Multiple studies have shown that ketamine is a fast acting treatment for depression, but a key issue with the studies is that many participants can tell if they have been given ketamine or a placebo.
A new study from Stanford Medicine has worked around this by administering participants scheduled for surgery with either ketamine or a placebo when the participants were in surgery and under general anesthesia.
Researchers and clinicians involved in the trial also were blinded to which treatment patients received and the treatments were revealed two weeks later.
The researchers found that both groups experienced a large improvement in depression symptoms usually seen with ketamine.
The study has been published in Nature Mental Health.
“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, PhD, assistant professor of anesthesiology, perioperative and pain medicine, and senior author of the study.
One day after treatment, both groups’ scores on the Montgomery-Åsberg depression rating scale dropped, on average, by half and 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.
The researchers concede that their study 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 is that participants’ positive expectations may play a key role in ketamine’s effectiveness. When participants were asked to guess which intervention they had received, a quarter said they didn’t know and more than 60% guessed ketamine.
Their guesses did not correlate with their treatment, which was confirmation of effective blinding, but rather with how much better they felt.
“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 added.
“The take-away should not be that ketamine “is just a placebo,” Heifets said.
Schatzberg continued: “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.”
The researchers suggest there may be physiological resonance between the placebo effect — 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.
