Efficacy and safety of Shugan Jieyu capsules in combination with zolpidem for insomnia disorder with depressive symptoms: a double-blind randomized controlled trial

OBJECTIVE: Insomnia disorder with depressive symptoms (IDDS) represents a significant clinical phenotype, with a bidirectional relationship where insomnia both contributes to and results from depression. This study aimed to assess the efficacy and safety of combining zolpidem with Shugan Jieyu in treating IDDS. METHODS: In a double-blind, randomized trial, 60 IDDS patients were assigned to zolpidem plus Shugan Jieyu (ZS) or zolpidem plus placebo (ZP) for 8 weeks, with 59 completing the study. Assessments included the Insomnia Severity Index (ISI), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7 (GAD-7), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), polysomnography (PSG), and sleep diary. Mixed-model repeated-measures (MMRM) analysis was performed to assess the least squares means difference (LSMD) among the groups after 4 and 8 weeks of treatment. Subgroup analysis was performed on patients with sleep fragmentation (WASO ≥ 30 min). RESULTS: Both groups showed significant improvements in ISI, PSQI, ESS, GAD-7, and PHQ-9, with no between-group differences. For the primary outcome (ISI), the between-group difference at week 8 was - 1.68 points (95% CI: -4.49 to 1.14; p = 0.238), corresponding to a small effect size (Cohen's d = 0.42). ZS significantly reduced WASO and increased TST at 8 weeks, whereas ZP showed no significant changes in these measures within the group. ZS reduced subjective sleep latency (sSL) significantly more than ZP at weeks 4 (LSMD - 12.21 min, 95% CI -22.54 to -1.87; p = 0.021; d = 0.23) and 8 (LSMD - 12.17 min, 95% CI -21.99 to -2.35; p = 0.016; d = 0.25). In the sleep fragmentation subgroup, ZS improved sSL and subjective sleep efficiency (sSE). Both treatments were well-tolerated. CONCLUSION: Compared with taking zolpidem alone, the combination of zolpidem with Shugan Jieyu did not significantly improve insomnia, but showed preliminary non-objective signals in improving patients' perception of falling asleep, particularly in patients with sleep fragmentation. TRIAL REGISTRATION: The study is registered in the ClinicalTrials.gov (NCT05764798). Date registered: 30 November 2022.