Major depressive disorder (MDD) is one of the main causes of disability in developed countries as well as in low and medium income countries.
The World Health Organization (WHO) estimates that by the year 2020 depression will be the second cause of morbidity worldwide.
Recent researches have focused on the role of nutrition as an important role in mental health, in particular, suboptimal levels of omega-3 polyunsaturated fatty acids (n-3 PUFA) are emerging as a potentially modifiable risk factor for mental illness.
Certain nutrients may be important in preventing the risk of development of MDD. These include group B vitamins, omega-3 fatty acids, and olive oil.
On the other hand, several recent studies have implicated inflammation in the physiopathology of depression. The so-called “Western” dietary pattern, rich in refined carbohydrates and sugars, in saturated fatty acids and trans-fatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, poor in omega-3 fatty acids and common in Northern Europe and USA may cause an activation of the inflammatory pathways.
This could mean that diets that promote inflammation could fuel depressive symptoms. Thus, diet influences inflammation, and dietary-related inflammation may in turn increase depression and depression can in turn advance inflammation. In contrast, the omega-3 fatty acids, found in fish, fish oil, walnuts, wheat germ, and some dietary supplements such as flax seed products can reduce inflammation.
Since their discovery in the 1970s as key components of brain tissue, long-chain n-3 PUFA have been postulated to serve critical roles in brain development, and function. Case-control studies have shown that patients suffering with depression and others mental health conditions (developmental disorders and mental retardation in childhood, bipolar disorder, schizophrenia and borderline personality disorder, stress, hostility and aggression in adulthood, cognitive decline, dementia and Alzheimer’s disease in late adulthood).
Evidence gathered throughout the years has shown that the two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish oil, have been found to have antidepressant effects that may be due to bioconversion of EPA to leukotrienes, prostaglandins, and other chemicals required by the brain and implicated in the body’s immune responses.
Among all the potential risk factors and triggers linked to MDD, nutrition is possibly the most basic factor and may be the easiest to modify.
Nutrition and depression at the forefront of progress Popa TA, Ladea M. 2012
POLYUNSATURATED FATTY ACIDS (PUFAs)
Omega-3 fatty acids are a type of polyunsaturated fatty acids (PUFAs). PUFAs are so-called because they are not 'saturated' with hydrogen atoms at multiple (poly) locations within the molecule and, as a result, contain two or more carbon-carbon double bonds.
They form one of the three main classes of fatty acids, the others being saturated, in which all available hydrogen atom positions are filled, and monounsaturated, in which a single carbon-carbon double bond exists. PUFAs are subdivided into the omega- 3 (n-3) series (the first double bond is 3 carbons from the end (omega) carbon atom of the molecule) that are synthetically derived from alpha-linolenic acid (ALA) and the omega- 6 (n-6) series which are derived from linoleic acid (LA), both 18 carbon atom containing fatty acids. LA and ALA are termed essential fatty acids because mammalian cells are unable to synthesize these fatty acids from simpler precursors. LA can be converted sequentially via a biosynthetic pathway into other omega-6 fatty acids, the 18 carbon gamma linolenic acid (GLA), and the 20 carbon arachidonic (AA) and dihomogammalinolenic acids (DGLA). Similarly, ALA si converted into longer chain omega-3 fatty acids such as 20 carbon eicosapentaeoic acid (EPA) and 22 carbon docosahexaenoic acid (DHA). Increasing evidence indicates, however, that although LA and ALA can be converted into their longer chain length metabolites, the rate of conversion in humans is very slow, resulting in an estimated 2 to 10% of ALA being converted to DHA or EPA. This suggests that a major source of the longer chain polyunsaturated fatty acid species such as EPA and DHA is likely to be dietary.
Long chain (LC) derivatives of ALA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are made by phytoplankton and transferred via the food-chain to marine organisms, particularly coldwater fish and marine animals. Therefore supplementation with fish oils can markedly elevate the cellular levels of both these omega-3 PUFAs.
Structurally, PUFAs are key components of phospholipids, comprising cellular and intracellular membranes.
OMEGA-3 PUFAs AND BRAIN
Brain lipids, composed of fatty acids, are structural constituents of membranes. It has been estimated that gray matter contains 50% polyunsaturated fatty acids out of which about 33% belong to the omega-3 family.
Although the circulation contains at least 10 times more n-6 than n-3 PUFAs, DHA predominates in the retina, brain and nervous system. DHA is also particularly concentrated at neural synapses.
Furthermore, increased n-6 to n-3 PUFAs ratios can also alter the fatty acid composition of neural membranes.
In line with a longstanding focus on the role of neurotransmitters such as dopamine and serotonin in mental illness, researches have focused on associations between PUFAs and central nervous system activity: levels of n-3 PUFAs have been associated with monoaminergic neurotransmission.
DHA deficiency has predicted reduced levels of phosphatidylserine (PS) in the brain, which is thought to play an important function in neural signaling activities and, in alcoholics, 5-hydroxyindoleacetic acid (5-HIAA) concentrations in cerebrospinal fluid, an indicator of low serotonin turnover rate in the frontal cortex.
Studies have further indicated that n-3 PUFAs may affect receptor properties or activation of signal transduction by receptors. Electrical impulse conduction is dependent on the exchange of ions through the cell membrane, which relies on the fluidity and physiological structure of cell membranes.
Furthermore, there are indications that PUFAs are involved in the synthesis and activities of brain peptides, which are involved in modulating the activities of neurotransmitters (like dopamine and serotonine). n-3 PUFAs are also thought to influence gene expression of a range of enzymes required for important neural functions including synaptic transduction, ion channel formation, energy metabolism and formulation of proteins vital for brain development and function.
Regular delivery of oxygen and nutrients via the blood is also critical for optimal brain function, and psychopathology is associated with both reduced cerebral blood flow and transportation of glucose, the brain’s primary energy source, to brain regions as required. In this regard, n-3 PUFAs are associated with production of nitric oxide, as well as anti-inflammatory and vasodilatory eicosanoids (notably PGI2), and are known to assist in endothelial-dependent vasodilation. They have also been associated with substantially increased transport of glucose across the blood-brain barrier.
META-ANALYSIS OF EFFECT UPON DEPRESSION
Combining all of the MDD and bipolar trials using meta-analytical techniques shows that omega-3 fatty acid supplementation is significantly more effective than placebo in the treatment of depression.
There is, however, significant heterogeneity between the studies. Three possible factors might influence that heterogeneity: baseline HDRS score, depression type and predominant omega-3 PUFAs species.
This analysis showed that the primary factor responsible for heterogeneity in the combined effect estimate is the PUFAs species utilized: results suggest that EPA plays a more significant role in the antidepressant effect of omega-3 PUFAs than does. Furthermore omega-3 fatty acids (DHA or EPA) may be more effective when given in combination with other antidepressant medications (selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants), possibly by altering the pharmacokinetics of the other drugs. On the other hand, some trials report that EPA administered in the absence of conventional antidepressants shows an antidepressant effect in childhood depression and in MDD during pregnancy suggesting that EPA does indeed have an intrinsic efficacy. In summary, some authors suggest that initiation of treatment with an SSRI and PUFAs simultaneously is advantageous in terms of efficacy when compared with treatment with SSRI as a monotherapy. The safety profile of such combination treatment is very favorable.
POSSIBLE MECHANISMS UNDERLYING THE PSYCOACTIVE EFFECT OF OMEGA-3 PUFA
For mood and/or anxiety disorders current treatments include compounds which enhance either serotonergic neurotransmission e.g. SSRI, noradrenergic neurotransmission e.g. selective noradrenergic reuptake inhibitors, monoamine oxidase inhibitors, or both e.g. tricyclic antidepressants. These drugs are thought to exert their beneficial effects by increasing the influence that neurons, originating in the locus coeruleus or dorsal raphe, have upon their targets in the limbic system, thalamus and prefrontal cortex. The efficacy of these drugs is thought to derive from their ability to enhance serotonergic or dopaminergic neurotransmission. Omega-3 PUFAs also have these effects and are hence supportive of a significant role in mood, anxiety and attentional disorders, but, importantly, not in schizophrenia. As a matter of fact omega-3 PUFA deficiency reduce ability of neurons to release dopamine in the frontal cortex and nucleus accumbens in response to tyramine, and release serotonin in the hippocampus in response to fenfluramine.
At the biochemical level how might omega-3 PUFAs deficiency and supplementation affect the nervous system? The conventional view of omega-3 PUFAs bioactivity is that they act as negative regulators of the eicosanoid signaling systems dependent upon the metabolism of the omega-6 PUFAs, AA e.g. the prostaglandin, leukotriene and HETE pathways.
Specifically, dietary supplementation with omega-3 PUFAs is thought to increase the abundance of omega-3 PUFAs in membrane phospholipids which can then inhibit AA-dependent signalling either directly, by replacing AA as the eicosanoid substrate of cyclooxygenases and lipoxygenases, or indirectly by altering the expression of proteins involved in the signalling cascade. Although EPA is a minor brain fatty acid compared to the abundant DHA, both omega-3 PUFAs are equally effective inhibitors of AA-derived eicosanoid synthesis, a finding which is at odds with the observation that EPA may be more clinically efficacious in the treatment of mood disorders. An in vitro observation indicates that long term supplementation with EPA can increase the stimulated release of AA from membrane phospholipids, whereas DHA has no effect. This role of EPA was likely due to it inhibiting the re-uptake of AA to reform an intact phospholipid, a two enzyme metabolic pathway which acts to reverse the hydrolysis of the AA-containing phospholipid by phospholipase A2. EPA can inhibit the expression and/or activity of the enzymes lysophospholipid acyltransferase (LPAT) or fatty acid CoA ligase (FACL), both of which are required for reuptake of AA to occur. Indeed, reduced activity of FACL appears to enhance AA-dependent signaling reactions since reduced reuptake will increase the supply of AA available for eicosanoid synthesis.
EPA and potentially other omega-3 PUFAs, appear to have two distinct cellular effects (and biochemical targets) with respect to phospholipid metabolism: at low doses they may enhance incorporation of both themselves and omega-6 PUFAs into the membrane, but at higher doses they decrease omega-6 incorporation.
EPA abundance in the brain (approximately 0.2% of fatty acids) is much lower than DHA (approximately 15% of fatty acids); that’s why adding DHA to EPA may be more effective than EPA alone.
Although supplementation with EPA does not change the fact that DHA predominates in the brain, such supplementation does have a much larger relative effect upon EPA abundance compared to DHA abundance. Thus, as EPA intake increases, the ratio of DHA to EPA in the brain markedly falls. Since it is only recently that purified EPA has been available for human consumption, little is known regarding the consequences for brain function that administering high doses of EPA in the absence of DHA may have.
Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid?
Oiling the Brain: A Review of Randomized Controlled Trials of Omega-3 Fatty Acids in Psychopathology across the Lifespan Natalie Sinn, Catherine Milte and Peter R. C. Howe
Omega-3 Fatty Acid Augmentation of Citalopram Treatment for Patients with Major Depressive Disorde Lev Gertsik, Russell E. Poland, Catherine Bresee and Mark Hyman