A review of possible relations between omega-3 PUFA and depression, anxiety and stress disorders
The central nervous system (CNS) has the highest concentrations of lipids in the body, after adipose tissue. In the brain, these lipids include the long-chain polyunsaturated fatty acids (LC-PUFA) docosahexaenoic acid (DHA, in the omega-3 family) and arachidonic acid (AA, in the omega-6 family). These acids are necessary for the correct development and functioning of the CNS. Human beings are thought to have evolved with a diet in which the omega-6:omega-3 ratio was approximately equal to one. After that, starting in the industrial era, the ratio changed and humans started to consume food with a higher amount of omega-6 than omega-3 PUFA. Besides the fact that the short-chain acids of the respective families (long-chain precursors) are essential acids, which the human body cannot synthesise and thus they have to be acquired in the diet, in the case of omega-3 conversion is very inefficient. In short, there is a lack of omega-3 LC-PUFA (DHA) and eicosapentaenoic acid (EPA).
Epidemiological studies have linked dietary omega-3 LC-PUFA deficiency to depression and clinical trials have shown that subjects diagnosed with depression, anxiety and stress disorders (e.g. post-traumatic stress disorder) have lower levels of omega-3 PUFA and a higher omega-6:omega-3 ratio in the blood (mainly in the red blood cell membrane) and the brain than do healthy subjects in their reference group (age and sex); and the same observations have been obtained from post-mortem studies. Animal studies have produced similar findings.
The results of the omega-3 LC-PUFA supplementation trials in patients with depressive disorders are mixed; some found that EPA and DHA have positive effects on the symptoms of depression, while others failed to observe such effects. This diversity of results could be attributed not only to the heterogeneity of the characteristics of the clinical trials (design, sample, duration), but also the quality and quantity of PUFA used, the type of placebo, the use or otherwise of concomitant medication and the severity of the symptoms at the start of the trial.
Recent trials suggest that the beneficial effects of omega-3 LC-PUFA in depressive disorders are mainly attributable to EPA, which has proved more effective than DHA in such cases. However, more studies are required to explain this effect (as DHA can part of EPA, and this conversion pathway involves the enzymes required for the production of omega-6 LC-PUFA, hence supplementation with EPA could lead to an increase in DHA and a drop in omega-6 LC-PUFA).
Despite advances in understanding of the physiopathology of depression, approximately 40% of patients do not respond to treatment. In numerous studies, supplementation with omega-3 LC-PUFA has reduced the severity of depressive symptoms in patients resistant to antidepressants, such as selective serotonin reuptake inhibitors.
Omega-3 LC-PUFA and its metabolites play important roles as signalling molecules that regulate inflammation, and contribute to signal transduction between neurons or between neurons and glial cells. There are higher concentrations of DHA than EPA in the brain (the latter rapidly oxidises and little of which is stored), so we will focus on the former. Once DHA enters the brain, it binds with membrane phospholipids (in both neurons and glial cells); it is then released from the phospholipids in response to neuronal stimulation, injury and stress and can activate specific receptors or be metabolised into specific metabolites that regulate specific pathways important to neurotransmission and neuroinflammation. Data from experimental studies indicate that several of these specific receptors could mediate in a direct effect of DHA on neurons to control emotional behaviour: retinoid X receptor (RXR); free fatty acid receptor (FFAR) GPR40 (FFAR1) and GPR120 (FFAR4). Future studies will determine whether DHA has a protective action on these receptors with regard to depression and anxiety disorders in humans. Regulation of the endocannabinoid system could also mediate the neuroprotective effect of omega-3 PUFAs, as both are thought to be involved in depression. The endocannabinoid system is known to be intimately involved in regulation of the hypothalamic-pituitary-adrenal axis, but it still needs to be established whether these mechanisms are interconnected in the effects of omega-3 PUFA deficiency-induced depression.
Knowledge of these mechanisms could open future possibilities of non-pharmacological strategies for the treatment of mood disorders and other psychiatric disorders.
Larrieu T, Layé S. Food for mood: relevance of nutritional omega-3 fatty acids for depression and anxiety. Front Physiol. 2018;9:1047.