Neuron
March 1, 2019
J. Krystal, C. Abdallah, G. Sanacora et al.
443 citations
Ketamine represents a new class of rapid-acting antidepressants effective for treatment-resistant mood disorders. Its development grew from a revised understanding of depression's biology. Research into how ketamine works is providing fresh insights into antidepressant mechanisms and challenging established views on the neurobiology of depression. The drug's fast, strong, and lasting effects on depressive symptoms appear ready to change how depression is treated.
Journal of Clinical Investigation
November 19, 2019
Danielle M. Gerhard, Santosh Pothula, Rong‐jian Liu et al.
345 citations
A single low dose of ketamine produces rapid and lasting antidepressant effects by blocking NMDA receptors containing the GluN2B subunit on specific GABA-releasing interneurons in the medial prefrontal cortex. Removing GluN2B from somatostatin-expressing interneurons prevented or masked ketamine's antidepressant actions and revealed sex-specific differences in excitatory signals onto principal neurons. The findings indicate that GluN2B-NMDA receptors on GABA interneurons are the initial cellular trigger for ketamine's rapid antidepressant effects.
Nature Communications
June 3, 2019
Farhan Ali, Danielle M. Gerhard, Katherine Sweasy et al.
201 citations
A subanesthetic dose of ketamine suppresses somatostatin-expressing (SST) interneurons in the medial prefrontal cortex of awake mice, leading to deficient dendritic inhibition. This causes greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, the authors show that this dendritic inhibitory mechanism affects frontal cortex-dependent behaviors and cortico-cortical connectivity. The results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as key local-circuit alterations driven by subanesthetic ketamine.
Neuropsychopharmacology
February 24, 2020
C. Abdallah, L. Averill, R. Gueorguieva et al.
181 citations
Ketamine produces rapid antidepressant effects within 24 hours, thought to involve mTORC1 activation. In a double-blind crossover trial, 20 depressed patients received either rapamycin (an mTORC1 inhibitor) or placebo before ketamine. Rapamycin did not block ketamine's 24-hour antidepressant effects. Over two weeks, rapamycin prolonged ketamine's benefits: response rates were 41% with rapamycin versus 13% with placebo, and remission rates were 29% versus 7%. These findings question whether systemic or local mTORC1 blockade matters and suggest rapamycin may extend ketamine's effects, potentially informing mechanisms of depression relapse.
Pharmacology, Biochemistry and Behavior
December 9, 2019
Satoshi Deyama, R. Duman
181 citations
Depression is linked to reduced levels of neurotrophic factors like BDNF and VEGF, which contribute to neuronal atrophy in brain regions such as the prefrontal cortex and hippocampus, and to decreased adult neurogenesis. Conventional antidepressants partially reverse these deficits by inducing BDNF or VEGF but have limitations, including a delayed therapeutic response and low efficacy. Ketamine, an NMDA receptor antagonist, produces rapid (within hours) and sustained (up to a week) antidepressant effects in treatment-resistant depression and rodent models. In rodents, ketamine quickly increases BDNF and VEGF release in the medial prefrontal cortex and hippocampus, boosting spine synapses and hippocampal neurogenesis. These neurotrophic actions appear to underlie ketamine's rapid and sustained antidepressant effects, pointing toward development of faster-acting antidepressants with fewer side effects.