Ketamine a Panacea for Resistant Depression? Not So Fast, Experts Say

Nancy A. Melville

April 04, 2019

CHICAGO — Ketamine's rapid antidepressant effects and its recent approval by the US Food and Drug Administration (FDA) has clinicians and patients alike buzzing with excitement.

However, for some experts, this excitement only serves to heighten concerns about the many unknowns and potential long-term side effects of the drug, which began its long history as an anesthetic.

Here, at the Anxiety and Depression Association of American (ADAA) 2019 Conference, experts debated the drug's merits and potential pitfalls.

"These are exciting times and I think ketamine has opened a new era," Carlos Zarate, MD, a ketamine researcher with the National Institutes of Health (NIH), said during an ADAA panel session. "The new standard will be to deliver drugs that work rapidly," he added.

However, weighing in on the side of caution, keynote speaker Alan Schatzberg, MD, professor of psychiatry and behavioral sciences at Stanford University, Palo Alto, California, was wary of esketamine (Janssen Pharmaceuticals), the intranasal formulation of ketamine that was approved by the FDA for treatment-resistant depression.

Alan Schatzberg, MD

"I'm more worried now than I was two years ago," he said. "We need to get phase 4 data looking at the effects when people stop ketamine treatment at different time points because right now, I don't think the concerns on this have been answered."

Schatzberg told Medscape Medical News that in light of these concerns, clinicians should prescribe cautiously, with priority to the acutely ill. "Acute treatment seems reasonable to me," he said.

"Sharp Relapse Rate"

A N-methyl-D-aspartate receptor antagonist, ketamine's side effects include abuse as well as cognitive, urological, and hepatic toxicities.

However, Schatzberg told meeting delegates that what troubles him most are the lesser known reports in recent FDA Briefing documents of troubling relapse trends with esketamine.

"There appears to be a sharp relapse rate. Even after 12 to 16 weeks of treatment with esketamine, patients relapse quickly," he said.

This relapse rate is documented in FDA files even though patients remained on the antidepressant medications they had been taking before and during the study.

"Even the antidepressant wasn't sufficient to prevent the relapse after discontinuing esketamine," said Schatzberg. "This represents a real problem. What are you going to do with these patients — tell them to keep taking the esketamine?"

Drug-Related Deaths?

FDA briefing documents submitted to advisory panels considering the esketamine's approval report six deaths in patients with resistant depression and three suicides — two at 12 and 20 days after the last dose of esketamine, and one 4 days after the last dose.

The two suicides that occurred at 12 and 4 days following the last dose were by patients who appeared to be improving, as indicated by scores on the Montgomery-Åsberg Depression Rating Scale.

The report concludes that "given the small number of cases, the severity of the patients' underlying illness and the lack of a consistent pattern among these cases, it is difficult to consider these deaths as drug-related." However, Schatzberg argued that the deaths show a troubling similarity to withdrawal from addiction.

"When you think about an opioid, you think about the fact that being off the drug is more important than on the drug. That's when you see the problem," he said.

"So to me, these deaths are indeed drug-related. They're related to going off the drug. To say [the suicides] are not related to the drug because they're within 3 weeks after stopping is simply not correct," he added.

As reported by Medscape Medical News, Schatzberg and his team recently published a study showing that ketamine's antidepressant effects require activation of opioid receptors in the brain. This contradicts previous beliefs that the drug's effects primarily stem from its impact on the glutamate system.

Overall, Schatzberg noted that clinicians should prescribe with caution.

"The issue that is unclear is: What is the optimal number of follow-on treatments to be sufficiently safe? That to me is still unanswered," he said.

"I do think ketamine and esketamine offer great advantages, but we have to figure out how to best use them and I would encourage [Janssen] and the National Institutes of Health to study them in greater detail," he added.

Deep Dive

A standing-room-only session held on the following day of the ADAA meeting featured an expert panel that addressed a growing trend in psychiatry — a growing acceptance of mind-altering drugs, including MDMA and psilocybin, in the treatment of anxiety and depression. There, ketamine remained the hot topic of discussion as experts weighed potential benefits with continuing concerns.

"Why should we have to wait for these 8- to 12-week trials of antidepressants to see if they will work? Ketamine is opening the door for psychotherapy research, as well, and patients are becoming more accepting of this," Zarate told meeting delegates.

However, he acknowledged concerns about the drug, particularly surrounding the abuse potential.

"Research on the mechanisms of ketamine is terribly slow," he said. "In the meantime, people are saying 'our patients are suffering and we need something like this right away.' So ketamine clinics are proliferating and this is a concern because we don't know the long-term effects of this yet."

A repeatedly voiced concern was about clinical trials of ketamine, as well as other drugs, and the difficulty in having a convincing placebo that is able to mimic the strong effects of these agents. Some trials have used midazolam as an "active" placebo for ketamine. However, there is ongoing worry that participants are easily able to determine whether they have received ketamine or not.

"This is a serious issue because the danger of converting a double-blind study into what amounts to an open series of patients is massive," said Schatzberg, who was among the panelists.

Urgently Needed PTSD Treatment

As an experienced researcher into post-traumatic stress disorder (PTSD), Adriana Feder, MD, Icahn School of Medicine at Mount Sinai, New York City, made the case for ketamine also as an urgently needed treatment for PTSD.

"I absolutely agree that long-term studies are needed, but I think it's important to also consider the other side, which is all the suffering and disability and risk for suicide in untreated depression and PTSD," Feder said.

"We have animal studies showing reversal of synaptic atrophy from chronic stress, and neuroimaging studies pre- and post-treatment appear to show a restoral of connectivity in the prefrontal cortex, which is really important for fear and emotion in depressed patients. So I'm very heartened by those findings," she added.

While a current ongoing study led by Feder on repeated administration of ketamine is still blinded, she shared an example of response in a woman who had suffered abuse from a stepfather from age 4 to 15 years.

"With the ketamine treatment, she said, 'Oh, this must be what it feels like to be normal.' And she said, 'At least my children will get to be exposed to a normal mother,' " Feder reported.

"So yes, I think this is important. We don't know the long-term effects, so we have to be very cautious; but on the other hand, there's a need out there," she said.

"People are committing suicide at ever-increasing rates and there are no effective treatments for them."

ADAA Weighs In

Commenting on the issue for Medscape Medical News, Beth Salcedo, MD, president of the ADAA and medical director of the Ross Center, Washington, DC, shared the cautious optimism voiced by many at the meeting.

"I think the field is so excited to have a new and novel treatment for this group of people with treatment-resistant depression," Salcedo said.

"The cost to their lives in terms of suffering with depression without relief is tremendous, the cost to society for treatment-resistant depression is tremendous, and the suicide rates are high and rising. So the field as a whole is very excited about a new treatment direction," she said.

Still, "we have to be very careful," she added. "The reason the FDA ran this through quickly is because it really is needed."

"It could potentially be misinterpreted, however, and used as a quick fix by some. So we have to be careful to adequately assess who should receive this," Salcedo said.

Schatzberg has received research funding from Janssen Pharmaceuticals and has served as a consultant for Alkermes, Avanir, Bracket, Compass, Brain Resource, Delpor Epiodyne, GLG, Jazz, Lundbeck, McKinsey, Merck, MSI, Myriad Genetics, Neuronetics, Owl, Pfizer, Sunovion, Takeda, and Xhale. He also has equity in BrainCells, Corcept, Delpor, Dermira, Epiodyne, Incyte Genetics, Madrigal, Merck, Owl, Seattle Genetics, Titan, and Xhale and is a named inventor or has pharmacogenetic patents on mifepristone use. Zarate receives funding from the NIH for his research. Feder is a named co-inventor on a pending patent application, filed by the Icahn School of Medicine at Mount Sinai, related to the use of ketamine for the treatment of PTSD. Salcedo has disclosed no relevant financial relationships.

Anxiety and Depression Association of America (ADAA) Conference 2019. Presented March 29 and 30, 2019.

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