How antidepressants work: new perspectives on the pathophysiology of depressive disorder

Background: New research in animals is beginning to change radically our
understanding of the biology of stress and the effects of
antidepressant agents. Aims: To relate recent findings from the basic
neurosciences to the pathophysiology of depressive disorder. Method:
Drawing together findings from molecular and physiological studies in
rats, social studies in primates and neuropsychological studies in
humans, we review the neurotrophic and neuroplastic effects of
antidepressants and stress. Results: Stress and antidepressants have
reciprocal actions on neuronal growth and vulnerability (mediated by the
expression of neurotrophins) and synaptic plasticity (mediated by
excitatory amino acid neurotransmission) in the hippocampus and other
brain structures. Stressors have the capacity to progressively disrupt
both the activities of individual cells and the operating
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
connectivity in the pathophysiology of depressive disorder.