Agomelatine improves symptom severity and quality of life in diarrhea-predominant irritable bowel syndrome: insights from a randomized controlled clinical trial.

Irritable bowel syndrome with diarrhea predominance (IBS-D) significantly impairs Quality of Life (QOL) and is often accompanied by psychological distress. Agomelatine, a melatonergic antidepressant, has shown promise in modulating gastrointestinal symptoms and mood disorders. This study aimed to evaluate the efficacy and safety of agomelatine in patients with IBS-D. In this 8-week, double-blind, randomized, placebo-controlled trial, 61 adults aged 18-65 years with IBS-D diagnosed by Rome IV criteria and confirmed normal colonic anatomy and labs were randomized to agomelatine (12.5 mg daily, titrated to 25 mg) or placebo. Baseline symptoms were recorded during a 1-week run-in using the Bristol Stool Form Scale (BSFS) and IBS Symptom Severity Score (IBS-SSS). Psychological status was assessed using the Hospital Anxiety and Depression Scale-Anxiety (HADS-A) and Depression (HADS-D) subscales, and QOL by the IBS Quality of Life questionnaire (IBS-QOL). The primary outcome was change in total IBS-SSS from baseline to week 8. Secondary outcomes included changes in individual IBS-SSS domains, stool consistency, bowel movement frequency, symptom days (pain, diarrhea, urgency, bloating), HADS-A, HADS-D, and IBS-QOL scores. Safety was monitored via adverse events and treatment discontinuations. All randomized participants were included in the intention-to-treat analysis. Both groups showed significant within-group reductions in total IBS-SSS (p < 0.001). Agomelatine produced greater reductions in total IBS-SSS than placebo (between-group difference in mean change, - 24.80 points; p = 0.034), abdominal pain severity, and abdominal pain frequency. The week-8 interference-with-life score was lower with agomelatine than with placebo, although the between-group difference in change from baseline was not statistically significant. The responder rate, defined as a reduction of at least 50 points in total IBS-SSS, was higher with agomelatine than with placebo (67.7% vs. 33.3%; p = 0.007). Daily bowel-movement frequency and days with pain, diarrhea, and urgency decreased significantly more with agomelatine (all p < 0.05). Anxiety and depression scores decreased, and IBS-QOL improved, significantly more with agomelatine than with placebo (all p ≤ 0.001). Adverse events were more frequent with agomelatine than placebo (61.3% vs. 23.3%; p = 0.004) and were predominantly mild to moderate. Two participants in the agomelatine group discontinued treatment because of adverse events, compared with none in the placebo group; no serious adverse events were reported. Agomelatine effectively improves gastrointestinal symptoms, psychological distress, and QOL in IBS-D patients and is generally well tolerated, supporting its therapeutic potential.Trial registration: The trial was registered at Iranian Registry of Clinical Trials ( https://irct.behdasht.gov.ir/trial/80432 ) (ID code: IRCT20120215009014N544) on November 30, 2024.