Long-term Safety of Ketamine in Treatment-resistant Depression

Long-term Safety of Ketamine and Esketamine

A recent systematic review has confirmed the long-term safety of ketamine and esketamine for patients with treatment-resistant depression (TRD). This review, published on August 17, 2026, in OpenAlex, analyzed data from 32 studies, including 11 randomized controlled trials (RCTs) and 21 non-randomized studies, with follow-up periods ranging from 3 months to 9 years. The findings showed no evidence of cumulative organ toxicity or iatrogenic addiction, providing reassurance to clinicians and researchers about the safety of these treatments over extended periods.

Mechanism and Context of Ketamine Use

Ketamine and its derivative, esketamine, have gained attention for their rapid antidepressant effects, particularly in patients who do not respond to conventional treatments. Approximately 30-40% of individuals with major depressive disorder fall into this category. The review synthesized safety outcomes across nine domains, including neurocognitive, dissociative, sedative, cardiovascular, hepatic, urinary, misuse/dependence, suicidality, and serious adverse events (SAEs).

Importantly, the review found that neither racemic ketamine nor intranasal esketamine demonstrated cumulative organ toxicity in cardiovascular, hepatic, or urinary domains during maintenance treatment. While dissociative and sedative effects were common, they were transient, resolving within 1-2 hours of administration. No treatment-emergent neurocognitive dysfunction was identified, and urologic complications were rare, resolving with treatment discontinuation.

Implications for Policy and Research

The findings of this review are significant for policymakers and researchers focusing on TRD. With no documented cases of iatrogenic addiction, drug-seeking, or withdrawal, ketamine and esketamine present a viable option for long-term management of TRD. Suicidal ideation scores showed reductions from baseline, although some suicide attempts and completions occurred during follow-up periods. The review suggests that both formulations have essentially equivalent long-term safety profiles, which could influence future guidelines and regulatory decisions regarding their use.

Risks and Unknowns

Despite the positive findings, the review highlighted some limitations, including heterogeneity in safety monitoring across studies. While serious adverse events attributable to treatment were rare, the occurrence of suicide attempts during follow-up underscores the need for ongoing monitoring and comprehensive patient support. The transient nature of acute effects also necessitates careful management to ensure patient safety and adherence to treatment protocols.

Looking Forward

As the use of ketamine and esketamine continues to expand in clinical settings, further research is needed to standardize safety monitoring and optimize treatment protocols. Future studies should focus on long-term outcomes beyond 9 years and explore potential interactions with other medications commonly used in TRD management. This systematic review provides a foundation for future investigations and supports the continued integration of these treatments into clinical practice.