Research Frontiers in Ketamine and Esketamine for Treatment-Resistant Depression

Morgan Hardy, MD, a psychiatrist at Yale School of Medicine specializing in interventional psychiatry, and William Li, MD, a third-year psychiatry resident in the research track at Yale, discussed ongoing and future research directions in ketamine-based treatment for severe, treatment-resistant depression (TRD).

Li described the group's most anticipated active project: a large, multi-site randomized controlled trial comparing intranasal esketamine to IV racemic ketamine for TRD. He acknowledged that results would not be available for several years but emphasized that the trial was designed to definitively address a central clinical question: whether meaningful efficacy differences exist between the 2 ketamine-based delivery modalities.

Both speakers addressed the adverse effect and safety profile of ketamine and related compounds. The group had previously published a review examining the neurotoxic potential of ketamine, with particular attention to the unknown chronic side effects associated with home delivery or use in unstructured clinical environments, which Li characterized as potentially dangerous.¹ The group was also leveraging a dataset of psychedelic compounds collected by the Rocky Mountain National Data Center to compare the adverse effect profiles of those agents against ketamine, with publication anticipated within the year.

On the question of misuse, Hardy drew a clear distinction between supervised medical use and recreational use. He noted that intranasal esketamine, by virtue of its FDA approval and mandatory Risk Evaluation and Management Strategy (REMS) program, had been virtually free of abuse.² IV ketamine, lacking equivalent regulatory oversight, presented a different risk picture. Nevertheless, Hardy indicated that from available data, the rate of patients receiving ketamine medically who subsequently abused it remained very low, noting that "the rise in abuse that we're seeing is entirely in the recreational realm where people are using these outside of a medical setting."

Hardy emphasized the broader clinical imperative, stating: "Ketamine is our best but it's our only rapid-acting antidepressant and as our study has shown and numerous others have shown is that it changes people's lives." Both experts concluded that psychiatrists were well-positioned to apply shared decision-making and guide patients toward individualized treatment goals, balancing the transformative potential of ketamine-based therapies against their risks through careful dose optimization and integration with behavioral interventions.

Dr Hardy is a psychiatrist at Yale School of Medicine specializing in interventional psychiatry.

Dr Li is a third-year psychiatry resident in the research track at Yale.

References

1. Li SW, Kumpf KT, Urrutia J, et al. Ketamine for depression, but at what cost? A review of ketamine's neurotoxic effects from preclinical and human studies. Am J Psychiatry. 2025;182(10):903-912.

2. Roncero C, Merizalde-Torres M, Szerman N, et al. Is there a risk of esketamine misuse in clinical practice? Ther Adv Drug Saf. 2025;16:20420986241310685.