How antidepressants work - New perspectives on the pathophysiology of depressive disorder

Background New research in animals is beginning to change radically our und erstanding of the biology of stress and the effects of antidepressant agent s. Aims To relate recent findings from the basic neurosciences to the pathophy siology of depressive disorder. Method Drawing together findings from molecular and physiological studies i n rats, social studies in primates and neuropsychological studies in humans , we review the neurotrophic and neuroplastic effects of antidepressants an d stress. Results Stress and antidepressants have reciprocal actions on neuronal grow th and vulnerability (mediated by the expression of neurotrophins) and syna ptic plasticity (mediated by excitatory amino acid neurotransmission) in th e hippocampus and other brain structures. Stressors have the capacity to pr ogressively disrupt both the activities of individual cells and the operati ng characteristics of networks of neurons throughout the life cycle, while antidepressant treatments act to reverse such injurious effects. Conclusions We propose a central role for the regulation of synaptic connec tivity in the pathophysiology of depressive disorder. Declaration of interest Our laboratory has received research funding from O rganon Laboratories and Wyeth UK.