Ketamine Appears to Repair Damaged Brain Circuits to Relieve Depression in Mice Study

Ketamine molecule drawing on green background

Ketamine is widely known as a party drug sold under the moniker Special K, as well as others. While it may provide a euphoric sensation for partiers, the drug also has properties that could be used to treat forms of depression.

A recent study showed that ketamine can possibly provide hours of relief for depression patients. According to a report published in the journal, Science, the use of ketamine on mice improved their functions. According to the report, “ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits.” After dosing the mice with ketamine, the antidepressant effect occurred independently of effects on spine formation, the researchers said.

Depression-related behavior in the mice was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons, the researchers said. The mice in the study were first dosed with a stress hormone that caused them to act depressed, NPR reported. This caused the animals to lose interest in many of their favorite activities, similar to what some people go through. When the mice were dosed with ketamine, the effects were reversed. The researchers said that the drug restored coordinated activity in multicellular ensembles that predicted motivated escape behavior.

The latest study on anesthetic ketamine provides a window into a greater understanding of how the drug can affect patients. Dr. Conor Liston, one of the researchers involved in the ketamine project, told NPR that part of the study was to examine the synapses in the mice brains. When the mice were induced with the stress hormone, researchers observed a loss of synapses. Then ketamine was introduced and the scientists were surprised.

“Ketamine was actually restoring many of the exact same synapses in their exact same configuration that existed before the animal was exposed to chronic stress," Liston told NPR.

The positive results from the ketamine dosing occurred within six hours of the treatment. Within just that short time frame, the mice stopped acting depressed, according to the report. After 12 hours, Liston said researchers saw a “big increase in the formation of new connections between neurons.”

The next question for the researchers will be to discover how to maintain the effect to provide a potential long-term benefit for human patients.

The study was published about a month after the U.S. Food and Drug Administration approved Janssen’s Spravato, an esketamine-based nasal spray treatment for major depressive disorder. Spravato is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, which is also known as a glutamate receptor modulator. Janssen believes the treatment works by restoring synaptic connections in brain cells in individuals with major depressive disorder. Esketamine is related to the well-known party drug ketamine.

Janssen isn't the only company focusing on ketamine-type treatments for depression. Allergan and VistaGen also have similar products in their pipeline. Last month though, Allergan announced that its MDD treatment rapastinel would not meet endpoints in a Phase III trial.

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