Psychiatric comorbidity in immune‐mediated inflammatory diseases
Authors: Ruth Ann Marrie, Charles N. Bernstein
Journal: World Psychiatry (2021)

Chronic immune-mediated inflammatory diseases (IMIDs) are a group of conditions characterized by immune dysregulation and aberrant organ system inflammation. Common examples of these conditions include rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and multiple sclerosis. Although these conditions affect different organ systems, they are all characterized by recurrent relapses and potentially debilitating disease progression. Collectively, IMIDs affect more than 1 in 20 people worldwide, and substantially burden affected persons, their families and societies. The adverse impacts of IMIDs include symptoms such as pain and fatigue, impairments in relationships and social participation, loss of employment, increased health care utilization, and reduced life expectancy. Comorbid conditions are common in people with IMIDs and also contribute substantially to their burden. Comorbid psychiatric disorders, including depression, anxiety disorders and bipolar disorder, are of particular interest. A growing body of evidence indicates that the incidence and prevalence of psychiatric disorders are elevated in persons with IMIDs as compared to the general population. For example, a population-based cohort of persons with rheumatoid arthritis, inflammatory bowel disease or multiple sclerosis had an elevated incidence of depression (incidence rate ratio, IRR=1.71; 95% CI: 1.64-1.79), anxiety (IRR=1.34; 95% CI: 1.29-1.40), bipolar disorder (IRR=1.68; 95% CI: 1.52-1.85) and schizophrenia (IRR=1.32; 95% CI: 1.03-1.69) compared to age-, sex- and geographically-matched controls1. The association between IMIDs and psychiatric disorders appears to be bidirectional, and the increased incidence of psychiatric disorders is not simply due to the challenges of living with a chronic disease. In a population-based study from Denmark involving 1,016,519 individuals, those with depression had a significantly higher risk of developing any IMID in the subsequent 11 years than individuals without depression2. In a population-based study from Canada, individuals with rheumatoid arthritis, inflammatory bowel disease or multiple sclerosis had an increased incidence of any psychiatric disorder, including depression, anxiety, bipolar disorder and schizophrenia, for 8-10 years prior to the diagnosis of their IMID, even after accounting for sociodemographic factors and number of physician visits3. Broadly, two health conditions may be comorbid (co-occur) for several reasons. Chance alone may account for comorbidity. Surveillance bias may also occur, wherein a person affected by one chronic health condition uses more health care services and consequently is more likely to get diagnosed with a second condition. Furthermore, conditions may co-occur due to “true etiologic mechanisms”. These mechanisms may include common genetic or environmental factors, or direct causation of the second condition by the first one. Finally, both conditions could be caused by an unrecognized third condition. Epidemiological and biological evidence suggests that IMIDs and psychiatric disorders are comorbid due to “true etiologic mechanisms”. In a cohort of 5,727,655 individuals, incident depression was associated with an increased risk of incident Crohn's disease (hazard ratio, HR=2.11; 95% CI: 1.65-2.70) and ulcerative colitis (HR=2.23; 95% CI: 1.92-2.60) after adjusting for age, sex, socioeconomic status, comorbid conditions, smoking status and use of antidepressants4. Notably, treatment with antidepressants was protective of developing Crohn's disease or ulcerative colitis among individuals with depression. The role of inflammation and immune dysregulation in IMIDs is well-recognized. Emerging evidence is highlighting the importance of immune dysfunction in psychiatric disorders as well, including depression, bipolar disorder, schizophrenia and anxiety disorders5. These latter disorders are associated with dysregulation of T cell function and pro-inflammatory cytokines, including interleukin-6 (IL-6), IL-2 receptor, IL-1β, IL-17A, and C-reactive protein; altered microglial activation; and disruption of the blood-brain barrier5, 6. Pharmacological and non-pharmacological therapies for depression are associated with reductions in peripheral inflammatory markers. Relatedly, the role of immunomodulatory therapies in the treatment of psychiatric disorders is also being explored. A randomized placebo-controlled trial in persons with major depression suggested that infliximab, a tumor necrosis factor antagonist, might improve depressive symptoms in persons who had elevated levels of C-reactive protein at enrollment7. With respect to common etiologic factors, several pleiotropic genetic loci are jointly associated with the risk of psychiatric disorders and IMIDs, as shown by an analysis of genome-wide association studies of five psychiatric disorders (major depressive disorder, bipolar disorder, schizophrenia, autism spectrum disorder and attention-deficit/hyperactivity disorder) and seven immune-mediated disorders (Crohn's disease, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes, systemic lupus erythematosus and psoriasis)8. Notably, shared genetic loci related to immune function were prominent. In addition to genetic factors, psychosocial factors also influence immune system function and inflammation. Acute stress leads to activation of the autonomic nervous system and hypothalamic-pituitary-adrenal axis, and upregulates inflammation. Chronic stress, such as childhood maltreatment, increases inflammation and suppresses cellular and humoral immunity. In turn, these changes increase the risk of chronic diseases such as IMIDs and psychiatric disorders. Social support can mitigate the adverse effects of psychosocial stressors on the risk of chronic diseases. Concordant with these observations, psychosocial interventions, in particular cognitive behavioral therapy and multi-modality therapies, are associated with sustained improvements in immune system function as measured by pro-inflammatory cytokines and immune cell counts9. Thus, epidemiological data support bidirectional relationships between psychiatric disorders and IMIDs, and inflammation and immune dysregulation are common to these conditions. Increasingly, treatment approaches applied to IMIDs are being tested for psychiatric disorders. However, much remains to be understood about the interface between psychiatric disorders and IMIDs.