Depression is common in late life: both major and minor depression are reported in 13% of community dwelling older adults, 24% of older medical out-patients, 30% of older acute care patients and 43% of nursing home dwelling older adults
. Depression is often reversible with prompt and appropriate treatment. However, if left untreated, depression may result in the onset of physical, cognitive and social impairment, as well as delayed recovery from medical illness and surgery, increased health care utilization and suicide. A wealth of evidence indicates that consumption of fish or dietary fish oils containing long-chain n-3 PUFA, is associated with cardiovascular benefits, including a reduction in circulating triglycerides and reduced mortality from coronary heart disease
. Moreover, n-3 PUFA have been proposed as potential treatment of depressive disorders
. Lower concentrations of n-3 PUFA are associated not only with cognitive impairment and dementia, but also with depression, a potential risk factor for cognitive decline
. Our data clearly demonstrate that elderly depression is characterized by very low levels of n-3 PUFA, in particular of EPA, in RBC membranes compared to healthy subjects. In this study, the supplementation with 2.5 grams/day of n-3 PUFA for eight weeks with an EPA/DHA ratio 2:1 reduced the GDS of the depressed subjects. This positive result appears to be related to the chosen supplementation protocol used in the study. As a matter of fact, the inconsistence of the outcomes of different meta-analyses has been ascribed to differences in dose and type of the n-3 PUFA supplements used for the treatment of major depression (MDD). Martins et al.
 reviewed recently the effects of n-3 PUFA dosages from 1 g to 6 g/day as well as of EPA and DHA alone or in different combinations of TG or ethyl esters for different treatment periods. These authors concluded that n-3 PUFA supplementation is beneficial in adult patients with MDD, but that its effect is strongly dependent upon the EPA content of the regimen. Thus, studies employing regimens containing more than 60% of EPA showed a highly significant pooled standard mean difference estimate, whereas those containing less than 60% of EPA did not .
Omega-3 supplements used at different EPA:DHA ratios, such as 1.2:1 at higher doses, were able to increase both EPA and DHA concentration in RBC membranes in adults affected by moderate hypertriglyceridemia
In this study, daily supplementation with 2.5 g/day of n-3 PUFA with EPA/DHA content of 2:1 appeared able to restore only EPA concentration in RBC membrane to normal values, while the blood EPA and DHA concentrations after supplementation did not increase to the value observed in healthy subjects. Moreover, in this study, after supplementation in depressed subjects EPA appeared to be enriched in PE, PS and PC of RBC phospholipids, while DHA selectively increased in PC. This may be relevant for the production of PUFA metabolites from phospholipids, arising from second messengers and intracellular signals.
In fact n-3 PUFA, especially DHA, are increasingly being recognized as reservoirs of lipid messengers for neuronal cells,
. Specific precursors are cleaved from membrane phospholipids, in particular from PC, upon stimulation by neurotransmitters, neurotrophic factors, cytokines, membrane depolarization, ion channel activation. The lipid messengers, such as neuroprotectins, that originate from the cleaved DHA regulate and interact with multiple signalling cascades, contributing to the growth, differentiation, function, protection and repair of the nervous system
. From this point of view, our data demonstrate that in depressed subjects the level of DHA is preserved in RBC membranes while it is decreased in whole blood. After n-3 PUFA supplementation, the incorporation of DHA exclusively in PC of membrane phospholipids may favor the production of DHA metabolites.
The incorporation of PUFA in the phospholipid's sn-2 acyl chain differs, depending on the brain area considered. For instance, it has been demonstrated that the cortex (where DHA levels are very high) is particularly affected by n-3 PUFA deficiencies
. In particular, prolonged dietary deficiency leads to decrements of DHA in the order of 40% in the frontal cortex and striatum of mice. DHA brain deficiency has important neurological consequences
; for instance, when maintained on an n-3 deficient diet, rats or mice exhibit poorer performance in the Y-maze
 and spatial learning
 tests. These alterations can be corrected by feeding rodents adequate amounts of omega-3 fatty acids
. Moreover, the action of mood stabilizers, such as lithium, carbamazepine, sodium valproate, or lamotrigine, in bipolar disorders has been linked to arachidonic acid turnover in brain phospholipids
. Lithium has proved to reduce AA, but not DHA turnover selectively in phosphatidylinositol, phosphatidylcholine, and phosphatidylethanolamine
Our data might reflect what is really happening in the brain of depressed subjects, indicating a n-3 PUFA deficiency, which is partially corrected after supplementation.
When n-3 PUFA concentration is low, abnormal function and metabolism of various neurotransmitters has been observed in addition to reduced activity of receptors associated with G-proteins and ionic channels. For instance, n-3 PUFA facilitate hippocampal synaptic transmission by targeting presynaptic nicotinic Ach receptors under the influence of protein kinase C (PKC)
. Therefore, a reduction of DHA and EPA body storage may limit the learning process and may imply derangement of cerebral activity
Various experimental studies demonstrate a positive correlation between decrease in n-3 PUFA and abnormal activity of dopaminergic, noradrenergic and serotoninergic systems
. In vitro, serotonin reuptake, a site of action for many antidepressants, is increased by n-3 PUFA
. In animal models, chronic dietary n-3 fatty acid deficiency is associated with increased extracellular serotonin (5-HT) concentrations, increased levels of 5-hydroxyindoleacetic acid (5-HIAA) and increase in 5-HIAA/5-HT ratio in the brain
. Moreover, preclinical data provide evidence supporting a functional link between n-3 PUFA deficiency and increased central 5-HT turnover,
. It has also been shown that n-3 PUFA modulates the expression of dopamine and serotonin receptors
. These observations are relevant, because it is well known that most depression events are associated with impairment of the serotoninergic and –at least in part- of the adrenergic system
. Recent data on animal models demonstrate that supplementation with n-3 PUFA produces antidepressant effects mediated by an increase in serotonergic neurotransmission, particularly in the hippocampus
As regards immunological parameters, to our knowledge this is the first study that examines the relationship between n-3 PUFA levels and immunological parameters i.e. CD2, CD3, CD4, CD8, CD16, CD19 lymphocyte subpopulations and IL-5 and IL-15, in depressed elderly subjects, who received either n-3 PUFA supplements or placebo.
It is known that n-3 PUFA deficiency impairs cellular aspects of the immune response
 and a combination of clinical, animal and in vitro studies suggest that consumption of n-3 PUFA has potential therapeutic effects in the treatment of inflammatory and autoimmune diseases
, although the results are conflicting.
In the present study, no differences were found either in the intervention or in the placebo group, when pre and post treatment immunological indices were compared, with the exception of the increase in CD16 lymphocyte subpopulation in the n-3 PUFA group. Data from animal models and humans
 have indicated that monocyte subsets considerably change with age. Actually it appears that CD16 monocytes can be crucial players in infection and inflammation, but the formal demonstration of their role in these pathological conditions will require selective elimination of these cells in vivo
A previous study indicated that the circulating monocyte pool dynamically changes during ageing in humans. The expansion of the non-classical CD14+CD16+ subtype, alterations of surface protein and chemokine receptor expression, as well as circulating monocyte-related chemokines, likely allow the preservation of monocyte pool function throughout the majority of adulthood
In this study, the correlation among immunological parameters, GDS score and AA/EPA ratio in blood and membrane, was surprisingly modest. We speculate that age-related immune imbalance might be the cause of these poor correlations, as already suggested by other authors . Therefore, further studies are needed in the field of n-3 PUFA and immunity in elderly subjects.