Neurotrophic Mechanisms of Depression
Early theories of depression and treatment response were centered on the monoamine neurotransmitters, but more recent work has focused on functional and structural synaptic plasticity and the role of neurotrophic factors, particularly brain derived neurotrophic factor (BDNF). Neurotrophic factors regulate all aspects of neuronal function, including adaptive plasticity, synapse formation, and neuronal survival. Chronic stress and depression cause reductions in levels of BDNF and other key factors, including vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2), in cortical regions that contribute to atrophy and loss of neurons observed in depressed patients and rodent stress models. In contrast, these neurotrophic factors are upregulated by chronic administration of typical antidepressants and are required for antidepressant responses. Moreover, fast acting, highly efficacious antidepressant agents such as ketamine rapidly increase BDNF release and synapse formation, paving the way for a new generation of medications for the treatment of depression.