Le samedi 21 octobre
10:45 – 11:45 (1 hr)
Salle de réunion : Finback (3rd floor – B Tower)
S. Evelyn Stewart*, MD; Elise Ewing, BSc; Clara Westwell-Roper, MD PhD

Rôles CanMEDS :

1. Érudit
2. Expert médical
3. Promoteur de la santé

À la conclusion de cette activité, les participants seront en mesure de : 1) Define the potential types and prognostic use of biomarkers in childhood-onset obsessive–compulsive disorder (OCD); 2) Describe relations between medical conditions and OCD symptoms in children and youth, focusing on the recent characterization of immune-related comorbidities; and 3) Explain the potential role of epigenetic biomarkers to improve our understanding and treatment of childhood-onset OCD.

Obsessive–compulsive disorder (OCD) is a common neuropsychiatric condition affecting 1% to 2% of children and youth. Although cognitive-behavioural therapy (CBT) and serotonin reuptake inhibitors are effective treatments, nonresponse is common and symptoms often persist into adulthood. Additional strategies are needed to identify subgroups of people who may benefit from targeted treatment approaches.
In this research symposium, we introduce biomarkers in mental health and their potential use in OCD, highlighting novel findings of three provincial research initiatives.
First, we present analyses of salivary immune markers in pediatric OCD, highlighting variables to consider when measuring analytes in the oral compartment and associations between pro-inflammatory cytokine levels and symptom severity. Second, we discuss the importance of medical comorbidities for both clinical management and biomarker development, focusing on the characterization of immune-related comorbidities in youth with OCD compared to those attending other psychiatric outpatient clinics. These data expand on our previous findings from an international multisite study in adults. Finally, we present findings from an epigenome-wide association study examining DNA methylation in buccal swabs from OCD-affected youth, compared to control subjects, before and after a course of CBT. We describe potential functions of co-methylated regions showing significant differential methylation, including annotation to genes with overlapping roles in neuronal development and immune function.
Taken together, these findings suggest novel approaches to combined clinical and laboratory phenotyping that will inform larger-scale studies characterizing the complex interplay between genetic and environmental factors that impact OCD symptoms and treatment response.

S14a – Comparison of Immune-Related Comorbidities in Pediatric Obsessive–Compulsive Disorder Versus a Heterogeneous Child Psychiatry Control Group
Elise Ewing, BSc

À la conclusion de cette activité, les participants seront en mesure de : 1) Learn about lifetime prevalence estimates of immune-related disorders in a pediatric obsessive–compulsive disorder (OCD) population; 2) Understand the prevalence of immune-related disorders in a tertiary pediatric psychiatry outpatient population; and 3) Appreciate immune-related comorbidity prevalence differences between pediatric OCD and psychiatric control groups.

Adults with childhood-onset obsessive–compulsive disorder (OCD) report higher than expected lifetime rates of immune-related disorders. It is unknown whether these associations are apparent prior to adulthood or specific to OCD among childhood-onset psychiatric disorders. This study compared immune-related disease cluster prevalence between pediatric OCD subjects and psychiatric control groups.
Methods: This study used clinical registry data from a tertiary pediatric hospital outpatient psychiatry program. Study groups included participants from the provincial OCD program and other outpatient psychiatry clinics. Demographic and medical data were collected via parent report. Six disease clusters for between-group comparisons included the following: allergies, asthma, eczema/chronic hives, serious infections, recurrent infections, and autoimmune disorders. Disease cluster prevalence differences between OCD and psychiatric control subjects were analyzed with Pearson chi-squared tests or Fisher’s exact test when expected cell counts were less than five. Prevalence differences were analyzed with logistic regression, adjusting for age, sex, ethnicity, and parent educational attainment.
Results: The study sample comprised 398 children and youth with OCD and 1,459 psychiatric control subjects. Three disease clusters had greater lifetime prevalence in OCD: allergies (pFDR = 0.002), eczema/chronic hives (pFDR = 0.002) and recurrent infections (pFDR = 0.002). OCD status remained predictive of these clusters following covariate-adjusted regression: allergies (odds ratio [OR] 1.48, pFDR = 0.032), eczema/chronic hives (OR 2.56 pFDR = 0.003), and recurrent infections (OR 11.8 pFDR = 0.003).
Conclusions: Findings suggest that elevated immune-related comorbidity rates within childhood-onset OCD are observable before adulthood and do not appear to represent a more generalized relation with psychiatric disorders.

Références :

1. Westwell-Roper C, Williams KA, Samuels J, et al. Immune-related comorbidities in childhood-onset obsessive compulsive disorder: lifetime prevalence in the Obsessive Compulsive Disorder Collaborative Genetics Association Study. J Child Adolesc Psychopharmacol 2019;29(8):615–624.
2. Cosco TD, Pillinger T, Emam H, et al. Immune aberrations in obsessive–compulsive disorder: a systematic review and meta-analysis. Mol Neurobiol 2019;56(7):4751–4759.

S14b – Association Between Obsessive–Compulsive Disorder Symptom Severity and Salivary Pro-Inflammatory Cytokines: Clinical Application and Youth Perspectives on Study Participation
Clara Westwell-Roper, MD PhD

À la conclusion de cette activité, les participants seront en mesure de : 1) Summarize evidence suggesting aberrant peripheral immune function in childhood-onset obsessive–compulsive disorder (OCD); 2) Identify advantages and limitations of using saliva for biomarker discovery in pediatric OCD; and 3) Appreciate the need for longitudinal biosample analyses in the context of interventional studies.

Childhood-onset obsessive–compulsive disorder (OCD) has been associated with immune dysregulation. Saliva may provide a minimally invasive tool for measuring putative inflammatory biomarkers. We compared salivary defence proteins and inflammatory mediators from participants with childhood-onset OCD and healthy control subjects and evaluated associations with clinical phenotype.
Methods: Saliva was collected from 41 children and youth attending a tertiary OCD program and 46 control subjects. OCD severity was assessed with the Child Yale-Brown Obsessive–Compulsive Scale. Participants completed oral health and medical questionnaires. Levels of lysozyme, α-amylase, salivary IgA (sIgA), C-reactive protein (CRP), and cytokines were quantified by immunoassay.
Results: Multiple linear regression models, including demographic variables, oral health measures, and OCD status, explained a significant proportion of the variance in IL-6, IL-1β, and sIgA but not TNF-α, CRP, α-amylase, or lysozyme levels. Diagnosis of OCD was associated with significantly higher IL-6 (β = 0.403, p = 0.026), while severity of OCD was a significant predictor of increased levels of all three cytokines (IL-6, β = 0.325, p = 0.009; IL-1β, β = 0.284, p = 0.020; TNF-α, β = 0.269, p = 0.036).
Conclusion: These data highlight the feasibility of saliva collection and analyses in pediatric OCD and suggest an association between pro-inflammatory cytokines and symptom severity. They informed the development of longitudinal interventional studies incorporating biosample collection, including a randomized controlled trial of adjunctive nonsteroidal anti-inflammatory therapy (NCT04673578). Findings from a national survey of youth with OCD and their families regarding perspectives on biomarker study sample collection will also be discussed.

Références :

1. Westwell-Roper C, Best JR, Naqqash Z, et al. Severe symptoms predict salivary interleukin-6, interleukin-1β, and tumor necrosis factor-α levels in children and youth with obsessive-compulsive disorder. J Psychosom Res 2022;155:110743.
2. Westwell-Roper C, Best JR, Elbe D, et al. Celecoxib versus placebo as an adjunct to treatment-as-usual in children and youth with obsessive-compulsive disorder: protocol for a single-site randomised quadruple-blind phase II study. BMJ Open 2022;12(1):e054296.

S14c – Epigenetics of Pediatric Obsessive–Compulsive Disorder
S. Evelyn Stewart, MD

À la conclusion de cette activité, les participants seront en mesure de : 1) Review their current understanding of obsessive–compulsive disorder (OCD) etiology regarding genetic and other factors; 2) Examine the potential significance of epigenetics in psychiatric disorders; and 3) Report on differences between pediatric OCD and control samples with respect to comethylated regions.

Obsessive–compulsive disorder (OCD) is a common debilitating psychiatric disorder with amplified complex genetic influence in its childhood-onset form. To date, specific OCD risk genes have not been identified. Epigenetic mechanisms, including methylation status, alter gene expression in response to environmental and other factors. Yet, OCD epigenetics are poorly understood, especially in pediatric cases.
We conducted an epigenome-wide association study of pediatric OCD cases and matched control subjects using co-methylation region-based DNA methylation patterns.
Methods: Pediatric subjects comprised 28 OCD-affected and 31 age/gender-matched control subjects with adequate epithelial cell proportions (> 0.5) derived from buccal swabs. Comethylated regions (n = 83,049) across the genome were examined for CpGs. Robust linear models were run adjusting for age, sex, ancestry principal components, buccal epithelial cell proportion and bisulfite conversion yield. Inflation correction was completed via BACON R. Biological effect size for DNA methylation (delta beta) was calculated by extracting the beta coefficient of OCD diagnosis from the EWAS CMR model.
Results: Nine comethylated regions significantly differentiated between OCD and control groups, with a false discovery rate of < 0.1 and delta beta > 0.035. These gene regions correspond to TLE3 and MTMR7 (with 4 CpGs); KRT4 (with 3 CpGs); and ARHGAP32, CMT32, CMTM4, TENM3, and VAV2 (with 2 CpGs).
Conclusion: Findings support the importance of epigenetic factors in the etiology of pediatric OCD.

Références :

1. Westwell-Roper C, Stewart SE. Challenges in the diagnosis and treatment of pediatric obsessive-compulsive disorder. Indian J Psychiatry 2019;61(Suppl 1):S119–S130.
2. Schiele MA, Lipovsek J, Schlosser P, et al. Epigenome-wide DNA methylation in obsessive-compulsive disorder. Transl Psychiatry 2022;12(1):221.