Efficacy and Safety of Morinda Officinalis Oligosaccharides Combined with Probiotics as a Therapeutic Strategy for Major Depressive Disorder with Gastrointestinal Symptoms: A Randomized, Double-Blind, Controlled Clinical Trial

Objective: This study aimed to evaluate the clinical efficacy and safety of Morinda officinalis oligosaccharides (MOO) combined with probiotics compared to placebo in individuals diagnosed with major depressive disorder (MDD) who also presented with gastrointestinal symptoms, a common comorbidity in this population. Methods: In an 8-week, randomized, double-blind, placebo-controlled trial conducted at Beijing Anding Hospital, 108 patients meeting DSM-5 criteria for MDD were recruited. Participants were randomly assigned to receive either MOO (2 capsules BID) plus probiotics (Lacticaseibacillus paracasei L9, Bifidobacterium animalis subsp. lactis A6, Bifidobacterium bifidum B09, and Lactiplantibacillus plantarum LP06) or MOO plus placebo. The primary outcome was the change in HAMD-17 (17-item Hamilton Rating Scale for Depression) scores from baseline to Week 8. Both intention-to-treat (ITT) and per-protocol (PP) analyses were conducted. Results: The ITT analysis revealed no significant difference in total HAMD-17 score reduction between groups (Z = 0.02, p = 0.983). However, the group receiving MOO plus probiotics demonstrated a significantly greater reduction in insomnia-related symptoms at Week 2 (Z = -2.23, p = 0.028). Although the overall depression severity did not differ, early response (Week 2) and response rates in the probiotics group were 35.19% and 51.85%, respectively, without significant group differences. Logistic regression suggested that female patients and those with a family history of psychiatric disorders were less likely to respond to treatment. Adverse events were mild, mainly gastrointestinal (eg, diarrhea, constipation), and occurred at the same rate (5.56%) in both groups. Conclusion: Although MOO combined with probiotics did not significantly improve overall depressive symptoms compared to placebo, it showed early and specific benefits for insomnia symptoms. The intervention was safe and well tolerated. These findings highlight the potential role of gut microbiota modulation in treating MDD-related symptoms and suggest further research is needed to explore underlying mechanisms and identify responsive subgroups. Trial Registration: The study was prospectively registered with the Chinese Clinical Trial Registry (ChiCTR2200055780; https://www.chictr.org.cn/showproj.html?proj=150742) on January 19, 2022.