Ketamine, a drug used as an anesthetic since the 1970s, has recently gained attention for its rapid antidepressant effects. In preclinical studies, it shows both neurotoxic and neuroprotective properties depending on context. At anesthetic doses during neurodevelopmental windows, it contributes to inflammation, autophagy, apoptosis, and increased reactive oxygen species. At subanesthetic doses, it activates neurotrophic signaling cascades with neuroprotective actions that are not always dependent on its primary receptor. This review summarizes the complex intracellular signaling pathways modulated by ketamine and contrasts its protective and harmful features.
Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects in adults with major depressive disorder by blocking NMDA receptors, which inhibits eukaryotic elongation factor 2 kinase, leading to increased protein synthesis and synaptic potentiation in the hippocampus. In juvenile animals, ketamine failed to produce an antidepressant response in the novelty suppressed feeding and forced swim tests and did not trigger synaptic potentiation in hippocampal slices, unlike in slices from older animals (6–9 weeks old). The NMDA receptor antagonist AP5 similarly triggered synaptic potentiation in mature hippocampus, indicating that global competitive blockade of NMDA receptors is sufficient for this effect. These findings suggest that global NMDA receptor blockade in developmentally mature hippocampal synapses is necessary for ketamine's antidepressant efficacy.
Ketamine produces fast-acting antidepressant effects in mouse models by blocking NMDAR, which deactivates eEF2 kinase, reducing eEF2 phosphorylation and de-suppressing translation of brain-derived neurotrophic factor. Inhibitors of eEF2 kinase also induce fast-acting antidepressant-like effects, suggesting regulation of protein synthesis by spontaneous neurotransmission as a therapeutic target for fast-acting antidepressants.