After research, the psychoactive medication ketamine has provided substantial and immediate relief to many patients suffering from severe depression. However, these trials have a crucial flaw: participants can typically distinguish whether they were administered ketamine or a placebo. Even in blinded trials when volunteers are not told which medication they received, ketamine’s typically psychedelic effects are a dead giveaway.
Stanford Medicine researchers created a cunning workaround to conceal the anesthetic’s hallucinogenic — or dissociative — characteristics in a recent study. They chose 40 people with moderate to severe depression who were also scheduled for routine surgery and then gave them either ketamine or a placebo while they were in surgery and under general anesthesia.
All study researchers and physicians were likewise kept in the dark about which treatment patients got. Two weeks later, the therapies were revealed.
The researchers were astounded to discover that both groups had a significant improvement in depressive symptoms 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 anesthesiology, perioperative and pain medicine, and senior author of the study published Oct. 19 in Nature Mental Health.
One day following treatment, both the ketamine and placebo groups’ scores on the Montgomery-Sberg depression rating scale (MADRS), a common measure of depression severity, declined by half on average. Throughout the two-week follow-up, their scores were relatively constant.
“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 admit that because their study took an unanticipated route, it raises more issues 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 assessed that the procedures and general anesthesia were unlikely to be responsible for the improvements because studies have shown that depression does not often improve after surgery; in fact, it occasionally worsens.
According to the researchers, a more likely view is that individuals’ optimistic expectations may play a crucial role in ketamine’s effectiveness.
Participants were asked to predict which intervention they had received at their most recent follow-up visit. A quarter of those polled indicated they had no idea. More than 60% of those who guessed ketamine were correct.
Their guesses did not connect with their therapy, indicating that adequate blinding was in place, but rather with how much better they felt.
Those who had made the most progress in their depression ratings were more likely to believe they had taken ketamine, even if they hadn’t, implying that they had some previous favorable expectations for ketamine.
Call it expectation bias, the placebo effect, or hope. Whatever the title, the psychological aspects of treatment can be extremely strong.
“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 could include how a study is described, encounters with health care providers, and, in this case, the unavoidable 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 take-away should not be that ketamine “is just a placebo,” Heifets emphasized.
Indeed, there may be physiological resonance between the placebo effect (hope) and how ketamine operates. Both may be handled in part by the brain’s -opioid receptors, which process pain, according to research.
“There is most definitely a physiological mechanism, something that happens between your ears, when you instill hope,” Heifets said.
The findings also imply that the psychedelic experience isn’t necessary for ketamine’s effects, though it does likely foster more favorable expectancies.
“Maybe with a non-hallucinogenic psychedelic analog you can get the same benefits without having to, you know, go to outer space,” Heifets said.
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