“It’s like a magic drug”, said the lead researcher of a team from Yale University in the US whose latest study suggests that ketamine, a drug normally used as an anasthetic, could be reformulated as an anti-depressant that takes effect in hours rather than the usual weeks and months of most available medications.

You can read how the researchers discovered this effect in a study they performed on rats which was published online on 20 August in the journal Science.

Senior author Dr Ronald Duman, professor of psychiatry and pharmacology at Yale, told the media that just one dose of the drug can work rapidly and lasts for seven to ten days.

This is the same ketamine that is used as a recreational drug, called “Special K”, or “K”.

He and his team found that the drug not only improved the rats’ depression-like behaviors, it also restored connections between neurons or brain cells that had been damaged by chronic stress. They called this “synaptogenesis”.

They hope their findings will help to speed up the development of a safe and easy to administer version of ketamine, which has already proved to be effective in severely depressed patients, they said.

About ten years ago, scientists at Connecticut Mental Health Center found that in lower doses, ketamine, normally used as a general anasthetic for children, appeared to relieve patients with depression.

Since then, other studies have shown that over two thirds of patients who don’t respond to all other types of anti-depressants improved hours after receiving ketamine, said Duman.

The problem with using ketamine more widely to treat depression has been the fact it has to be given intravenously under medical supervision, and it can also cause short-term psychotic symptoms.

So Duman and colleagues decided to investigate the effect of ketamine on the brain to see if it might reveal suitable targets for other safer and easier to adminster drugs.

” … the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified,” they wrote.

They found that ketamine acts on a pathway that controls the formation of new synaptic links between neurons, encouraging synaptogenesis; they wrote that they observed:

” … increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats.”

Moreover, they found that a critical point on the pathway, involving the enzyme mTOR, controls production of proteins needed to form the new synapses.

The researchers concluded that:

“Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.”

Duman and colleagues told the press that they can already see ways to sustain the rapid effect of ketamin by intervening at other points downstream of this critical one. These could be additional targets for new drugs.

This discovery not only brings new hope to the 40 per cent or so of patients with depression who don’t respond to medication, but to many others who only experience relief after months and sometimes years of treatment.

The researchers also noted that ketamine has already shown to be effective as a rapid way to treat people with suicidal thoughts, many such patients usually only respond weeks later with traditional drugs.

The National Institute of Mental Health, the Connecticut Mental Health Center and Yale University School of Medicine paid for the study.

“mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists.”
Nanxin Li, Boyoung Lee, Rong-Jian Liu, Mounira Banasr, Jason M. Dwyer, Masaaki Iwata, Xiao-Yuan Li, George Aghajanian, Ronald S. Duman
Science, 20 August 2010: Vol. 329. no. 5994, pp. 959 – 964
DOI: 10.1126/science.1190287

Additional source: Yale University.

Written by: Catharine Paddock, PhD