In recent years, media reports touting ketamine as a fast-acting, highly effective treatment for severe depression have increased. In part, this phenomenon is due to the US Food and Drug Administration's (FDA's) 2019 approval of ketamine's cousin, esketamine (Spravato), the first antidepressant in a new drug class for treatment-resistant depression (TRD).
Yet, news coverage of ketamine for depression often fails to include important differences between these two agents, leading to confusion among patients and clinicians alike, Lisa Harding, MD, former vice president of the American Society of Ketamine Physicians, told Medscape Medical News.
While ketamine and esketamine are chemically related, they are very distinct in terms of their chemical compositions, the FDA-approved indications, dosing, and administration, as well as the level of study and data supporting their safe and effective use, explained Harding, assistant clinical professor of psychiatry at Yale School of Medicine, New Haven, Connecticut.
Ketamine is a dissociative anesthetic approved in the United States for inducing and maintaining anesthesia via intravenous infusion or intramuscular injection. It is not indicated for major depressive disorder (MDD) or TRD, although it is frequently used off-label for these indications.
Esketamine, the (S) enantiomer of racemic ketamine, is FDA-approved for adults with TRD and adults with MDD with suicidal thoughts or actions in combination with an oral antidepressant.
Administered intranasally, it has a "well-studied, proven safety and efficacy profile" across 31 global clinical trials in more than 2200 patients, said Harding.
Unlike ketamine, esketamine is administered only in a physician's office with a strict treatment protocol enforced by a mandatory Risk Evaluation and Mitigation Strategy program.
By contrast, there is no drug safety program for ketamine, and physicians continue to have flexibility in off-label prescribing.
Rapid Proliferation of Ketamine Clinics
Under relaxed Drug Enforcement Agency (DEA) guidelines introduced during the COVID-19 pandemic, DEA-licensed practitioners can prescribe ketamine via telemedicine, without an in-person evaluation.
As a result, the United States has experienced a rapid proliferation of ketamine clinics to treat depression that operate with little, to no, regulation.
Some clinics are now prescribing ketamine lozenges that patients take at home. "There is no evidence to support treating patients by that route of administration," Harding said.
"I judge patients less because all of them are just trying to get relief from depression, which is a leading cause of disability worldwide, and there are very few effective treatments. And this is a very promising treatment, but it's just not for everybody, and the person has to be evaluated appropriately," she added.
She noted that treating psychiatric patients with ketamine or esketamine is still a developing, and nuanced, skill in psychopharmacology. A psychiatric assessment to identify appropriate candidates should be completed by a trained mental health expert who understands the clinical administration of both ketamine and esketamine and their respective indications.
The rapidly changing landscape of ketamine — both as a medical therapeutic and a recreational substance — has prompted calls for increased regulation and oversight. Harding and her Yale colleagues at Yale have been at the vanguard of this initiative.
"For a long time, we've been worried about the lack of regulation and coordination among clinics that provide ketamine as an off-label therapy for mental illness," Samuel Wilkinson, MD, assistant professor of psychiatry and associate director of the Yale Depression Research Program, told Medscape Medical News.
"We have been trying to lobby regulators and funders to establish a registry for ketamine use for many years but have not had success," he noted.
Significant Promise, Serious Risk
Emerging evidence suggests ketamine is becoming more widely used as a recreational substance. As previously reported by Medscape Medical News, a recent study found ketamine poisonings in the United States increased 81% between 2019 and 2021.
"People who decide to use ketamine recreationally need to be educated about potential risks," said Joseph Palamar, PhD, with New York University Grossman School of Medicine, New York City, who led this study. What's particularly worrisome, said Wilkinson, is the use of take-home ketamine, which some clinics now provide.
A tragic case in point, he said, is the recent death of Matthew Perry, in which ketamine was determined to play a contributing role in the actor's death.
"We don't know if the ketamine in his system was obtained illicitly or was prescribed to him, but there are preliminary reports that a significant portion of people who use ketamine at home, purportedly for therapeutic use, under the supervision of a clinician, actually end up using more than they are supposed to. Above all else we need to be cautious," Wilkinson said.
"Given how similar ketamine and esketamine are, it's hard to justify treating a patient with ketamine in a way that is fundamentally inconsistent with the strict guidelines the FDA has placed around the use of esketamine. Certainly, I don't think it would be very defensible from a legal perspective if something were to go wrong," he added.
Gerard Sanacora MD, PhD, professor of psychiatry and director of Yale Depression Research Program, told Medscape Medical News that physicians, "need to be very careful and responsible in how we consider the balance of the patients' need for novel treatments that are effective in TRD with the potential risk ketamine poses to individuals and society as a whole."
"The problem, said Sanacora, is that "at present, we are not collecting any meaningful data that will help us better understand true risk-benefit ratio of using ketamine in less restrictive treatment protocols. At a minimum, it would seem careful tracking of all ketamine use, similar to the data collected for intranasal esketamine, seems reasonable."
Wilkinson noted that this is not the first time that the medical community has had to deal with a potential treatment that has significant therapeutic promise but also serious risk.
"The opioid epidemic is another example. Hopefully, [with ketamine], we can do a better job of erring on the side of safety," he said.
Wilkinson, Sanacora, and Palamar are authors of a viewpoint on the rapidly shifting ketamine landscape in the United States, published online on January 3 in JAMA Psychiatry. They reported no relevant conflicts of interest.