A ketamine pill may help hard-to-treat depression with fewer side effects, early research suggests

By Brenda Goodman, CNN

(CNN) — A new ketamine pill may help hard-to-treat depression with fewer side effects than other forms of the treatment, early research suggests.

Technically, no form of ketamine has been approved by the US Food and Drug Administration to treat any psychiatric disorder, including depression. A derivative of ketamine, called esketamine, was approved in 2019 to treat depression. It’s a nasal spray called Spravato. There’s also FDA-approved injected ketamine, brand-named Ketalar, which can be prescribed off-label.

Both can be a fast-acting lifeline for people living with depression that hasn’t been relieved by other types of treatments. Getting the drug, or a derivative of it, through a vein or as a squirt up the nose requires close medical supervision in a clinic, however, making these options hard for some people to access or even to do.

“It’s very logistically involved. You have to come in and be observed for a couple hours,” said Dr. Brian Barnett, clinical director of the Psychiatric Treatment Resistance Program at the Cleveland Clinic, who was not involved in the study. “The field has really been looking for a way to take advantage of ketamine for depression but let patients take this at home in the form of a pill.”

To confuse matters even further, compounded ketamine lozenges and pills are available through online pharmacies and can be obtained with a prescription, but the FDA warned patients and providers about using compounded ketamine last fall because these products have not been evaluated for safety and effectiveness. Some doctors who prescribe ketamine for depression say they are wary of the oral forms because it’s not clear how much of the drug actually makes it to a patient’s bloodstream.

Patients need to be monitored closely because ketamine, which was originally used to dull pain in surgery, can cause feelings of disconnection or disassociation from their bodies and the world around them. It also distorts thinking and decision-making. Some find this hallucinogenic experience beneficial and even pleasant, but others have described it as terrifying. These forms of the drug can also cause a person’s blood pressure to go up, which may make them off-limits for those with heart conditions.

The clinic setting limits who can get the treatment as well, Barnett said. Not all areas have clinics that can do this kind of intensive monitoring, and patients aren’t allowed to drive until the morning after an infusion, so treatments may be out-of-reach if they can’t get a ride or afford a hotel stay.

From a public health standpoint, Barnett said, you can serve more people with a pill than with clinic-based treatments. A 2021 study estimated that in any given year, 2.8 million American adults have treatment-resistant depression.

“It would be very beneficial for many people to have this available as a medication that they could take at home. But obviously, we want a medication like that to have very minimal dissociative side effects,” Barnett said.

That’s where slow-release ketamine pills come in.

Studying drug withdrawal to see if it works

For the study, which was published Monday in the journal Nature Medicine, researchers in New Zealand enrolled 231 adults who had been diagnosed with treatment-resistant depression, meaning they had tried at least two different antidepressants to lift their mood without success.

The study participants scored an average of 30 points on a clinical scale that measures depressive symptoms, a score that’s considered moderate depression, and on average, they’d tried nearly five different treatments without relief.

For the first five days of the study, all of the participants took a daily dose of 120 milligrams of ketamine in the form of a slow-release pill. On day eight, the researchers assessed who had responded to the drug. Slightly more than half the group – 132 – had remission of their symptoms, meaning they scored under 10 on the clinical scale. Overall, 168 had some degree of benefit and were considered responders to the pill. People who had not responded to the drug were not eligible to continue with the research.

Those 168 adults were randomly assigned to one of five treatment groups; 37 people got a placebo, or dummy pill, while roughly equal-size groups took one of four daily doses of ketamine that ranged from 30 milligrams to 180 milligrams.

By 14 weeks, everyone taking ketamine still continued to see some relief from their depression, but for most groups, the differences compared with placebo were not statistically significant, meaning they could have been observed due to chance alone.

Researchers did see what’s called a dose response, however, meaning the higher the dose of the drug, the more relief participants had in their depressive symptoms, which is usually a sign that the drug is having a real effect.

People who took the highest dose, 180 milligrams a day, did see a statistically significant benefit, a reduction in their depression score of about six points compared with the placebo group.

“The results here, they look encouraging,” Barnett said, noting that a two-point drop in the clinical rating scale the researchers used is considered meaningful to patients.

A six-point drop is “similar to what we’ve seen in recent clinical trials of psilocybin for treatment-resistant depression,” Barnett said, referring to a chemical in certain mushrooms that’s currently being studied.

During the first five days of the study, when everyone was taking the drug, the most common side effects reported were dizziness, headache, dissociation, fatigue, feeling abnormal and nausea.

About 11% of people taking the 120 milligram ketamine pill at the beginning of the study said they experienced dissociation or feeling disconnected. But this appeared to be much milder than the dissociation reported by people who get ketamine infusions. On a commonly used rating scale, people taking the ketamine pill ranked below a score of 3 in the first phase of the study, but another study found that people getting IV ketamine rated their dissociation around a 7.

Effects on blood pressure were also minimal with the slow-release pill.

Weighing study biases

Experts agree that the study was an important first step.

“The report is important since it is the first large placebo-controlled study to be published attempting to explore the benefits of oral ketamine,” Dr. Gerard Sanacora, director of the Yale Depression Research Program, who was not involved in the study, wrote in an email.

But Sanacora said the design of the study, which is known as a randomized withdrawal trial, probably biased the results in favor of making the drug look more effective than it might be in the real world, something the study authors acknowledge, too.

By studying only people who responded to the drug, the study authors noted that they hoped to avoid the high failure rates of many antidepressants tested in a general population, where as many as 50% of trials fail to show an effect compared with a placebo.

Sanacora said it’s very likely that the study participants could have known they were getting ketamine, rather than the placebo, and therefore expected it to work.

“It is usually easier to guess correctly once you have been exposed to the active treatment and then receive the inactive treatment,” he wrote.

Therefore, he said, it would be really important for the pills to be retested in a larger population to get an idea of how well they might work in the real world.

He noted that there’s a “tremendous tension” between wanting the important benefits of a drug like ketamine to be more available to people and making sure the treatment can be given safely and responsibly.

“This is a step in the right direction, but we clearly need more high-quality data before we can say much more about the overall efficacy and safety of the new form of treatment and especially the safety of doing this at home,” Sanacora wrote.

Challenges of oral dosing

Perhaps unsurprisingly, the study, which led to withdrawal and depression relapse for many, had a high drop-out rate. Of the 168 people who initially saw benefit from the pills, 100 didn’t complete the trial. Ninety-four left because they stopped being helped by their treatment. One person left because of an adverse event. Four others left for unspecified reasons. A 65-year-old man died as a result of suicide.

The researchers say the study’s independent review committee judged that the death was a result of the patient’s depression rather than the treatment.

“Attempted and completed suicide is a sad reality of treatment trials in patients with depression,” noted study author Dr. Paul Glue, a professor in the Department of Psychological Medicine at the University of Otago in Dunedin, New Zealand, in an email.

Both Barnett and Sanacora agreed that it was difficult to know whether the drug played any role in a study this size and said that larger studies were needed to tease out any serious safety signals.

Among the participants, women and younger adults tended to have stronger treatment effects than men and older adults.

That may have something to do with the way the pills are metabolized, Barnett said.

“One of the challenges with oral ketamine, one of the reasons that we haven’t used as much for depression as IV, is that it can be sort of unpredictable, and how much is getting into the bloodstream?” he said. However, he thought the slow-release form of the pill probably helped with maintaining a steadier dose.

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