BACKGROUND & AIMS Low-dose amitriptyline was superior to placebo for irritable bowel syndrome (IBS) in the ATLANTIS trial. We performed post hoc analyses of ATLANTIS to assess whether combinations of gastrointestinal and psychological symptoms influenced response to amitriptyline. METHODS We used latent class analysis (LCA) to subtype participants in ATLANTIS into clusters using both gastrointestinal and psychological symptoms. We assessed differences in response rates with amitriptyline, compared with placebo, by cluster, using mean difference in IBS Severity Scoring System (IBS-SSS) and multivariate odds ratios (ORs), along with 95% confidence intervals (CIs) adjusted for age, sex, baseline symptom severity score, and IBS subtype. RESULTS Among 401 participants followed up at 6 months, a four-cluster solution yielded clusters with mild gastrointestinal and psychological symptoms (cluster 1), predominant gastrointestinal symptoms with milder psychological symptoms (cluster 2), predominant psychological symptoms with milder gastrointestinal symptoms (cluster 3), and more severe gastrointestinal and psychological symptoms (cluster 4). Mean change in IBS-SSS by cluster according to treatment allocation was not significant overall (treatment-by-cluster interaction, p=0.76). However, for cluster 3, mean difference in IBS-SSS from baseline to 6 months was significantly greater with amitriptyline than placebo (-103.44 (SD 117.81) versus -61.89 (SD 101.49) p=0.045). Participants in cluster 4, with more severe gastrointestinal and psychological symptoms, were significantly more likely to discontinue trial medication before 6 months (p=0.0023). Mean Antidepressant Side Effect Checklist scores at 6 months were highest in cluster 4, irrespective of treatment allocation, although they were generally higher with amitriptyline than placebo in this cluster. CONCLUSIONS These exploratory analyses demonstrate clusters of people with IBS based on gastrointestinal and psychological symptoms, which may predict response to, and tolerability of, amitriptyline. CLINICAL TRIAL REGISTRATION ISRCTN48075063.
