Ketamine’s effects on depression may depend on hope

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In study after study, the psychoactive drug ketamine has provided profound and rapid pain relief to many people with severe depression. But these studies have a serious flaw: Participants can often tell whether they were given ketamine or a placebo. Even in blinded trials in which participants are not told which drug they received, ketamine’s side effects are sometimes a deadly giveaway.

In a new study, Stanford Medicine researchers have devised a clever workaround to mask the hallucinogenic dissociative properties of an anesthetic first developed in 1962. They recruited Forty participants with moderate to severe depression were also scheduled for routine surgery, followed by a dose of ketamine or a placebo. when participants had surgery and general anesthesia.

All researchers and clinicians involved in the trial also did not know which treatment the patients received. The treatment was revealed two weeks later.

The researchers were surprised to find that both groups experienced large improvements in common depressive symptoms when using ketamine.

“I was surprised to see these results,” said Boris Heifets, MD, “especially when talking to several patients who said ‘My life has changed, I have never felt this way before. ‘ but they were in the placebo group. , PhD, assistant professor of anesthesiology, surgery and pain medicine, and senior author of the study published October 19 in the journal Natural mental health.

Just one day after treatment, the scores of both the ketamine group and the placebo group on the Montgomery Asberg Depression Rating Scale, a standard measure of depression commonly known as MADRS, decreased, on average. half. Their scores remained roughly the same during the two-week follow-up.

“In simple terms, that brings them down to the mildly depressed level compared to the depressed level,” said Theresa Lii, MD, a postdoctoral scholar in the Heifets lab and lead author of the study. weakness of depression”.

What does it all mean?

The researchers admit that their study, which took an unexpected turn, raised more questions than it answered.

Alan Schatzberg, MD, Kenneth T. Norris, Jr. “All the explanations are open now,” said the professor of Psychiatry and Behavioral Sciences and co-author of the study. “It’s like looking at a Picasso painting.”

The researchers determined that it was unlikely that surgery and general anesthesia could bring about improvement because studies have found that depression often does not change after surgery; Sometimes, it gets worse.

A more likely explanation, the researchers say, is that participants’ positive expectations may play an important role in ketamine’s effectiveness.

At the most recent 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’s confirmation of effective blinding but with how much better they felt.

Those who had greater improvements in depression scores were more likely to think they had received ketamine, even if they had not used it, implying some pre-existing positive expectations towards ketamine.

Positive expectations

Call it expectation bias, call it the placebo effect or call it hope. Whatever they are called, the psychological factors involved in treatment can have a powerful impact.

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

These factors may include how a study is described; interact with healthcare professionals; and in this case, the inevitable media hype surrounding ketamine.

“We will need to come up with smarter experiments to separate the direct pharmacological effects from the psychological effects of taking ketamine and other hallucinogenic drugs,” Schatzberg said.

Not just a placebo

Heifets emphasized that the takeaway is not that ketamine is “just a placebo.”

“Saying ‘it’s just a placebo’ is really an insult to the placebo,” he said. “It’s not ‘I’ll feel better if I say it enough times’ and it doesn’t mean the patient doesn’t have a problem.”

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

“There must be some physiological mechanism, something that happens between your ears when you arouse hope,” Heifets said.

The results also suggest that the psychedelic experience may not be important for ketamine’s benefits, although it may encourage more positive expectations.

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

More information:
Theresa R. Lii et al., Randomized trial of ketamine masked to surgical anesthesia in depressed patients, Natural mental health (2023). DOI: 10.1038/s44220-023-00140-x

Magazine information:
Natural mental health

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