Yale scientists have figured out the inner workings of the novel antidepressant, ketamine, and how exactly it is able to bring relief in hours rather than the weeks or months typically needed by similar drugs on the market. The findings, published in the August 20 issue of the journal Science, may quicken the development of a safe and convenient form of ketamine that can be prescribed for alleviating depression.
Yale researchers found that, in rats, ketamine rapidly decreases depression-like behaviors and also re-establishes connections between brain cells damaged by constant stress. The effects of the drug have proven incredibly effective on severely depressed human patients as well.
“It’s like a magic drug—one dose can work rapidly and last for seven to 10 days,” said Ronald Duman, senior author of the study and professor of psychiatry and pharmacology at Yale.
Traditionally, ketamine has been used as a general anesthetic for children, but about a decade ago, it was found by researchers at the Connecticut Mental Health Center to bring relief to depressed patients when given in small doses, said Duman.
These first clinical studies, later replicated by the National Institute of Mental Health, showed that almost 70 percent of patients previously resistant to all other forms of antidepressants improved within hours of receiving ketamine. Its clinical use, however, has been limited up until now because it must be delivered intravenously under medical supervision. It is also capable of triggering short-term psychotic symptoms. Ketamine has been used as a recreational drug, sometimes called “Special K” or simply “K.”
This led Duman, his colleague George Aghajanian and the Yale researchers to team up in order to study ketamine’s molecular action in the prefrontal cortex of rats, with the anticipation of finding potential targets needed to create a safe and more easy-to-use form of the drug.
The scientists discovered that ketamine acts on a pathway that rapidly produces new synaptic connections between neurons—a process known as “synaptogenesis.” In addition, they were able to pinpoint a critical enzyme in the pathway, mTOR, which controls protein synthesis necessary for new synaptic connections. There were also promising leads on how to sustain the initial rapid effects of ketamine by intervening at particular downstream targets.
“The pathway is the story. Understanding the mechanism underlying the antidepressant effect of ketamine will allow us to attack the problem at a variety of possible sites within that pathway,” said Aghajanian.
Approximately 40 percent of people suffering from depression do not respond to medication, and there are many more who only respond after many months or years of trying various treatments. The authors point out that ketamine has been tested and proven as a successful means of rapidly diminishing suicidal thoughts. This is an important advantage that is typically not seen before weeks of treatment with traditional antidepressants.
Other Yale authors of the paper are Nanxin Li, Boyoung Lee, Rong-Jian Liu, Mounira Banasr, Jason M. Dwyer, Masaaki Iwata and Xiao-Yuan Li. National Institute of Mental Health, the Connecticut Mental Health Center and Yale University School of Medicine funded the work.
Source: Yale University