Objective To investigate the effect of esketamine combined with transcutaneous auricular vagus nerve stimulation (taVNS) during anesthetic induction on short-term postoperative depressive symptoms in patients undergoing thyroidectomy and to explore its potential mechanisms.

Methods A total of 159 patients scheduled for elective thyroidectomy were randomly allocated to three groups (n = 53 each): a control group (Group C), an esketamine group (Group E), and an esketamine combined with taVNS group (Group EV). All patients received standardized general anesthesia management. Patients in Groups C and E received sham stimulation, whereas patients in Group EV received real taVNS intervention. Patients in Group E received low-dose esketamine during anesthetic induction, anesthesia maintenance, and postoperative analgesia, and patients in Group EV received the same esketamine regimen combined with taVNS. The primary outcome was the Hospital Anxiety and Depression Scale-Depression subscale (HADS-D) score assessed one day before surgery and on postoperative day 5. Secondary outcomes included the Leeds Sleep Evaluation Questionnaire (LSEQ) score, Numerical Rating Scale (NRS) pain scores at 12, 24, and 48 hours postoperatively, incidence of rescue analgesia, indices of vagal tone, 5-hydroxytryptamine (5-HT), interleukin-6 (IL-6), C-reactive protein (CRP), intraoperative anesthetic consumption, and perioperative adverse events. An exploratory mediation analysis was further performed.

Results At postoperative day 5, the HADS-D scores in groups C, E, and EV were (6.9 ± 3.1), (5.5 ± 2.9), and (3.9 ± 2.5), respectively, with a statistically significant difference among groups (F = 14.62, P ＜ 0.01); the LSEQ scores at postoperative day 5 were (62 ± 11), (69 ± 12), and (78 ± 10), respectively (F = 21.36, P ＜ 0.01). The NRS scores at 12, 24, and 48 h postoperatively all showed statistically significant differences among groups (F = 15.32, 18.37, and 21.64, P ＜ 0.01). At postoperative day 5, the RMSSD, HF, LF/HF, and 5-HT levels all showed statistically significant differences among groups (F = 20.84, 18.56, 23.91, and 15.37, P ＜ 0.01); the IL-6 and CRP levels also showed statistically significant differences (F = 18.76 and 16.42, P ＜ 0.01). The intraoperative dosages of remifentanil and propofol showed statistically significant differences among groups (F = 9.31 and 8.02, P ＜ 0.01). Mediation analysis revealed that RMSSD, 5-HT, IL-6, and postoperative 24-h NRS scores partially mediated the effect of the combined EV intervention on HADS-D scores at 5 days after surgery. No serious adverse events occurred in any of the three groups. The incidences of hypotension, hypertension, dizziness, and agitation showed no statistically significant differences among groups (P＞0.05).

Conclusions Esketamine combined with taVNS during anesthetic induction may improve short-term postoperative depressive symptoms in patients undergoing thyroidectomy without significantly increasing adverse events. This combined intervention shows comprehensive advantages in sleep quality, pain control, autonomic nerve regulation, 5-HT levels, and inflammatory response, and its effects may be associated with multiple pathways involving autonomic nerve regulation, neurotransmitter changes, inflammation inhibition, pain relief, and sleep improvement.