The Omega 3 Depression Connection: Treatment, Prevention, or Cure?
Question: Can fish oil help treat depression?
Answer: An omega 3 depression prevention strategy fits the current evidence much better. "Treat" is probably too strong a word. This article cuts through the confusion and arms you with data from the clinical and scientific literature you need to supplement with confidence.
The Omega 3 Depression Connection: the basics
Our brains probably evolved on a diet rich in fish. In fact, theorists have argued that many chronic inflammatory diseases result from a population-wide deficiency of omega-3 in our diets (1). Since DHA represents about 20% of the dry weight of the brain, it is no intellectual leap to imagine that a deficiency in omega-3s could impact your mood. In fact, observational studies have consistently shown that depressed individuals have lower plasma EPA and DHA levels, as well as lower omega-3/omega-6 ratios, than corresponding non-depressed control subjects (2). Furthermore, some studies drilled down to a deeper level of precision by correlating this ratio with the severity of depression. Basically, researchers have consistently observed strong omega 3 depression correlations.
But first, let's play devil's advocate here. The omega 3 depression observational studies relating DHA and EPA levels to symptoms are interesting, but maybe it's no surprise. Couldn't it also mean that depressed people are going out for sushi less frequently? Or maybe it's all the ice cream binges and fatty fast foods that drives up the omega 6 part of the ratio. You can make plausible counter-arguments here, but statistical measures were taken in these studies as a control. Regardless, statistics will always be dicey. The more important test is whether the results make sense in light of other data. In point of fact, they do.
Animal studies have been pretty clear on the neurological benefits of fish oil, and particularly with regard to depression. On the negative side, various studies with rodents have shown that omega-3 deficiency can lead to a wide range of neurological dysfunctions (3). But as for benefits, experiments in rats have shown that the levels of various neurotransmitters and hormones like dopamine, serotonin, and BDNF are increased with fish oil supplementation. We all know about increasing serotonin levels to treat depression, and we'll get back to that later. In particular, I find the effects on BDNF most compelling. Brain-derived neurotrophic factor (BDNF) is responsible for nerve growth and neuronal plasticity. BDNF levels are a good proxy for overall brain health, as they are known to decrease with poor nutrition, physical and psychological stress and depression severity, while they can be increased by new learning experiences, exercise and antidepressants (4).
So, we have good animal data supporting an omega 3 depression connection made by statistical trends in humans. Does that mean we have an omega 3 depression treatment?
Of course not.
Fish oil clinical trials
One of the problems with trying to understand nutritional clinical trials is you always wind up comparing apples to oranges. Half a dozen fish oil trials for depression later and no one has tested the same EPA/DHA ratio. Is it any surprise that the results are mixed? To be clear, in seven clinical trials, 3 showed positive outcome, one showed slightly positive outcome, and three were negative (2). Fortunately, a few trends in the data that give us important clues as to what's going on here. In their very astute review of the trials, Sontrop and Campbell point out two key points:
1. Successful omega 3 depression clinical trials all had patients on anti-depressants as well. Two out of three negative trials did not include antidepressants.
2. Positive omega 3 depression trials also had high levels of EPA (>1g/day). Three negative trials all had only DHA or much lower quantities of EPA.
First, the anti-depressants. Pharmaceutical companies have been going after depression using a very narrow spectrum of chemical tools focused on increasing serotonin by limiting it's metabolism (MAOIs) or reuptake (SSRIs). With that said, Prozac, Paxil, Wellbutrin, et al definitely work for some people. The studies that show a positive outcome with antidepressants are probably telling us that EPA and DHA repletion is a good idea for patients undergoing antidepressant therapy. One way you can think about this data is that fish oil supplementation contributes to a return to normal brain chemistry. You can think about SSRI's the same way, with the key difference that they are demonstrated to work on their own. Fish oil is not.
Next, the EPA. This is where things get interesting.
Post-partum depression has been attributed to the massive DHA loss incurred by recent mothers when babies literally suck the stuff right out of them in the last trimester and first months of breast feeding. And indeed, extensive animals studies show a link between DHA status in the brain and dopamine and serotonin function (5). But EPA is not noted to be in the brain. So why does EPA appear to play a critical role in fish oil-based depression therapy? The answer remains somewhat mysterious, but fits with the observations of a 2004 study comparing the fatty acid levels of people attempting suicide with recent accident victims as a control. In the study, a much more pronounced and statistically significant difference in EPA levels was observed than DHA (6).
As we covered elsewhere, we know that EPA tones down the production of inflammatory mediators and cytokines, decreasing background inflammation and reducing risk for numerous other diseases (7,8).
The omega 3 depression connection is based in inflammation
One major theory of the physiology of depression invokes the connection between depression and widespread immune system activation (9). According to this theory, increased production of immune system side products like interleukins IL-1 and IL-6 create hormonal abnormalities via the hypothalmic-pituitary-adrenal (HPA)-axis. Increased levels of inflammation can also lead to abnormalities of important neurotransmitters like serotonin and norepinephrine. As pointed out by Peet and Stokes, this theory suggests that specialized anti-inflammatory drugs like COX-2 inhibitor Celecoxib would have anti-depressant properties (10). While some evidence supports this theory, the best we can say is that EPA, and fish oil in general, appears to have an indirect role in the prevention of depression. This connection between DHA activity in the brain and EPA influence in the body has been advanced as an avenue for a "mind-body interface" underneath the omega 3 depression connection (11).
What's the bottom line on the omega 3 depression connection?
We've covered only a tiny sliver of the literature on this omega 3 depression subject, and it all points in the same direction. At the core of this issue, we have a number of statistical correlations and some sound scientific reasoning suggesting that fish oil intake can improve symptoms related to depression. We don't have a cure here. Instead, we have something you can take that has been shown to bring the brain back into alignment with optimal health.
1. Simopolous "Evolutionary aspects of dieth, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases." Biomed Pharm 60 (2006) 502-7.
2. Sontrop, J, Campbell, MK. "Omega-3 polyunsaturated fatty acides and depression: A review of the evidence and a methodological critique." Prevent Med 42 (2006) 4-13.
3. Logan, AC. "Neurobehavioral aspects of omega-3 fatty acids: possible mechanisms and therapeutic value in major depression." Altern Med Rev 8 (2003) 410-25.
4. Russo-Neustadt, A. "Brain derived neurotrophic factor, behavior, and new directions for the treatment of mental disorders." Semin Clin Neuropsychiatry. 8 (2003) 109-18.
5. Chalon, S, Vancassel, S, Zimmer, L, et al. "Polyunsaturated fatty acids and cerebral function: focus on monoaminergic neurotransmission." Lipids 36 (2001) 937-44.6. Huan, M, Hamazaki, K, Sun, Y, et al. "Suicide attempt and n-3 fatty acid levels in red blood cells: a case control study in China." Biol Pyschiatry 56 (2004) 490-6.7. Calder, PC. "Immunomodulation by omega-3 fatty acids." Prostoglandins Leukotrienes and Essential Fatty Acids 77 (2007) 327-35.
8. James, MJ, Gibson, RA, Cleland, LG. "Dietary polyunsaturated fatty acids and inflammatory mediator production." Am J Clin Nutr 71 (2000) 342S-8S.
9. Maes, M, Smith, R, Scharpe, S. "The monocyte-T-lymphocyte hypothesis of major depression." Psychoneuroendocrinology 20 (1995) 111-6.
10. Peet, M, Stokes, C. "Omega-3 fatty acids in the treatment of psychiatric disorders." Drugs. 65 (2005) 1051-59.
11. Su, K-P. "Biological mechanism of antidepressant effect of omega-3 fatty acids: how doe fish oil act as a 'mind-body interface'?" Neurosignals 17 (2009) 144-52.