Ketamine: Leading the Way Toward Fast-Acting Antidepressants

2013-01-09

It’s an anesthetic popular with veterinarians, but the latest studies show ketamine also shows promise as a potential antidepressant.

Ketamine produces hallucinations, out-of-body feelings, disorientation and even amnesia that can last a few hours, which has made it not just a staple in veterinary clinics but occasionally in nightclubs as well, as a recreational drug.

In a research review published last October in the journal Science, however, researchers called the growing connection between ketamine and depression “the most important advance in the field” in the depression field over the past 50 years. And now scientists report on two formulations of drugs with ketamine’s benefits, but without its consciousness-altering risks, that could advance the drug even further toward a possible treatment for depression.

Prozac and other methods of stabilizing mood, including talk therapy, take weeks, not hours, to show benefits. A rapid-acting antidepressant like one based on ketamine could potentially be lifesaving for those with depression, since those waiting for treatment to take effect are often at high risk of suicide.

In late November, the first randomized controlled trial of a ketamine-like drug, AZD6765 (made by AstraZeneca), was published in Biological Psychiatry. The study, which was funded by the National Institute of Mental Health, included 22 participants with depression who had failed to respond to other treatments. Those randomly assigned to the ketamine compound showed a 32% improvement in mood, typically within an hour, compared with only 15% of those assigned to placebo. Overall, 18% of patients reached full remission, lasting two days, on the drug, in contrast with 10% of those taking placebo.

But while the drug had no significant side effects, the ketamine mimic was not nearly as effective as ketamine itself. “The antidepressant effects of AZD6765 were not as robust or sustained as those observed in our previous study of ketamine,” the authors write. With ketamine, 71% of patients had a significant positive response within a day of taking the drug — more than double that seen with the new medication — and the effects lasted for a week, not just two days.

Despite its weaker performance, AZD6765 does have an advantage over the original — it does not seem to impair consciousness, so it could still prove to be a useful medication. “Future studies with this compound are warranted on the basis of the positive antidepressant signal here, particularly those exploring efficacy and tolerability associated with higher or repeated doses,” the study concludes.

Preliminary data on another ketamine-like antidepressant, GLYX-13, was also presented at the December meeting of the American College of Neuropsychopharmacology. A safety test on 116 people with treatment-resistant depression found that the drug did not impair consciousness, had minimal side effects and did significantly reduce depression symptoms for up to two weeks.

However, because this trial was designed to test the agent’s safety, its effects were not compared with those of a placebo.

But with the emerging evidence suggesting a connection between ketamine and improved mood and with both of the ketamine-like compounds still under study, some clinicians are starting to offer ketamine to patients whose depression is not responding to other approaches. Since it is FDA-approved for use as an anesthetic, doctors can provide the drug off-label to patients, as long as they inform users that the medication has not been tested for use as an antidepressant.

Others, like Dr. James Murrough, assistant professor of psychiatry at the Icahn School of Medicine at Mount Sinai, are conducting clinical trials of ketamine as a treatment for depression but are reluctant to offer the drug outside of research. “I’m excited because it has potential, but it’s not quite ready yet,” Murrough says. If the studies do support the safety and effectiveness of ketamine or ketamine-like agents for treating depression, however, these drugs could become an important part of the psychiatric arsenal in addressing symptoms of mood disorders quickly — before they lead to more serious symptoms like suicide.