Intraoperative Low-Dose S-Ketamine Reduces Depressive Symptoms in Patients with Crohn's Disease Undergoing Bowel Resection: A Randomized Controlled Trial

Crohn's disease (CD), a chronic inflammatory gastrointestinal disorder, affects individuals primarily between 18 and 35 years old. A significant portion (35%) of CD patients experience depressive symptoms, a rate potentially higher in those requiring surgery (70%). Preoperative depression in CD patients is associated with increased disease exacerbation and more difficult postoperative recovery, highlighting the need for interventions to alleviate postoperative depression. Ketamine, a commonly used anesthetic, also shows promise in treating depression. While racemic ketamine carries risks like psychotic side effects, S-ketamine offers potentially better efficacy and a safer profile. The FDA's approval of S-ketamine nasal spray for refractory depression underscores its rapid antidepressant effects. S-ketamine's mechanism involves NMDA receptor blockage, leading to increased synaptic number and function, which counteracts stress-induced dendritic spine reduction in mood-regulating circuits. However, the effects of S-ketamine on surgical patients remain inconclusive due to variations in surgery type, dosage, analgesic interactions, and assessment methods. Prior studies have shown positive effects of low-dose S-ketamine on postoperative depression in breast and cervical cancer patients. This study aimed to investigate the effects of intraoperative low-dose S-ketamine preconditioning on postoperative depression, pain, and inflammation in CD patients undergoing bowel resection with mild to moderate depression.

Existing literature supports a strong correlation between Crohn's disease and depression. Studies show that a substantial percentage of CD patients experience depressive symptoms, with this percentage potentially increasing in individuals needing surgery. The impact of preoperative depression on disease exacerbation and recovery has been well-documented. Ketamine, known for its anesthetic properties, has emerged as a potential treatment for depression, with S-ketamine gaining attention for its improved safety profile compared to racemic ketamine. Studies on the antidepressant effects of S-ketamine in non-surgical settings are encouraging. While some research has explored the use of S-ketamine in reducing postoperative depression in other surgical contexts (breast and cervical cancer), a gap in the literature exists regarding its effects on CD patients undergoing bowel resection. This study aimed to fill this gap by investigating the efficacy and safety of low-dose S-ketamine in this specific patient population.

This double-blind, randomized, prospective controlled trial enrolled 124 adult CD patients (aged 18–60) requiring bowel resection and exhibiting mild-to-moderate depression (Hamilton Depression Rating Scale [HAMD-17] score of 8–24). Patients were randomly assigned to receive either intraoperative S-ketamine (0.25 mg/kg IV drip followed by a continuous infusion of 0.12 mg/kg/h for >30 min) or a placebo (0.9% saline). General anesthesia was induced with midazolam, sufentanil, propofol, and cisatracurium, with maintenance using propofol, remifentanil, dexmedetomidine, cisatracurium, and sevoflurane. Postoperative analgesia was standardized with patient-controlled intravenous analgesia (PCIA). The primary outcome measure was the HAMD-17 score, assessed preoperatively, and on PODs 1, 3, 7, and 30. Secondary outcomes included the PHQ-9, QoR-15, NRS (pain scores), CRP and IL-6 levels (PODs 1, 3, and 5), length of hospital stay, and total opioid consumption (converted to morphine equivalents). Statistical analysis using linear mixed-effect models compared outcomes between groups, accounting for time and potential interactions. The study was registered with ClinicalTrials.gov (NCT05506787).

The study included 124 patients, with 60 in each group after accounting for dropouts. Baseline characteristics were comparable between groups. Linear mixed-effects modeling revealed a significant interaction between group and time for HAMD-17 (F=84.974, p<0.001) and PHQ-9 (F=86.994, p<0.001). Postoperative HAMD-17 and PHQ-9 scores were significantly lower in the S-ketamine group compared to the placebo group on PODs 1, 3, and 7 (Bonferroni-adjusted p<0.001 for all comparisons). The QoR-15 scores were significantly higher in the S-ketamine group on PODs 3 and 5 (p<0.001). NRS pain scores were significantly lower in the S-ketamine group in the PACU, and on PODs 1 and 2 (p<0.001). There were no significant differences between groups in CRP, IL-6 levels, length of hospital stay, or postoperative complications. Postoperative opioid consumption was significantly lower in the S-ketamine group within 2 days post-surgery (p<0.05).

This study demonstrates that intraoperative low-dose S-ketamine effectively reduces depressive symptoms and postoperative pain in CD patients undergoing bowel resection. The significant improvements observed in HAMD-17, PHQ-9, and QoR-15 scores in the S-ketamine group support the hypothesis that S-ketamine can enhance postoperative mood and resilience. The reduction in opioid consumption also suggests a potential benefit in reducing opioid-related adverse events. The lack of a significant anti-inflammatory effect might be attributed to the substantial inflammatory response triggered by the surgery itself, potentially overshadowing any anti-inflammatory effects of S-ketamine. The findings align with previous studies showing the efficacy of S-ketamine in reducing postoperative depression, although variations in antidepressant effect duration may be influenced by factors such as disease type, dosage, and drug interactions. The consistent improvements in specific HAMD-17 and PHQ-9 items relating to core depressive symptoms further strengthen these results.

This study provides evidence supporting the use of intraoperative low-dose S-ketamine as a safe and effective strategy for mitigating depressive symptoms and postoperative pain in CD patients undergoing bowel resection. The short-term benefits observed suggest a potential role for S-ketamine in improving postoperative recovery and reducing opioid dependence in this vulnerable patient population. Future multicenter studies with longer follow-up periods and exploring different S-ketamine dosages are needed to confirm these findings and assess long-term effects.

Several limitations should be considered. The study lacked measurement of serum BDNF and 5-HT levels, which could provide further insights into the mechanisms underlying S-ketamine's effects. Potential drug interactions with other anesthetics used, such as dexmedetomidine, warrant further investigation. The study only compared one dose of S-ketamine to placebo, and did not compare it against standard oral antidepressants. The 3-month follow-up period might not be sufficient to capture long-term outcomes in CD patients.