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.