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

Crohn’s disease often affects individuals in early adulthood and is associated with a high burden of depressive symptoms, particularly among those requiring surgery. Depression in CD correlates with worse disease outcomes and may hinder postoperative recovery. Ketamine has rapid antidepressant properties; S-ketamine (esketamine) offers improved efficacy and fewer adverse effects compared with racemic ketamine and is approved intranasally for treatment-resistant depression. Whether intraoperative S-ketamine improves postoperative mood in surgical patients, and specifically in CD, is unclear due to heterogeneity in prior studies. The study’s aim was to test the hypothesis that continuous intraoperative low-dose S-ketamine reduces postoperative depressive symptoms in CD patients with mild-to-moderate depression undergoing bowel resection, and to assess effects on pain, recovery quality, inflammation, and safety.

Prior work shows S-ketamine can exert rapid antidepressant effects by NMDA receptor antagonism leading to synaptogenesis in mood-regulating circuits. Small perioperative S-ketamine doses reduced postoperative depression in breast and cervical cancer surgeries, though duration of effect varied by dose and context. Depression and inflammatory bowel disease share immune-inflammatory pathways; higher inflammatory markers (e.g., CRP, IL-6) correlate with depressive symptoms in IBD. Ketamine may have anti-inflammatory effects in depression, with reductions in pro-inflammatory cytokines reported in treatment-resistant depression. Low-dose ketamine is also known to reduce postoperative pain and opioid requirements when used as an adjuvant, though findings vary by dosing and surgical context.

Design: Double-blind, randomized, placebo-controlled, single-center trial at Jinling Hospital, Nanjing University Medical School; IRB approved (2020NZKY-062-01) and registered at ClinicalTrials.gov (NCT05506787). Period: 1 September 2020 to 1 March 2022. Participants: Adults 18–60 years with CD scheduled for bowel resection, ASA I–III, HAMD-17 between 8–24, provided informed consent. Exclusions: allergy to study drugs; severe systemic disease (heart, kidney, liver); chronic opioid therapy (>2×/week for >3 months); inability to use numeric pain scale; antidepressant use within the last month. Randomization and blinding: Computer-generated randomization with allocation concealed in sequentially numbered, sealed, opaque envelopes. Study drugs prepared and labeled by an assistant not involved in care; subjects, anesthesiologists, and assessors were blinded until study completion. Interventions: S-ketamine group received 0.25 mg/kg IV during induction (diluted to 1 mg/mL; 50 mL syringe), followed by continuous infusion at 0.12 mg/kg/h for >30 minutes via infusion pump; placebo group received 0.9% saline in identical volume/rate. Standardized anesthesia: midazolam 40 µg/kg; sufentanil 3 µg/kg; propofol 1–2 mg/kg; cisatracurium 0.2 mg/kg for induction; maintenance with target-controlled propofol and remifentanil, remifentanil 0.2–0.5 µg/(kg·min), dexmedetomidine 0.5 µg/(kg·h), cisatracurium 5–8 mg/(kg·min), and 2–3% sevoflurane. Postoperative analgesia: 24-h PCIA with dezocine, sufentanil, and ondansetron. Perioperative monitoring was standardized. Outcomes: Primary—HAMD-17 scores. Secondary—PHQ-9; QoR-15 (0–150; good recovery ≥118); NRS pain (0–10) in PACU, POD 1, 2, 7; CRP and IL-6 on POD 1, 3, 5; hospital length of stay; total in-hospital opioid use (converted to IV morphine equivalents). Questionnaires assessed preoperatively and on POD 1, 3, 7, and 30 (phone follow-up if discharged). All patients followed ≥3 months. Biomarkers: IL-6 by ELISA; CRP from routine labs. Exploratory serum markers were declined by patients. Sample size: α=0.05, power 90%, σ=10, effect size D1=5, 5% dropout; PASS 15.0 determined 60 per arm. Statistical analysis: Normality assessed with Kolmogorov–Smirnov. Continuous data reported as mean±SD or median (IQR); comparisons via independent t-test, Mann–Whitney U, χ2, or Fisher’s exact tests as appropriate. Linear mixed-effects models with random intercepts evaluated fixed effects for group (S-ketamine vs placebo), time, and interaction on repeated measures (HAMD-17, PHQ-9, QoR-15, NRS, CRP, IL-6); covariance structure chosen by AIC. In presence of interaction, contrasts at specific timepoints used with Bonferroni correction. Two-sided p<0.05 considered significant. Analyses in SPSS 25.0.

Enrollment: 151 screened; 124 randomized (S-ketamine n=61; placebo n=63); 4 lost to follow-up (1 vs 3); 120 analyzed (60 per arm). Baseline demographics and intraoperative parameters were similar between groups. Mood outcomes: Significant group-by-time interactions for HAMD-17 and PHQ-9 (both p<0.001). Group differences favored S-ketamine at POD 1, 3, and 7 (all p<0.001), with no difference at day 30. At day 7, change from baseline showed larger improvements with S-ketamine: HAMD-17 −8.8±3.27 vs −3.5±2.17 (treatment difference −5.3 points [SE 0.50], 95% CI −6.3 to −4.3; p<0.001); PHQ-9 −6.7±2.53 vs −2.2±1.49 (treatment difference −4.5 points [SE 0.38], 95% CI −5.2 to −3.7; p<0.001). Quality of recovery: Significant group-by-time interaction (p<0.001); higher QoR-15 in S-ketamine at POD 3 and 7 (both Bonferroni-adjusted p<0.001); no difference at POD 1 or day 30. Pain outcomes: Significant interaction for NRS (p<0.001) with lower pain scores in S-ketamine at PACU, POD 1, POD 2 (all adjusted p<0.001); no difference at POD 7. Postoperative opioid consumption within 2 days was lower with S-ketamine (mean 16.4 mg [SD 5.9] vs 23.9 mg [SD 8.4] IV morphine equivalents; p<0.05). Inflammatory markers: CRP and IL-6 decreased over time (CRP time effect F=169.501, p<0.001; IL-6 time effect F=8.230, p<0.001) with no group effect or group-by-time interaction (all p>0.5). Safety and recovery: No significant differences in postoperative complications, side effects (most common: dizziness, nausea, irritability; all self-limited), time to extubation, prolonged postoperative ileus, or length of hospital stay (median 20 vs 21 days; p=0.185).

The intraoperative administration of low-dose S-ketamine in CD patients with preoperative mild-to-moderate depressive symptoms produced meaningful reductions in depressive scores for up to one week after surgery and improved quality of recovery, while also reducing early postoperative pain and opioid needs. These findings support the hypothesis that perioperative S-ketamine can modulate mood in the stressful surgical context, consistent with prior reports in other surgical populations. The absence of group differences in CRP and IL-6 suggests that any anti-inflammatory effects of S-ketamine were not discernible against the robust postoperative inflammatory response after bowel surgery. Importantly, S-ketamine did not increase psychiatric adverse events or postoperative complications, indicating favorable tolerability at the doses used. Clinically, reduced depressive symptoms and lower opioid exposure are particularly relevant for CD patients, given associations between opioid use and adverse outcomes in IBD.

Among CD patients undergoing bowel resection with mild-to-moderate depressive symptoms, intraoperative low-dose S-ketamine reduced depressive symptoms through the first postoperative week, improved recovery quality, and decreased early postoperative pain and opioid consumption without compromising safety. Future multicenter trials should evaluate optimal dosing, comparative effectiveness versus standard antidepressants, mechanistic biomarkers (e.g., BDNF, 5-HT, cytokines), and longer-term mood and disease outcomes across diverse surgical settings.

• Biomarker mechanistic assessments (e.g., serum BDNF and 5-HT) were not performed, precluding correlations with mood changes.
• Potential pharmacologic interactions (e.g., with intraoperative dexmedetomidine) may have influenced outcomes.
• Only a single low-dose S-ketamine regimen was tested; no comparison with other doses or with oral antidepressants, which often require >1 week for effect.
• Follow-up was limited to 3 months, insufficient to assess long-term CD course and sustained antidepressant effects.
• Exploratory additional serum analyses were declined by patients.
• The strong postoperative inflammatory response may have masked any anti-inflammatory effects of S-ketamine on CRP/IL-6.