A New Antidepressant Inspired by Ketamine

A promising treatment for clinical depression that works like a club drug has passed its first round of testing.

Paul Yeung/Reuters

The latest "breakthrough" in depression treatment is a drug that's supposedly able to relieve symptoms in a little over an hour. It works in patients who were previously resistant to treatment that, in any case, could take weeks to start working.

The strongest effects of the new drug, which is being tested by the National Institutes of Health, only lasted for about a half-hour, sometimes lingering for two more days. But the researchers are encouraged because so far, the drug seems to be just as promising as ketamine.

Yep, that ketamine. The club drug, as a positive side effect of its other, dissociative side effects, is able to rapidly relieve symptoms of depression in the most hopeless of cases. The news from this past October was that its ability to do so was helping scientists to rethink the way they conceptualize the depressed brain. As I reported then, the focus was shifting away from the "low levels of serotonin" model of depression:

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.

Reporting on these findings, Yale researchers writing in Science expressed the hope that they'd be able to develop faster-acting, longer-lasting antidepressants that work through the same mechanism, but that they'd feel more comfortable prescribing than a drug that variably causes "pleasant dream-like states, vivid imagery, hallucinations, and emergence delirium." The promise this holds for people with depression, especially those for whom SSRIs and electroconvulsive therapy have proven ineffective, can't be overstated.

The results from the NIH's clinical trial are a first step in this direction. The new drug isn't as headline-grabbing as ketamine -- it's definitely going to need a better name than its current "AZD6765" -- but when tested on 22 patients, it had a 32 percent success rate, which is approaching the 52 percent seen with ketamine. Strengthening its case, AZD6765 worked significantly better than a placebo, and had fewer ketamine-like side effects.

The trial established "proof of concept," meaning that although there's still much more testing and refinement to do before it can begin to be offered to the wider public, researchers are at least heading in the right direction.