Titrated low-dose amitriptyline (a tricyclic antidepressant) was superior to placebo as a second-line treatment for irritable bowel syndrome (IBS) in primary care according to results from a new randomized, double-blind, placebo-controlled phase III trial (ATLANTIS). Across 55 general practices in England, 463 participants with IBS (mean age 48.5 years; 68% female, 32% male) were randomly assigned to either low-dose amitriptyline (10 mg once daily) or placebo, with dose titration over 3 weeks (up to 30 mg once daily). A statistically significant difference in IBS Severity Scoring System score was observed in the amitriptyline group versus placebo at 6 months (primary outcome; −27.0, 95% CI −46.9 to −7.10; P = 0.0079). Notably, amitriptyline was safe and well tolerated.