Introduction

Omega-3 Fatty Acids and Depression

Epidemiological Data

Omega-3 status in Major Depressive Disorder

Possible mechanisms of omega-3 EFA for Depression

Detailed reviews of the possible neurobehavioral mechanisms of omega-3 fatty acids have been previously published and are beyond the scope of this review [35,36]. The influence of omega-3 fatty acids within the central nervous system is far from completely understood, and our current knowledge is largely based on the consequences of omega-3 deficiency within animal models. There are two major areas of omega-3 fatty acid influence worthy of further discussion. The first is the importance of omega-3 fatty acids in neuronal membranes.

Omega-3 fatty acids are an essential component of central nervous system (CNS) membrane phospholipid acyl chains and are therefore critical to the dynamic structure and function of neuronal membranes [37].  Proteins are embedded in the lipid bi-layer of the cell and the conformation or quaternary structure of these proteins is sensitive to the lipid components. The proteins in the bi-layer have critical cellular functions as they act as transporters and receptors. Omega-3 fatty acids can alter membrane fluidity by displacing cholesterol from the membrane [38]. An optimal fluidity, influenced by EFAs, is required for neurotransmitter binding and the signaling within the cell [39]. EFAs can act as sources for second messengers within and between neurons [35].

The second area where omega-3 fatty acids may exert significant influence in major depression is via cytokine modulation. A growing body of research has documented an association between depression and the production these proinflammatory immune chemicals. These cytokines, including interleukin-1 beta (IL-1β), -2 and -6, interferon-gamma, and tumor necrosis factor alpha (TNFα), can have direct and indirect effects on the CNS. Some of the documented activities of these cytokines include lowered neurotransmitter precursor availability, activation of the hypothalamic-pituitary axis, and alterations of the metabolism of neurotransmitters and neurotransmitter mRNA [40]. Researchers have found elevations of IL-1β, and TNFα are associated with the severity of depression [41]. Psychological stress can cause an elevation of these cytokines. It is worth noting that various tricyclic and selective serotonin re-uptake inhibiting antidepressants can inhibit the release of these inflammatory cytokines [40].

Omega-3 fatty acids, and eicosapentaenoic in particular, are well documented inhibitors of proinflammatory cytokines such as IL-1 β and TNFα. In addition, it has recently been suggested that the anti-inflammatory role of omega-3 fatty acids may influence brain derived neurotrophic factor (BDNF) in depression [36]. BDNF is a polypeptide that supports the survival and growth of neurons through development and adulthood. Serum BDNF has been found to be negatively correlated with the severity of depressive symptoms [42]. Antidepressant medications and voluntary exercise can enhance BDNF, while diets high in saturated fat and sucrose, and psychological stress inhibit BDNF production [36].

The epidemiological and laboratory studies, along with the research which shows depressed patients appear to have lowered omega-3 status, have naturally led to clinical investigations. A number of case reports have appeared in the literature, the first of which was over 20 years ago. In this initial series of case reports, flaxseed oil (source of the parent omega-3 ALA) at various dosages, was reported to improve the symptoms of bipolar depression and agoraphobia [43]. An additional case report documented an improvement in depressive symptoms during pregnancy with the use of 4 g EPA/2 g DHA per day. Interestingly, improvements in symptoms (measured via the Hamilton Rating Scale for depression – HRDS) occurred at four weeks, and with the exception of insomnia and anxious thoughts, all symptoms resolved at six weeks [44].

Despite the interesting results, there are major scientific problems with case reports, most notably the placebo response. A recently published case report published took advantage of modern brain imaging to corroborate clinical improvements. In this case a patient with treatment resistant depression was placed on a daily dose of 4 g pure eicosapentaenoic (EPA), and after one month there were significant improvements, including a co-morbid social phobia. After nine months the patient was reportedly symptom free. It was found that over the course of the nine months of treatment, there was a 53 percent increase in cerebral phosphomonoesters and the ratio of cerebral phosphomonoesters to phosphodiesters increased 79 percent, indicating reduced neuronal phospholipid turnover. Utilizing MRI technology, the researchers found that the EPA treatment was associated with structural brain changes, including a reduction in lateral ventricular volume. This is likely to be a result of increased phospholipid biosynthesis and reduced phospholipid breakdown [45]. Given the recent research indicating a decrease in volume in various areas of the brain of depressed patients, this is certainly an important case study [46].

A series of case reports also suggest that 1 – 4 g of pure EPA may be helpful in anorexia nervosa, a condition with the highest risk of morbidity and mortality among psychiatric disorders [47]. In all six of the cases, EPA was reported to improve mood to varying degrees. For some, discontinuing EPA therapy resulted in deteriorations in mood and other psychiatric symptoms.

An interesting study examined fish oil vs. marine oil extracted from Antarctic krill in premenstrual syndrome. Krill is similar to fish oil, with the exception that it contains naturally-occurring phospholipids, and contains more EPA per gram than standard fish oil capsules (240 mg/g EPA in krill vs.180 mg/g in standard fish oil). In the 3-month trial, patients (n = 70) received 2 g of krill oil or 2 g fish oil daily for one month, then for eight days prior to, and two days during, menstruation for the following two months. Evaluation at 45 days and three months showed that krill oil significantly improved depressive symptoms of premenstrual syndrome. The absence of significant effects of fish oil on mood suggests that the presence of the phospholipids and/or higher amounts of EPA may be responsible for the therapeutic effect of krill oil [48].

There have been some controlled studies that have examined omega-3 fatty acids and a placebo intervention in depression. The first small clinical study (n = 30) showed that four months of treatment with 9.6 g of omega-3 fatty acids (6.2 g EPA/3.4 g DHA) was of therapeutic value in bipolar disorder. Specifically, this study showed a highly significant effect in treating depression (p < 0.001 HRSD scores) [49]. In a separate double-blind, placebo-controlled study (n = 22), the addition of 2 g of pure EPA to standard antidepressant medication enhanced the effectiveness of that medication vs. medication and placebo. This 3-week study, involving patients with treatment-resistant depression, showed that EPA had an effect on insomnia, depressed mood, and feelings of guilt and worthlessness. There were no clinically relevant side effects noticed [50].

In a small pilot study (n = 30), Harvard researchers found that just 1 g of EPA could reduce aggression (modified Overt Aggression Scale) and depressive symptom scores (Montgomery-Asberg Depression Rating Scale) among borderline personality disorder patients. The results of this 2-month, placebo-controlled study are encouraging, given the difficulty in treating borderline personality disorder. It is also of note that 90 percent of participants remained in the study and no clinically relevant side effects were noticed with EPA [51].

In a double-blind, placebo-controlled trial over two months, high dose fish oil (9.6 g/day) was added to standard antidepressant therapy in 28 patients with MDD. In this study the patients who received the omega-3 fish oil capsules had a significantly decreased score on the HRSD compared to those taking the placebo. Once again, the fish oil, even at this high dose, was well tolerated with no adverse events reported [52].

Various doses of pure EPA have also been investigated in depression. In a 12-week, randomized, double-blind, placebo-controlled study, patients (n = 70) were given ethyl-EPA at doses of 1 g, 2 g or 4 g. The patients in this case had experienced persistent depression, despite ongoing standard antidepressant pharmacotherapy at adequate does. Interestingly, in this study, "less was more." Those in the 1 g per day group had the best outcome. The patients who received 1 g per day of EPA were the only group to show statistically significant improvements. Among the 1 g/day group, 53 percent achieved a 50 percent reduction in HRSD scores. The 1 g EPA led to improvements in depression, anxiety, sleep, lassitude, libido, and suicidal ideation. These findings suggest that omega-3 fatty acids can augment antidepressant pharmacotherapy and/or alleviate depression by entirely different means than standard medications [53]. A large study examining the effects of omega-3 or placebo added to cognitive-behavior therapy would be of interest.

To date, the published data on supplementation with pure EPA on MDD or depressive symptoms have been positive. With regard to DHA or a combination of EPA and DHA, there have been three negative reports. A trial on DHA alone as monotherapy in the treatment of MDD was recently reported. In this study, 2 g pure DHA or placebo was administered to 36 patients with depression for six weeks. The response differences between the groups, as measured by scores on the Montgomery-Asberg Depression Rating Scale did not reach statistical significance [54]. In an open label pilot study, the combination of 1.7 g of EPA and 1.2 g of DHA failed to show benefits among seven women with a past history of post-partum depression. The omega-3 monotherapy was initiated between the 34^th – 36^th week of pregnancy and was assessed through 12 weeks post-partum. In these women the fish oil combination did not reduce the risk of relapse [55]. Finally, a pure DHA supplement, at low doses of 200 mg per day for 4 months post-partum, did not improve self-rated or diagnostic measures of depression over placebo. However, the women enrolled (n = 89) in this study were not clinically depressed as a group, which precludes interpretation that DHA is ineffective in post-partum depression [56].

It is important to consider the nutrients which can ultimately influence omega-3 status. Among them, four important dietary factors also relate to MDD: zinc, selenium, folic acid and dietary antioxidants. A number of studies have shown that zinc levels are lower among patients with depression and a recent study found that 25 mg zinc supplementation may improve depressive symptoms [57]. Interestingly, 25 mg of zinc supplemented for two months has also been shown to significantly increase omega-3 status in the plasma phospholipids at the expense of saturated fat [58]. Lowered levels of selenium have been associated with negative mood scores in at least 5 studies [59]. Selenium plays a significant role in the human antioxidant defense system. In addition, selenium deficiency can interfere with the normal conversion of ALA into eicosapentaenoic and DHA, and results in an increase in the omega-6:omega-3 ratio [60].

Regarding folic acid, a growing body of research has documented the low levels of folic acid among patients with depression [61]. In addition, there are