Ketamine Korner: Edition 8
Ketamine Korner is a bi-weekly newsletter exploring advances in ketamine therapy, originally started by Mind Pain Relief Institute Co-Founder Dr. Rohit Aiyer.
Each edition is republished with permission from Dr. Aiyer.
Latest Research Highlight:
Research Update: As ketamine-based treatments move from rescue interventions to longer-term care strategies, questions of maintenance, relapse prevention, and safety have come to the forefront.
One of the most influential studies addressing this issue is SUSTAIN-1, a randomized, double-blind, relapse-prevention trial published in The New England Journal of Medicine in 2019 (Daly et al.). In this study, patients with treatment-resistant depression who achieved stable remission or response with intranasal esketamine plus an oral antidepressant were randomized to continue esketamine or switch to placebo.
Results showed that continuation of esketamine significantly delayed time to relapse, with relapse rates of 26% in the esketamine group versus 45% in the placebo group among responders, and an even larger separation among those in stable remission.
Longer-term safety data come from SUSTAIN-2, an open-label, multicenter study published in The Journal of Clinical Psychiatry (Wajs et al., 2020). This trial followed patients receiving intermittent esketamine for up to one year. The study found that cognitive performance remained stable over time, no new safety signals emerged, and dissociative or blood pressure effects were generally transient and diminished with repeated dosing.
Together, these studies provide some of the strongest evidence to date that ketamine-based therapies can be used safely and effectively in a maintenance framework, when delivered with appropriate monitoring.
A Brief History of Ketamine and Maintenance Treatment:
Early Focus on Rapid Relief: Initial ketamine trials in the early 2000s emphasized its rapid antidepressant effects, often lasting days to a week after a single infusion (Zarate et al., Archives of General Psychiatry, 2006). While revolutionary, these short-lived benefits highlighted the problem of relapse.
Recognizing the Relapse Gap: By the 2010s, repeated-infusion studies demonstrated that even successful acute responders frequently relapsed within weeks of stopping treatment (Murrough et al., Biological Psychiatry, 2013). This shifted attention toward continuation and maintenance strategies.
Esketamine and Regulatory Turning Points: The FDA approval of intranasal esketamine in 2019 marked a major inflection point, as it was accompanied by large-scale relapse-prevention and long-term safety trials. This helped move ketamine treatment from experimental use toward structured, evidence-based protocols.
Current Perspective: Today, ketamine and esketamine are increasingly conceptualized not as one-time interventions, but as part of longitudinal treatment plans, with dosing frequency tapered over time and combined with psychotherapy and standard pharmacologic care.
Mythbuster:
Myth: Ketamine treatments are too unsafe or destabilizing for long-term use.
Reality:
Relapse-Prevention Evidence Exists: Randomized trials show that continued esketamine significantly reduces relapse risk compared with discontinuation (Daly et al., NEJM, 2019).
Long-Term Safety Has Been Studied: One-year data demonstrate stable cognition and manageable side effects under supervised care (Wajs et al., J Clin Psychiatry, 2020).
Structure Matters: Safety outcomes depend heavily on controlled dosing, medical monitoring, and integration into a broader treatment plan.
Ketamine is not risk-free, but neither is untreated or recurrent severe depression. Evidence increasingly supports its measured, supervised use over time in appropriate patients.
Key Takeaway:
The future of ketamine therapy is no longer defined solely by speed of response. Increasingly, the field is focused on staying well—preventing relapse, ensuring safety, and integrating ketamine into durable, long-term care models.
As maintenance-oriented research grows, clinicians are gaining clearer guidance on how ketamine-based treatments can be used responsibly, sustainably, and effectively in modern psychiatric practice.
As the science evolves, so does our understanding of ketamine’s place in psychiatry. Staying informed helps us separate fact from myth and shape the future of evidence-based care. Until next time, stay curious and engaged with the possibilities ahead.