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Esketamine, Spravato, was approved by the FDA for treatment-resistant depression in February 2019. Then on August 3, 2020, it was also approved to treat depressive symptoms in adults with major depression and symptoms other than suicidal ideation. But there have been a series of articles critical of the approvals, noting as Joanna Moncrieff and Mark Horowitz did in the BMJ, that it was licensed on flimsy evidence. They said: “The scientific community should instead be calling on the European Medicines Agency to resist the proposal to unleash another chemical on the unsuspecting public that has unproven benefits and untested harms.”
Research led by Chaira Gastaldon of the University of Verona caught the attention of Medscape Medical News in: “Serious, ‘Unexpected’ Adverse Events from Nasal Esketamine.” Gastaldon told the European Psychiatric Association 2021 Congress that esketamine “may carry a clear potential for serious and unexpected adverse events that were not reported by approval trials.” She noted that adverse events (AEs) like rapid-onset euphoria, dissociation and feeling drunk indicate there is a risk for misuse similar to ketamine. Esketamine (S-ketamine) is the left-handed isomer of ketamine.
Gastaldon and her fellow researchers collated records from the FDA Adverse Event Reporting System (FAERS) database for March 2019 to March 2020. Analysis showed that several AEs were significantly associated with esketamine when compared with other drugs. Serious treatment-related AEs were significantly more common among women; patients given higher doses of esketamine; those also taking other medications such as mood stabilizers, antipsychotics, and benzodiazepines. Gastaldon said these findings were important because esketamine was approved as an add-on medication, meaning it is to be used along with other antidepressants. Gastaldon, emphasized that these AEs were expected because they were also found in the approved trials for esketamine.
Robert McIntyre of the University of Toronto, who was not involved in the study was the lead author of an expert opinion article published in The American Journal of Psychiatry, “Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression.” The researchers concluded that while intranasal esketamine demonstrated efficacy, safety, and tolerability for up to one year in adults with treatment-resistant depression, the evidence for its long-term safety and tolerability was insufficient. He noted there is always a calculus in medicine; what are the risks and what are the benefits of a treatment. He acknowledged there is something to be concerned about at this point. “But at this stage, by no means would I say that the risk would warrant not considering giving this to a patient with depression.”
Along with other researchers, Gastaldon critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science. In “Esketamine for treatment resistant depression: a trick of smoke and mirrors?”, Gastaldon et al. questioned whether the rapid change in depression scores was due to improvement in depression or just a temporary effect of the drug on brain mechanisms. In other words, had “esketamine just modified some brain processes that impacted the depression scores, as many psychoactive substances are able to induce.”
For esketamine, understanding whether this rapid change in depression scores is due to an improvement of depression or just to a temporary effect of the drug on some brain mechanisms is of paramount relevance, as depression is a recurrent condition, and TRD is a particularly severe form of depression with symptoms persisting over long periods of time. It would be important to know if this acute effect is maintained in the long- term. For esketamine, however, long-term data are completely lacking.
Given that data on the safety of ketamine indicated the risk of abuse and associated harms, the FDA determined that a Risk Evaluation and Mitigation Strategy (REMS) was needed to see if the benefits of the drug outweigh the risks. REMS are a drug safety program required of medications with serious safety concerns. Gastaldon et al. argued that this action implied that esketamine was approved without knowledge of the potential negative consequences of esketamine prescribing. The results of the REMS could help in addressing some safety issues, “but this will require a long time and exposure of many persons with depression to this new agent.”
Reanalysis of the three efficacy trials revealed that the risk of dissociation was around 25%, almost seven times higher in the esketamine group as compared to placebo. “Again, we argue that further evidence on safety is urgently needed, given these preliminary signs suggesting that esketamine may not be safer than ketamine.”
Gastaldon also was the lead author on, “Post-Marketing Safety Concerns with Esketamine,” published in Psychotherapy and Psychosomatics. The authors concluded esketamine carries “a clear potential” for serious adverse events. “Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine [Effexor].” Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, and benzodiazepines were more likely to suffer from serious AEs.
Only the abstract of “Post-Marketing Safety Concerns with Esketamine” was available to me without paying $39 to Psychotherapy and Psychosomatics. However, Mad in America looked at Gastaldon et al.’s analysis of the FDA adverse event reports in, “New Research Questions Safety of Esketamine for Depression.” Rare AEs, not reported in regulatory trials of esketamine, such as self-injurious ideation, depressive symptoms, panic attack, paranoia and mania were detected. The most frequently reported adverse events (AEs) 5% or above were: Dissociation (9%), Sedation (7%) and Drug ineffectiveness (5%). The researchers concluded:
This study showed that the esketamine safety profile in the real-world population might be slightly different from that described in regulatory trials, and therefore further data from clinical practice would be required to better understand the safety profile of esketamine and provide an evidence-based framework for rational prescription. More real-world research is urgently needed, including pragmatic clinical trials, observational studies, and individual-participant meta-analyses on rare and unexpected AEs.
Concerns with esketamine are nothing new. There were problems noted with the FDA approval of Spravato, including only modest evidence of its effectiveness in limited trials; and no information provided on the safety of Spravato beyond 60 weeks, despite its potential for abuse. One member of the FDA advisory committee that ultimately approved Spravato thought its benefit was almost certainly exaggerated; another thought true treatment-resistant patients were weeded out of the trials. The FDA lowered the criteria bar for determining “treatment resistant depression.” Now patients had to fail to respond to two different antidepressant pills, not two different classes of antidepressants. This change meant that 49 of the 227 participants included in Janssen’s only successful efficacy trial failed just one class of oral antidepressants, not two.
Erick Turner, a member of that advisory committee, wrote about concerns he had about the efficacy of esketamine and its FDA approval for The Lancet. He noted seven concerns, including a lax definition of treatment-resistant depression, an 81% of response to esketamine with placebo, and a failure to formally demonstrate rapid onset. “In any case, only about 10% of patients who received esketamine achieved a rapid clinical response.” He wondered whether the novel mechanism of action encouraged leniency with the concerns he listed.
See “Hype and Concern with Esketamine,” “Doublethink with Spravato?” and “Red Flags with Spravato” for more on these concerns.
Not to be deterred by these findings, a group of employees of Janssen, the company that brought Spravato (esketamine) to market, responded to Gastaldon et al. in “Comments to Drs. Gastaldon, Raschi, Kane, Barbui and Schoretsantis.” Their reply was also published in Psychotherapy and Psychosomatics. They acknowledged the work of Gastaldon et al. in identifying potential safety signals related to esketamine. But they thought Gastaldon et al.’s interpretation of their findings was overstated.
In summary, our comprehensive surveillance has not revealed any new safety signal and confirms that Spravato® [esketamine] product labeling adequately addresses esketamine’s risks. Additionally, data are being collected in a prospective long-term safety study (NCT02782104). Janssen remains committed to ongoing esketamine safety monitoring via robust risk management and pharmaco-vigilance surveillance programs, including REMS, to ensure that up-to-date safety information is available to prescribers and patients.
It seems to me that this is the heart of the problem. Supporters of esketamine see its safety monitoring and REMS as providing “up-to-date safety information” to prescribers and patients. Critics see the need for a REMS as pointing out that esketamine was rushed to market without first gathering information on its potential long-term negative consequences. The drug companies themselves are responsible for managing and reporting the results of a REMS to the FDA. Can Janssen be trusted to not strategically massage the data found by NCT02782104 in order to present a favorable outcome with esketamine?