Over the years, studies have demonstrated the psychoactive drug ketamine’s effect on depression, providing profound and fast relief to many people. But these studies have a critical flaw: 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 published in Nature Mental Health, 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 single infusion of ketamine (0.5 mg kg−1) or placebo (saline) during usual anaesthesia.
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, PhD, assistant professor of anaesthesiology, perioperative and pain medicine, and senior author.
Just one day after treatment, both the ketamine and placebo groups’ scores on the Montgomery-Åsberg depression rating scale (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, 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 anaesthesia 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.
Source: Stanford Medicine