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.

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:

1. 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.
2. 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:

1. Proton Magnetic resonance spectroscopy (MRS), to assess changes in glutamate concentrations in the right and left ventrolateral prefrontal cortex and the anterior cingulate cortex.
2. 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.