Does Drug Effect or Power of Belief Explain Ketamine’s Antidepressant Effect?

Summary: Researchers conducted a unique study to uncover the efficacy of ketamine in treating depression, bypassing its unmistakable psychedelic effects by administering it during surgery.

Surprisingly, both the ketamine and placebo groups showed substantial improvement in depression symptoms. The unexpected results hint at the strong influence of positive expectations on treatment outcomes, prompting further questions about the placebo effect.

The research also raises the possibility of ketamine’s benefits without the need for the associated psychedelic experience.

Key Facts:

  1. To maintain the blind, ketamine or a placebo was administered to participants undergoing surgery, thereby bypassing ketamine’s noticeable psychedelic effects.
  2. Both ketamine and placebo groups showed similar and significant improvements in depression symptoms, challenging conventional beliefs about ketamine’s efficacy.
  3. The findings hint at the power of positive expectations, or the placebo effect, with over 60% of participants believing they received ketamine based on how much better they felt.

Source: Stanford

In study after study, the psychoactive drug ketamine has given profound and fast relief to many people suffering from severe depression. But these studies have a critical shortcoming: Participants usually can tell whether they have been given ketamine or a placebo. Even in blinded trials in which participants are not told which they received, ketamine’s oftentimes trippy effects are a dead giveaway.

In a new study, Stanford Medicine researchers devised a clever workaround to hide the psychedelic—or dissociative—properties of the anesthetic first developed in 1962. They recruited 40 participants with moderate to severe depression who were also scheduled for routine surgery, then administered a dose of ketamine or placebo when the participants were in surgery and under general anesthesia.

This shows a man sitting in lights.
The takeaway should not be that ketamine “is just a placebo,” Heifets emphasized. Credit: Neuroscience News

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

The researchers were amazed to find that both groups experienced the large improvement in depression symptoms usually seen with ketamine.

“I was very surprised to see this result, especially having talked to some of those patients who said ‘My life is changed, I’ve never felt this way before,’ but they were in the placebo group,” said Boris Heifets, MD, Ph.D., assistant professor of anesthesiology, perioperative and pain medicine, and senior author of the study published Oct. 19 in Nature Mental Health.

Just one day after treatment, both the ketamine and placebo groups’ scores on the Montgomery–Åsberg depression rating scale—a standard measure of depression severity often referred to as the MADRS—dropped, on average, by half. Their scores stayed roughly the same throughout the two-week follow-up.

“To put that into perspective, that brings them down to a category of mild depression from what had been debilitating levels of depression,” said Theresa Lii, MD, a postdoctoral scholar in the Heifets lab and lead author of the study.

What does it all mean?

The researchers concede that their study, having taken an unexpected turn, raises more questions than it answers.

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

The researchers determined that it was unlikely the surgeries and general anesthesia account for the improvements because studies have found that depression generally does not change after surgery; sometimes, it worsens.

A more likely interpretation, the researchers said, is that participants’ positive expectations may play a key role in ketamine’s effectiveness.

At their last follow-up visit, participants were asked to guess which intervention they had received. About a quarter said they didn’t know. Of those who ventured a guess, more than 60% guessed ketamine.

Their guesses did not correlate with their treatment—confirmation of effective blinding—but rather with how much better they felt.

Those who had improved more in their depression scores were more likely to think they received ketamine, even when they didn’t, implying some preexisting positive expectations for ketamine.

Positive expectations

Call it expectancy bias, call it placebo effect or call it hope. Whatever the label, the psychological factors involved in treatment can be powerful.

“In some ways none of this is new,” Heifets said. “Placebo is probably the single most effective, consistent intervention in medicine, full stop. It’s seen in every trial, and we should probably be paying more attention to the factors that give rise to it.”

These factors might include how a study is described; interactions with health care professionals; and in this case, the unavoidable media hype around ketamine.

“We’ll need to devise more clever experiments to tease apart the direct pharmacological effects from the psychological effects of taking ketamine and other psychedelics,” Schatzberg said.

Not just a placebo

The takeaway should not be that ketamine “is just a placebo,” Heifets emphasized.

“Saying ‘it’s just a placebo’ is really a disservice to what placebo is,” he said. “It isn’t ‘I’ll feel better if I say it enough times,’ and it does not imply that there was nothing wrong with the patient.”

In fact, there may be physiological resonance between the placebo effect—in other words, hope—and how ketamine works. Studies suggest that both may be mediated in part by the brain’s μ-opioid receptors, which process pain.

“There is most definitely a physiological mechanism, something that happens between your ears, when you instill hope,” Heifets said.

The results also suggest that the psychedelic experience may not be crucial to ketamine’s benefits, though it likely encourages more positive expectations.

“Maybe with a non-hallucinogenic psychedelic analog you can get the same benefits without having to, you know, go to outer space,” Heifets said.

About this psychology and psychopharmacology research news

Author: Nina Bai
Source: Stanford
Contact: Nina Bai – Stanford
Image: The image is credited to Neuroscience News

Original Research: Closed access.
Randomized trial of ketamine masked by surgical anesthesia in patients with depression” by Theresa R. Lii et al. Nature Mental Health


Randomized trial of ketamine masked by surgical anesthesia in patients with depression

Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. Here we present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (, NCT03861988).

Adult patients (N = 40) with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg kg−1) or placebo (saline) during usual anesthesia. All participants, investigators and direct-patient-care staff were masked to treatment allocation.

The primary outcome was depression severity measured by the Montgomery–Åsberg Depression Rating Scale at 1, 2 and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received.

A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (−5.82, 95% confidence interval −13.3 to 1.64, P = 0.13). Of all participants, 36.8% guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions.

In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder.

This trial successfully masked treatment allocation in patients with moderate-to-severe depression using surgical anesthesia.

Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment to minimize participant-expectancy bias.

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