Ketamine May Quickly Ease Tough-to-Treat Depression
Ketamine, once most famous as a "club" drug, can rapidly improve hard-to-treat depression and curb suicidal thoughts, a new review confirms.
In recent years, ketamine has emerged as something of a wonder drug for some people who do not get better with standard antidepressants.
For those patients, who may have tried multiple conventional medications, ketamine can quickly ease depression symptoms -- even within a day. Experts say that speedy response is especially critical for people at risk of self-harm.
The new review, published recently in the British Journal of Psychiatry Open, pulls together all published research on ketamine as a treatment for psychiatric disorders. And it found that for treatment-resistant depression and suicidal thoughts, the drug can have quick, "robust" effects -- albeit short-lived.
"It is important to emphasize the drug doesn't work for everyone," said senior researcher Celia Morgan, a professor at the University of Exeter in England.
Nor is ketamine simple to take. It has to be given under medical supervision, Morgan noted, so doctors can watch for "dissociative" effects -- or what lay people might call a "trip."
The drug is not a psychedelic, but typically triggers altered perceptions of reality, such as hallucinations, soon after it's given. It can also cause a short-term spike in blood pressure, Morgan said.
So before anyone tries ketamine for depression, she said, they have get a full medical and psychiatric evaluation to make sure it is appropriate for them.
Ketamine was first approved in the United States decades ago as an anesthesia drug. Because of its mind-altering effects, it also came to be abused as a party drug, known by such nicknames as "special K."
But researchers have long been aware of the drug's potential, at low doses under well-controlled conditions, to treat psychiatric symptoms. Ketamine is not approved by the U.S. Food and Drug Administration for treating depression. But doctors can and do prescribe it "off label" for that reason.
And in 2019, the FDA approved a ketamine derivative -- called esketamine (Spravato) -- for depression that has not responded to at least two standard antidepressants.
Unlike ketamine, which is given by IV, esketamine is a nasal spray. But it still must be given under medical supervision, because it has the same side effects.
Since esketamine is FDA-approved for depression, it has become the more practical choice over ketamine, according to psychiatrists not involved in the review.
"It's much easier to get insurance coverage for esketamine," said Dr. Paul Nestadt, co-director of the Johns Hopkins Anxiety Disorders Clinic in Baltimore.
So while he has been involved in ketamine research, Nestadt said that in practice, he is prescribing esketamine.
It's not entirely clear how either drug so rapidly eases depression. But researchers know ketamine has different brain targets than standard antidepressants, and that includes boosting activity in a chemical called glutamate, which helps brain cells communicate with each other. Studies also suggest ketamine fosters the regrowth of synapses -- connections among brain cells that can be depleted in people with longstanding depression.
With esketamine, Nestadt said, there is a set treatment protocol: It's used in combination with a standard antidepressant, starting with two doses per week for the first month, then one weekly dose for the next month, and tapering further thereafter.
The length of that maintenance period, though, is "undefined," said Dr. Joshua Berman, an assistant professor of psychiatry at Columbia University Irving Medical Center in New York City.
In the earlier years of research, he noted, the focus was on understanding ketamine's rapid effects.
"We, collectively, had never seen anything like it," Berman said.
Now, the ongoing research question is, how long do the antidepressant effects truly last?
It's also unclear, according to the review, whether ketamine helps with other psychiatric disorders, like post-traumatic stress disorder, obsessive-compulsive disorder and drug dependence.
The researchers examined 89 published studies, some of which tested ketamine for those conditions in the short term. But while there were some "positive" effects, Morgan's team said, the results should be interpreted with caution at this point.
For people with depression, both Berman and Nestadt emphasized the importance of a full psychiatric evaluation, along with a medical history, before starting ketamine or esketamine.
There are ketamine "clinics" popping up around the United States, but some are run by anesthesiologists, not mental health professionals.
"[Ketamine] is not a first-line therapy for depression," Nestadt stressed. "You want a good evaluation first, and you should start with treatments that have been studied for decades."
In addition, Nestadt said he keeps patients on their current treatment -- antidepressants as well as talk therapy -- during the esketamine intervention. And while the maintenance phase of esketamine is not clearly defined, neither it nor ketamine is meant to be given "indefinitely," Nestadt said.
Berman pointed to an additional reason to be under the care of a mental health professional: If ketamine does not work, patients should have other options presented to them.
Johns Hopkins has more on esketamine for depression.
SOURCES: Celia Morgan, PhD, professor, psychopharmacology, University of Exeter, England; Joshua Berman, MD, Ph.D., assistant professor, psychiatry, Columbia University Irving Medical Center, New York City; Paul Nestadt, MD, assistant professor, psychiatry and behavioral sciences, co-director, Johns Hopkins Anxiety Disorders Clinic, Johns Hopkins University School of Medicine, Baltimore; British Journal of Psychiatry Open, Dec. 22, 2021, online