Efficacy and mechanism of combined treatment with transcranial direct current stimulation and zolpidem for treatment-resistant insomnia: a study protocol for a prospective, double-blind, randomized controlled trial.

Background: Treatment-resistant insomnia remains a major unmet clinical challenge, as a substantial proportion of patients fail to achieve long-term remission with cognitive behavioral therapy or pharmacotherapy alone. Transcranial direct current stimulation (tDCS) has shown promise in modulating cortical excitability and improving sleep quality through non-invasive neuromodulation, whereas zolpidem (ZOL), a GABA-A receptor agonist, provides rapid but transient symptomatic relief. However, whether their combination offers additive therapeutic benefits and how such effects are represented at the neural level remain unknown. Methods: This prospective, double-blind, randomized controlled trial will enroll 165 patients with treatment-resistant insomnia. Participants will be randomly assigned (1:1:1) to one of three groups: (A) active tDCS + ZOL, (B) active tDCS + placebo, and (C) sham tDCS + ZOL. The intervention lasts four weeks, with 20 tDCS sessions (2 mA, 20 min/day, 5 days/week, anode over left and cathode over right dorsolateral prefrontal cortex) and nightly oral administration of ZOL or placebo. The primary outcome is the response rate at week 4, defined as the percentage of those having at least a 50% reduction in insomnia symptoms from baseline as measured via the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes include response rates at 8 and 12 weeks, clinical remission (PSQI<5), changes in PSQI and Insomnia Severity Index scores, sleep architecture monitored by a wearable device, and mood assessments using Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale. Resting-state functional MRI (rs-fMRI) will be acquired at baseline and 4 weeks to explore alterations in regional brain activity and functional connectivity. Discussion: This trial will systematically evaluate the efficacy and neurobiological mechanisms of tDCS combined with zolpidem in treatment-resistant insomnia. By integrating subjective clinical assessments, objective digital sleep monitoring, and neuroimaging biomarkers, it aims to elucidate whether these combined pharmacological and neuromodulatory interventions produce additive effects. The findings are anticipated to establish a mechanistic foundation for personalized, multimodal sleep therapeutics, thereby potentially advancing the management paradigm for treatment-resistant insomnia. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=288195, identifier ChiCTR2500111601.