Anaesthetic drug ketamine has been recently studied in depressive illness that has not responded to standard medication. Researchers have now found the exact mechanism of how the drug works in the brains of individuals with depression and can keep the symptoms down for more than a week. The results of the study titled, “Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation,” were published in the latest issue of the journal Science.
The team of researchers found that ketamine in the brains of lab mice could improve the functions of certain circuits and this could help elevate mood. Within a few hours, they explain, the drug starts to restore the connections between the cells of these circuits. It is believed that these connections are damaged in persons who suffer from depression.
Last month in March, the Food and Drug Administration approved Spravato – a nasal spray that comprises of a isomer of ketamine and is indicated for treatment of people with depression who do not respond to standard medication. Spravato has been used to treat depression in thousands of individuals. This study shows that exact method by which this drug works.
Dr. Conor Liston, a neuroscientist and psychiatrist at Weill Cornell Medicine in New York and co-author of the study said that studying the effects of ketamine on mice brain with depression was a challenge because depression does not occur in mice. The team from US and Japan thus devised a way to create depression like situation in the mice brain by giving the mice a stress hormone. When given the hormone the mice failed to find interest in doing their favourite activities such as exploring a maze or eating sugar etc. thereafter the brains of the mice were studied using a special laser microscope. Liston explained, “Stress is associated with a loss of synapses in this region of the brain that we think is important in depression.”
Thereafter when ketamine was administered to the mice, there was a restoration of these synapses. Liston said, “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.” The team backed up their findings by testing the drug on living brain cells in the lab as well. Liston explained, “You can kind of imagine Van Gogh's Starry Night. The brain cells light up when they become active and become dimmer when they become inactive.” As the circuits were repaired with ketamine, the brain cells lit up together, they noted.
The team was surprised to see in the mice that they started to act normal and non-depressed within a couple of hours of administering ketamine and this was even before their circuits were fully repaired. “It wasn't until 12 hours after ketamine treatment that we really saw a big increase in the formation of new connections between neurons,” Liston said.
The team also found that 12 hours after ketamine treatment the mice began to develop dendritic spines in their neural circuitry in their prefrontal cortex area of the brain. This region of the brain is associated with complex thinking. These dendritic spines were lost initially when the mice were stressed. To see if these spines were helping treat the depression, the team then used laser to destroy the spines a day after the ketamine treatment. This reversed the improvement that the mice had shown with ketamine with them reverting to their depressed behaviour.
The team speculated that there was a two-step process that could relieve depression. As a first step the drug aids the faulty brain circuits to function better on a temporary basis and then in the long term it restores the circuits and connections between the cells.
Anna Beyeler, a neuroscientist at the University of Bordeaux in France wrote an accompanying commentary saying, “I don’t think we can say this is the mechanism of action. It’s one part of it. The drug is impacting the entire brain.” “Getting a better handle [on] the mechanisms that might maintain ketamine’s effects could be really useful for new strategies for augmenting it,” Liston said.
The study was funded by the National Institute of Mental Health (NIMH) which is part of the National Institutes of Health.