The Neurotrophic Hypothesis of Depression Revisited: New Insights and Therapeutic Implications

Abstract The molecular and cellular mechanisms underlying the pathogenesis of depression remain unclear. Over the past two decades, studies have highlighted a potential role for neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF), in contributing to the pathophysiology and treatment of depression. Studies indicate opposing effects of stress and antidepressant treatment on BDNF expression in cortical and subcortical brain regions. Stress-evoked reduction of BDNF is implicated in dendritic atrophy, decline in hippocampal neurogenesis, and enhanced depressive-like behavior in animal models. In contrast, antidepressant-induction of BDNF expression is implicated in reversing neuronal atrophy, neurogenic decline, and enhanced despair in animal models of depression. In this chapter, we revisit the neurotrophic hypothesis of depression, examining evidence for, as well as against, the notion that reduced trophic support in key limbic brain regions contributes to the pathogenesis of depression, whereas enhanced trophic factor signaling participates in the therapeutic actions of antidepressants.