Omega Three Fatty Acids and Depression Part Two

By: Erin Stair, MD, MPH

This is Omega Three Fatty Acids and Depression Part Two. Please read Part One first for this to be the most helpful to you.

In the last blog I explained the different theories for depression. They’re will probably be 20 more theories in 20 years, but that’s how research and science works.  What follows is a current comprehensive summary of the studies that support using omega-3 fatty acids for depression and the studies that don’t.  Before you go on,  just know that a double-blind, placebo-controlled, randomized clinical trial is considered the “gold standard” for evidence. Therefore, the results of those studies are considered stronger evidence. Case Control studies and Cohort studies are not considered to be as rigorous. But they still count as evidence. When I use the words “Significant improvement” or “Significantly improves,”  that means that STATISTICALLY the study showed improvement in the study population. A statistically significant improvement sometimes does not manifest as such in the real world, although it has a much better chance than a study that yields an insignificant result.  All that said, please read the different studies that either support or do not support supplementing with fish oil, and I’ll let you be the judge as to whether you think you should supplement or not.


THE EVIDENCE For Omega-3 Fatty Acids as Related to Depression: 

A 2017 randomized controlled trial showed that adults (18-65) diagnosed with depression showed a significant reduction in symptoms after following a Mediterranean diet and supplementing with fish oil capsules for 6 months. Researchers also noted a correlation between higher Omega-3s, Lower Omega-6s and improved mental health.

A 2016 analysis of data from a randomized controlled trial involving 122 people diagnosed with depression showed that levels of EPA and DHA in red blood cells PLUS a high EPA:DPA ratio in depressed individuals correlated with a significantly higher reduction in depressive symptoms.

The Sun cohort study by the University of Navarra in collaboration with the Harvard School of Public Health involved a total of 7,903 participants.  Researchers measured participants’ dietary intake of omega-3 fatty acids and measured the study’s chief outcome (the incidence of depression) using questionnaires. Researchers found that a moderate consumption of fish (between 83.3 – 112 g/day) had a 30% risk reduction of developing major depression, however a dose-response relationship was not found. ( Dose response means the symptoms of depression should decrease proportionally to the amount of fish oil being consumed.) An interesting observation is that participants with a high baseline consumption of omega-3 fatty acids, who also increased their consumption during the study, developed an increased risk for mental illness. Researchers proposed that a possible explanation for this finding is that a potentially high mercury content in fish could independently increase the risk of depression, since organic mercury is known to cause neurological damage.

A double-blind, randomized, placebo-controlled study was conducted in Iran, a country where fish consumption is very low (6.1 kg/capita/year).  33 elderly participants were randomized to receive fish oil (omega-3 fatty acids) capsules and 33 were randomized to receive a placebo. Major depression was measured using the Geriatric Depression Scale-15( GDS-15), and results showed that while the GDS-15 score improved for both the fish oil and placebo groups, it showed a 25% increase in improvement in the fish oil group. This study used a very low dose (300 mg) of fatty acids for 6 months, and the researchers speculate that the study population may have been under-dosed. However, given that it was an elderly population, the lower-dose was chosen to avoid potential cross-reactions with other medications.

Rizzo et al. conducted a randomized, double-blind, placebo-controlled trial involving 46 depressed elderly patients, half of which were randomized to receiving fish oil supplements dosed at 2.5 g/day, and half of which received a placebo. Results of their study show that the Arachidonic Acid to EPA ratio was significantly lower in the group receiving fish oil, and there was also a significant improvement in depressive symptomology in the fish oil group. ( Arachidonic Acid is a precursor to cells involved in inflammation, so having a lower ratio of Arachidonic Acid to EPA is a good thing.)   This study used an EPA:DHA ratio of 2:1, which is worth mentioning because it supports others studies which suggest that the effect an omega-3 supplement has on depression is driven by the EPA content. The research suggests that all fish oil treatment protocols contain at least 60% of EPA in order to be effective.

Another randomized, double-blind, placebo-controlled study was conducted by Su et al. in 2003. Su et al. randomly assigned 28 depressed patients to receive 9.6/day of omega-three fatty acids or a placebo. Utilizing the Hamilton Rating Scale for Depression to measure the symptoms of depression, the results of the study show a statistically significant improvement in the group consuming the omega-threes.

Puri et al. conducted a case study showing that 4 g of pure EPA not only significantly improved symptoms of depression, but the study also utilized brain imaging technology that showed an increase in brain tissue in the depressed patients. Puri’s study implies that advanced brain imaging may play a critical role in future research on how omega-three fatty acids alter brain structures.

A randomized, double-blind, placebo-controlled study by Nemets et al. showed that adding omega-three fatty acids via fish oil capsules to concurrent antidepressant therapy significantly improved treatment results. Specifically,  study participants receiving the fish oil reduced their Hamilton depression scale score by 12.4 points, whereas the placebo group only reduced their Hamilton Depression Scale score on average by 1.6 points, by week 3 of treatment.


A 2004 cohort study by Jacka et al. found no significant difference in omega-three fatty acid intake in depressed and non-depressed women, although the authors note that this particular sample of depressed women had, on average, a severe level of depression.

A systematic review of the effectiveness of omega-three fatty acids for depression was conducted by Williams et al,.  in which was pointed out that several clinical trials involving omega-threes as treatment failed to demonstrate a significant effect. It should be noted that the ratios of DHA to EPA utilized were not specified.

Marangell et al. conducted a double-blind, placebo-controlled study in which 36 depressed patients were assigned to receive 2 grams of DHA or a placebo.  The Montgomery Asberg Depression Rating Scale ( MADRS) was utilized to measure the extent of depression symptoms, and Marangell et al. found no significant difference between the control group and the group receiving DHA.

A large cohort study that was conducted in Finland involving 29,133 men ages 50-69 years found no significant association between fish consumption/ omega-three fatty acids with self-reported depression, hospital treatment for depression or death from suicide.  It should be noted that the total intake of omega-threes was relatively low in comparison to other studies ( 2.2 g/ day or .47 g/day from fish).

Keck et al. conducted a randomized, double-blind, placebo-controlled study on the use of EPA for the treatment of depression associated with bipolar depression. A very high dose of EPA was used (6 g) yet no significant difference in outcome was produced between the study participants taking EPA and those assigned to the placebo group.  While this study targets bipolar depression, it is worth noting since a very high dose of EPA was used, yet did not yield a significant positive outcome.

A large case-control study designed to assess the effectiveness of omega-three fatty acids on depression in lung cancer patients was conducted in Japan. Fatty acids were measured using gas chromatography and depression was measured using the Hospital Anxiety and Depression Scale, involved 717 subjects from a large lung cancer database.  Results of the study show that there was no significant association between omega-3 fatty acid level and major depression. This study is noteworthy because it highlights that the sample population under study may influence the effectiveness of omega-3s in depression. It also implies that depression in cancer may be a unique, “reactive” phenomenon to a highly stressful event and may not respond similarly to treatment as other depressions might. We need more population-specific research in the area of treatment and depression.


If you want to try fish oil, the recommended ratio between EPA and DHA varies. In fact, it is speculated that the different outcomes of omega-three fatty acid and depression studies partially depends on whether a higher ratio or lower ratio of EPA:DHA is utilized. As Dr. Horrobin states: “High doses of EPA/DHA may not be necessary and due to the effect on cytokines and intra-cellular communication, lower levels of pure EPA may be of benefit.”

Peet and Horrobin conducted a large study that was published in the Archives of General Psychiatry. They measured the effects different doses of pure EPA ( 1g, 2g, or 4g) had on depression, and their results showed that the 1 g of EPA led to the most significant improvements.

Studies involving DHA as monotherapy generally yield insignificant results, which is the conclusion Martins et al. made after conducting a large meta-analysis of 124 studies on EPA/DHA and depression.

YOUR TAKE-HOME POINT:  You want a fish oil capsule that has at least 50% EPA.

Do I take fish oil capsules?

I USUALLY try to get everything from my diet.  But that’s just me.

Comments and questions? Leave below.


Speaking of depression et al…, have you read Manic Kingdom yet?  What are you waiting for…



One Response to “Omega Three Fatty Acids and Depression Part Two”

  1. I agree. I also rarely hear about any negative side effects from fish oil. And ditto on the way depression is measured. It’s unfortunately the only way we currently have, but hopefully, in the future, it will become more specific and sensitive.
    I’ll continue to take my Krill oil… 🙂

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