Ketamine and Esketamine: Emerging Roles in Psychiatry

Introduction to Ketamine and Esketamine in Psychiatry

Treatment-resistant depression (TRD) poses a significant challenge in psychiatry, affecting patients who do not respond adequately to conventional antidepressants. Recent developments have introduced ketamine and its derivative, esketamine, as promising alternatives in this domain. This narrative review, published on May 9, 2026, in OpenAlex, provides a comprehensive overview of these substances' roles in treating TRD, emphasizing their mechanisms, administration, and safety profiles.

Mechanisms and Administration

Ketamine and esketamine primarily act on glutamatergic pathways, offering a distinct mechanism compared to traditional antidepressants that typically target monoaminergic systems. Ketamine is generally administered intravenously in a controlled clinical setting, ensuring patient safety and monitoring. In contrast, esketamine is available as an intranasal formulation, providing a more convenient but still supervised option. These administration methods reflect the need for careful consideration of tolerability and monitoring requirements.

Policy and Research Implications

The introduction of ketamine and esketamine in clinical practice signifies a shift towards interventional psychiatry, where novel therapeutic approaches are explored for complex psychiatric conditions. Policymakers and researchers must focus on optimizing treatment protocols, understanding long-term outcomes, and refining patient selection criteria. This will involve extensive clinical trials and collaborative efforts to ensure these treatments are both effective and safe.

Risks and Unknowns

Despite their potential, ketamine and esketamine are not without risks. Concerns about their safety profiles, potential for misuse, and long-term effects necessitate ongoing research. Clinicians must weigh these risks against the benefits, particularly in patients with severe, treatment-resistant conditions. The need for comprehensive guidelines and monitoring protocols is critical to mitigate potential adverse effects.

Looking Forward

As the field of interventional psychiatry continues to evolve, ketamine and esketamine represent promising avenues for addressing TRD. Future research should aim to deepen our understanding of their mechanisms, optimize dosing strategies, and explore their use in broader psychiatric contexts. Collaboration between researchers, clinicians, and policymakers will be essential to fully realize the potential of these treatments while ensuring patient safety and efficacy.