Ketamine's Influence on Depression and Behavior

Ketamine banishes depression by slowly coaxing nerve cells to sprout new connections, a study of mice suggests. The finding may help explain how the hallucinogenic anesthetic can ease some people’s severe depression. The results are timely, coming on the heels of the U.S. Food and Drug Administration’s March 5 approval of a nasal spray containing a form of ketamine called esketamine for hard-to-treat depression. But lots of questions remain about the drug.

The new study adds strong evidence that newly created nerve cell connections are involved in ketamine’s antidepressant effects. While typical antidepressants can take weeks to begin working, ketamine can make people feel better in hours.

To approximate depression in people, researchers studied mice that had been stressed for weeks, either by being restrained daily in mesh tubes, or by receiving injections of the stress hormone corticosterone. These mice began showing signs of despair, such as losing their taste for sweet water and giving up a struggle when dangled by their tails. Three hours after a dose of ketamine, the mice’s behavior righted, as the researchers expected. But the team found no effects of the drug on nerve cells’ dendritic spines — tiny signal-receiving blebs that help make new neural connections.

When the researchers looked over a longer time span, though, they found that these new synapses were key. About 12 hours after ketamine treatment, new dendritic spines began to pop into existence on nerve cells in part of the mice’s prefrontal cortex, the brain area responsible for complex thinking. These dendritic spines seemed to be replacing those lost during the period of stress, often along the same stretch of neuron. To test if these newly created spines were important for the mice’s improved behavior, the researchers destroyed the spines with a laser a day after the ketamine treatment. That effectively erased ketamine’s effects, and the mice again exhibited behavior resembling depression, including struggling less when held by their tails. (The mice kept their regained sugar preference.)

CITATIONS R.N. Moda-Sava et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. Vol. 364, April 12, 2019, p.147. doi:10.1126/science.aat8078.