Long-term Safety of Ketamine and Esketamine for TRD

Ketamine and Esketamine: Promising Safety Profiles for TRD

A recent systematic review published on August 7, 2026, provides critical insights into the long-term safety of ketamine and esketamine for treatment-resistant depression (TRD). The study, which synthesized data from 32 studies, found no evidence of cumulative organ toxicity or iatrogenic addiction, making these treatments viable options for maintenance therapy. This review is significant for clinicians and researchers, offering reassurance regarding the safety profiles of these treatments over extended periods.

Mechanisms and Context of the Review

The review analyzed data from studies with follow-up periods ranging from 3 months to 9 years, focusing on nine safety domains: neurocognitive, dissociative/psychotomimetic, sedation, cardiovascular, hepatic, urinary, misuse/dependence, suicidality, and serious adverse events (SAEs). Despite the transient nature of dissociative and sedative effects, which resolved within 1-2 hours post-administration, the review found no long-term neurocognitive dysfunction or significant urologic complications. Importantly, the study highlighted the absence of drug-seeking behavior or withdrawal symptoms, addressing a common concern about the potential for addiction.

Implications for Policy and Research

The findings of this review have important implications for both policy and future research. The absence of cumulative organ toxicity and addiction risk supports the integration of ketamine and esketamine into long-term treatment protocols for TRD. However, the review also underscores the need for standardized safety monitoring protocols across studies to ensure consistency and reliability in safety assessments. This standardization could facilitate more robust comparisons and enhance the generalizability of findings.

Risks and Unknowns in Long-term Use

Despite the positive findings, some risks and unknowns remain. The review noted that while suicidal ideation scores generally decreased, suicide attempts and completions did occur during follow-up periods, highlighting the need for careful monitoring of patients. Additionally, the heterogeneity in safety monitoring across studies presents a challenge in drawing definitive conclusions about long-term safety. These gaps underscore the necessity for continued research and vigilance in clinical practice.

Looking Forward: The Future of Ketamine and Esketamine in TRD

As the use of ketamine and esketamine in treating TRD continues to evolve, the findings from this review provide a foundation for their broader acceptance in clinical practice. Future research should focus on addressing the current gaps in safety monitoring and exploring the long-term efficacy of these treatments. By doing so, the medical community can better understand the full potential and limitations of ketamine and esketamine in managing treatment-resistant depression.