BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are associated with mood disorders, such as anxiety or depression, but it is not clear whether one contributes to development of the other, or if the interaction is bi-directional (anxiety or depression contributes to the progression of IBD, and IBD affects psychological health). We performed a 2-year longitudinal prospective study of patients in secondary to care investigate the bi-directionality of IBD and mood disorders. METHODS: We collected data from 405 adult patients with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) from November 2012 through June 2017. Demographic features, subtypes of IBD, treatments, symptoms, somatization, and fecal level of calprotectin were recorded at baseline. IBD activity was determined at baseline and after the follow-up period (2 years or more) using the Harvey-Bradshaw Index for CD and the Simple Clinical Colitis Activity Index for UC (scores ≥5 used to define disease activity). Anxiety and depression data were collected using the Hospital Anxiety and Depression Scale (HADS), at baseline and after the follow-up period. Objective markers of disease activity, including glucocorticosteroid prescription or flare of disease activity, escalation of therapy, hospitalization secondary to IBD activity, and intestinal resection during follow-up were assessed via case note review. A brain-gut direction of disease activity was defined as development of new IBD activity in patients with quiescent IBD and abnormal HADS scores at baseline. A gut-brain direction of disease activity was defined by subsequent development of abnormal HADS scores in patients with active IBD and normal HADS scores at baseline. We performed multivariate Cox regression controlling for patient characteristics and follow-up duration. RESULTS: Baseline CD or UC disease activity were associated with an almost 6-fold increase in risk for a later abnormal anxiety score (hazard ratio [HR], 5.77; 95% CI, 1.89-17.7). In patients with quiescent IBD at baseline, baseline abnormal anxiety scores were associated with later need for glucocorticosteroid prescription or flare of IBD activity (HR, 2.08; 95% CI, 1.31-3.30) and escalation of therapy (HR, 1.82; 95% CI, 1.19-2.80). These associations persisted when normal IBD activity index scores and fecal level of calprotectin <250 μg/g were used to define quiescent disease at baseline. CONCLUSIONS: In a 2-year study of patients with CD or UC, we found evidence for bi-directional effects of IBD activity and psychological disorders. Patients with IBD should be monitored for psychological well-being.