Effects of a High EPA Multinutrient Supplement on Negative Affect in Young Adults.

Study Overview
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Brief Summary
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This is a 12-week-long, randomised, double-blind, placebo-controlled trial exploring the efficacy of a high-EPA multinutrient supplement in the management of sub-clinical anxiety and depression. The investigators focus on young and healthy, adult university students, who may otherwise not be eligible for pharmacological or cognitive behavioural therapy interventions.

Detailed Description
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First-line treatment for anxiety disorders comprises Cognitive Behavioural Therapy, which is ineffective in a considerable minority of individuals, and pharmacological treatments, which often confer significant side effects. On the other hand, fish-oil-based supplements have been shown to be safer, efficacious alternatives, especially for individuals not eligible for behavioural or pharmacological therapies. Evidence from randomised controlled trials (RCTs) suggests that the long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may exert beneficial anxiolytic effects. It is also suggested that dietary components such as vitamins and minerals e.g. a-tocopherol (vitamin E) and Magnesium (Mg), may also play a role in mood. It is furthermore theorised that minor allelic carriage of desaturase and apolipoprotein E (APOE) polymorphisms may also influence the putative anxiolytic potential of dietary components. However, despite the abundance of findings in RCTs and animal studies, the putative synergism, additive effects and precise mechanism of action of these macro- and micronutrients on anxiety in humans are largely unknown. Furthermore, the evidence suggests that in depressive states, glutamate homeostasis is dysregulated in frontal brain regions, and in bipolar patients, glutamate concentration is increased in the anterior cingulate cortex. Supplementation with EPA-rich regimes for 12 weeks confers beneficial changes in glutamate concentrations and improvement in functional connectivity between brain regions associated with mood and improvement in global symptoms. The investigators have designed a randomised, double-blind, placebo-controlled trial to explore the above. Students from the University of Roehampton, aged 18-29 years (Emerging Adulthood), are randomised on a 1:1 allocation ratio, in two groups, for 12 weeks: Active treatment group to be supplemented with a high-EPA multinutrient supplement providing a daily dose of 1,125 mg EPA, 441 mg DHA, 330 mg magnesium and 7.5 mg α-tocopherol. Placebo group to be supplemented with an inert oil mix providing a daily dose of 3,060 mg sunflower seed oil, 60 mg lecithin, 300 mg glyceryl monostearate and 465 mg fish-oil (18%/12% EPA/DHA respectively) for blinding. Brain hemodynamic and neurochemical changes in response to supplementation with the EPA-rich regime are explored in a subgroup of volunteers by magnetic resonance imaging (MRI). Analyses take place at the Combined Universities Brain Imaging Centre (CUBIC), Royal Holloway, University of London and comprise: Proton Magnetic resonance spectroscopy (MRS), to assess changes in glutamate concentrations in the right and left ventrolateral prefrontal cortex and the anterior cingulate cortex. Functional MRI (fMRI) to assess changes in seed-to-voxel functional connectivity using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds; regions in the brain implicated in the control of emotion and mood. The choice of the population was made on the basis of its high-risk nature; university students in Emerging Adulthood (18-29 years of age) experience persistent levels of high-academic stress, social disconnection and sleep disruption which increase anxiety levels and exacerbate psychological distress and disengagement from study. University students are thus a high-risk, vulnerable group characterised by higher and increasing rates of anxiety disorders compared to the general population. Furthermore, this population is largely neglected by the therapeutic literature. The study hypothesis is that: Generally healthy, non-clinically anxious university students in Emerging Adulthood experiencing sub-clinical levels of anxiety, will benefit from supplementation with a high-EPA multinutrient supplement, in that the latter will exert beneficial anxiolytic effects. Mg and vitamin E will exert additive anxiolytic effects. Interindividual variations in fatty acid desaturases (FADS) and APOE genotypes will influence the putative anxiolytic potential of the high-EPA multinutrient supplement under investigation. Prefrontal and anterior cingulate cortex glutamate concentrations, and functional connectivity between OFC and AMY, will improve in response to supplementation. The investigators will perform mixed-model analysis of covariance for the study primary and secondary endpoints, on an intention-to-treat (ITT) and per-protocol (PP) basis. The investigation which will take place at the Department of Life Sciences of the University of Roehampton and the Combined Universities Brain Imaging Centre (CUBIC), Royal Holloway, University of London, harmonised with local and national guidelines and risk assessments, the code of Good Clinical Practice and the Declaration of Helsinki. The study findings will be reported in accordance with the CONSORT statement.

Official Title
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The Effects of a High Eicosapentaenoic Acid Multinutrient Supplement on Measures of Stress, Anxiety and Depression in Young Adults: a Randomised, Double-blind, Placebo-controlled Trial.

Conditions
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Depression, Anxiety

Intervention / Treatment
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* Dietary Supplement: High-EPA multinutrient supplement.
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-29 years GAD-7 Score ≥ 5 PHQ-8 Score ≥ 4 English language fluency. Overall good health. Exclusion Criteria: Self reported BMI ≥ 30 kg/m^2. Current tobacco smoker. Diagnosis of anxiety, depression/major depressive disorder episode, psychosis, schizophrenia, bipolar disorder, eating disorders, haemophilia, or life-threatening disease during the preceding six months from the beginning of the trial. Use of antidepressant drugs during the preceding six months from the beginning of the trial. Participation to psychological and/or behavioural interventions during the preceding six months from the beginning of the trial. Inability to ingest pills. Pregnancy. Breastfeeding. Known allergy or intolerance to LCn-3 PUFAs, seafood and any of the constituents of the supplement under investigation. High intake (more than twice per week) of oily fish (e.g. herring, pilchards, salmon, swordfish, sardines, sprats, trout or mackerel). Use of fish oil supplements during the preceding six months from the beginning of the trial. Inability to participate in the study for 12 consecutive weeks.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 29 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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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active treatment<br>High-EPA multinutrient supplement. | Dietary Supplement: High-EPA multinutrient supplement.<br>* Three capsules with the largest meal of the day providing: 1,125 mg EPA 441 mg DHA 330 mg Magnesium 7.5 mg a-tocopherol<br>* Other names: Libretto;|
| Placebo Comparator: Placebo<br>Inert oil mix. | Other: Placebo<br>* Three capsules with the largest meal of the day providing: 3,060 mg sunflower seed oil 60 mg lecithin 300 mg glyceryl monostearate 465 mg EPA/DHA (18%/12% respectively for blinding)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Anxiety on the 21-point Generalised Anxiety Disorder Assessment (GAD-7) at Week 12. | GAD-7 is a 7-item, validated, self-reported instrument used to screen for generalised anxiety disorder and to assess its severity over the past two weeks. Possible scores range from 0 (none) to 21 (severe). | Baseline and Week 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Depression on the 24-point Patient Health Questionnaire (PHQ-8) at Week 12. | PHQ-8 is an 8-item, validated, self-reported instrument used as a diagnostic and severity measure for depressive disorders. Possible scores range from 0 (none) to 24 (severe). | Baseline and Week 12. | 
| Change from Baseline in Depression, Anxiety and Stress on the 21-item Depression, Anxiety and Stress Scale (DASS-21) at week 12. | DASS-21 is a validated tool comprising three self-report scales designed to measure the emotional states of depression, anxiety and stress. | Baseline and Week 12. | 
| Change from Baseline in the Proportion of Trials Selected as Happy Compared to the Alternative Emotion, Adjusted to a Scale of 0 to 15 on the Emotional Bias Task (EBT) at Week 12. | EBT is a 4-minute-long, computer-based test that detects perceptual bias in facial emotion perception. The key outcome measure for the EBT is the bias point; the proportion of trials selected as happy compared to the alternative emotion, adjusted to a scale of 0 to 15. This is used to determine the extent and direction of the participant's bias. Additionally, latency measures and measures of how many times each emotion was selected are also available. | Baseline and Week 12. | 
| Change from Baseline in Measures of Sustained Attention on the Rapid Visual Information Processing (RVP) at Week 12. | RVP is a 7-minute-long, computer-based test measuring sustained attention. Outcome measures cover latency (speed of response), probability of false alarms and sensitivity. | Baseline and Week 12. | 
| Change from Baseline in Measures of Retention and Manipulation of Visuospatial Information on Spatial Working Memory (SWM) at Week 12. | SWM is a 4-minute-long, computer-based test that measures strategy and working memory errors as a measure of retention and manipulation of visuospatial information. Outcome measures include errors (selecting boxes that have already been found to be empty and revisiting boxes which have already been found to contain a token) and strategy. | Baseline and Week 12. | 
| Change from Baseline in Measures of Response Inhibition on Stop Signal Task (SST) at Week 12. | SST is an up-to 14-minute-long, computer based test that measures response inhibition (impulse control). Outcome measures cover direction errors, proportion of successful stops, reaction time on Go trials, and stop signal reaction time (SSRT). | Baseline and Week 12. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anxiety, Depression, Anxiolytic, Antidepressant, Omega-3 PUFAs, Eicosapentaenoic Acid, Docosahexaenoic Acid, Long-chain Polyunsaturated Fatty Acids, Dietary Supplement, Stress, Functional magnetic resonance imaging, Magnetic resonance spectroscopy