Elsevier

Biological Psychiatry

Volume 59, Issue 12, 15 June 2006, Pages 1116-1127
Biological Psychiatry

Review
A Neurotrophic Model for Stress-Related Mood Disorders

https://doi.org/10.1016/j.biopsych.2006.02.013Get rights and content

There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neruotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.

Section snippets

Opposing Actions of Stress and Antidepressant Treatment on BDNF

The time delay for the therapeutic action of antidepressant treatment suggests that adaptations of receptor-coupled signal transduction proteins and their corresponding genes could contribute to the actions of antidepressants. In contrast, alterations in the expression of signaling proteins could also contribute to the effects of stress-related mood disorders. A role for BDNF in the effects of stress and the response to antidepressant treatment is supported by studies demonstrating opposing

BDNF Polymorphisms in Mood Disorders

Based on basic and clinical work on BDNF, recent studies have been undertaken to identify and evaluate BDNF polymorphisms in mood disorders. A functional variant of BDNF at codon 66 (val66met) has been identified with the met allele that results in abnormal intracellular packaging and secretion of BDNF (Egan et al 2003). Carriers of the met allele are reported to have poorer episodic memory and reduced hippocampal N-acetyl aspartate (Egan et al 2003). Studies of the val66met alleles in

Influence of BDNF in Cellular Models of Depression

The regulation of BDNF and other neurotrophic factors by stress and antidepressant treatment could result in alterations at the cellular and behavioral levels. At a cellular level, one of the most interesting areas of research is neurogenesis in the adult hippocampus and the opposing actions of stress and antidepressant treatment. The potential use of neurogenesis as a cellular model for studies of depression and antidepressant response is covered in more detail in another review in this issue.

Influence of BDNF in Behavioral Models of Depression

Studies of adult neurogenesis are useful for identifying cellular actions of antidepressants, but ultimately, it is essential that the behavioral actions of neurotrophic factors are also determined. In this context, the role of BDNF in several established models of depression has been determined. In addition to providing a review of these behavioral data, this section will provide a brief review of the current models of depression/antidepressant response, including the strengths and weaknesses

Limitations of the Neurotrophic Hypothesis

Although there is strong evidence from basic and clinical studies to support a neurotrophic hypothesis of depression, there are also several limitations. Some of the limitations or inconsistencies have been discussed. These include: 1) not all studies report an upregulation of BDNF by antidepressant treatments (Table 1); and 2) not all studies of mutant mice demonstrate a role for BDNF in models of depression. Some of these concerns can be explained by the experimental paradigm used (e.g., dose

Summary

The results of this review support the hypothesis that a reduction of BDNF could contribute to depression and that antidepressants mediate their therapeutic benefit, in part, by increasing levels of this factor in the hippocampus. In addition, the regulation of other neurotrophic/growth factors, including VEGF, IGF-I, and FGF2, may also play a role in the pathophysiology and/or treatment of depression. Two common actions of these different classes of factors are the activation of tyrosine

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