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Mental Health and Chronic Immune Diseases //

For the years 2014-2019 our group got a CIHR grant for $2.5 million to study psychiatric comorbidity in persons with chronic immune mediated diseases. The 3 diseases we focused on have been IBD, rheumatoid arthritis and multiple sclerosis. We enrolled approximately 1000 persons with any of IBD (we enrolled 254 persons), rheumatoid arthritis, multiple sclerosis or with depression and/or anxiety and no chronic immune diseases. We have been exploring the extent to which depression and/or anxiety affect persons with chronic immune disease; the types of treatment for depression and anxiety that have been studied specifically in persons with chronic immune diseases; the optimal survey tools to use to identify when depression and anxiety are present; the impact a diagnosis of depression or anxiety has on persons with a chronic immune disease. We have a large team including experts in neurology (Ruth Ann Marrie, MD, the nominated principle investigator), rheumatology (Carol Hitchon MD), psychiatry (Murray Enns, MD, Jitender Sareen, MD, James Bolton, MD, Scott Patten, MD), Clinical Psychology (Lesley Graff, PhD, John Walker, PhD, Renee El Gabalawy, PhD, John Fisk, PhD), Statistics (Lisa Lix, PhD, Randy Walld, PhD) and Family Practice (Alex Singer, MD, Alan Katz, MD).


Li Y, Bernstein CN, Xu W, Hu P. Polygenic risk and causal inference of psychiatric comorbidity in inflammatory bowel disease among patients with European ancestry. Journal of Translational Medicine 2022; in press


Approximately 40% of persons with IBD experience psychiatric comorbidities. Previous studies demonstrated the polygenetic effect on both IBD and psychiatric comorbidities. In this study, we evaluated the contribution of genetic variants to psychiatric comorbidities among the IBD population. Additionally, we evaluated whether this effect is mediated by the expression level of the RBPMS gene, which was identified in our previous studies as a potential risk factor of psychiatric comorbidities in persons with IBD.

The polygenic risk score was estimated among persons with IBD of European ancestry (n = 240) from the Manitoba IBD Cohort Study by using external genome-wide association studies (GWAS). The association and prediction performance were examined between the estimated polygenic risk score and psychiatric comorbidities status among persons with IBD. Finally, regression-based models were applied to explore whether the imputed expression level of the RBPMS gene is a mediator between estimated polygenic risk score and psychiatric comorbidities status in IBD.

The estimated polygenic risk score had a significantly positive association with psychiatric comorbidities status (for the highest effect: P-value threshold = 5 × 10-3, odds ratio = 2.0, P-value = 1.5 × 10-5). Around 13% of the causal effect between the polygenic risk score and psychiatric comorbidities status in IBD was mediated by the expression level of the RBPMS gene. The area under the curve of the PRS-based psychiatric comorbidities prediction model is around 0.7 at the threshold of 5 × 10-4.

PC status in IBD depends on genetic influences among persons with European ancestry. The polygenic risk score could potentially be applied to psychiatric comorbidities risk screening to identify persons with IBD at a high risk of psychiatric comorbidities. Around 13% of this genetic influence could be explained by the expression level of the RBPMS gene.

Stone JA, Shafer LA, Graff LA, Witges K, Lix L. Sexton KA, Haviva C, Targownik LE, Bernstein CN. The association of efficacy, optimism, uncertainty and health anxiety with inflammatory bowel disease activity. Journal of Psychosomatic Research 2022; in press.

Positive and negative psychological attributes have been shown to influence disease outcomes in many chronic health conditions. We aimed to evaluate the association between self-efficacy, optimism, health anxiety and intolerance of uncertainty and disease activity in IBD.  Adults with confirmed and recently active IBD enrolled in a prospective cohort study. Demographics, disease information, validated measures of psychological functioning related to general self-efficacy, optimism, health anxiety and intolerance of uncertainty were collected at baseline, week 26 and week 52. Clinical disease activity was assessed using the Inflammatory Bowel Disease Symptom Inventory (IBDSI), self-reported flares, and intestinal inflammation using fecal calprotectin (FCAL), collected at baseline, weeks 26 and 52. Generalized estimating equations were used to test the association between psychological functioning and disease activity. There were 154 participants of whom 64.1% had Crohn's disease. Adjusting for demographic variables, higher self-efficacy was associated with lower likelihood of flare by self-report (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.71, 0.91) and IBDSI (OR 0.89, 95% CI 0.80, 0.99), while higher health anxiety was associated with greater likelihood of flare by self-report (OR 1.07, 95% CI 1.01, 1.18) and higher symptomatic disease activity (IBDSI; OR 1.14, 95% CI 1.05, 1.24). The psychological attributes were not significantly associated with active disease as measured by inflammation (FCAL).

We concluded that general self-efficacy and health anxiety are relevant in understanding patient experience with disease activity, and may be appropriate targets for psychological intervention in the care of individuals with IBD.

Wang H, Labus JS, Griffin F, Gupta A, Bhatt RR, Sauk JS , Turkiewicz J, Bernstein CN, Kornelsen J,  Mayer EA. Functional Brain Rewiring and Altered Cortical Stability in Ulcerative Colitis. Molecular Psychiatry 2022; in press.

Despite recent advances, there is still a major need to better understand the interactions between brain function and chronic gut inflammation and its clinical implications. Alterations in executive function have previously been identified in several chronic inflammatory conditions, including inflammatory bowel diseases. Inflammation-associated brain alterations can be captured by connectome analysis. Here, we used the resting-state fMRI data from 222 participants comprising three groups (ulcerative colitis (UC), irritable bowel syndrome (IBS), and healthy controls (HC), N = 74 each) to investigate the alterations in functional brain wiring and cortical stability in UC compared to the two control groups and identify possible correlations of these alterations with clinical parameters. Globally, UC participants showed increased functional connectivity and decreased modularity compared to IBS and HC groups. Regionally, UC showed decreased eigenvector centrality in the executive control network (UC < IBS < HC) and increased eigenvector centrality in the visual network (UC > IBS > HC). UC also showed increased connectivity in dorsal attention, somatomotor network, and visual networks, and these enhanced subnetwork connectivities were able to distinguish UC participants from HCs and IBS with high accuracy. Dynamic functional connectome analysis revealed that UC showed enhanced cortical stability in the medial prefrontal cortex (mPFC), which correlated with severe depression and anxiety-related measures. None of the observed brain changes were correlated with disease duration. Together, these findings are consistent with compromised functioning of networks involved in executive function and sensory integration in UC

Furer P, Graff LA, Jackson GL, Kredenster M, Anderson S, Dirkse D, Pryor T, Bernstein CN.  Development of an Internet-delivered Cognitive Behavioral Program for Inflammatory Bowel Disease: A Pilot Study. Journal of Depression and Anxiety Disorders 2022; 4(1):106-114.


The prevalence of IBD varies worldwide and is rapidly rising, with the highest rates being reported in Europe and North America. The approximately 2 million individuals with IBD in the US and Canada are projected to double over the next decade. The disease has a high burden for patients, with unpredictable, painful symptoms that can interfere with home and work life.


It is well established that individuals with IBD have significantly higher rates of anxiety and depression than the general population. Persistent high levels of stress predict worsening IBD symptoms, which in turn increases the risk of developing chronic anxiety and depression.


This pilot study examined a new internet-delivered cognitive behavior therapy program (iCBT) for anxiety, depression and/or stress in adults with inflammatory bowel disease (IBD).


The internet-delivered cognitive behavioral therapy (iCBT) intervention tailored for adults with IBD to address stress, anxiety and/or depression is outlined in Table 1. The program included 9 core modules and 1 optional module. Modules took approximately 1-2 hours each to complete and included

text, patient videos illustrating learning points, and practice exercises to complete between modules.



Adults were recruited from the Manitoba sample of the Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects (IMAGINE) study, a large cohort of Canadian patients with physician-confirmed IBD. Eighteen of 21 participants completed the 9-module program.

Measures of anxiety, depression, and stress were administered at baseline, and at 6-, 12-, and 24-weeks post-baseline.



Compared to baseline, there was a significant reduction in anxiety (HADS-A) and in stress (PSS-4) over time. There were no statistically significant changes in depression scores (HADS-D). However, inspection of average depression scores over time suggests a trend for a decrease in scores at the 6- and 12-week points, with a subsequent increase at 24 weeks.

Participant satisfaction on the CSQ-8 ranged from 18 to 28 with a mean of 23.65 reflecting good satisfaction with the online intervention.


The results of this pilot study suggest it is a promising clinical intervention and support further investigation of this online CBT intervention for adults with IBD. Clinically meaningful reductions in anxiety and stress were achieved with this relatively low-resource intensity and accessible intervention. Participant engagement was high, with an excellent completion rate.



Wan A, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM, Hitchon C, Marriott JJ, Marrie RA. Childhood maltreatment and psychiatric comorbidity in immune-mediated inflammatory disorders. Psychosomatic Medicine 2022; 84:10-19.


To determine whether childhood maltreatment is associated with immune-mediated inflammatory disorders (multiple sclerosis [MS], IBD and rheumatoid arthritis). We further aimed to determine the relationship between maltreatment and psychiatric comorbidity in immune-mediated inflammatory and whether these relationships differed across immune-mediated inflammatory. 925 participants (MS: 232, IBD: 216, rheumatoid arthritis: 130, healthy controls: 103) completed a structured psychiatric interview to identify psychiatric disorders, and the Childhood Trauma Questionnaire to evaluate five types of maltreatment: emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. We evaluated associations between maltreatment, immune-mediated inflammatory and psychiatric comorbidity using multivariable logistic regression models. The prevalence of having ≥1 maltreatment was similar across immune-mediated inflammatory, but higher than in controls (MS: 63.8%, IBD: 61.6%, rheumatoid arthritis: 62.3%, healthy controls: 45.6%). Emotional abuse was associated with having an immune-mediated inflammatory (adjusted odds ratio [aOR] 2.37; 1.15-4.89). In the sex-specific analysis, this association was only present in women. History of childhood maltreatment was associated with a lifetime diagnosis of a psychiatric disorder in the immune-mediated inflammatory cohort (OR 2.24; 1.58-3.16), but this association did not differ across diseases. In those with immune-mediated inflammatory, total types of maltreatments (aOR 1.36; 1.17-1.59) and emotional abuse (aOR 2.64; 1.66-4.21) were associated with psychiatric comorbidity. 

We concluded that childhood maltreatment is more common in immune-mediated inflammatory than in a healthy population, and is associated with psychiatric comorbidity. Given the high burden of psychiatric disorders in the immune-mediated inflammatory population, clinicians should be aware of the contribution of maltreatment and the potential need for trauma-informed care strategies. 

Graff LA, Fowler S, Jones JL, Benchimol EI, Bitton A, Huang JG, Kuenzig ME, Kaplan GG, Lee K, Mukhtar MS, Tandon P, Targownik LE, Windsor JW, Bernstein CN. Crohn's and Colitis Canada's 2021 Impact of COVID-19 and Inflammatory Bowel Disease in Canada: Mental Health and Quality of Life.  Journal of the Canadian Association of Gastroenterology 2021 Nov 5;4(Suppl 2): S46-S53.


There has been a dramatic rise in mental health difficulties during the coronavirus COVID-19 pandemic. While young adults have the lowest risk of hospitalization and mortality due to COVID-19, they have been identified as being at highest risk of detrimental mental health outcomes during the pandemic, along with women, those with lower socioeconomic status and those with pre-existing mental health conditions. Somewhat of a crisis in mental health has emerged across the general population through the evolution of the pandemic. A national Canadian survey identified a quadrupling of those experiencing pervasive elevated anxiety symptoms early in the pandemic compared to pre-pandemic levels, and a doubling of those with pervasive elevated depressive symptoms. Independent of the pandemic, persons with IBD can face multiple challenges related to their disease, which can result in a significant psychosocial burden and psychologic distress. Anxiety and depression have been found to be more prevalent in persons with IBD. Many potential factors contribute to the increased psychologic distress and negative impacts on mental health of the COVID-19 pandemic on persons with IBD. These include the fears of contracting COVID-19 or infecting other people. Many believe that IBD or its treatments predispose them to an increased risk of COVID-19 or a worse outcome if acquired. Concerns about access to health care add to mental distress. People with IBD generally report lower quality of life compared to community controls. Psychologic interventions, in addition to adequate disease control, have been shown to improve health-related quality of life. Uncertainty is another factor associated with reduced health-related quality of life. Most studies suggest that persons with IBD have suffered quality of life impairment during the pandemic in comparison to the pre-pandemic period. Uncertainties brought on by the pandemic are important contributors for some of the reduction in quality of life.

Harel D, Levis B, Sun Y, Fischer F, Ioannidis JPA, Cuijpers P, Patten SB, Ziegelstein RC, Markham S, Benedetti A, Thombs BD, and the DEPRESsion Screening Data DEPRESSD) PHQ Collaboration (member of group authorship). External Validation of a Shortened Screening Tool Using Individual Participant Data Meta-Analysis: a Case Study of the Patient Health Questionnaire-Dep-4. Methods 2021; Nov 12:S1046-2023(21)00262-0.


Shortened versions of self-reported questionnaires may be used to reduce respondent burden. When shortened screening tools are used, it is desirable to maintain equivalent diagnostic accuracy to full-length forms. This manuscript presents a case study that illustrates how external data and individual participant data meta-analysis can be used to assess the equivalence in diagnostic accuracy between a shortened and full-length form. This case study compares the Patient Health Questionnaire-9 (PHQ-9) and a 4-item shortened version (PHQ-Dep-4) that was previously developed using optimal test assembly methods. Using a large database of 75 primary studies (34,698 participants, 3,392 major depression cases), we evaluated whether the PHQ-Dep-4 cutoff of ≥ 4 maintained equivalent diagnostic accuracy to a PHQ-9 cutoff of ≥ 10. Using this external validation dataset, a PHQ-Dep-4 cutoff of ≥ 4 maximized the sum of sensitivity and specificity. While equivalence with a PHQ-9 cutoff of ≥ 10 was not established, we found the sensitivity of the PHQ-Dep-4 to be non-inferior to that of the PHQ-9, and the specificity of the PHQ-Dep-4 to be marginally smaller than the PHQ-9.

Negeri ZF, Levis BF, Sun Y, Chen HE, Krishnan A, Wu Y, Bandhari PM, Neupane D, Brehaut E, Benedett A, Thombs BD, and the  Depression Screening Data (DEPRESSD) PHQ Group (member of group authorship). Accuracy of the Patient Health Questionnaire-9 for screening to detect major depression: updated systematic review and individual participant data meta-analysis. BMJ 2021 Oct 5;375:n2183.


The objective of this study was to determine the accuracy of the Patient Health Questionnaire-9 (PHQ-9), the most commonly used depression screening tool in general practice, for detecting major depression overall and by study or participant subgroups. The study design was a systematic review and individual participant data meta-analysis. Data was available from 44 503 total participants (27 146 additional from the original update) were obtained from 100 of 127 eligible studies (42 additional studies; 79% eligible studies; 86% eligible participants). Among studies with a semistructured interview reference standard, pooled PHQ-9 sensitivity and specificity (95% confidence interval) at the standard cut-off value of ≥10, which maximised combined sensitivity and specificity, were 0.85 (0.79 to 0.89) and 0.85 (0.82 to 0.87), respectively.  We concluded that researchers and clinicians could use results to determine outcomes, such as total number of positive screens and false positive screens, at different PHQ-9 cut-off values for different clinical settings using the knowledge translation tool at

Hitchon CA, Peschken CA, Walld R, Bernstein CN, Bolton JM, El-Gabalawy R, Fisk JD, Katz A, Lix LM, Marriott JM, Patten SB, Sareen J, Singer A, Marrie RA. The Impact of Psychiatric Comorbidity on Health Care Use in Rheumatoid Arthritis: A Population-Based Study. Arthritis Care and Research 2021; 73(1):90-99. 

Psychiatric comorbidity is frequent in rheumatoid arthritis and complicates treatment. The present study was undertaken to describe the impact of psychiatric comorbidity on health care use (utilization) in rheumatoid arthritis. We accessed administrative health data (1984-2016) and identified a prevalent cohort with diagnosed rheumatoid arthritis. Cases of rheumatoid arthritis (n = 12,984) were matched for age, sex, and region of residence with 5 controls (CNT) per case (n = 64,510). Within each cohort, we identified psychiatric morbidities (depression, anxiety, bipolar disorder, and schizophrenia [PSYC]), with active PSYC defined as ≥2 visits per year. For the years 2006-2016, annual rates of ambulatory care visits (mean ± SD per person) categorized by provider (family physician [FP], rheumatologist, psychiatrist, other specialist), hospitalization (% of cohort), days of hospitalization (mean ± SD), and dispensed drug types (mean ± SD per person) were compared among 4 groups (CNT, CNT plus PSYC, RA, and RA plus PSYC) using generalized linear models adjusted for age, sex, rural versus urban residence, income quintile, and total comorbidities. Estimated rates are reported with 95% confidence intervals (95% CIs). We tested within-person and RA-PSYC interaction effects. Subjects with RA were mainly female (72%) and urban residents (59%), with a mean ± SD age of 54 ± 16 years. Compared to RA without PSYC, RA with PSYC had more than additive (synergistic) visits (standardized mean difference [SMD] 10.92 [95% CI 10.25, 11.58]), hospitalizations (SMD 13% [95% CI 0.11, 0.14]), and hospital days (SMD 3.63 [95% CI 3.06, 4.19]) and were dispensed 6.85 more medication types (95% CI 6.43, 7.27). Cases of RA plus PSYC had increased visits to FPs (an additional SMD 8.92 [95% CI 8.35, 9.46] visits). PSYC increased utilization in within-person models.

We concluded that managing psychiatric comorbidity effectively may reduce utilization in RA.

Dolovich C, Bernstein CN, Singh H, Nugent Z, Tennakoon A, Shafer LA, Marrie RA, Sareen J, Targownik L. Anxiety and Depression Leads to Anti-Tumor Necrosis Factor Discontinuation in Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology. 2021;19(6):1200-1208. 

Anxiety and mood disorders are common among persons with inflammatory bowel diseases (IBD) and are associated with increased health care use and lower quality of life. We assessed the effects of anxiety and mood disorders on persistence on anti-tumor necrosis factor (anti-TNF) therapy in patients with IBD, and risk of IBD-related adverse outcomes after therapy initiation. We identified all persons with IBD in Manitoba who were dispensed an anti-TNF agent from 2001 through 2016 and then identified those with a validated administrative definition of anxiety and mood disorders in the 2 years before initiation of therapy. Survival analysis was used to assess the association between active anxiety and mood disorders and anti-TNF discontinuation and the first occurrence of an IBD-related adverse outcome (defined as IBD-related hospitalization or surgery, new or recurrent corticosteroid use, switching to an alternative anti-TNF, or death). We identified 1135 persons with IBD who began anti-TNF therapy; 178 of these patients (15.7%) met the diagnostic criteria for an anxiety and mood disorder. Anxiety and mood disorders significantly increased risk of discontinuation of anti-TNF therapy (adjusted hazard ratio, 1.28; 95% CI, 1.03-1.59) and discontinuation in the 1 year following anti-TNF initiation (hazard ratio, 1.50; 95% CI, 1.15-1.94). There was no association between AMDs and subsequent risk of IBD-related adverse events.

We concluded that patients with IBD and an AMD within 2 years before starting anti-TNF therapy are at increased risk of discontinuing therapy, compared to patients with IBD without anxiety and mood disorders. Studies are needed to determine if treatment of anxiety and mood disorders increases compliance with treatment.

Marrie RA, Bernstein CN. Psychiatric comorbidity in immune-mediated inflammatory diseases. World Psychiatry 2021; 20: 298-299. 


Chronic immune‐mediated inflammatory diseases 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, immune‐mediated inflammatory diseases affect more than 1 in 20 people worldwide, and substantially burden affected persons, their families and societies. The adverse impacts of immune‐mediated inflammatory diseases 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 immune‐mediated inflammatory diseases 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 immune‐mediated inflammatory diseases 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 controls.

The association between immune‐mediated inflammatory diseases 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 immune‐mediated inflammatory diseases in the subsequent 11 years than individuals without depression. 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 immune‐mediated inflammatory diseases, even after accounting for sociodemographic factors and number of physician visits.

Broadly, two health conditions may 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 immune‐mediated inflammatory diseases 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 antidepressants. 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 immune‐mediated inflammatory diseases is well‐recognized. Emerging evidence is highlighting the importance of immune dysfunction in psychiatric disorders as well, including depression, bipolar disorder, schizophrenia and anxiety disorders. 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 barrier. 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 enrollment.

With respect to common etiologic factors, several pleiotropic genetic loci are jointly associated with the risk of psychiatric disorders and immune‐mediated inflammatory diseases, 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). 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 immune‐mediated inflammatory diseases 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 counts.

Thus, epidemiological data support bidirectional relationships between psychiatric disorders and immune‐mediated inflammatory diseases, and inflammation and immune dysregulation are common to these conditions. Increasingly, treatment approaches applied to immune‐mediated inflammatory diseases are being tested for psychiatric disorders. However, much remains to be understood about the interface between psychiatric disorders and immune‐mediated inflammatory diseases.



Kredentser M, Graff LA, Bernstein CN. Psychological Comorbidity and Interventions in Inflammatory Bowel Disease. Journal of Clinical Gastroenterology 2021; 55: 30-35. 


IBD is associated with significant psychological comorbidities, with associated impacts on patient quality of life, disease course, and health care costs. The present article reviews the latest evidence on the etiology of psychological comorbidities in IBD, with a focus on shared inflammatory pathways. The current state of practice in managing and understanding psychological comorbidities from the perspective of both gastroenterology practice and psychological treatment is reviewed, with a focus on evidence-based treatments shown to be effective in managing depression, anxiety, stress, and improving IBD-related health outcomes.

Thomann AK, Knödler LL, Karthikeyan S, Atanasova K, Bernstein  CN, Ebert MP , Lis S, Reindl W. The interplay of biopsychosocial factors and quality of life in inflammatory bowel diseases – a network analysis. Journal of Clinical Gastroenterology 2021; in press.



Thomann A, Mak WY, Wang ZJ, Wuestenber T, Ebert M, Sung JJY, Bernstein CN, Reindl W, Ng S. Review article: Bugs, inflammation and mood – a microbiota-based approach to psychiatric symptoms in IBD. Alimentary Pharmacology and Therapuetics 2020;52(2):247-266.


Endoscopy is an essential component in the management of IBD. There is a risk of SARS-CoV-2 transmission during endoscopic procedures. The International Organization for the study of IBD [IOIBD] has developed 11 position statements, based on an online survey, that focus on how to prioritize endoscopies in IBD patients during the COVID-19 pandemic, alternative modes for disease monitoring, and ways to triage the high number of postponed endoscopies after the pandemic. We propose to pre-screen patients for suspected or confirmed COVID-19 and test for SARS-CoV-2 before endoscopy if available. High priority endoscopies during pandemic include acute gastrointestinal bleed, acute severe ulcerative colitis, new IBD diagnosis, cholangitis in primary sclerosing cholangitis, and partial bowel obstruction. Alternative modes of monitoring using clinical symptoms, serum inflammatory markers, and fecal calprotectin should be considered during the pandemic. Prioritizing access to endoscopy in the post-pandemic period should be guided by control of COVID-19 in the local community and availability of manpower and personal protective equipment. Endoscopy should be considered within 3 months after the pandemic for patients with a past history of dysplasia and endoscopic resection for dysplastic lesion. Endoscopy should be considered 3-6 months after the pandemic for assessment of postoperative recurrence or new biologic initiation. Endoscopy can be postponed until after 6 months of pandemic for routine IBD surveillance and assessment of mucosal healing.

Olafson K, Marrie RA, Bolton JM, Bernstein CN, Bienvenu OJ, Kredentser MS, Logsetty S,  Chateau D,  Nie Y, Blouw M, Afifi TO, Stein MB, Leslie WD, Katz LY, Mota N, El-Gabalawy R, Enns MW, Leong C, Sweatman S, Sareen J. The Five-Year Pre- and Post-Hospitalization Treated Prevalence of Mental Disorders and Psychotrophic Medication Use in Critically Ill Patients:  A Canadian Population-Based Study. Intensive Care Medicine. 2021; in press.


The interplay between critical illness and mental disorders is poorly understood. The purpose of this study is to measure both the treated prevalence of mental disorders and psychotropic medication use before and after hospitalization and the impact of intensive care unit admission on these outcomes. Using a population-based administrative database in Manitoba, Canada, 49,439 intensive care unit patients admitted between 2000 and 2012 were compared to two matched comparison groups (hospitalized; n = 146,968 and general population; n = 141,937). Treated prevalence of mental disorders and psychotropic medication prescriptions were measured in the 5-year periods before and after the hospitalization. The 5-year treated mental disorder prevalence in the intensive care unit population increased from 41.5% pre-hospitalization to 55.6% post-hospitalization. Compared to non- intensive care unit hospitalized patients, the adjusted treated mental disorder prevalence in intensive care unit patients was lower prior to hospitalization (1-year adjusted prevalence rate, APR 0.94, 95% CI 0.92-0.97, p < 0.0001; 5-year APR 0.99, 95% CI 0.98-1.00, p = 0.1), but higher following discharge (1-year APR 1.08, 95% CI 1.05-1.11, p < 0.0001, 5-year APR 1.03, 95% CI 1.01-1.05, p < 0.0001). A high proportion of ICU patients received antidepressant, anxiolytic and sedative-hypnotic prescriptions before and after their hospitalization. In multivariable analyses, intensive care unit exposure was associated with an increase in mood, anxiety and psychotic disorders, and sedative-hypnotics use (p < 0.0001 for all Time × Group interactions).


We concluded that during the 5 years after admission to ICU, there is a significant increase in treated prevalence of mental disorders and psychotropic medication use compared to the 5 years prior to ICU and compared to general population and hospital cohorts. Prevention and intervention programs that identify and treat mental disorders among survivors of critical illness warrant further study.

Kornelsen J, Witges K, Labus J, Mayer EA, Bernstein CN. Brain structure and function changes in ulcerative colitis. Neuroimage Reports 2021: in press.

As the importance of the brain-gut axis in the pathobiology of inflammatory bowel disease continues to evolve, a greater understanding of brain structure and functional connectivity in diseases such as ulcerative colitis are necessary. In this magnetic resonance imaging (MRI) study, we investigated differences in brain structure and in functional connectivity of brain regions in 76 participants with ulcerative colitis and 74 healthy controls. Voxel based morphometry analysis indicate greater grey matter volume in multiple brain regions in ulcerative colitis as compared to healthy controls. Differences in functional connectivity between groups were identified in the cerebellar, default mode, visual, and dorsal attention networks. functional connectivity differed by sex for the visual and dorsal attention networks. These differences warrant further investigation to determine if they help direct the evolution of ulcerative colitis or if they evolve in response to the presence of ulcerative colitis. These differences provide further evidence that the brain-gut axis is altered in ulcerative colitis.

Su S, Marrie RA, Bernstein CN. Factors associated with social participation in persons living with inflammatory bowel disease. Journal of Canadian Association of Gastroenterology 2021; in press. 


IBD imposes a significant burden on health-related quality of life, particularly in social domains. We sought to investigate the factors that limit social participation in patients with IBD. We assessed a cohort of 239 Manitobans with IBD. We collected sociodemographic information, medical comorbidities, disease phenotype, symptom activity and psychiatric comorbidity (using the Structured Clinical Interview for DSM-IV). Participants completed the 8-item Ability to Participate in Social Roles and Activities (APSRA) questionnaire, which assesses participation restriction, including problems experienced in social interaction, employment, transportation, community, social, and civic life. Poorer social participation scores were associated with earning less than $50, 000 CAD income annually (p<0.001), actively smoking (p=0.006), higher symptom scores (p<0.001 for Crohn’s disease, p=0.004 for ulcerative colitis), and having an increasing number of chronic medical conditions (R= -0.30). History of depression (p<0.001) and anxiety (p=0.001) and having active depression (p<0.001) and anxiety (p=0.001) all predicted poor social participation scores. IBD phenotype or disease duration was not predictive. Based on multivariable linear regression analysis, significant predictors of variability in social participation were medical comorbidity, psychiatric comorbidity, psychiatric symptoms, and IBD-related symptoms. 

In conclusion, the factors that predict social participation by IBD patients include income, smoking, medical comorbidities, IBD symptom burden, and psychiatric comorbidities. Multivariable linear regression suggests that the most relevant factors are medical comorbidity, psychiatric comorbidity, psychiatric symptoms, and IBD symptoms.

MacDonald TM, Fisk JD, Bernstein CN, El-Gabalawy R, Hitchon CA, Kornelsen J, Patten SB, Tisseverasinghe A, Marrie RA. The association between childhood maltreatment and pain catastrophizing in individuals with immune-mediated inflammatory diseases. Journal of Psychosomatic Research 2021;145:110479. 

Childhood maltreatment is associated with pain catastrophizing. Both childhood maltreatment and pain catastrophizing are prevalent in certain immune-mediated inflammatory disease populations. However, it is unknown whether childhood maltreatment contributes to the high rates of pain catastrophizing in immune-mediated inflammatory diseases cohorts. We assessed the relationship between childhood maltreatment and pain catastrophizing in individuals with immune-mediated inflammatory diseases, and whether this differed across immune-mediated inflammatory diseases. Between November 2014 and July 2016 we recruited individuals with multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatoid arthritis. Participants completed the Childhood Trauma Questionnaire-Short Form, the Pain Catastrophizing Scale, and Hospital Anxiety and Depression Scale. We tested the association between childhood maltreatment and pain catastrophizing using multivariable logistic regression.  We included 577 individuals with immune-mediated inflammatory (MS: 232, IBD: 215, rheumatoid arthritis: 130). Overall, 265 (46%) participants with immune-mediated inflammatory diseases reported any childhood maltreatment, with the most common type of maltreatment being emotional neglect. Childhood maltreatment was associated with pain catastrophizing (OR 3.32; 95% CI 1.89-5.85) independent of other risk factors, including sociodemographics and symptoms of anxiety and depression.

We concluded pain that catastrophizing is highly prevalent in our immune-mediated inflammatory diseases population, and strongly associated with childhood maltreatment in this population. Interventions that consider childhood maltreatment and pain catastrophizing should be incorporated into the clinical management of immune-mediated inflammatory diseases patients.

Carney H, Marrie RA, Bolton JM, Patten SB, Graff LA, Bernstein CN, Kowalec K. Prevalence and Risk Factors of Substance Use Disorder in Inflammatory Bowel Disease. Inflammatory Bowel Diseases 2021; 27: 58-64.

Substance use disorders impose a substantial individual and societal burden; however, the prevalence and associated factors in persons with inflammatory bowel disease (IBD) are largely unknown. We evaluated the prevalence and risk factors of substance use disorders in an IBD cohort. Inflammatory bowel disease participants (n = 247) were recruited via hospital- and community-based gastroenterology clinics, a population-based IBD research registry, and primary care providers as part of a larger cohort study of psychiatric comorbidity in immune-mediated inflammatory diseases. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV was administered to participants to identify lifetime substance use disorders, anxiety disorders, and major depressive disorders. Additional questionnaires regarding participants' sociodemographic and clinical characteristics were also completed. We examined demographic and clinical factors associated with lifetime substance use disorders using unadjusted and adjusted logistic regression modeling. Forty-one (16.6%) IBD participants met the criteria for a lifetime diagnosis of a substance use disorder. Factors associated with elevated odds of substance use disorders were ever smoking (adjusted odds ratio [aOR], 2.96; 95% confidence interval [CI], 1.17-7.50), male sex (aOR, 2.44; 95% CI, 1.11-5.36), lifetime anxiety disorder (aOR, 2.41; 95% CI, 1.08-5.37), and higher pain impact (aOR, 1.08; 95% CI, 1.01-1.16).

We concluded that one in six persons with IBD experienced a substance use disorder, suggesting that clinicians should maintain high index of suspicion regarding possible substance use disorders, and inquiries about substance use should be a part of care for IBD patients, particularly for men, smokers, and patients with anxiety disorders.

Marrie RA, Walld R, Bolton J, Sareen J, Patten SB, Singer A, Lix L, Hitchon C Marriott JJ, El-Gabalawy R, Katz A, Fisk JD, Bernstein CN. Effect of comorbid mood and anxiety disorders on breast and cervical cancer screening in immune-mediated inflammatory disease. PLOS One 2021; Aug 5;16(8):e0249809.


We aimed to examine rates of breast and cervical cancer screening in women with immune-mediated inflammatory diseases, IBD, multiple sclerosis (MS) and rheumatoid arthritis versus a matched cohort with immune-mediated inflammatory diseases; and examine the association of psychiatric comorbidity with screening in these populations. We conducted a retrospective cohort study in Manitoba, Canada using administrative data. We identified women with IBD, MS and rheumatoid arthritis, and controls without these immune-mediated inflammatory diseases matched on age and region. Annually, we identified individuals with any active mood/anxiety disorder. Using physician claims, we determined the proportion of each cohort who had cervical cancer screening within three-year intervals, and mammography screening within two-year intervals. We modeled the difference in the proportion of the immune-mediated inflammatory diseases and matched cohorts who underwent mammography; and pap tests using log-binomial regression with generalized estimating equations, adjusting for sociodemographics, comorbidity and immune therapy use. We tested for additive interactions between cohort and mood/anxiety disorder status. During 2006-2016, we identified 17,230 women with immune-mediated inflammatory diseases (4,623 with IBD, 3,399 with MS, and 9,458 with rheumatoid arthritis) and 85,349 matched controls. Having an IMID was associated with lower (-1%) use of mammography; however, this reflected a mixture of more mammography in the IBD cohort (+2.9%) and less mammography in the MS (-4.8 to -5.2%) and RA (-1.5%) cohorts. Within the IBD, MS and rheumatoid arthritis cohorts, having an active mood/anxiety disorder was associated with more mammography use than having an inactive mood/anxiety disorder. The MS and rheumatoid arthritis cohorts were less likely to undergo Pap testing than their matched cohorts. In the absence of an active mood/anxiety disorder, the IBD cohort was more likely to undergo Pap testing than its matched cohort; the opposite was true when an active mood/anxiety disorder was present. Among women with an immune-mediated inflammatory diseases, mood/anxiety disorder influence participation in cancer screening.



Afifi TO, Bolton SL, Mota N, Marrie RA, Stein MB, Enns MW, El-Gabalawy R, Bernstein CN, Mackenzie C, VanTil L, MacLean MB, Wang JL, Patten S, Asmundson GJG, Sareen J. Rationale and Methodology of the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS): A 16-year Follow-up Survey. Canadian Journal of Psychiatry 2021; 66: 942-950.


Knowledge is limited regarding the longitudinal course and predictors of mental health problems, suicide, and physical health outcomes among military and veterans. Statistics Canada, in collaboration with researchers at the University of Manitoba and an international team, conducted the Canadian Armed Forces Members and Veterans Mental Health Follow-Up Survey (CAFVMHS). Herein, we describe the rationale and methods of this important survey. The CAFVMHS is a longitudinal survey design with 2 time points (2002 and 2018). Regular Force military personnel who participated in the first Canadian Community Health Survey Cycle 1.2-Mental Health and Well-Being, Canadian Forces Supplement (CCHS-CFS) in 2002 (N = 5,155) were reinterviewed in 2018 (n = 2,941). The World Mental Health Survey-Composite International Diagnostic Interview was used with the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. The CAFVMHS includes 2,941 respondents (66% veterans; 34% active duty) and includes data on mental disorder diagnoses, physical health conditions, substance use, medication use, general health, mental health services, perceived need for care, social support, moral injury, deployment experiences, stress, physical activity, military-related sexual assault, childhood experiences, and military and sociodemographic information.

The CAFVMHS provides a unique opportunity to further understand the health and well-being of military personnel in Canada over time to inform intervention and prevention strategies and improve outcomes. The data are available through the Statistics Canada Research Data Centres across Canada and can be used cross-sectionally or be longitudinally linked to the 2002 CCHS-CFS

Bruinooge A, Liu Q, Tian Y, Jiang W, Li Y, Xu W, Bernstein CN, Hu P. Genetic predictors of gene expression associated with psychiatric comorbidity in patients with inflammatory bowel disease – a pilot study. Genomics 2021 May;113(3):919-932. 


IBD affects millions of people in North America, and patients with IBD have a high incidence of psychiatric comorbidities. The genetic mechanisms underlying the link are, in general, poorly understood. A transcriptome-wide association study was performed using genetically regulated gene expression profiles imputed from the genetic profiles of 240 IBD patients in the Manitoba IBD Cohort Study. The imputation was performed using the 44 non-diseased human tissue-specific reference models from the GTEx database. Linear modeling and gene set enrichment analysis were performed to identify genes and pathways that are significantly associated with IBD patients with psychiatric comorbidities compared to IBD alone in each of the 44 non-diseased human tissues. Finally, an enrichment map was generated to investigate networks of the enriched gene sets associated with IBD patients with psychiatric comorbidities. The genes RBPMS in skeletal muscle (adjusted p = 0.05), KCNA5 in the cerebellar hemisphere of the brain (adjusted p = 0.09), GSR, SMIM34A, and LIPT2 in the frontal cortex of the brain (adjusted p = 0.09 for each) were the top genetically regulated genes with a suggestive association with IBD patients with PC. We identified three gene set networks, which include gene sets and pathways with a suggestive association with IBD patients with psychiatric comorbidities: one with 7 gene sets overlapping in apolipoprotein B mRNA editing subunit genes, one with 3 gene sets including pigmentation gene sets, and the other one with 3 gene sets including peptidyl tyrosine phosphorylation regulation related gene sets.


We concluded that our transcriptome-wide association study analysis has identified genes and pathways with a suggestive association with IBD patients with psychiatric comorbidities. These findings can be potentially used for illustrating the mechanism of developing psychiatric comorbidities in the patients with IBD and developing diagnosis tool or drug targets for IBD.

Sareen J, Bolton SL, Mota N, Afifi T, Enns M, Taillieu T, Stewart-Tufescu A, El-Gabalawy R, Marrie RA, Patten S, Richardson D, Stein M, Bernstein CN, Bolton J, Garber B, Wang J, Thompson J, Van Til L, Maclean MB, Logsetty S. Lifetime Prevalence and Comorbidity of Mental Disorders in the Two-Wave 2002-2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS). Canadian Journal of Psychiatry 2021; 66: 951-960.

The current study used the Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS) to (1) examine the incidence and prevalence of mental disorders and (2) estimate the comorbidity of mental disorders over the follow-up period. The CAFVMHS (2018) is a longitudinal study with two time points of assessment. The sample is comprised of 2,941 Canadian Forces members and veterans who participated in the 2002 Canadian Community Health Survey: Canadian Forces Supplement. The World Health Organization Composite International Diagnostic Interview (WHO-CIDI) was utilized to diagnose -IV post-traumatic stress disorder (PTSD), major depressive episode, generalized anxiety disorder, social anxiety disorder, and alcohol abuse and dependence. Self-report health professional diagnoses were assessed for attention deficit hyperactivity disorder, mania, obsessive compulsive disorder, and personality disorder. We established weighted prevalence of mental disorders and examined the association between mental disorders using logistic regression. In 2018, lifetime prevalence of any WHO-CIDI-based or self-reported mental disorder was 58.1%. Lifetime prevalence of any mood or anxiety disorder or PTSD was 54.0% in 2018. major depressive episode (39.9%), social anxiety disorder (25.7%), and PTSD (21.4%) were the most common mental disorders. There was a substantial increase in new onset or recurrence/persistence of mental disorders between the two measurement points (16-year assessment gap); 2002-2018 period prevalences were 43.5% for mood and anxiety disorder and 16.8% for alcohol abuse or dependence. The prevalence of self-reported attention deficit hyperactivity disorder, obsessive compulsive disorder, any personality disorder, and mania were 3.3%, 3.0%, 0.8%, and 0.8%, respectively. Comorbidity between mental disorders increased over the follow-up.

This study demonstrates a high burden of mental disorders among a large Canadian military and veteran cohort. These findings underscore the importance of prevention and intervention strategies to reduce the burden of mental disorders and alcohol use disorders in these populations.

Fischer F, Levis L, Falk C, Sun Y, Ioannidis JPA, Cuijpers P, Shrier I, Benedetti A, Thombs BD, and the Depression Screening Data (DEPRESSD) PHQ Collaboration (C Bernstein member of group authorship). Comparison of different scoring methods based on latent variable models of the PHQ-9: an individual participant data meta-analysis. Psychological Medicine 2021; 2021; Feb 22:1-12.


Previous research on the depression scale of the Patient Health Questionnaire (PHQ-9) has found that different latent factor models have maximized empirical measures of goodness-of-fit. The clinical relevance of these differences is unclear. We aimed to investigate whether depression screening accuracy may be improved by employing latent factor model-based scoring rather than sum scores. We used an individual participant data meta-analysis (IPDMA) database compiled to assess the screening accuracy of the PHQ-9. We included studies that used the Structured Clinical Interview for DSM (SCID) as a reference standard and split those into calibration and validation datasets. In the calibration dataset, we estimated unidimensional, two-dimensional (separating cognitive/affective and somatic symptoms of depression), and bi-factor models, and the respective cut-offs to maximize combined sensitivity and specificity. In the validation dataset, we assessed the differences in (combined) sensitivity and specificity between the latent variable approaches and the optimal sum score (⩾10), using bootstrapping to estimate 95% confidence intervals for the differences. The calibration dataset included 24 studies (4378 participants, 652 major depression cases); the validation dataset 17 studies (4252 participants, 568 cases). In the validation dataset, optimal cut-offs of the unidimensional, two-dimensional, and bi-factor models had higher sensitivity (by 0.036, 0.050, 0.049 points, respectively) but lower specificity (0.017, 0.026, 0.019, respectively) compared to the sum score cut-off of ⩾10.


We concluded that in a comprehensive dataset of diagnostic studies, scoring using complex latent variable models do not improve screening accuracy of the PHQ-9 meaningfully as compared to the simple sum score approach.

Wu Y, Levis B, Sun Y, He C, Krishnan A, Neupane D, Bhandari PM, Negeri Z, Benedetti A, Thombs BD, DEPRESsion Screening Data (DEPRESSD) HADS Group. Accuracy of the Hospital Anxiety and Depression Scale Depression subscale (HADS-D) to screen for major depression: systematic review and individual participant data meta-analysis. (C Bernstein is a member of group authorship). BMJ 2021; May 10;373:n972.

To evaluate the accuracy of the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) to screen for major depression among people with physical health problems. This was a systematic review and individual participant data meta-analysis drawn from Medline, Medline In-Process and Other Non-Indexed Citations, PsycInfo, and Web of Science (from inception to 25 October 2018). Eligible datasets included HADS-D scores and major depression status based on a validated diagnostic interview. Primary study data and study level data extracted from primary reports were combined. For HADS-D cut-off thresholds of 5-15, a bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, in studies that used semi-structured diagnostic interviews (eg, Structured Clinical Interview for ), fully structured interviews (eg, Composite International Diagnostic Interview), and the Mini International Neuropsychiatric Interview. One stage meta-regression was used to examine whether accuracy was associated with reference standard categories and the characteristics of participants. Sensitivity analyses were done to assess whether including published results from studies that did not provide raw data influenced the results.

Individual participant data were obtained from 101 of 168 eligible studies (60%; 25 574 participants (72% of eligible participants), 2549 with major depression). Combined sensitivity and specificity was maximised at a cut-off value of seven or higher for semi-structured interviews, fully structured interviews, and the Mini International Neuropsychiatric Interview. Among studies with a semi-structured interview (57 studies, 10 664 participants, 1048 with major depression), sensitivity and specificity were 0.82 (95% confidence interval 0.76 to 0.87) and 0.78 (0.74 to 0.81) for a cut-off value of seven or higher, 0.74 (0.68 to 0.79) and 0.84 (0.81 to 0.87) for a cut-off value of eight or higher, and 0.44 (0.38 to 0.51) and 0.95 (0.93 to 0.96) for a cut-off value of 11 or higher. Accuracy was similar across reference standards and subgroups and when published results from studies that did not contribute data were included.

We concluded that when screening for major depression, a HADS-D cut-off value of 7 or higher maximized combined sensitivity and specificity. A cut-off value of 8 or higher generated similar combined sensitivity and specificity but was less sensitive and more specific. To identify medically ill patients with depression with the HADS-D, lower cut-off values could be used to avoid false negatives and higher cut-off values to reduce false positives and identify people with higher symptom levels.

Bernstein CN, Hitchon CA, Walld R, Bolton JM, Lix LM, El-Gabalawy R, Sareen J, Singer A, Katz A, Marriott J, Fisk JD, Patten SB, Marrie RA. The Impact of Psychiatric Comorbidity on Health Care Utilization in Inflammatory Bowel Disease: A Population-Based Study. Inflammatory Bowel Diseases 2021;27(9):1462-1474. 


IBD is associated with an increase in psychiatric comorbidity compared with the general population. We aimed to determine the impact of PC on health care utilization in persons with IBD. We applied a validated administrative definition of IBD to identify all Manitobans with IBD from April 1, 2006, to March 31, 2016, and a matched cohort without IBD. A validated definition for psychiatric comorbidity in IBD population was applied to both cohorts; active psychiatric comorbidity status meant ≥2 visits for psychiatric diagnoses within a given year. We examined the association of active psychiatric comorbidity with physician visits, inpatient hospital days, proportion with inpatient hospitalization, and use of prescription IBD medications in the following year. We tested for the presence of a 2-way interaction between cohort and PC status. Our study matched 8459 persons with IBD to 40,375 controls. On crude analysis, IBD subjects had ≥3.7 additional physician visits, had >1.5 extra hospital days, and used 2.1 more drug types annually than controls. Subjects with active psychiatric comorbidity had >10 more physician visits, had 3.1 more hospital days, and used >6.3 more drugs. There was a synergistic effect of IBD (vs no IBD) and psychiatric comorbidity (vs no psychiatric comorbidity) across psychiatric disorders of around 4%. This synergistic effect was greatest for anxiety (6% [2%, 9%]). After excluding psychiatry-related visits and psychiatry-related hospital stays, there remained an excess health care utilization in persons with IBD and PC.

We concluded that persons with IBD with psychiatric comorbidity increases health care utilization compared with matched controls and compared with persons with IBD without psychiatric comorbidity. Active psychiatric comorbidity further increases health care utilization.

Marrie RA, Graff LA, Fisk JD, Patten S, Bernstein CN for the CIHR Team in Defining the Burden and Mitigating the Impact of Psychiatric Comorbidity in Immuno-inflammatory Disease. The relationship between symptoms of depression and anxiety and disease activity in IBD over time. Inflammatory Bowel Diseases 2021;27(8):1285-1293.

We aimed to examine associations between elevated symptoms of depression and anxiety and disease activity in inflammatory bowel disease (IBD). Previous findings have been inconsistent and have not accounted for variability in the courses of these conditions over time. We followed 247 participants with IBD (153 Crohn's disease, 94 ulcerative colitis) for 3 years. Annually, participants underwent an abdominal examination, reported therapies used for IBD, and completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. We evaluated associations of elevated symptoms (scores ≥11) of anxiety (HADS-A) and depression (HADS-D) with the presence of active IBD as measured using the Powell Tuck Index for ulcerative colitis and the Harvey-Bradshaw Disease Activity Index for Crohn's disease. Of 247 participants, 15 (6.1%) had elevated symptoms of depression (HADS-D ≥11) at enrollment, 41 (16.6%) had elevated symptoms of anxiety (HADS-A ≥11), and 101 (40.9%) had active IBD. On average, individuals with elevated symptoms of depression (odds ratio [OR], 6.27; 95% CI, 1.39-28.2) and anxiety (OR, 2.17; 95% CI, 1.01-4.66) had increased odds of active IBD. Within individuals, elevations in symptoms of depression over time were associated with increased odds of active IBD (OR, 2.70; 95% CI, 1.15-6.34), but elevated symptoms of anxiety were not. After adjustment for covariates (including disease activity), elevated symptoms of depression were also associated with increased odds of biologic therapy use (OR, 2.02; 95% CI, 1.02-4.00).

We concluded that symptoms of depression and anxiety are associated with disease activity in IBD over time. Reducing these mental health symptoms should be incorporated into the management of IBD

Marrie RA, Patel R, Bernstein CN, Bolton J, Graff LA, Marriott J, Hitchon CA, Figley C, Kornelsen J, Fisk J. Anxiety and Depression Affect Performance on the Symbol Digit Modalities Test Over Time in MS and Other Immune Disorders. Multiple Sclerosis 2021 Jul; 27(8): 1284-1292.

Longitudinal studies assessing depression and anxiety effects on cognition in multiple sclerosis (MS) are limited. We tested whether within-person fluctuations in symptoms of depression or anxiety over time affect cognition in persons with MS, IBD, rheumatoid arthritis, and a lifetime history of depression/anxiety disorders (DEP/ANX) but without an immune-mediated inflammatory diseases. We followed participants (MS: 255, IBD: 247, rheumatoid arthritis: 154, and DEP/ANX: 306) for 3 years. Annually, they completed the hospital anxiety and depression scale (HADS) and cognitive tests including the symbol digit modalities test (SDMT). We evaluated associations of elevated symptoms (scores ⩾ 11) of anxiety (HADS-A) and depression (HADS-D) with SDMT z-scores using multivariable linear models-estimating between-person and within-person effects. Participants with MS performed worse on the SDMT than participants in the DEP/ANX cohort (β = -0.68; 95% CI: -0.88, -0.48). Participants with elevated HADS-A scores performed worse on the SDMT than those without elevated scores (β = -0.43; 95% CI: -0.65, -0.21), particularly those with rheumatoid arthritis. Time-varying within-person elevations in depressive symptoms were associated with worse SDMT performance (β = -0.12; 95% CI: -0.21, -0.021).

We concluded that across persons, elevated symptoms of anxiety adversely affected information processing. Elevated symptoms of depression within-persons over time were associated with declines in information processing speed. This was true in all of these immune-mediated inflammatory diseases including IBD



Sareen J, Olafson K, Kredentser MS, Bienvenu OJ, Blouw M, Bolton JM, Logsetty S, Chateau D, Nie Y, Bernstein CN, Afifi TO, Stein MB, Leslie WD, Katz LY, Mota N, El Gabalwy R, Sweatman S, Marrie RA. The Five-Year Incidence of Mental Disorders in a Population Based ICU Survivor Cohort. Critical Care Medicine 2020; Aug; 48(8): e675-e683. 

In this study we aimed to estimate incidence of newly diagnosed mental disorders among patients that had been admitted to an intensive care unit (ICU) We used the population-based administrative data of Manitoba Health for this study. A total of 49,439 ICU patients admitted between 2000 and 2012 were compared with two control groups (hospitalized persons: n = 146,968 and general population: n = 141,937), matched on age (± 2 yr), sex, region of residence, and hospitalization year. Outcomes included incident mental disorders (mood, anxiety, substance use, personality, posttraumatic stress disorder, schizophrenia, and psychotic disorders) not diagnosed during the 5-year period before the index ICU or hospital admission date (including matched general population group), but diagnosed during the subsequent 5-year period. Multivariable survival models adjusted for sociodemographic variables, Charlson comorbidity index, admission diagnostic category, and number of ICU and non-ICU exposures.

The ICU cohort had a 14.5% (95% CI, 14.0-15.0) and 42.7% (95% CI, 42.0-43.5) age- and sex-standardized incidence of any diagnosed mental disorder at 1 and 5 years post-ICU exposure, respectively. In multivariable analysis, the ICU cohort had increased risk of any diagnosed mental disorder at all time points versus the hospitalized cohort (year 5: adjusted hazard ratio, 2.00; 95% CI, 1.80-2.23) and the general population cohort (year 5: adjusted hazard ratio, 3.52; 95% CI, 3.23-3.83). A newly diagnosed mental disorder was associated with younger age, female sex, more recent admitting years, presence of preexisting comorbidities, and repeat ICU admission.

We concluded that ICU admission is associated with an increased incidence of mood, anxiety, substance use, and personality disorders over a 5-year period.

Tennenhouse L, Marrie RA, Bernstein CN, Lix L. Machine-learning models for depression and anxiety in individuals with immune-mediated inflammatory disease. Journal of Psychosomatic Research 2020 Jul; 134:110126. 

Individuals with immune-mediated inflammatory disease (IMID, diseases such as IBD, multiple sclerosis, rheumatoid arthritis) have a higher prevalence of psychiatric disorders than the general population. We utilized machine-learning to identify patient-reported outcome measures (PROMs) that accurately predict major depressive disorder (MDD) and anxiety disorder in an IMID population. Participants with IMID were enrolled in a cohort study and completed a Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID), and multiple PROMs. PROM items were ranked separately for MDD and anxiety disorder by the standardized mean difference between individuals with and without psychiatric disorders. Items were added sequentially to logistic regression (LR), neural network (NN), and random forest (RF) models. Discriminative performance was assessed with area under the receiver operator curve and calibration was assessed with Brier scores. Ten-fold cross-validation was used. Of 637 participants, 75% were female and average age was 51 years. Area Under the Curve and Brier scores respectively ranged from 0.87-0.91 and 0.07 (i.e., no variation) for MDD models, and from 0.79-0.83 and 0.09-0.11 for anxiety disorder models. In LR and NN, few PROM items were required to obtain optimal discriminatory performance. RF did not perform as well as LR and NN when few PROM items were included.

We concluded that predictive model performance was respectable and revealed insight into PROM items that are predictive of MDD and anxiety disorder. Models that included only the items 'I felt depressed' and 'I felt like I needed help for my anxiety' performed similarly to models that included all items from multiple PROMs.

Jain A, Marrie RA, Shafer LA, Graff LA, Patten S, El-Gabalawy3R, Sareen J, Bolton J, Fisk J, Bernstein CN. Incidence of adverse psychiatric events during treatment of inflammatory bowel disease with biologic therapies: A systematic review. Crohn’s and Colitis 360 2020 Jan; 2(1) 1-7.


We conducted a systematic review and a fixed effects meta-analysis to determine if incident adverse psychiatric events including depression, anxiety, psychosis or suicide, were associated with biologic therapy in IBD. Six randomized controlled trials and a cohort study met criteria, reporting an incidence of adverse psychiatric events in 4,882 patients. The risk difference per 100 person-months of any adverse psychiatric events with a biologic medication was 0.01 (95% confidence interval = 0.00-0.02). There was insufficient evidence available in randomized controlled trials to conclude that biologic therapy in IBD is associated with an increased incidence of adverse psychiatric events. In conducting this analysis it is clear that researchers are not documenting adverse psychiatric events in clinical trials of biologicals. However, there is not signal that biological therapy in IBD causes adverse psychiatric events.


Hansen TM, Sabourin BC, Oketola B, Bernstein CN, Singh H, Targownik LE. Cannabis use in persons with inflammatory bowel disease and vulnerability to substance misuse. Inflammatory Bowel Diseases 2020; 26: 1401-1406.

It is unknown whether cannabis users self-medicating their IBD symptoms are more likely to have comorbid mental health or personality risk factors associated with an increased potential for substance misuse compared with recreational cannabis users.

We surveyed individuals with IBD about their cannabis use, their mental health symptoms, and personality risk factors associated with substance misuse. We compared risk factors for substance misuse between individuals using cannabis to manage IBD symptoms and those using cannabis recreationally. Of 201 persons with IBD who completed the questionnaire, 108 reported lifetime cannabis use. Of those, a larger proportion of Crohn's disease patients used cannabis to manage IBD symptoms (53% [34/64] vs 28% [12/43]; P = 0.01). Individuals self-medicating with cannabis were more likely to use cannabis for coping reasons (P = 0.016) and demonstrated higher levels of impulsivity (P = 0.004) and depressive symptoms (P = 0.012) when compared with individuals using cannabis recreationally. Logistic regression revealed that cannabis was 4.1 times (P = 0.05) and 3.7 times (P = 0.05) more likely to be used for IBD symptoms by smokers and individuals with moderate-severe depressive symptoms, respectively. Individuals high in impulsivity were 4.1 times more likely to use cannabis for their IBD symptoms than those low in impulsivity (P = 0.005).

We concluded that persons with IBD self-medicating with cannabis have characteristics associated with increased vulnerability to substance misuse when compared with those using cannabis recreationally. Screening for mental health comorbidities and vulnerability to substance misuse should be undertaken if cannabis is to be used to treat IBD symptoms.

Reinhorn I, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM, Hitchon C, Marrie RA. Social Phobia in Immune-Mediated Inflammatory Diseases. Journal of Psychosomatic Research 2020; 2020 Jan; 128: 109890.

Immune-mediated inflammatory diseases such as multiple sclerosis (MS), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are associated with a high prevalence of psychiatric comorbidity but little is known about the prevalence of social phobia in Immune-mediated inflammatory diseases, or the factors associated with social phobia. We aimed to determine the prevalence of social phobia in MS, IBD and RA, and the factors associated with social phobia in these immune-mediated inflammatory diseases. We obtained data from the enrollment visit of a cohort study in immune-mediated inflammatory diseases of whom 654 participants were eligible for this analysis (MS: 254, IBD: 247, RA: 153). Each participant underwent a semi-structured psychiatric interview which identified depression and anxiety disorders including social phobia (lifetime and current), an assessment of disease activity, and reported sociodemographic information. Overall, 12.8% of participants had a lifetime diagnosis of social phobia (MS: 10.2%, IBD: 13.0%, RA: 17.0%). Social phobia was associated with younger age (OR 0.98; 0.97-1.00), having a high school education or less (OR 1.78; 1.08-2.91), comorbid major depressive disorder (OR 2.79; 1.63-4.78) and comorbid generalized anxiety disorder (OR 2.56; 1.30-5.05). Persons with RA had increased odds of having social phobia as compared to persons with MS (OR 2.26; 1.14-4.48) but not IBD.

We concluded that persons with immune-mediated inflammatory diseases have a relatively high lifetime prevalence of social phobia, exceeding that reported for the Canadian general population. Strategies aimed at early detection, and effective clinical management of social phobia in immune-mediated inflammatory diseases are warranted.


Blaney C, Sommer J, El Gabalawy R, Bernstein CN, Walld R, Hitchon CA, Bolton J, Sareen J, Patten SB, Singer A, Lix LM, Katz A, Fisk JD, Marrie RA.  Incidence and Temporal Trends of Co-Occurring Personality Disorder Diagnoses in Immune-Mediated Inflammatory Diseases. Epidemiology and Psychiatric Sciences 2020 Jan 9; 29:e84.​

Although immune-mediated inflammatory diseases are associated with multiple mental health conditions, there is a paucity of literature assessing personality disorders in these populations. We aimed to estimate and compare the incidence of any personality disorders in IMID and matched cohorts over time, and identify sociodemographic characteristics associated with the incidence of personality disorders. We used population-based administrative data from Manitoba, Canada to identify persons with incident inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) using validated case definitions. Unaffected controls were matched 5:1 on sex, age and region of residence. personality disorders were identified using hospitalisation or physician claims. We used unadjusted and covariate-adjusted negative binomial regression to compare the incidence of personality disorders between the immune-mediated inflammatory diseases and matched cohorts. We identified 19 572 incident cases of immune-mediated inflammatory diseases (IBD n = 6,119, MS n = 3,514, RA n = 10 206) and 97 727 matches overall. After covariate adjustment, the immune-mediated inflammatory diseases cohort had an increased incidence of personality disorders (incidence rate ratio [IRR] 1.72; 95%CI: 1.47-2.01) as compared to the matched cohort, which remained consistent over time. The incidence of personality disorders was similarly elevated in IBD (IRR 2.19; 95%CI: 1.69-2.84), MS (IRR 1.79; 95%CI: 1.29-2.50) and RA (IRR 1.61; 95%CI: 1.29-1.99). Lower socioeconomic status and urban residence were associated with an increased incidence of personality disorders, whereas mid to older adulthood (age 45-64) was associated with overall decreased incidence. In a restricted sample with 5 years of data before and after immune-mediated inflammatory diseases diagnosis, the incidence of personality disorders was also elevated before immune-mediated inflammatory diseases diagnosis among all immune-mediated inflammatory diseases groups relative to matched controls.

We concluded that immune-mediated inflammatory diseases are associated with an increased incidence of personality disorders both before and after an immune-mediated inflammatory diseases diagnosis. These results support the relevance of shared risk factors in the co-occurrence of personality disorders and immune-mediated inflammatory disease conditions.

Kornelsen J, Wilson A, Witges K, Labus J, Mayer EA, Bernstein CN. Brain resting state network alterations associated with Crohn’s disease. Frontiers in Neurology 2020 Feb 18; 11: 48.


IBD is a chronic disease that is associated with aspects of brain anatomy and activity. In this preliminary MRI study, we investigated differences in brain structure and in functional connectivity of brain regions in 35 participants with Crohn's disease and 21 healthy controls. Voxel-based morphometry analysis was performed to contrast Crohn’s disease and healthy controls structural images. Region of interest analyses were run to assess functional connectivity for resting-state network nodes. Independent component analysis identified whole brain differences in functional connectivity associated with resting-state networks. Though no structural differences were found, region of interest analyses showed increased functional connectivity between the frontoparietal network and salience network, and decreased functional connectivity between nodes of the default mode network. Independent component analysis results revealed changes involving cerebellar, visual, and salience network components. Differences in functional connectivity associated with sex were observed for both region of interest analysis and Independent component analysis.

Taken together, these changes are consistent with an influence of Crohn's disease on the brain and serve to direct future research hypotheses.


Levis B, Benedetti A, Ioannidis J, Sun Y, Negeri Z, He C, Wu Y, Krishnan A, Bhandari PM, Neupane D, Imran M, Rice D, Riehm KE, Saadat N, Azar M, Boruff J, Cuijpers P, Gilbody P, Kloda LA, McMillan D, Patten S, Shrier I, Ziegelstein I, Alamri S, Amtmann D, Ayalon L, Baradaran HR, Beraldi A, Bernstein CN, Bhana A, Bombardier CH, Carter G, Chagas M, Chibanda D, Clover K, Conwell Y, Diez-Quevedo C, Fann JR, Dr. Felix Fischer, Gholizadeh L, Gibson L, Green E, Greeno C, Hall B, Haroz E, Ismail K, Jette N, Khamseh ME, Kwan Y, Lara MA, Liu SI, Loureiro S, Löwe B, Marrie RA, Marsh L, McGuire A, Muramatsu K, Navarrete L, Osório FL, Petersen I, Picardi A, Pugh S, Quinn T, Rooney AG, Shinn E, Sidebottom A, Spangenberg L, Tan PL, Taylor-Rowan M, Turner A, van weert H, Vöhringer P, Wagner LI, White J, Winkley K, Thombs B. Patient Health Questionnaire-9 scores do not accurately estimate depression prevalence: individual participant data meta-analysis. Journal of Clinical Epidemiology 2020; 122: 115-128.


Depression symptom questionnaires are not for diagnostic classification. Patient Health Questionnaire-9 (PHQ-9) scores greater than or equal to 10 are nonetheless often used to estimate depression prevalence. We compared PHQ-9 greater than or equal to 10 prevalence to Structured Clinical Interview for DSM (SCID) major depression prevalence and assessed whether an alternative PHQ-9 cutoff could more accurately estimate prevalence. This study was a meta-analysis of datasets comparing PHQ-9 scores to SCID major depression status. 9,242 participants (1,389 SCID major depression cases) from 44 primary studies were included. Pooled PHQ-9 ≥ 10 prevalence was 24.6% (95% CI: 20.8%, 28.9%); pooled SCID major depression prevalence was 12.1% (95% CI: 9.6%, 15.2%); pooled difference was 11.9% (95% CI: 9.3%, 14.6%). Mean study-level PHQ-9 greater than or equal to 10 to SCID-based prevalence ratio was 2.5 times. PHQ-9 greater than or equal to 14 and the PHQ-9 diagnostic algorithm provided prevalence closest to SCID major depression prevalence, but study-level prevalence differed from SCID-based prevalence by an average absolute difference of 4.8% for PHQ-9 greater than or equal to 14 (95% prediction interval: -13.6%, 14.5%) and 5.6 % for the PHQ-9 diagnostic algorithm (95% prediction interval: -16.4%, 15.0%).


We concluded that PHQ-9 greater than or equal to 10 substantially overestimates depression prevalence. There was too much heterogeneity to correct statistically in individual studies.

Lewis K, Marrie RA, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM; CIHR Team in Defining the Burden and Managing the Effects of Immune-Mediated Inflammatory Disease. The prevalence and risk factors of undiagnosed depression and anxiety disorders among patients with inflammatory bowel disease. Inflammatory Bowel Diseases 2019; 25 (10), 1674-1680.

Inflammatory bowel disease is associated with a high prevalence of comorbid depressive and anxiety disorders. A significant proportion of IBD patients with comorbid psychiatric disorders remain undiagnosed and untreated, but factors associated with diagnosis are unknown. We evaluated the prevalence of undiagnosed depression and anxiety in an IBD cohort, along with the associated demographic and clinical characteristics. We obtained data from the enrollment visit of a cohort study of psychiatric comorbidity in immune-mediated diseases including IBD. Each participant underwent a Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) to identify participants who met lifetime criteria for a diagnosis of depression or anxiety. Those with a SCID-based diagnosis were classified as diagnosed or undiagnosed based on participant report of a physician diagnosis. Of 242 eligible participants, 97 (40.1%) met SCID criteria for depression, and 74 (30.6%) met criteria for anxiety. One-third of participants with depression and two-thirds with anxiety were undiagnosed. Males were nearly 3.5x more likely to have an undiagnosed depressive disorder. Nonwhite participants were 80% less likely to have an undiagnosed anxiety disorder. Our findings highlight the importance of screening for depression and anxiety in patients with IBD, with particular attention to those of male sex and with a lower education level.


Bernstein CN, Hitchon CA, Walld R, Bolton JM, Sareen J, Walker JR, Graff LA, Pattem SB, Singer A, Lix LM, El-Gabalawy R, Katz A Fisk JD, Marrie RA. Increased burden of psychiatric disorders in inflammatory bowel disease. Inflammatory Bowel Disease 2019 Jan 10;25(2): 352-359.

Psychiatric comorbidity in inflammatory bowel disease (IBD) is well known; however, data from a truly representative sample are sparse. We aimed to estimate the incidence and prevalence of psychiatric disorders in an IBD cohort compared with a matched cohort without IBD. Using the population-based University of Manitoba IBD Epidemiology Database, we identified all persons with incident IBD from 1989 to 2012 and a general population matched cohort (5:1). We applied validated algorithms for IBD, depression, anxiety disorders, bipolar disorder, and schizophrenia to determine the annual incidence of these conditions post-IBD diagnosis and their lifetime and current prevalence. There were 6119 incident cases of IBD and 30,573 matched individuals. After adjustment for age, sex, socioeconomic status, region of residence, and year, there was a 60% higher incidence in the IBD cohort compared with controls for depression (incidence rate ratio [IRR], 1.58; 95% confidence interval [CI], 1.41-1.76), 40% for anxiety disorder (IRR, 1.39; 95% CI, 1.26-1.53), 80% for bipolar disorder (IRR, 1.82; 95% CI, 1.44-2.30), and 65% for schizophrenia (IRR, 1.64; 95% CI, 0.95-2.84). Incidence rate ratios were similar for Crohn's disease and ulcerative colitis and between males and females and were stable over time. However, within the IBD cohort, the incidence rates of depression, anxiety, and bipolar disorders were higher among females, those aged 18-24 years vs those older than 44 years, urbanites, and those of lower socioeconomic status. The lifetime and current prevalence rates of psychiatric disorders were also higher in the IBD than the matched cohort. We concluded that the incidence and prevalence of psychiatric disorders are elevated in the IBD population.

Marrie RA, Walker JR, Graff LA, Patten SB, Bolton JM, Marriott JJ, Fisk JD, Hitchon C, Bernstein CN for the CIHR Team in Defining the Burden and Managing the Effects of Immune-mediated Inflammatory Disease. Gender differences in information needs and preferences regarding depression among individuals with multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. Patient and Education Counseling 2019; Apr 6. pii: S0738-3991(19)30132-6.

We assessed the information needs of persons with any of three immune-mediated inflammatory diseases (multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis) regarding depression, as a first step toward developing patient-relevant information resources, ultimately to facilitate self-management and appropriate care. We also compared information needs across genders. We surveyed participants with multiple sclerosis, IBD and rheumatoid arthritis regarding depression-related information needs including types of treatments, effectiveness, risks, benefits, and perceived helpfulness of treatments. We compared responses between groups using multivariate regression. 328 participants provided complete responses (Multiple sclerosis: 141, IBD: 114, rheumatoid arthritis: 73). Most of the topics queried were perceived as very important, and similarly important for all groups. Women placed higher importance than men on most topics. The most popular formats for receiving information were discussion with a counselor (very preferred: 67.4%) and written information (very preferred: 65.5%); this did not differ between groups. We concluded that persons affected by multiple sclerosis, IBD and rheumatoid arthritis are interested in receiving information about multiple topics related to depression treatment, from multiple sources. Women desire more information than men. PRACTICE IMPLICATIONS: These findings can be used to design information resources to meet information needs regarding depression in multiple sclerosis, IBD and rheumatoid arthritis.

Whitehouse CE, Fisk JD, Bernstein CN, Berrigan LI, Bolton JM, Graff LA, Hitchon CA, Marriott JA, Peschken CA, Sareen JA, Walker JR, Stewart SH, Marrie RA for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Comorbid anxiety, depression and cognition in MS and other immune-mediated disorders. Neurology 2019; 92(5):e406-417.


In this report we aimed to determine whether anxiety and depression were associated with cognition in multiple sclerosis, and whether these associations were similar in other immune-mediated inflammatory diseases like IBD, and rheumatoid arthritis, and in anxious/depressed individuals without a chronic immune mediated disease.  There were 255 persons with multiple sclerosis, 247 persons with IBD, 154 persons with rheumatoid arthritis and 308 persons with anxiety and/or depression. All persons completed a structured psychiatric interview (SCID), the Hospital Anxiety and Depression Scale (HADS), and cognitive testing, including the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT-II), and Letter Number Sequencing (LNS). All cohorts exhibited higher rates of cognitive impairment in the domains of processing speed, verbal learning, and delayed recall memory relative to general population norms. Higher levels of anxiety symptoms were associated with slower processing speed, lower verbal learning, and lower working memory performance (all p < 0.001); higher levels of depression symptoms were associated with slower processing speed. These associations did not differ across cohorts.

We concluded that anxiety and depression were associated with lower cognitive function in multiple sclerosis with a similar pattern observed in persons with other IBD and rheumatoid arthritis, and persons without a a chronic immune disease. Managing symptoms of anxiety and of depression in chronic immune diseases is important to mitigate their effect on cognition.

Bernstein CN. Addressing mental health in persons with IBD. Journal of Canadian Association of Gastroenterology 2018;1:97-98.


This editorial discusses the importance of addressing mental health issues in patients with IBD.


Marrie RA, Graff LA, Walker JR Fisk JD, Patten SB, Walld R, Hitchon C, Lix L, Bolton JM, Sareen J, Singer A, Lix L, Katz A, Berrigan LI, Marriott JM, Singer A, El-Gabalawy R, Peschken CA, Zarychanski R, Bernstein CN. Effects of Psychiatric Comorbidity in Immune-Mediated Inflammatory Disease: Protocol for a Prospective Study. JMIR Research Protocols 2018; Jan 17;7(1):e15.


In this paper we reported the research protocol we have pursued in studying psychiatric comorbidity (having a concurrent mental health diagnosis) in persons with a chronic immune disease (any of IBD, multiple sclerosis or rheumatoid arthritis). We described how participants were recruited and how we interviewed participants on an annual basis. We also described the aspects of the research program that did involve direct patient contact. This included using administrative health data (insurance data from Manitoba Health) to understand how common it was in the general population to have both a mental health diagnosis and one of the chronic immune disease diagnoses; and also how likely it was that these mental health disorders occurred long before the onset of the chronic immune disease. Another aspect of our research program was to undertake systematic reviews of the medical research to understand the degree to which research has been undertaken exploring treatment of mental health diseases in these chronic immune diseases and what the outcomes of that research were.

Litster B, Bernstein CN, Graff LA, Walker JR, Fisk JD, Patten SB, Bolton JM, Sareen J, El-Gabalawy R, Marrie RA. Validation of the PHQ-9 for suicidal ideation in persons with inflammatory bowel disease. Inflammatory Bowel Diseases 2018; 24: 1641-8.

Suicide is a leading cause of death worldwide. Transition from suicidal ideation (SI) to suicide attempt is high within a year of SI onset. The risk of suicide and SI is elevated in persons with IBD versus the general population. We aimed to validate the Patient Heath Questionnaire (PHQ)-9 as a screening tool for SI in IBD and to determine factors associated with SI in IBD. IBD participants in our research program exploring psychiatric comorbidity in chronic immune diseases completed the PHQ-9 and participated in the Structured Clinical Interview for DSM-IV (SCID). We determined the sensitivity, specificity, and positive and negative predictive value (PPV and NPV) of the PHQ-9 in identifying SI as compared to the SCID. In other words, we determined how robust a tool the PHQ-9 was at predicting SI.  SI was endorsed by 24 (9.7%) participants on the PHQ-9 and 5 (2.0%) based on the SCID. The PHQ-9 had good sensitivity (100%), specificity (92.2%), and NPV (100%) but low PPV (20.8%) for SI. Factors strongly associated with SI were depression (OR 13.1; 95%CI: 4.46, 40.5), anxiety (OR 11.3; 95%CI: 4.46, 28.6), and active disease (OR 3.87; 95%CI: 1.54, 9.71). On multivariable analysis, the only factors that predicted SI were depression (OR 5.54; 95%CI: 1.67, 18.4) and pain (OR 1.14; 95%CI: 1.03, 1.25). People with depression were more than 5 times as likely to have SI than people without depression.) We concluded that overall the PHQ-9 is a valid screening tool for SI in IBD patients, and routine implementation of this tool would support screening for depression and SI effectively and efficiently in clinical practice.

Marrie RA, Fisk J, Walker JR, Patten S, Lix L, El Gabalawy R, Hitchon CA, Walld R, Katz A, Bernstein CN.  Physical Comorbidities Increase the Risk of Psychiatric Comorbidity in Immune-Mediated Inflammatory Disease. General Hospital Psychiatry; 2018; 51: 71-78.


As part of our research program exploring psychiatric comorbidity in chronic immune diseases we tested the association between physical comorbidity and incident depression, anxiety disorder and bipolar disorder in IBD), multiple sclerosis and rheumatoid arthritis compared to matched controls. Using population-based administrative data we identified 6119 persons with IBD, 3514 persons with MS, 10,206 persons with RA and 97,727 matched controls. We identified incident cases of depression, anxiety disorder and bipolar disorder in these populations. The risk of incident depression, anxiety disorders and bipolar disorder was higher in each chronic immune disease cohort compared with controls. The risk of newly diagnosed mental health disorders increased with an increasing number of physical comorbidities for each mental health disorder evaluated, across all 3 immune diseases. In conclusion within each chronic immune disease cohort physical comorbidity increases the risk of psychiatric comorbidity.

Bernstein CN, Zhang L, Lix LM, Graff LA, Walker JR, Fisk JD, Patten SB, Hitchon CA, Bolton JM, Sareen J, El-Gabalawy R, Marriott J, Marrie RA.  The validity and reliability of screening measures for depression and anxiety disorders in inflammatory bowel disease. Inflammatory Bowel Diseases 2018; 24(9):1867-1875.

We evaluated the validity and reliability of multiple symptom scales for depression and anxiety for persons with IBD. IBD participants in a cohort study completed a Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed the Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Kessler-6 Distress Scale, PROMIS Emotional Distress Depression Short-Form 8a (PROMIS Depression) and Anxiety Short-Form 8a (PROMIS Anxiety), Generalized Anxiety Disorder 7-item Scale, and Overall Anxiety and Severity Impairment Scale. The SCID diagnoses was the reference standard. Of 242 participants, the SCID classified 8.7% as having major depression and 17.8% as having anxiety disorders. Among the depression scales, the PHQ-9 had the highest sensitivity (95%). Specificity was generally higher than sensitivity and was highest for the HADS-D (cut-point of 11; 97%). The area under the ROC curve (AUC) did not differ significantly among depression scales. Among the anxiety scales, sensitivity was highest for the PROMIS (79%). Specificity ranged from 82% to 88% for all tools except the HADS-A (cut-point of 8; 65%). The AUC did not differ between depression and anxiety tools. We concluded that overall, the symptom scales for depression and anxiety were similar in their psychometric properties. The anxiety scales did not perform as well as the depression scales. Alternate cut-points may be more relevant when these scales are used in an IBD sample.

Enns M, Bernstein CN, Kroeker K, Graff LA, Walker JR, Lix LM, Hitchon CA, El-Gabalawy R, Fisk JD, Marrie RA. The association of fatigue, pain, depression and anxiety with work and activity impairment 2 in immune mediated inflammatory diseases. PLOS One 2018; Jun 7;13(6):e0198975.


Impairment in work function is a frequent outcome in patients with chronic conditions such as immune-mediated inflammatory diseases (IMID), depression and anxiety disorders. The personal and economic costs of work impairment in these disorders are immense. Symptoms of pain, fatigue, depression and anxiety are potentially remediable forms of distress that may contribute to work impairment in chronic health conditions such as IMID. The present study evaluated the association between pain [Medical Outcomes Study Pain Effects Scale], fatigue [Daily Fatigue Impact Scale], depression and anxiety [Hospital Anxiety and Depression Scale] and work impairment [Work Productivity and Activity Impairment Scale] in four patient populations: multiple sclerosis (n = 255), IBD (n = 248, rheumatoid arthritis (n = 154) and a depression and anxiety group (n = 307), using quantile regression, controlling for the effects of sociodemographic factors, physical disability, and cognitive deficits. Each of pain, depression symptoms, anxiety symptoms, and fatigue individually showed significant associations with work absenteeism, presenteeism, and general activity impairment. When the distress variables were entered concurrently into the regression models, fatigue was a significant predictor of work and activity impairment in all models (quantile regression standardized estimates ranging from 0.2 to 0.5). These findings have important clinical implications for understanding the determinants of work impairment and for improving work-related outcomes in chronic disease.

Marrie RA, Walld R, Bolton J, Sareen J, Patten S, Singer A, Lix L, Hitchon C, El-Gabalawy R, Katz A, Fisk J, Bernstein CN. Psychiatric comorbidity increases mortality in immune-mediated inflammatory diseases. General Hospital Psychiatry 2018; 53:65-72.

We determined the association between any common mental disorder (depression, anxiety disorder, bipolar disorder) and mortality and suicide in three immune-mediated inflammatory diseases (IMID), inflammatory bowel disease (IBD), multiple sclerosis and rheumatoid arthritis, versus age-, sex- and geographically-matched controls. Using administrative data, we identified 28,384 IMID cases (IBD: 8695; Multiple sclerosis: 5496; rheumatoid arthritis: 14,503) and 141,672 matched controls. We determined annual rates of mortality, suicide and suicide attempts. We evaluated the association of any common mental disorder with all-cause mortality and suicide using multivariable Cox regression models. In the IMID cohort, any common mental disorder was associated with increased mortality. We observed a greater than additive interaction between depression and IMID status (attributable proportion 5.2%), but a less than additive interaction with anxiety (attributable proportion -13%). Findings were similar for multiple sclerosis and rheumatoid arthritis. In IBD, a less than additive interaction existed with depression and anxiety on mortality risk. The IMID cohort with any common mental disorder had an increased suicide risk versus the matched cohort without common mental disorder. We concluded that common mental disorders are associated with increased mortality and suicide risk in IMID. In multiple sclerosis and rheumatoid arthritis, the effects of depression on mortality risk are greater than associations of these IMID and depression alone.

Marrie RA, Walld R,Bolton JM, Sareen J, Walker JR, Patten SB, Singer A, Lix LM, Hitchon CA,El-Gabalawy R, Katz A, Fisk JD, Bernstein CN. Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. Journal of Psychosomatic Research 2017;101:17-23.

We studied the incidence (number of new diagnoses) of psychiatric comorbidity in chronic immune mediated diseases. We used the administrative health data of Manitoba Health, the single provincial health provider, for the years of 1989-2012. We identified 19,572 incident cases of persons with chronic immune diseases including 6119 persons with IBD, 3514 persons with multiple sclerosis, 10,206 persons with RA, and 97,727 age-sex- and geographically-matched controls. The relative 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) were elevated in the chronic immune diseases cohort. This means that persons with these chronic immune diseases were nearly twice as likely to have depression as persons without those diseases and 40% more likely to have an anxiety disorder. Depression and anxiety affected the multiple sclerosis population more often than the IBD and rheumatoid arthritis populations. This increased risk appears non-specific as it is seen for all three chronic immune diseases and for all psychiatric disorders studied, implying a common underlying biology for psychiatric diseases in those with chronic immune diseases.

Marrie RA, Walld R,  Bolton JM, Sareen J, Walker JR, Patten SB, Singer A, Lix L, Hitchon C, El-Gabalawy R, Katz A, Fisk JD, Bernstein CN. Rising Incidence of Psychiatric Disorders Before Diagnosis of Immune-Mediated Inflammatory Diseases. Epidemiology and Psychiatric Sciences 2017; Nov 3:1-10.


We have shown that after the diagnosis of chronic immune-mediated inflammatory diseases such as IBD, multiple sclerosis and rheumatoid arthritis, the incidence of psychiatric diagnoses is increased relative to the general population. We aimed to determine whether the incidence of psychiatric disorders is increased in the 5 years before the diagnosis of having chronic immune-mediated inflammatory diseases as compared with the general population. Using administrative health data from Manitoba, we identified all persons with newly diagnosed IBD, multiple sclerosis and rheumatoid arthritis between 1989 and 2012, and matched controls from the general population. We identified 12 141 new cases of chronic immune diseases (3766 IBD, 2190 multiple sclerosis, 6350 rheumatoid arthritis). As early as 5 years before diagnosis, the incidence of depression [incidence rate ratio (IRR) 1.54; 95% CI 1.30-1.84) and anxiety disorders (IRR 1.30; 95% CI 1.12-1.51) were elevated in the chronic immune diseases cohort as compared with the controls. This means that for as long as 5 years prior to the diagnosis of their chronic immune disease these patients were 30-50% more likely to have depression or an anxiety disorder than members of the general population. Similar results were obtained for each of the IBD, multiple sclerosis and rheumatoid arthritis cohorts. We concluded that the incidence of psychiatric diagnoses is elevated in the chronic immune diseases population as compared with a matched population as early as 5 years before diagnosis. Future studies should elucidate whether this reflects shared risk factors for psychiatric disorders and chronic immune diseases, a shared final common inflammatory pathway or other etiology.

Bernstein CN. The brain-gut axis and stress in inflammatory bowel disease. Gastroenterology Clinics in North America 2017; 46(4):839-846.


This review article discusses the important connection between the brain and the gut in IBD and how stress may impact on outcomes in IBD.

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