Serious, 'Unexpected' Adverse Events From Nasal Esketamine

Patients who receive esketamine for treatment-resistant depression (TRD) are at increased risk for serious and unexpected adverse events (AEs), new research suggests.

Results showed that participants who were treated with esketamine were at significantly greater risk for dissociation, sedation, and suicidal ideation than those treated with other antidepressants. They were also at increased risk for autoscopy, panic attacks, and paranoia.

The risk was more pronounced among women, patients with comorbidities, and those who were taking multiple medications.

"These results are important because this is the first real-world data on the safety profile of esketamine," lead author Chaira Gastaldon, MD, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy, told attendees as at the virtual European Psychiatric Association (EPA) 2021 Congress.

"This drug might carry a clear potential for serious and unexpected adverse events that were not reported by approval trials," she added.

Gastaldon also noted that AEs such as rapid-onset euphoria, dissociation, and feeling drunk show there is a risk for misuse "that can make this drug like a recreational drug, which is what happened to ketamine."

In addition to being presented at the EPA meeting, the results were recently published in Psychotherapy and Psychosomatics.

Limited Safety Data

Gastaldon noted that although esketamine nasal spray was approved by the US Food and Drug Administration (FDA) for TRD in 2019, there are limited data on its safety.

This is partly because of the relatively small sample sizes in the randomized controlled trials used for the approval application, "so it is impossible to detect rare adverse events," she said.

Those studies also "usually employ highly selected populations," such as persons without suicidal ideation, those without comorbidities, and those who are not taking other medications. Such a population is "different from the real-world one we are used to treating," she added.

For this analysis, the investigators collated records from the FDA Adverse Event Reporting System database for the period of March 2019 to March 2020.

They used a consolidated case/noncase approach in which AEs related to the use of esketamine that were reported at least four times were matched with those relating to other drugs. This approach is similar to a case-controlled analysis.

The researchers identified 2274 esketamine-related AEs among 962 patients (mean, 2.4 events per person); 389 patients had a serious AE, and there were 22 deaths.

Expected, Unexpected Findings

Serious treatment-related AEs were significantly more common among women; patients given higher doses of esketamine; those who were also taking mood stabilizers, antipsychotics, benzodiazepines, or somatic medications; and patients with comorbidities (P < .001 for all).

These findings are important because esketamine has not been approved to be used "alone but as an add-on medication, so it needs to be added to other antidepressants," Gastaldon said.

Disproportionality analysis showed that several AEs were significantly associated with use of esketamine compared with other drugs. These included dissociation (reporting odds ratio [ROR], 1612.64), sedation (ROR, 238.46), feeling drunk (ROR, 96.17), suicidal ideation (ROR, 24.03), and completed suicide (ROR, 5.75).

Gastaldon emphasized that these AEs were expected because they were "also reported by the approval trials."

However, she noted that, compared with those taking other antidepressants, patients taking esketamine also had higher rates of disorder-related AEs, such as self-injurious ideation (ROR, 42.80), depression (ROR, 9.17), and crying (ROR, 9.01).

There were also a series of unexpected AEs that were significantly increased in the esketamine group. These included autoscopy (ROR, 166.44), derealization (ROR, 56.98), euphoric mood (ROR, 46.03), logorrhea (ROR, 44.34), panic attack (ROR, 13.57), and paranoia (ROR, 13.48).

Although these findings are also important, Gastaldon noted that it is impossible in this type of study to infer causality or to calculate the "real incidence of these adverse events because we don't have the total number of prescriptions" for the patients.

Risk-Benefit Calculation

Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, who was not involved in the current study, was lead author on a recent expert opinion article on the current evidence regarding the use of ketamine and esketamine for TRD.

The researchers concluded that although intranasal esketamine "demonstrates efficacy, safety, and tolerability for up to one year in adults with TRD," the evidence for its long-term safety and tolerability is "insufficient."

In particular, they noted safety concerns regarding "psychiatric, neurologic/cognitive, genitourinary, and hemodynamic effects." They also suggested that the drug "should be administered only in settings with multidisciplinary personnel including, but not limited to, those with expertise in the assessment of mood disorders."

However, McIntyre told Medscape Medical News that "there's always a calculus in medicine." In other words, "what is the bad and what is the good of the treatment?" he asked.

"We're talking about treatment-resistant depression, the world's leading cause of disability, and it's the disorder that's most often associated with suicide, which is claiming over a million lives a year. So this is a serious public health problem [and is] obviously going to affect the risk-benefit calculation," he said.

Nevertheless, McIntyre said he "always" has a concern that with ketamine and esketamine, there could be the potential for abuse and even "gateway activity," meaning using them could set the stage for the misuse of other drugs. This is of particular concern given the recent opioid crisis in the United States and Canada, he added. "So, I have a 'small-c' concern," he said.

McIntyre noted that ketamine has been around since 1970 and is now "one of the most utilized drugs in the world and is on the World Health Organization's list of essential medicines."

Consequently, there have been a number of votes of confidence in the drug and its isomer esketamine, despite the need for vigilance regarding the risk for AEs identified in the current and other studies.

At this point, the data suggest that "we have sufficient evidence to say that this is something we should be concerned about, we should keep an eye on. But at this stage, by no means would I say that the risk would warrant not considering giving this to a patient with depression," McIntyre said.

He emphasized that patient selection is key.

"If we select the right patients and you give it professionally as part of good clinical practice and you have fidelity to the product monograph recommendation around monitoring, I would say that I don't see [safety] as a major concern at this time," McIntyre concluded.

Gastaldon has reported no relevant financial relationships. McIntyre has relationships with CIHR/GACD/Chinese National Natural Research Foundation, AbbVie, Bausch Health, Eisai, Intra-Cellular, Janssen, Kris, Lundbeck, Minerva, Neurocrine, Novo Nordisk, Eli Lilly, Otsuka, P!zer, Purdue, Sunovion, and Takeda. He is also the CEO of Champignon Brands, Inc.

European Psychiatric Association (EPA) 2021 Congress: Abstract O230. Presented April 11, 2021.

Psychother Psychosom. 2021;90:41-48. Abstract

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