performed the literature search as well as decisions regarding study eligibility, data extraction, and quality assessment. Disagreements were resolved through consensus.
Search results and study characteristics
The initial search generated 434 unique references of which 50 were selected for full-text review. Finally, 14 original studies were included in the meta-analysis based on the aforementioned criteria (Berent et al., 2014, Carvalho et al., 2013, Carvalho et al., 2014, Clark-Raymond et al., 2014, Dome et al., 2009, Elfving et al., 2014, Fornaro et al., 2013, Galecki et al., 2013, Kahl et al., 2009, Kotan et al., 2012, Lee and Kim, 2012, Schweiger et al., 2008, Takebayashi et al., 2010, Ventriglia
Discussion
In the present study, we consistently observed that peripheral VEGF levels were significantly elevated in persons with MDD when compared to healthy controls. Previous reviews without employment of meta-analytic techniques failed to identify a clear direction for the alterations in peripheral VEGF levels in individuals MDD compared to healthy controls (Clark-Raymond and Halaris, 2013, Fournier and Duman, 2012). A significant degree of heterogeneity between the different studies was observed in
Conclusions
In conclusion, our meta-analysis demonstrates that VEGF levels are significantly elevated in individuals with MDD as compared to healthy controls, providing additional support to the neurotrophic hypothesis of depression. If increased levels of VEGF are causally related to MDD, or if they are a consequence of the development of the disease, remains to be determined.
Conflict of interest
Roger S. McIntyre has received research grants from Stanley Medical Research Institute, National Alliance for Research on Schizophrenia and Depression (NARSAD), National Institutes of Mental Health, Astra Zeneca, Eli Lilly, Jannsen-Ortho, Lundbeck, Pfizer, and Shire; has served on advisory boards for Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, France Foundation, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Merck, Organon, Pfizer, and Shire; has served on speakers bureaus for Astra Zeneca, Eli
Authors contribution
AFC and CAK contributed equally as first authors of this manuscript. AFC and CAK performed the search and extracted data. All authors contributed to the design of this meta-analysis and played a substantial contribution in manuscript redaction. All authors had approved the final version of this article.
Funding
None.
Acknowledgements
AFC and JQ are recipients of research fellowship awards from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil). CAK is the recipient of a postdoctoral fellowship award from CAPES (Brazil). BSF is supported by a postdoctoral scholarship and by a research grant MCTI/CNPQ/Universal 14/2014461833/2014-0, both from CNPq, Brazil. MB is supported by a NHMRC Senior Principal Research Fellowship 1059660. Laboratory of Neurosciences (Brazil) is one of the centers of the
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These authors contributed equally to this work.