An Investigation of the Relationship Between Omega-3 Fatty Acid Nutrition and Mental Health in Children and Adolescents

Study Overview
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Brief Summary
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This is an observational case-control add-on study to an investigator-initiated clinical trial (IICT) (ClinicalTrials.gov Identifier: NCT03167307): Omega-3 fatty acids as firstline treatment in pediatric depression. A 36-week multi-centre, double-blind, placebo-controlled randomized superiority study. This project will recruit a healthy control group matched for age and sex to a sub-group of patients with diagnosed pediatric major depressive disorder (pMDD) enrolled in the IICT. The aim is to investigate the relationship of n-3 FA intake and status with mental health in children and adolescents with and without diagnosed pMDD, and explore potential biochemical mechanisms underlying this relationship by measuring biomarkers related to n-3 FA metabolism, mental health and cognitive function.

Detailed Description
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According to a recent school survey, one out of ten adolescents in Zurich have moderate to marked depressive symptoms. Early onset of paediatric major depressive disorder (pMDD) is a risk factor for chronic and recurrent forms of depression in adulthood (MDD). MDD is associated with difficulties in relationships, impaired school and work performance, and an increased risk of substance abuse. Furthermore, MDD is a major contributor to the burden of suicide and poor long-term health late in life. The emerging potential of n-3 polyunsaturated fatty acids (n-3 PUFAs), also known in short as omega-3 fatty acids (n-3 FAs), for the treatment of MDD is being investigated in several studies. Previous observational studies suggest a link between the consumption of n-3PUFA-rich food and the level of depressive symptoms. However, studies that investigated the potential beneficial effects of n-3 PUFA supplementation for the treatment of MDD compared with placebo showed inconsistent findings. Primary objectives of this project are: To determine the relationship of n-3 FA intake and status with mental health in children and adolescents with and without diagnosed pMDD. To explore biochemical mechanisms underlying this relationship by measuring biomarkers related to n-3 FA metabolism, mental health, cognitive function, and potential pathways linking n-3 FA intake/status and brain health (e.g. immune system, gut microbiome-brain-axis). Participants meeting the following criteria are eligible for the study: Inclusion criteria: Participants of female and male sex Children aged 8 to ≤ 13 years or teenagers 13 to < 18 years at time of study entry Written informed assent of the subject and written informed consent from the subject's parents/legal representatives No present primary diagnosed psychiatric disorder according to the M.I.N.I. KID Test Exclusion criteria: More than 4 weeks of regular n-3 FA supplementation Women who are self-reported pregnant or breast feeding Pre-existing neurological or medical conditions likely to be a risk factor for developing depressive symptoms In a first step participants will be screened for in- and exclusion criteria. If participants can be included into the study we will Measure participant's mental health with behavioural and cognitive assessments Collect biological samples from participants (blood, urine, saliva, hair, and stool) This study aims to recruit a total of 200 participants: 100 cases (from IICT) and 100 controls (recruited for this study). There will be a total recruiting period of 18 months.

Official Title
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An Investigation of the Relationship Between Omega-3 Fatty Acid Nutrition and Mental Health in Children and Adolescents: A Case-control Study

Conditions
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Major Depressive Disorder, Depression, Child Mental Disorder

Participation Criteria
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Eligibility Criteria
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For cases: participants enrolled in the IICT and therefore meeting the criterie for participation in the IICT will be selected. For controls, participants fulfilling all of the following inlclusion criterie are eligible for the study Inclusion Criteria: Participants of female and male sex Children aged 8 to ≤ 13 years or teenagers 13 to < 18 years at time of study entry Written informed assent of the subject (appendix informed consent forms) and written in formed consent form from the subjects' parents/legal representatives No present primary diagnosed psychiatric disorder according to the M.I.N.I. KID Test. No use of chronic medication Able to communicate in German; degree of understanding sufficient to comply with trial procedure Exclusion Criteria: More than 4 weeks of regular n-3 FA supplementation (>2 daily capsules standard strength providing > 600 mg combined EPA/DHA) within the last 6 months. Women who are self-reported pregnant or breast feeding. Self-reported pre-existing neurological (such as e.g. brain tumour, temporal lobe epilepsy, HIV encephalopathy) or medical conditions (ICD-10 F06-F07) likely to be a risk factor for developing depressive symptoms Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cases<br>Patients with pMDD, enrolled in the Investigator-initiated clinical trial IICT (ClinicalTrials.gov Identifier: NCT03167307) | |
| Controls<br>Controls matched to cases according to age, sex and school education | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| n-3 fatty acid intake | Estimation of dietary omega-3 intake with a validated self-reported Omega-3 Food Questionnaire | 6 months | 
| n-3 fatty acid status | Measurement of relative amount of n-3 fatty acids | 1 day | 
| Pediatric depressive symptoms | Quantification of depressive symptoms with Children's Depression Rating Scale - Revised (CDRS-R) total score; Scale from 17 to >72; values >40 rated as moderate depression | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatty acid metabolism | Measurement of lipid mediators | 1 day | 
| Biomarkers related to brain health | Measurement of brain-derived neurotrophic factor (BDNF), kynurenine pathway metabolites, and monoamine neurotransmitters | 1 day | 
| Biomarkers related to systemic inflammation | Measurement of C-reactive Protein (CRP), alpha-1-acid glycoprotein, and cytokines | 1 day | 
| Biomarkers related to gut microbiota | Measurement of gut microbiome composition with 16S rRNA sequencing Faecal calprotectin Intestinal fatty acid binding protein | 1 day | 
| Biomarkers related to nutritional status | Measurement of iron and iodine status | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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n-3 fatty acids, pediatric Major Depressive Disorder