Publications

 

Liang G, Zhu F, Mirza AI, Arnold D, Bar-Or A, Bernstein CN, Bonner C, Forbes JD, Graham M, Hart J, Knox NC, Marrie RA,Mahony JO, Van Domselaar G, Yeh EA, Zhao Y, Banwell B, Waubant E, Tremlett H, and the Canadian Paediatric Demyelinating Disease Network. Stability of the gut microbiota in persons with pediatric-onset multiple sclerosis and related demyelinating diseases. Multiple Sclerosis Journal 2022; in press

 

We aimed to determine if the gut microbiota composition changes across repeated samples collected over the short-term in individuals with pediatric-onset MS or monophasic acquired demyelinating syndromes (monoADS). Individuals who provided stool samples on at least 2 occasions were eligible. Stool samples were collected across the Canadian Pediatric Demyelinating Disease Network and banked at the University of Manitoba IBD Clinical and Research Centre Biobank. Metagenome analysis was undertaken at the National Microbiology Laboratory, Winnipeg, Canada. Stool sample-derived DNA was amplified, sequenced, and clustered into amplicon sequence variants (ASVs). Alpha/beta diversities were explored, and genus-level ASVs were analysed using nonparametric microbial interdependence tests (NMIT) and linear mixed effect models. 36 individuals were eligible (18 MS/18 monoADS). 15 MS/16 monoADS participants provided two samples, and the remainder three, totalling 77 samples. Alpha/beta diversities did not differ between stool samples (P>0.09). Solobacterium genus varied significantly over-time (P=0.001). Nonparametric microbial interdependence tests revealed no difference in longitudinal sample composition between MS and monoADS participants (P>0.2).

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We concluded that the gut microbiota composition in individuals with pediatric-onset MS and monoADS exhibited stability between stool samples over a 2-25 month period. While preliminary, findings suggest that procurement of single stool samples is a reasonable first approach.

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Mirza AI, Zhu F, Knox N, Forbes JD, Van Domselaar G, Bernstein CN, Graham M, Marrie RA, Hart, J Yeh EA, Arnold D, Bar-Or A, O’Mahony J, Zhao Y, Hsiao W, Banwell B, Waubant E, Tremlett H. Metagenomic analysis of the pediatric-onset multiple sclerosis gut microbiome. Neurology 2022; in press.

 

This study examined the gut metagenome in individuals with and without pediatric-onset multiple sclerosis (MS). Stool samples were collected across the Canadian Pediatric Demyelinating Disease Network and banked at the University of Manitoba IBD Clinical and Research Centre Biobank. Metagenome analysis was undertaken at the National Microbiology Laboratory, Winnipeg, Canada. Study participants were 21 years old or younger, with MS (disease-modifying drug [DMD] exposed and naïve) or unaffected controls all less than age 22. 20 MS patients (McDonald criteria) with symptom onset prior to age18 years were matched to 20 controls by sex, age, stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha-diversity, relative abundance, and prevalence using Wilcoxon rank-sum, ALDEx2 and Fisher's exact tests, respectively. Alpha-diversity of enzymes and proteins did not differ by disease or DMD status (p>0.20), but metabolic pathways, gene annotations and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio=10, p=0.044), and Methanobrevibacter abundance (log2 fold-change [LFC]=1.7, p=0.0014), but lower homolactic fermentation abundance (LFC=-0.48, p=0.039). Differences by DMD status included lower phosphate butyryltransferase for DMD-naïve vs exposed MS patients (LFC=-1.0, p=0.033).

 

We concluded that the gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS versus controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.

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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. 

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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. 

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Tremlett H, Zhu F, Arnold D, Bar-Or A, Bernstein CN, Forbes JD, Graham M, Hart J, Knox NC, Marrie RA, Mirza A, O’Mahony J, Van Domselaar G, Yeh EA, Zhao Y, Banwell B, Waubant E, and the US Network of Pediatric MS Centers and the Canadian Paediatric Demyelinating Disease Network. The gut microbiota in pediatric multiple sclerosis and demyelinating syndromes. Annals of Clinical and Translational Neurology 2021; 8(12):2252-2269.

 

This study examined the gut microbiota in individuals with and without pediatric-onset multiple sclerosis (MS). Stool samples were collected across the Canadian Pediatric Demyelinating Disease Network and banked at the University of Manitoba IBD Clinical and Research Centre Biobank. Microbiome analysis was undertaken at the National Microbiology Laboratory, Winnipeg, Canada. Study participants were 21 years old or younger, with MS (disease-modifying drug [DMD] exposed and naïve) or monophasic acquired demyelinating syndrome [monoADS] (symptom onset prior to age 18 years), and unaffected controls. All were at least 30 days without antibiotics or corticosteroids. V4 region 16S RNA gene-derived amplicon sequence variants (Illumina MiSeq) were assessed using negative binomial regression and network analyses; rate ratios were age- and sex-adjusted (aRR). There were 32 MS, and 41 monoADS and 36 control participants Although microbiota diversity (alpha, beta) did not differ between participants (p > 0.1), taxa-level and gut community networks did. MS (vs. monoADS) exhibited > fourfold higher relative abundance of the superphylum Patescibacteria (aRR = 4.2;95%CI:1.6-11.2, p = 0.004, Q = 0.01), and lower abundances of short-chain fatty acid (SCFA)-producing Lachnospiraceae (Anaerosporobacter) and Ruminococcaceae (p, Q < 0.05). DMD-naïve MS cases were depleted for Clostridiales vadin-BB60 (unnamed species) versus either DMD-exposed, controls (p, Q < 0.01), or monoADS (p = 0.001, Q = 0.06) and exhibited altered community connectedness (p < 10-9 Kruskal-Wallis), with SCFA-producing taxa underrepresented. Consistent taxa-level findings from an independent US Network of Pediatric MS Centers case/control (n = 51/42) cohort included >eightfold higher abundance for Candidatus Stoquefichus and Tyzzerella (aRR = 8.8-12.8, p < 0.05) in MS cases and 72%-80% lower abundance of SCFA-producing Ruminococcaceae-NK4A214 (aRR = 0.38-0.2, p ≤ 0.01). 

 

We concluded that the gut microbiota community structure, function and connectivity, and not just individual taxa, are of likely importance in MS.

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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.

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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).

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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

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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

 

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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 Gastroentrology 2021; in press.

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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. 

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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.

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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; in press. 

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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.

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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.

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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; 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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Marrie RA, Walld R, Bolton JM, Sareen J, Patten SB, Singer A, Lix L, Hitchon CA,

Marriott JJ, El-Gabalawy R, Katz A, Fisk JD, Bernstein CN; for the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Uptake of influenza vaccination among persons with inflammatory bowel disease, multiple sclerosis or rheumatoid arthritis: a population-based matched cohort study. CMAJ Open 2021; 9: E510-E521.

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Individuals with immune-mediated inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, are at increased risk for influenza and related complications. We examined and compared the uptake of influenza vaccination among people with and without these diseases, as well as the influence of psychiatric comorbidity on vaccine uptake. Using administrative data from Apr. 1, 1984, to Mar. 31, 2016, we conducted a retrospective matched cohort study in Manitoba, Canada. We matched persons 18 years of age or older who had a diagnosis of inflammatory bowel disease, multiple sclerosis or rheumatoid arthritis (the immune-mediated inflammatory disease cohorts) with persons who did not have these diagnoses (the control cohorts) on age, sex and region. We then identified cohort members with any mood or anxiety disorder (depression, anxiety disorders, bipolar disorder). We identified influenza vaccinations through billing codes. Using binomial regression, we modelled the difference in the proportion of the immune-mediated inflammatory disease and matched cohorts vaccinated annually, with adjustment for sociodemographic characteristics, comorbidity and immune therapy. We tested additive interaction effects between a person's cohort and presence of a mood or anxiety disorder. We identified 32 880 individuals with 1 or more immune-mediated inflammatory diseases (10 148 with inflammatory bowel disease, 6158 with multiple sclerosis and 16 975 with rheumatoid arthritis) and a total of 164 152 controls. In fiscal year 2015, 8668 (41.3%, 95% confidence interval [CI] 40.6% to 42.0%) of the 20 982 persons with an immune-mediated inflammatory disease received an influenza vaccination, a rate higher than among controls (35 238 of 104 634; 33.7%, 95% CI 33.4% to 34.0%). After adjustment, participants with an immune-mediated inflammatory disease but no mood or anxiety disorder had 6.44% (95% CI 5.79% to 7.10%) greater uptake of vaccination than participants without such a disease. Among participants without an immune-mediated inflammatory disease, having a mood or anxiety disorder was associated with 4.54% (95% CI 4.20% to 4.89%) greater uptake of vaccination. However, we observed a subadditive interaction between immune-mediated inflammatory disease and psychiatric status (-1.38%, 95% CI -2.26% to -0.50%).

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Uptake of influenza vaccination was consistently low in populations with immune-mediated inflammatory disease, and although psychiatric morbidity is associated with greater vaccine uptake by Manitobans, it negatively interacts with these diseases to reduce uptake. Changes in care delivery are needed to mitigate this gap in care.

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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

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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.

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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.

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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. 

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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 Diagnostic and Statistical Manual of Mental Disorders), 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.

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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 maximized 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.

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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.