Esketamine, Off-Label Ketamine, and the Regulatory Gap: A Conversation With Lisa Harding, MD

TALKING WITH TITANS

At the 2026 Jersey City Psychiatry Conference, Psychiatric Times' Editor in Chief, John J. Miller, MD, sat down with leaders in the field to discuss the topics they find most important. On day 1 of the conference, he sat down with titan Lisa Harding, MD, a psychiatrist at Yale University in New Haven, Connecticut, who also works in private practice. They discussed how intranasal esketamine (Spravato) has been used clinically, how little its suicidality indication is used, and why off-label racemic ketamine faces so few rules.

Yale researchers first described ketamine's rapid antidepressant effect in the 1990s.¹ Harding finished training at Yale as chief of interventional psychiatry just as esketamine's phase 3 program was ending and the drug was moving toward FDA approval. Esketamin, the S-enantiomer of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, was approved in 2019 for treatment-resistant depression (TRD). In 2020, it was approved for depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior (MDSI).

An Underused Indication

Harding called the MDSI indication "the one untapped indication" for esketamine. Unlike the TRD indication, it does not require prior antidepressant failures. She said economics play a part, but so does how comfortable clinicians feel. Harding has helped launch esketamine in Australia, Saudi Arabia, Brazil, Mexico, and Colombia. She said about 90% of her work over the past 7 years has gone to helping clinicians feel comfortable with the treatment, including the blood pressure checks at the start, middle, and end of each session.

She stressed that the MDSI approval does not mean esketamine treats suicidality. In the 2 registration trials, hospitalized participants started on 84 mg, with 1 permitted reduction to 56 mg for adverse effects. Depressive symptoms fell quickly enough to help clinicians plan next steps for the patient.² "No medicine to date has been given an FDA approval to target suicidal ideation," Harding said. "It targets those depressive symptoms, so that clinicians can make other interventions to keep the patient safe."

Harding also pointed to the gap between trial populations and patients seen in practice; the latter often have more advanced illness and more medical and psychiatric comorbidities. She also named logistics as an issue. Treatment centers must be certified under a Risk Evaluation and Mitigation Strategy (REMS), and staff must be able to manage both physiologic events and dysphoric reactions. She said these demands help explain why the drug is underused.

The Ketamine Regulatory Gap

Miller asked why racemic ketamine can be given orally, sublingually, intramuscularly, or intravenously, and even mailed to patients, without the REMS rules that govern esketamine. Harding noted that regulators do not govern off-label prescribing. In her view, the larger problem is that ketamine is a Schedule III substance. Pandemic-era relaxation of the Ryan Haight Act's in-person evaluation rule allowed prescribing across state lines, and some may have exploited this fault.

Racemic ketamine was approved as an anesthetic meant to stay in the hospital, so it never needed a REMS. Harding said gaps in compounding pharmacy rules, reporting to prescription drug monitoring programs, and data sharing between states have created "a legal loophole that has been exploited." She cited news reports in which families linked suicides to oral ketamine mailed to their homes. She also noted that the FDA, through the Reagan-Udall Foundation, held a 2-day public meeting on ketamine use in 2024.

Patient Selection Drives Outcomes

Harding estimates she has given esketamine more than 10,000 times. She credits her outcomes to careful screening, not to the drug itself. Patients must first be medically cleared, since contraindications include aneurysmal vascular disease. They must then fit the psychiatric criteria. According to her business manager, about 30 of every 1000 screened patients go on to treatment.

"The crux of this is screening the appropriate patient for the treatment," Harding said. "The right patient has to be treated, and to reduce the amount of treatment emergent adverse events, it is patient preparation."

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Volunteer Consulting Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

Dr Harding is an assistant clinical professor at Yale School of Medicine, and is the medical director at the Mood Institute.

References

1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.

2. Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191.