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Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.

Conventional behavioural mouse models of depression are often used to study the disorder, but cannot capture the full picture of the human disease. Here, scientists present two views about the best research strategies to adopt if treatments are to be improved.

Exposure to abnormal light–dark cycles causes depression-like behaviour and learning deficits in mice. The defects seem to occur independently of disturbances to sleep and other processes regulated by the biological clock. See Letter p.594 Disruption of the body's circadian clock by exposure to irregular light cycles can affect sleep–wake patterns and cause sleep deprivation, both of which are often associated with mood alterations and cognitive disruptions. This study in mice shows that irregular light schedules can directly affect mood and cognitive function, independent of sleep and circadian rhythms. The aberrant light effects are dependent on melanopsin-containing retinal ganglion cells, and administration of antidepressant drugs restores learning ability, suggesting that the depressive effect precedes learning impairment.