Ketamine’s effect on depression may hinge on hope

In study after study, the psychoactive drug ketamine has brought significant and rapid relief to many people suffering from severe depression. However, these studies have significant shortcomings. Participants can usually tell whether they were given ketamine or a placebo. Ketamine’s often trippy effects are perfectly clear, even in blind trials in which participants don’t know which dose they’ve taken.

In a new study, researchers at Stanford Medicine have devised a clever workaround to hide the psychedelic, or dissociative, properties of an anesthetic drug first developed in 1962. They recruited 40 participants with moderate to severe depression who were also scheduled for routine surgery and then gave them a dose. Ketamine or a placebo was administered while participants underwent surgery and were under general anesthesia.

All researchers and clinicians involved in the trial were also blinded to what treatment the patients received. The cure was revealed two weeks later.

The researchers were surprised to find that both groups significantly improved symptoms of depression typically seen with ketamine.

“I was very surprised to see the results, especially when I spoke to some of the patients who said, ‘It’s changed my life, I’ve never felt anything like this before,’ and they were in the placebo group.” said Dr. Boris Heifetz. , Ph.D., assistant professor of anesthesiology, perioperative and pain medicine, and lead author of this paper. study Published on October 19th natural mental health.

After just one day of treatment, scores on the Montgomery-Asberg Depression Rating Scale (a standard measure of depression severity, often referred to as MADRS) in both the ketamine and placebo groups dropped by half, on average. Their scores remained nearly the same throughout the two-week follow-up.

Teresa Lee, MD, PhD, a postdoctoral fellow in the Heifetz lab and the study’s lead author, said, “If you look at the big picture, we’re moving from a previously debilitating level of depression to a category of mild depression.” It will be classified.”

What exactly does that mean?

The researchers admit that the unexpected direction their study took has raised more questions than answers.

“It’s now open to all sorts of interpretations,” said Alan Schatzberg, MD, Kenneth T. Norris Jr. Professor of Psychiatry and Behavioral Sciences and co-author of the study. “It’s like looking at a Picasso painting.”

The researchers determined that surgery and general anesthesia were unlikely to be responsible for the improvement, as studies have found that depression generally does not change after surgery. In some cases, it may even get worse.

The researchers said a more likely interpretation is that participants’ positive expectations may play an important role in ketamine’s effectiveness.

At the final follow-up visit, participants were asked to guess which intervention they received. About a quarter said they did not know. Of those who ventured to guess, more than 60% guessed it was ketamine.

Their guesses did not correlate with the treatment (confirming effective blinding), but rather with how much better they felt.

Those with more improved depression scores were more likely to think they had taken ketamine, even if they had not actually taken it, suggesting a pre-existing positive expectation of ketamine.

positive expectations

We call it expectation bias, we call it the placebo effect, we call it hope. Whatever the label, the psychological factors involved in treatment can be powerful.

“In some ways, none of this is new,” Heifetz said. “Placebos are probably the most effective and consistent medical intervention, a complete intervention. We see this in every trial, and perhaps we should pay more attention to the factors that cause it.”

These factors may include how the study is described. Interacting with medical professionals. And in this case, the media hype about ketamine is inevitable.

“We need to devise smarter experiments to distinguish between the direct pharmacological and psychological effects of ingesting ketamine and other hallucinogens,” Schatzberg said.

It’s not just a placebo

The point, Heifetz stressed, is not that ketamine is “just a placebo.”

“Saying, ‘It’s just a placebo’ really desecrates what a placebo is,” he said. “It doesn’t mean, ‘If you say it enough times, you’ll feel better,’ and it doesn’t mean there’s nothing wrong with the patient.”

In fact, there may be a physiological resonance between the effects of the placebo effect, or hope, and ketamine. Research suggests that both may be partially mediated by the brain’s μ-opioid receptors, which process pain.

“There’s definitely a physiological mechanism where when you create hope, something happens between your ears,” Heifetz says.

The results also suggest that psychedelic experience may not be important for ketamine’s benefits, but is likely to foster more positive expectations.

“Maybe with non-hallucinogenic psychedelic analogues, you can get the same effect without going into space,” Heifetz said.