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Background: Low-dose amitriptyline, a tricyclic antidepressant (TCA), was superior to placebo for irritable bowel syndrome (IBS) in the AmitripTyline at Low-dose ANd Titrated for Irritable bowel syndrome as Second-line treatment (ATLANTIS) trial., Objective: To perform post hoc analyses of ATLANTIS for predictors of response to, and tolerability of, a TCA., Design: ATLANTIS randomised 463 adults with IBS to amitriptyline (232) or placebo (231). We examined the effect of baseline demographic and disease-related patient characteristics on response to amitriptyline and the effect of amitriptyline on individual symptoms and side effects by subtype., Results: There was a quantitative difference in amitriptyline effectiveness in those ≥50 years vs <50 on the IBS severity scoring system (IBS-SSS) (interaction p=0.048, mean difference in ≥50 years subgroup -46.5; 95% CI -74.2 to -18.8, p=0.0010), and subjective global assessment of relief (interaction p=0.068, OR in ≥50 years subgroup 2.59; 95% CI 1.47 to 4.55, p=0.0010), and those in the 70% most deprived areas of England compared with the 30% least deprived for a ≥30% improvement in abdominal pain (interaction p=0.021, OR in 70% most deprived subgroup 2.70; 95% CI 1.52 to 4.77, p=0.0007). Stronger treatment effects were seen in men, with higher Patient Health Questionnaire-12 scores, and with IBS with diarrhoea. Mean differences in individual IBS-SSS components favoured amitriptyline, and side effects were similar, across almost all IBS subtypes., Conclusion: These exploratory analyses demonstrate there are unlikely to be deleterious effects of amitriptyline in any particular IBS subtype and could help identify patients in whom amitriptyline may be more effective., Trial Registration Number: ISRCTN48075063., Competing Interests: Competing interests: AW-H: NIHR grant funding paid to her institution, Data Monitoring and Ethics Committee and Trial Steering Committee member of NIHR and MRC funded projects, travel reimbursement for expert Committee membership of the Yorkshire and Northeast Regional Advisory Committee for NIHR Research for Patient Benefit. P-LO: none. SLA: NIHR, YCR and Health Data Research UK grant funding paid to her institution, consulting fees from West Yorkshire Integrated Care Board paid to her institution, speaker’s payments from Xytal, and grant funding panel member for NIHR. MJR: NIHR grant funding paid to his institution. RF: NIHR and YCR grant funding paid to his institution, Chair of NICE Implementation Strategy Group. FLB: none. MC: none. CF: none. EAG: NIHR and Leeds Hospitals Charity grant funding paid to her institution. DPM: none. CAT: none. AJF: NIHR grant funding paid to her institution, Data Monitoring and Ethics Committee and Trial Steering Committee member of NIHR and BHF funded projects, and NIHR senior investigator. HAE: NIHR grant funding paid to her institution. ACF: NIHR grant funding paid to his institution., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Irritable bowel syndrome (IBS) can cause troublesome symptoms impacting patients' quality of life and incur considerable health service resource use. Guidelines suggest low-dose amitriptyline for IBS as second line treatment, but this is rarely prescribed in primary care., Aim: To explore patients' and general practitioners' (GPs) views and experiences of using low-dose amitriptyline for IBS., Design and Setting: Qualitative interview study with patients and GPs in England, nested within the ATLANTIS trial of low-dose amitriptyline versus placebo (ISRCTN48075063)., Methods: Semi-structured telephone interviews with 42 patients at 6-months post-randomisation, 19 patients again at 12-months post-randomisation, and 16 GPs. Reflexive thematic analysis was used to analyse patient and GP data separately, then together, to identify unique and cross-cutting themes., Results: We found concerns about amitriptyline being an antidepressant, medicalising IBS, and side-effects. Perceived benefits included the low and flexible dose, ease of treatment, familiarity of amitriptyline and its potential to offer benefits beyond IBS symptom relief. These concerns and perceived benefits were expressed in the context of desire for a novel approach to IBS: GPs were keen to offer more options for IBS and patients sought a cure for their symptoms., Conclusions: Patients and GPs felt the potential benefits from trying low-dose amitriptyline for IBS outweighed their concerns. When offering low-dose amitriptyline for IBS, GPs could address patient concerns about taking an antidepressant for IBS, highlighting the low and flexible dosage and other potential benefits of amitriptyline such as improved sleep., (Copyright © 2024, The Authors.)