NEUROBIOLOGY OF STRESS, DEPRESSION, AND RAPID ACTING ANTIDEPRESSANTS: REMODELING SYNAPTIC CONNECTIONS

Stress and depression cause atrophy and loss of neurons in brain regions involved in emotion and cognition, which may contribute to depressive symptoms. Standard antidepressants, which target monoamine neurotransmitters, have limited effectiveness and require long-term use, and they only weakly counteract these stress-induced structural changes. Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects in difficult-to-treat patients. Preclinical studies show ketamine rapidly increases synaptic connections in the prefrontal cortex by boosting glutamate signaling and activating pathways that control synaptic protein synthesis, and it reverses synaptic deficits caused by chronic stress in rodents. These findings reveal new targets for rapid-acting antidepressants with fewer side effects and improve understanding of stress, depression, and treatment response.

Study at a glance

Abstract

Stress and depression are associated with atrophy and loss of neurons in limbic and cortical brain regions that could contribute to the symptoms of depression. Typical monoamine reuptake inhibitor antidepressants have only modest efficacy and require long-term treatment, and are only weakly effective in blocking or reversing these structural changes caused by stress. Recent findings demonstrate that ketamine, an NMDA receptor antagonist, produces rapid antidepressant actions in difficult to treat depressed patients. In addition, preclinical studies demonstrate that ketamine rapidly increases synaptic connections in the prefrontal cortex by increasing glutamate signaling and activation of pathways that control the synthesis of synaptic proteins. Moreover, ketamine rapidly reverses the synaptic deficits caused by exposure to chronic stress in rodent models. Studies of the signaling mechanisms underlying the actions of ketamine have provided novel approaches and targets for new rapid acting antidepressants with decreased side effects, as well as a better understanding of the neurobiology of stress, depression, and treatment response.