Can fish oil supplementation cause depression?
January 12 2022
Here is my review of the recent, controversial study in JAMA on fish oil/omega 3 and depression. Remember, fish oil is the most commonly used non-mineral/vitamin supplement in US.
Why did they do the study?
- Trials show fish oil to have modest benefits for folks with depression.
- However, in the general population or people without depression, no trials have studied if fish oils/ omega 3 can prevent depression or even improve mood.
- So the primary question was can fish oil supplementation (Omega-3) prevention depression or improve mood in people over the age of 50.
What was the fish oil/omega 3 study design?
- Participants: Around 18.5K men and women (>50 yrs) with no symptoms of depression nor undergoing treatment for depression were randomized into 2 groups.
- Interventions: The intervention group took omega-3 supplements (1-g/d dosage of 465mg of EPA & 375mg of DHA) while the placebo group took a matching placebo for an avg. of 5.3 years
- Outcomes: The primary outcomes were risk of depression and mood changes based on questionnaires.
What were the results?
- Depression Increased: There were more depression events (651) in the fish oil groups (7.1%), while 583 (6.3%) events in the placebo group. Contrary to the study hypothesis, fish oils showed a statistically significant (p=0.03) 13% increase in depression!! (Hazard Ratio:1.13)
- Mood unchanged: The second primary outcome of a change in mood showed little difference between groups.
What the heck does a 13% increase in depression mean??
- Absolute risk: Although the researchers powered the study for a 15% “decrease” in depression and they saw a 13% increase, the absolute risk difference was only (7.1-6.3) 0.8%
- Natural frequency: A better way to express risk is through frequencies. So out of 100 people who took placebo, 6 will end the depression. And if 100 people take fish oils, 7 will end up with depression. So that means, one person more will get depression in 5 years!
- Numbers needed to treat: Or 125 folks will have to take fish oils for 5 years for one person to report depression.
Clearly, the individual risk is very low. But this small risk could translate to a big number if millions supplement with fish oils.
Any gender difference in depression?
Women at higher risk: Pre-specified, subgroup analysis showed a higher risk for women, but not men. These were in line with an increase in anhedonia (inability to feel pleasure) and sadness in mood questionnaire items. Keep in mind that these are exploratory and need a further study to be confirmed.
What were the major limitations?
- Strengths: Let’s start with strengths - huge sample size, long duration (5.3 yrs) and high supplement adherence (90%), 55% increase in Omega-3 in blood, pre-registered, double-blinded, and intention to treat analysis.
- Limitation: The major limitation is this was not the parent trial and hence all the participants (only 18.5K out of 26K) were not included. Although baseline measures appeared similar, unmeasured confounders could be a problem. So the certainty is low to moderate.
Since we are at it, the parent trial (VITAL) showed Omega-3 and Vitamin D did not reduce cancer nor cardiovascular events - yet another negative study in the long line of disappointing trials on fish oil supplements and CV disease.
What are the recommendations for heart health?
- American Heart Association (AHA) DO NOT recommend fish oils for people not at high risk of heart disease
- For people with existing heart disease, such as a recent heart attack, the AHA recommends approximately 1 g/day EPA plus DHA, preferably from oily fish
- AHA recommends one to two servings of seafood/ week for reduction of CV outcomes
Conclusions
- Clearly, the study does not support the use of fish oil / omega-3 supplements in adults to prevent depression or to have positive mood. So forget prevention!
- More importantly, fish oils showed an increase in depression, although the individual risk is small and of low to moderate certainty. (And a gentle reminder even supplements need to be rigorously tested in long-term trials)
- As always, the decision to take fish oil supplements for other benefits is an individual choice based on the risk, benefits, and your values.
VITAL-DEP Trial (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention)
VITAL (Vitamin D and Omega-3 Trial)
