Is it time to reassess the BDNF hypothesis of depression?

Abstract

The brain-derived neurotrophic factor (BDNF) hypothesis of depression postulates that a loss of BDNF is directly involved in the pathophysiology of depression, and that its restoration may underlie the therapeutic efficacy of antidepressant treatment. While this theory has received considerable experimental support, an increasing number of studies have generated evidence which is not only inconsistent, but also directly contradicts the hypothesis. This article provides a critical review of the clinical and preclinical studies which have been responsible for this controversy, outlining pharmacological, behavioural and genetic evidence which demonstrates the contrasting role of BDNF in regulating mood and antidepressant effects throughout the brain. I will also review key studies, both human and animal, which have investigated the association of a BDNF single-nucleotide polymorphism (Val66Met) with depression pathogenesis, and detail the number of inconsistencies which also afflict this novel area of BDNF research. The article will conclude by discussing why now is a critical time to reassess the original BDNF hypothesis of depression, and look towards the formation of new models that can provide a more valid account of the complex relationships between growth factors, mood disorders and their treatment.

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

“…We had previously demonstrated that chronic treatment with the SNRI antidepressant duloxetine is able to normalize Bdnf deficits in these animals, also through the modulation of Bdnf exon I and IV (Calabrese et al, 2010, present results). Such data are in agreement with the possibility that repeated, but not acute, treatment with major classes of antidepressants may improve neuronal plasticity through the modulation of Bdnf expression (Calabrese et al, 2007;Castren et al, 2007;Molteni et al, 2009a;Russo-Neustadt and Chen, 2005), and that this effect may contribute to their therapeutic action (Berton and Nestler, 2006;Calabrese et al, 2009;Calabrese et al, 2011;Groves, 2007;Martinowich et al, 2007).…”

Editorial

“…It was proposed that stress-associated increases in cortisol can lead to impaired neurogenesis in the hippocampus, which might then (via uncertain mechanisms) result in depressive symptoms. The data in support of this theory, including findings of low serum BDNF levels in untreated depressed patients (Karege et al 2002), are intriguing but have recently been challenged (Groves 2007).…”

“…BDNF plays an important role in facilitating neuronal outgrowth of stem cells in the subventricular zone and the subgranular region of the hippocampus. It may additionally provide a measure of neuroprotection to existing neurons (Groves 2007). Duman and colleagues also observed that antidepressant treatment (regardless of proximal mechanism of action) in animals prevented or reversed these changes in BDNF levels and increased hippocampal neurogenesis.…”

The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model

“…One possibility is that environmental stimuli during adolescence might foster depressive symptoms in youth through the ventral tegmental area to nucleus accumbens (VTA-NAc) pathway, whereas environmental influence on adult depression might be mediated through the hippocampus. Recall that research suggests that BDNF has opposite effects in the two brain regions across these developmental epochs (Feder et al 2009;Krishnan and Nestler 2008).That is, more BDNF in the hippocampus reduces depression (Duman and Monteggia 2006), whereas in the nucleus accumbens (NAc) it facilitate depression (Groves 2007;Martinowich et al 2007). Another candidate mechanism involves stress-reactivity, as there is also evidence that younger adults carrying Met-BDNF, relative to their Val-Val counterparts, evince blunted hypothalamicpituitary-adrenal (HPA) axis responses to psychological stressors (Alexander et al 2010;Shalev et al 2009).…”

“…Rodent studies indicate that maternal behavior including postnatal maternal separation (negative) and higher quality maternal care (positive) can influence offspring's BDNF expression in brain (Bath et al 2013;Cutuli et al 2015;Mashoodh et al 2012). Noteworthy, too, is accumulating evidence of the diverse role of BDNF on depression in different brain regions (Yu and Chen 2011), such that in the hippocampus BNDF inhibits depression (Duman and Monteggia 2006) whereas in the nucleus accumbens (NAc) it facilitates depression (Groves 2007;Martinowich et al 2007). Collectively, these results provide the basis for the hypothesis that BDNF Val66Met and maternal parenting interactively influence abnormal BDNF levels in the brain and thus contribute to depressive symptoms.…”