Causality is more than a one-way street, suggests new research.

Rates of depression among Crohn’s disease (CD) patients appear to be higher than the general population. The key question is whether depression influences the manifestation and severity of CD, if suffering from a debilitating chronic disease like CD causes depression, or both.

A recent study published in Inflammatory Bowel Diseases suggests there is reverse causality between patient-reported CD activity and depression. Lawrence Gaines, Ph.D., associate professor in the Departments of Psychiatry and Behavioral Sciences and Medicine at Vanderbilt University Medical Center, was the study’s lead author.

“The essence of depression’s role to me is the early onset of negative self-referential thinking; we think this may represent a psychological liability that influences Crohn’s disease morbidity,” Gaines said, adding, “We wanted to avoid a spurious relationship because some symptoms like sleep disorders and loss of appetite occur in both Crohn’s and depression.”

“The early onset of negative self-referential thinking may represent a psychological liability that influences Crohn’s disease morbidity.”

Comorbidity Factors

The reverse causality study is the second in a trio of studies on the CD-depression relationship that is a collaborative effort between researchers at Vanderbilt and the University of North Carolina. Study participants were volunteers in CCFA Partners, an online registry sponsored by the Crohn’s and Colitis Foundation of America that collects information on disease impact and health status from patients across the country.

“Studies by Miller and others would say the comorbidity of depression and Crohn’s disease is based on a biological model, and that hypothalamic-pituitary-adrenal mechanisms explain increased exacerbations among Crohn’s patients with depression,” Gaines said. Exactly how depression activates dysfunction in these mechanisms to worsen CD has not yet been explained, he noted.

In their first paper, Gaines and colleagues looked at whether depression is a risk factor for worsening of CD. While they concluded that CD patients who also have affective-cognitive symptoms of depression are more likely to develop more severe CD symptoms, the study results raised the question of “which was the chicken and which was the egg,” Gaines said.

Testing the Hypothesis

The second, most recent study tested whether the unidirectional finding was the result of possible reverse causality. Researchers looked at 3,307 adult volunteers with a self-reported CD diagnosis who had completed a baseline survey that included demographics, CD activity, and an affective-cognitive index of depression. Gaines’ team compared baseline data to additional Crohn’s disease status and depression index measurements taken six and 12 months later. Structural equation models evaluated the effects of CD activity or depression on future symptoms, to understand which condition was more predictive of the other.

The results show that an affective-cognitive model of depression is a stronger predictor of patient-reported CD activity – 218 times more likely to account for the data than the converse.

“We don’t think Crohn’s disease is caused by depression; we’re saying it’s one of many things that can contribute to worsening symptoms,” Gaines said. “We’re looking for proximal variables: is the patient still walking to work, playing with grandkids, staying active – or have they withdrawn? We want to understand what factors of depression lead to exacerbation.”

Impact of Health Behaviors

Gaines said a third study, not yet published, uses the same data to examine possible consequences of negativity. It looks at health behaviors as putative mediators – sleep quality, smoking, and physical activity – in the depression-CD relationship.

“With these studies, we hope to provide a better understanding of the comorbidity underlying the temporal relationship between depression and Crohn’s disease exacerbation.”


Lawrence Gaines, Ph.D.

Lawrence Gaines, Ph.D., is an associate professor of psychiatry and behavioral sciences at Vanderbilt University Medical Center and a clinical psychologist for the Vanderbilt IBD Clinic. His research focuses on symptom dimensions of depression and chronic disease, particularly inflammatory bowel disease and colitis.