Esketamine Lowers Postoperative Anxiety/Depression in Colorectal Surgery: New RCT Evidence

Esketamine Reduces Early Postoperative Anxiety and Depression in Colorectal Cancer Surgery

Intravenous esketamine administered during anesthesia induction and postoperative analgesia significantly reduced early postoperative anxiety and depression in patients undergoing laparoscopic radical resection for colorectal cancer. This finding comes from a prospective, randomized, placebo-controlled trial published on September 11, 2026 (OpenAlex W7212220090). Adult patients were randomized to receive either standard general anesthesia and patient-controlled intravenous analgesia (PCIA) or an esketamine-enhanced protocol: 0.5 mg/kg esketamine at induction and 1 mg/kg added to PCIA. The primary outcome, Hospital Anxiety and Depression Scale (HADS) scores on postoperative day 1, was significantly lower in the esketamine group. Secondary outcomes, including HADS scores on days 3 and 7, sleep quality, and patient satisfaction, also favored esketamine without increasing complications or hospital stay length.

Mechanism and Clinical Context: Expanding Esketamine’s Role

Esketamine, the S-enantiomer of ketamine, is known for its rapid antidepressant effects in treatment-resistant depression, but its perioperative mental health benefits are less established. The mechanism likely involves N-methyl-D-aspartate (NMDA) receptor antagonism, leading to downstream effects on glutamate signaling and neuroplasticity. In the perioperative setting, patients face acute psychological stressors—pain, anesthesia, cancer diagnosis, and surgical trauma—that can precipitate or exacerbate anxiety and depression. This trial is among the first to demonstrate that esketamine, when integrated into standard anesthesia and analgesia protocols, can measurably improve early mental health outcomes in a surgical oncology population. Notably, the protocol used both a bolus at induction and a continuous infusion via PCIA, a regimen that may optimize both analgesic and psychotropic effects while minimizing dissociation or hemodynamic instability.

Policy and Research Implications: Beyond Treatment-Resistant Depression

The results of this trial suggest esketamine could be considered for perioperative mental health management, especially in high-risk populations such as cancer surgery patients. While esketamine is currently approved by the U.S. Food and Drug Administration (FDA) for treatment-resistant depression and suicidal ideation, its off-label perioperative use remains largely unexplored in regulatory guidance. This study adds to a small but growing body of evidence supporting ketamine’s utility for acute psychiatric distress outside chronic mood disorders. For hospital systems and anesthesia departments, these findings may prompt protocol reviews and further pragmatic trials, particularly as patient satisfaction and mental health outcomes gain prominence in quality metrics. Importantly, the study’s design—using a real-world surgical population and standard-of-care comparators—provides actionable data for clinicians considering perioperative esketamine integration.

• Non-obvious insight: The trial’s use of both induction and PCIA-phase esketamine highlights a dosing strategy that may be more effective than single-dose regimens, a detail often overlooked in prior studies and practice guidelines.

Risks, Limitations, and Unknowns

While the trial did not observe increased complication rates or prolonged hospital stays, esketamine’s safety profile in surgical populations requires further scrutiny. Known risks include dissociation, transient hypertension, and potential for misuse, though these are less common at subanesthetic doses. The study’s follow-up was limited to the first postoperative week; longer-term effects on mood, cognition, and functional recovery remain unknown. Additionally, the results may not generalize to other surgical types, patient populations (e.g., those with pre-existing psychiatric disorders), or healthcare settings with different perioperative protocols. Regulatory and reimbursement pathways for perioperative esketamine are also undefined, and widespread adoption would require robust safety monitoring and staff training.

Looking Forward: Research and Clinical Integration

This trial represents a meaningful step in expanding the evidence base for esketamine beyond chronic psychiatric indications, but further research is essential. Future studies should address optimal dosing regimens, long-term mental health outcomes, and comparative effectiveness against other perioperative interventions. Clinicians and hospital administrators should weigh the potential benefits against safety, regulatory, and operational considerations. As patient-centered care models evolve, perioperative mental health may become a new frontier for psychedelic and dissociative agents—provided robust evidence and clear protocols guide their use.

How we research: This article was written and reviewed by Dr. Alex Chen, MD, PhD (psychiatry, clinical trials), on 2026-09-12. Primary data were sourced directly from the published trial (OpenAlex W7212220090) and cross-checked against FDA and hospital practice guidelines.