Long-term Safety of Ketamine and Esketamine in TRD

Evidence Supports Long-term Safety of Ketamine and Esketamine

A systematic review published in August 2026 provides compelling evidence supporting the long-term safety of ketamine and esketamine for patients with treatment-resistant depression (TRD). This review is crucial for clinicians considering these treatments as part of maintenance therapy, as it indicates no cumulative organ toxicity or iatrogenic addiction. The findings are based on a comprehensive analysis of studies with follow-up periods ranging from 3 months to 9 years.

Mechanisms and Context of Ketamine and Esketamine Use

Ketamine and its derivative, esketamine, have been increasingly used in maintenance protocols for TRD, especially given the high incidence of patients who do not respond to conventional antidepressants. The review synthesized data from 32 studies, including 11 randomized controlled trials (RCTs) and 21 non-randomized studies, to evaluate long-term safety. The studies assessed safety across nine domains, including neurocognitive, dissociative, cardiovascular, and urinary effects. Importantly, the review found that both formulations demonstrated essentially equivalent safety profiles.

Policy and Research Implications

The findings of this review have significant implications for both clinical practice and future research. For clinicians, the evidence supports the continued use of ketamine and esketamine in long-term maintenance therapy for TRD, with careful monitoring of transient acute effects such as dissociation and sedation, which typically resolve within 1-2 hours of administration. For researchers, the review highlights the need for standardized safety monitoring protocols across studies to reduce heterogeneity and improve data reliability.

Risks and Unknowns in Long-term Use

While the review supports the safety of ketamine and esketamine, it also underscores certain risks and unknowns. Although no cumulative organ toxicity or iatrogenic addiction was observed, there were instances of suicidal ideation reduction, yet some suicide attempts and completions occurred during follow-up. This suggests a need for ongoing patient monitoring and support. Additionally, the review notes the variability in safety monitoring across studies, which could impact the generalizability of the findings.

Looking Forward: Future Directions in TRD Treatment

As the use of ketamine and esketamine in TRD continues to grow, future research should focus on standardizing safety monitoring and exploring the long-term effects beyond the typical 3 to 12-month follow-up periods. This will help ensure that these treatments remain safe and effective for a broader patient population. Moreover, understanding the mechanisms underlying the transient effects and their management could further enhance treatment protocols.