Yale study finds new benefits from old drug

Developed as an anesthetic nearly 50 years ago, the drug ketamine has drawn new attention in recent years after research suggested it could produce antidepressant effects within hours, even in patients whose depression did not respond to other treatments.

But ketamine is a risky drug. It can cause hallucinations, delirium and acute psychosis. It has similarities with PCP and is used illicitly, known by the street name “Special K.” And, until recently, little was known about how its antidepressant properties actually worked.

Now researchers at Yale University have identified how ketamine can relieve depression quickly. Studying rat brains, they found that the drug can lead the brain to restore connections between brain cells that are damaged by stress and depression.

The findings, which will be published Friday in the journal Science, could point the way toward developing a drug for depression that acts like ketamine but comes without the potential for abuse and problematic side effects.

“Hopefully this is going to lead to even more efficacious and safer drugs that we can use for treating this illness,” said Ronald Duman, a professor of psychiatry and pharmacology at Yale and senior author of the study.

Major depressive disorder affects nearly one in six American adults at some point in their lives, according to a national survey conducted in 2001 and 2002. Existing medications can take weeks or months to work, and nearly two-thirds of patients do not respond to the first medication they receive.

Duman’s lab has been studying antidepressants for nearly 30 years, trying to understand the mechanisms that make them work.

“Even though there are antidepressant medications available, it’s still not really well understood how they work,” he said.

To figure out ketamine’s effects on depression, Duman’s team focused on the prefrontal cortex, a region of the brain known to be involved in depression. Portions of the prefrontal cortex are involved in emotional control and cognition, and are altered in depressive illness, Duman said.

Previous research has shown that connections between cells in the prefrontal cortex appeared to be atrophied in patients exposed to depression or stress, Duman said.

At the right doses, Duman’s research found, ketamine produces the opposite effect, increasing the number of connections between neurons. It did so by activating a process in the brain called the mammalian target of rapamycin, or mTOR, which controls the production of proteins required to form new connections between brain cells.

Ketamine’s antidepressant effect worked at low doses but not at the higher doses used for anesthesia, the Yale researchers found. Duman said that could be because ketamine acts on multiple sites in the brain. The sites that produce antidepressant effects are likely more sensitive than the others and can begin working with lower levels of ketamine, while higher doses lead to anesthetizing.

Researchers also examined other antidepressants, including a Prozac-like drug and electroconvulsive seizure, and found that they did not have a significant influence on mTOR activity.

Similarities between rat and human brains, particularly in the mechanisms that are important in the brain’s response to stress and antidepressants, make it possible for rat studies to offer insights into how the human brain would respond, Duman said.

Pharmaceutical companies are interested in developing antidepressant drugs that can act rapidly, like ketamine, but without the side effects or other concerns it brings, Duman said. His lab, meanwhile, has an interest in understanding how stress affects the brain, something that the findings of the ketamine research could potentially help explain, he said.

The study was funded by the National Institute of Mental Health, the Connecticut Mental Health Center and Yale University School of Medicine.