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SAN FRANCISCO -- Esketamine nasal spray (Spravato) was effective for alleviating symptoms of treatment-resistant depression when added to a standard antidepressant, but clinicians should be cautious with it, researchers said here.

In a phase III trial, 197 patients with moderate to severe treatment-resistant depression on an antidepressant were randomized to receive 56 mg (or up to 84 mg if well-tolerated) of esketamine nasal spray or placebo twice weekly.

After 28 days, those on the active drug plus an antidepressant saw a significantly greater drop in mean Montgomery-Åsberg Depression Rating Scale (MADRS) scores compared with the placebo group (least squares mean difference -4.0 points, 95% CI -7.31 to -0.64, one-sided P=0.010) -- achieving the study's primary endpoint, reported co-investigator Michael Thase, MD, of the Perelman School of Medicine at the University of Pennsylvania, at the American Psychiatric Association's (APA) annual meeting.

What's unique about this treatment was the rapid onset of symptom improvement. Only 24 hours after the initial dosing, patients receiving esketamine had a mean 3.3-point improvement in MADRS score relative to placebo (95% CI -5.75 to -0.85).

Preliminary data were first presented at last year's APA meeting. The final results were also simultaneously published Tuesday in the (AJP).

Based on the phase III trial data, the FDA approved the novel treatment earlier this year. It includes a boxed warning regarding the risk for mind-altering side effects such as problems with thinking, attention, judgment, as well as the risk for abuse and suicidal ideations.

During a press conference here, Thase noted that "this treatment has addiction liability -- it is a Schedule III controlled substance in the eyes of the Drug Enforcement [Administration] -- that is identical to the parent drug, ketamine. Schedule III is the same rating for benzodiazepines."

During the follow-up phase of the study, however, there were no reports of craving or drug abuse among those who received esketamine.

"It is [a] good standard of practice to have a 2-hour observation period," Thase said when explaining how the treatment is administered in clinical practice twice a week -- as it's not an at-home treatment. "During that time, their blood pressure should be monitored, they should be monitored for sedation. If someone needs to get up and go to the bathroom, make sure they don't have dizziness ... and occasionally, patients need a supportive, warm decent human to help them with an unpleasant psychoactive experience."

The parent drug ketamine (esketamine is the chirally pure S-enantiomer) is known for causing so-called dissociative symptoms, which can be disorienting but is also why it's a street drug known as "Special K."

As far as insurance coverage goes, this remains a barrier to access for some patients as of late. "There's never before been anything like [esketamine], and so many of us, our insurances plans have not yet determined or finalized how it will be covered," said Thase. On the other hand, he said he's "pleased to say so far in my experience, the adoption [of coverage] has been faster than it was, say, for example, for transcranial magnetic stimulation."

Nevertheless, Alan Schatzberg, MD, of Stanford University School of Medicine, , raised many concerns associated with this new treatment. He called the data "somewhat worrisome" and that we need "a better sense of how to use the drug."

"Relapse rates on discontinuing esketamine reached 40% by 3-4 months even though patients were receiving known antidepressants. This raises the question as to whether patients should be receiving esketamine for even longer periods -- or would that be even more risky?" he wrote.

Schatzberg, a former APA president, also spoke at the press conference where he noted that six deaths had occurred in esketamine's clinical trial program, including three suicides. The latter occurred 4, 12, and 20 days after the patients' last dose of esketamine. There were no suicides reported in the placebo group.

"The patients who committed suicide 12 and 4 days after their last dose both appeared to be improved based on their MADRS scores (from baseline of 27 to 9, and 41 to 25, respectively). The patient who committed suicide 20 days after his last dose was experiencing worsening symptoms (from MADRS 7, 13 days prior to heath to MADRS 21, 6 days prior to death)," according to .

The clinical challenge is to identify which patients are responding to esketamine, press conference panelists agreed.

"When people are really responders, they are responders. They really go into remission," Schatzberg emphasized, pointing to that showed dramatic responses in certain patients but not others. He suggested that, for depressed patients, clinicians try esketamine "a couple times" and then "move on" if the patients don't improve quickly.

"It's not kooky, but it does have some risks. We need to study it more. We need to do more. In the end, we're trying to help the patients. But at the same time, we're trying to keep people safe," he added.

Thase echoed this sentiment, saying that in the subset of participants on esketamine in the trial who were very responsive to the drug, they saw much greater than the average 4-point improvement in MADRS score by 28 weeks. "It's a large chunk of patients who are getting massive benefit. For the responders, it's a 20-point advantage. But when you mix the data, it looks modest."

"It's the Holy Grail trying to identify who's the most likely to benefit," said Thase, noting that the same is true for conventional antidepressants. "I have a hunch that you can see this happening within the first week or two and you can at least concentrate the resource on the patients who are gaining the large benefit."

When asked if genomic testing could help differentiate responders from non-responders, Thase noted that in the current literature, the only known predictor is a family history of alcoholism.

"This is the only example in therapeutics that I know of in which having relatives with alcoholism is an advantage," he said.

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