• Posted October 24, 2023

Ketamine's Antidepressant Benefit: Is It All in Your Head?

The party drug ketamine has gotten a lot of notice for its potential to help people with severe and persistent depression who haven't responded to other treatments.

But a new study has discovered the drug's effect may be in the heads of patients who take it.

Researchers from Stanford Medicine administered either ketamine or a placebo to 40 patients with depression who were already getting anesthesia while undergoing surgery. Importantly, none of the patients or their doctors knew whether they got the drug or the placebo.

What the team found came as a surprise: People in both groups reported a large improvement in depression symptoms.

"What we expected was that patients who received placebo"¦ would continue to not do much better after their procedure and their infusion and that the patients who got ketamine would do better,"said lead study author Dr. Theresa Lii, a postdoctoral scholar in the Heifets Lab at Stanford Medicine in California.

"That was what we predicted. And, actually, what really surprised us is that everyone got better,"Lii said.

An explanation could be that something more nebulous, maybe hope and a person's expectations, may play a role in the drug's success, the authors suggested.

Ketamine is an anesthetic that was developed in the early 1960s. In the early 2000s, a psychiatrist started testing the drug in patients who had treatment-resistant depression and patients quickly entered remission, Lii said.

"Since then, the research has taken off in the psychiatric field, really trying to replicate the almost, I would say miracle, of ketamine in resistant depression,"Lii said.

Lii and Dr. Boris Heifets, an assistant professor of anesthesiology, perioperative and pain medicine, wondered if administering ketamine might help patients who were undergoing surgery become less depressed after their procedures.

The investigators also thought the surgery aspect might be a way to truly test ketamine blindly.

Among the ways that the researchers assessed what happened was using what's called the Montgomery-AÌŠsberg depression rating scale.

They assessed patients one day after the treatment using this scale, and found that depression scores dropped, on average, by half. That finding persisted through the two-week follow-up.

That means the patients then had depression that could be classified as mild, compared to the debilitating depression they felt before their surgeries.

The researchers don't think that the surgery and general anesthesia were the reasons for the change because past studies have not seen depression improve because of surgery.

They credit, instead, the role of positive expectations and the care for them by their clinical team.

Patients who had more improvement in depression scores were more likely to think they had received ketamine, which implies they had an expectation they would improve.

The authors noted this result could be called hope, placebo effect or expectancy bias.

"It is not a trivial thing to take someone who has been poorly served by the mental health machine and then instill hope in them that something good might happen, and then give them an experience to tie it to,"Heifets said.

With the study's results and its design, it doesn't definitively answer the question of whether there was any actual ketamine effect or it was all placebo effect.

But placebo effect isn't necessarily what the average person might think it is, Lii explained.

"I think a more technical term, but one that isn't as stigmatizing, is something that we researchers often refer to as non-specific effects. And that encompasses a large range of things,"Lii said.

It can be expectations that patients have. It can involve the interactions a participant has with their care team. And all of that can lead to people feeling better, she added.

Ketamine is a drug that's not without risks and there has been a proliferation of unsupervised prescription of this drug, Heifets noted.

What this trial shows is that a key to success with ketamine is these non-drug factors, like setting expectations and close clinical follow-up, he added.

Heifets said there may be some physiological reaction between hope and ketamine.

That may involve the brain's opioid receptors, which are involved in processing pain, according to the researchers.

The trial results also suggested that the antidepressant response is not really tied to the psychic experience of the drug, said study co-author Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford Medicine.

"I think that is very important,"Schatzberg noted.

That patients who felt their depression was reduced assumed they received ketamine shows that the expectation bias is critical, he said.

The findings were published Oct. 19 in the journal Nature Mental Health.

"I think I'm actually heartened to know that the more we see our patients and we interact with patients, if that is in fact responsible for the confoundedness of this data, then I'm glad that it says that the more we care for our patients, the more they get better,"said Dr. Lisa Harding, an intervention psychiatrist at Depression MD in Connecticut.

Harding does a lot of work with ketamine for those with treatment-resistant depression and specifically suicidal ideation. She was not involved in this research.

Harding also noted that the general public thinks of a sugar pill when they hear the word placebo, but that there are many non-medical interventions that can change a person's mood.

"And it's not that there's no effect happening,"Harding said. "Something has happened."

Harding said it should be a lesson that no care with ketamine should be given in isolation.

"I think that is the overarching lesson from this study, that the treatment setting matters, the expertise of the personnel around the treatment is what matters,"Harding said.

Research has shown about one-third of the patients treated with antidepressants won't respond to them, she added.

Ketamine targets the brain in a different way than antidepressants.

"I tell patients, instead of working on the juice of the circuit, we're working on the circuitry itself,"Harding explained.

More information

The U.S. National Institutes of Health has more on ketamine for depression.

SOURCES: Theresa Lii, MD, postdoctoral scholar, Stanford Medicine, Calif.; Boris Heifets, MD, PhD, assistant professor, anesthesiology, perioperative and pain medicine, Stanford Medicine, Calif.; Alan Schatzberg, MD, professor, psychiatry and behavioral sciences, Stanford Medicine, Calif.; Lisa Harding, MD, psychiatrist, Depression MD, Milford, Conn.; Nature Mental Health, Oct. 19, 2023