'The Biggest Breakthrough in Depression Research' in 50 Years Is ... Ketamine?

What using a club drug to treat depression reveals about the brain


Olivia Harris/Reuters

The most intriguing way of putting it is that a notoriously unpredictable and dangerous club drug may be the solution to depression.

Perhaps unsurprisingly, this isn't the entire story.

So why, in a review published late last week in Science, have researchers declared that findings on the effects of ketamine -- what the kids call "Special K" -- on the depressed brain are "the biggest breakthrough in depression research in a half century"?

Anyone who's experienced major depressive disorder, either personally or through a loved one, would understandably be excited about the news that taking ketamine can lift depression in mere hours in patients who are resistant to typical antidepressants. The commonly prescribed serotonin selective reuptake inhibitors (SSRIs) take weeks to kick in, if they end up working at all (they don't, for more than a third of depressed patients). It's during this painfully long waiting period that suicide, for two to twelve percent of patients, can begin to be seen as the quickest way out of the darkest depressions.

So yes, ketamine's potent and rapid effects seem downright miraculous, even though the relief it provides from depression only lasts seven to ten days. But researchers at the Yale School of Medicine have known this for a decade now. And the drug has actually been approved by the FDA for use as an injected anesthetic, albeit one with short-term, but psychologically intense, side-effects:

The psychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, and emergence delirium. In some cases these states have been accompanied by confusion, excitement, and irrational behavior which a few patients recall as an unpleasant experience. The duration ordinarily is no more than a few hours; in a few cases, however, recurrences have taken place up to 24 hours postoperatively. No residual psychological effects are known to have resulted.

What is new -- and legitimately exciting -- about all this is that scientists are beginning to realize that we may have been thinking about the depressed brain in the wrong way. The effects seen with ketamine suggest that the common explanations for depression -- that it's caused by a "chemical imbalance" in the brain, or by low levels of serotonin -- may not be what's really causing the disorder after all.

Instead, the studies reviewed here support a different theory, one which suggests that depression is the result of damage to the brain cells responsible for controlling mood. In mice, at least, this atrophy of neurons occurred in response to stress. Although the reasons stress causes this to happen are unclear, the weakening of synaptic connections appears to be at the root of depression and other stress-related disorders.

SSRIs are intended to increase brain levels of serotonin, but they do also, eventually, restore neurons. Ketamine is able to repair these synaptic connections in mice with near-miraculous speed. Indirect evidence from brain imaging supports the theory that this "synaptogensis" is the mechanism allowing for ketamine's rapid effects in humans as well.

For the most extreme and SSRI-resistant cases of depression, an emergency dose of ketamine just might be an actual treatment option. But it's no miracle cure, and it certainly couldn't be prescribed as a long-term solution. The abuse potential for ketamine in its current form is high, and the drug is also associated with damage to the bladder and kidneys.

Ron Duman, who co-authored the review with George Aghajanian, told NPR, "The hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed that ultimately provide a much better way of treating depression." There have been some preliminary results for drugs that work like ketamine without producing hallucinations and other side effects, but they don't work as rapidly.

But if what these findings suggest turns out to be true, and if further studies, as the authors predict, "define the neuronal and synaptic alterations underlying depression and ... contribute to the development of safer, more efficacious antidepressants that last longer and act faster," the claims about ketamine may turn out to be just as promising as they sound.