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Omega-3 Fatty Acids
(including Fish Oil)
(revised 11/2006)

• Introduction
• Do they work? 
• Table of research studies
• Risks? 
• Side effects?
• Conclusions

Omega-3 fatty acids, given in the form of fish oil tablets, were shown in a 1999 controlled trial^Stoll to maintain mood stability far better than an olive oil placebo. This was a very exciting result, especially as the trial was inspired by "bench chemistry" --  omega-3 fatty acids were recognized to have intracellular effects similar to lithium and valproate.  Now some other small studies are beginning to be reported.  

There are two "omega-3" fatty acids in fish oil: EPA (eicosapentaenoic) and DHA (docusahexaenoic).  Some studies in people with depression or bipolar disorder have used EPA alone, including one of the most recent with the strongest positive results; but one of the larger earlier studies using EPA alone showed no benefit.  Many of the other studies shown below, including the first one from Harvard, used fish oil tablets which provided both EPA and DHA. For now it seems safe to conclude that having both does not interfere with the antidepressant and mood stabilizing actions; and that EPA alone might be sufficient. 

You may have heard of omega-3's or fish oil as having some benefit in reducing heart disease as well.  That research is a little farther along than the mood research. I have not followed it closely but it seems that the focus there is more on DHA than EPA. This means that if you want both benefits, you may need to stick with a source that has both EPA and DHA. Luckily, it turns out that the cheapest version has both, and has been lowest in the tests of mercury (undetectable levels). So for now it looks like the cheapest source may be the best -- an unusual situation in my business! Details on which kind to consider, and how many pills you'll need, can be found on the "more fish (oil) stories" page.  For another excellent source of information, a bit more technical but more complete, see the Mayo Clinic pages on omega-3 fatty acids. 

Do they work? 

[Update 1/2004: a statistical study also recently showed fish-eating countries have lower bipolar rates than those where fish is not common in the diet.^Noaghiul  Another study looked at whether patients with bipolar disorder have lower omega-3 levels than "healthy controls", and found lower DHA but not EPA levels in their blood cell walls.  Even with a small sample they found a pretty big difference.^Chiu]

Here's a summary of fish oil research regarding use in mood disorders, updated Jan 2006 (some studies of weak statistical quality are not included); followed by some details and conclusions.  Note that in all the bipolar studies, and several of the depression studies, the omega-3 fatty acid dose was added to prior medications.  These data should not be interpreted to indicate that O-3's alone are a treatment for mood disorders.   

(A vitamin company is maintaining a version of this table which has some additional studies; the rest of their site in Finnish!) 

First, some details from these studies, then the conclusions: 

The most recent study here is the 2006 report by Frangou and colleagues. This appeared in the British Journal of Psychiatry, a well-respected journal. The study design was good.  The sample is somewhat small, which may explain why they did not see an EPA-placebo difference unless they lumped both EPA groups together.  But when lumped, there appears to be a clear effect. The effect is not large, however. Note also that their patients were also taking mood stabilizers, so this is fish oil as an add-on, not by itself as in the original study by Stoll that started this whole thing. Nevertheless, it suggests that a manageable dose of EPA might be sufficient (as opposed to larger 4-gram dose used in the Stanley Bipolar Foundation study reported by Post and colleagues, which was not effective). Interestingly, in this 2006 study, the response appears to show up by the 4th week of treatment (they didn't look sooner, trying to minimize the placebo effect of their attentions).  

A patient whose long-term course is reported in Bipolar Network News demonstrated a stunning improvement which lasted over 1 year on omega-3's.  Look at her life-chart picture on page 7 ( v.8, Issue 2, scroll to page 7) for the dramatic change in course, but notice how it took about a year to really take hold (or so we might guess, from this report, although the author points out that there could have been other variables to account for this change also).  Notice also that the change was to stop depressive episodes, in this woman who had not had a manic phase in several years by that time on the medications which were continued as the omega-3's were added.  

Finally, notice that the dose was 6 grams.  In the accompanying article, which you can read via the link to that issue, some data are cited suggesting that a 6 gram dose of E-EPA may be too high and that a 1-4 gram dose may be preferable.  However, if you want to hear a real fan letter for omega-3's, from a fellow who's taking more than 4 grams a day, read this testimonial.  A local colleague takes just 2 grams of fish oil a day (500 mg of omega-3's total).  She is certain it helped dramatically with PMS and mild mood swings (family history of bipolar disorder).  She found 1 gram pills for $8.00/300 at Costco, so her cost is about $1.60 per month. 

Update 2007: a recent study indicates that people with severe Major Depression had less omega-three in a region of the brain associated with mood problems (frontal cortex).^McNamara  Interestingly, only DHA, not EPA, was decreased in this region.  Does this mean that DHA matters?  Much of the recent focus in omega-three treatment studies has been on EPA, but I'm not convinced that we know enough yet to focus on one or the other.

Update 2006: Now six years after the Stoll study I'm still talking about fish oil with my patients but still not very convinced it has great value as a mood stabilizer. However, as an add-on tool for depression, I think that's where it may indeed be useful. I've probably not been using large enough doses. The dose in the new Frangou study, 2006, is the equivalent in EPA of seven pills of the type I've been recommending -- because it's the cheapest, with no greater risk -- where I've generally had people taking 4 pills per day. I'll definitely be trying a higher dose when I talk with patients now, and looking for a cheap route to 1 gram of EPA (if you find one on the internet that will cost 20-30 cents per day and require less than 7 pills, write me and say where!).  

[Update 8/2005: I now have one patient who had such severe symptoms she was labeled "borderline", for whom complete symptom control required three mood stabilizers (although this was during an awful divorce). She later tapered off all three of these medications, but her symptoms returned (milder, years after the divorce, but clearly causing problems in her life). She had to go back on a two-mood-stabilizer regimen to control these symptoms. I just saw her yesterday: she is now on fish oil alone, at 0.75 grams of omega-3, and doing pretty well, far better than she did on no medications.  She still has some symptoms, however, so we are trying a very low dose of a single medication to augment the fish oil.  If this result sticks, she would be one of my first patients, over several years of discussing fish oil with most of my patients, to get to near-zero medications by using fish oil.  And we have to wait to see if this result will stick.  [Still doing okay as of December 2005]. That might give you some idea of the relative power of this approach, as best we can tell at this point:  looks like it does something, but rarely enough to allow taking no mood stabilizers at all.]  

Risks

There are basically no known risks with fish oil.  Three which have been discussed can be nearly dismissed, as shown here. This does not mean there are no risks; it means there are no significant known risks.  Notice the difference. On the other hand, one cannot say anything as nearly reassuring about any of our regular medications. Here are three risks which have been discussed. 

1. Mercury and other heavy metals
2. Hypomania
3. Increased risk of easy bleeding if taking other medications known to do likewise. 

1. Mercury. One of the cheapest fish oils, shown in the following table, has "undetectable levels" so you could stop worrying about it right there.  But being reassured like that doesn't work for a lot of people, so here are more details if you like. Otherwise, skip forward to #2)

Some would not entirely trust the United States Food and Drug Administration (FDA) for advice, but this at least gives you a yardstick of some kind. The fetal brain is more susceptible to mercury-induced damage, so here here is what the FDA tells pregnant mothers (not everyone, you see, just pregnant mothers):  

• Do not eat Shark, Swordfish, King Mackerel, or Tilefish because they contain high levels of mercury.

• Eat up to 12 ounces (2 average meals) a week of a variety of fish and shellfish that are lower in mercury.

  • Five of the most commonly eaten fish that are low in mercury are shrimp, canned light tuna, salmon, pollock, and catfish.

  • Another commonly eaten fish, albacore ("white") tuna has more mercury than canned light tuna. So, when choosing your two meals of fish and shellfish, you may eat up to 6 ounces (one average meal) of albacore tuna per week.

• Check local advisories about the safety of fish caught by family and friends in your local lakes, rivers, and coastal areas. If no advice is available, eat up to 6 ounces (one average meal) per week of fish you catch from local waters, but don't consume any other fish during that week.

The table below gives mercury in a different unit, making comparison with the above yardstick difficult.  A review article on fish oil for the American Heart Journal in March of 2006^DeFillipis summarized this issue by noting that the FDA believes 10 mcg/L, which is found in some fish oils (see table below) is "negligible". Less than 6 mcg/L, as with the Kirkland brand, means "undetectable" using these laboratory tests.   

Consumers Reports (CR) also has conducted tests. Their conclusion: "None showed evidence of spoilage, and none contained a significant amount of mercury, PCBs, or dioxin.  CR found no significant differences in the quality or purity of these supplements. Therefore, consumers can choose them based on price." (quoting from a summary in a senior newsletter so you don't have to pay for the Consumer Reports report itself, which of course you could pursue if interested). 

2. Hypomania.  Notice the emphasis in the research studies on depression, versus bipolar disorder.  There is a report of hypomania developing while on omega-3's^Kinrys (and in the Harvard study as well^Stoll), although whether the fatty acids were the "cause" of this episode is of course not certain. I'm watching for more such reports. 

3. Bleeding risks. There are reports of fish oil interfering with blood coagulation if you taking aspirin or coumadin (warfarin).  According to one referenced site, this is not true.  Similarly, there are reports that it might interfere with glucose regulation.  According to that same referenced site, also not true. 

Side Effects

There is really only one: fish burps ("When I burp I feel like a seal").  This is easily managed by taking the pills with meals. If that isn't sufficient to stop the problem, put the pills in the refrigerator, or freezer, between meals. This makes them sort of an "extended release" capsule. Watch out for condensation inside the bottle if you live in a moist climate. You could just keep a week's supply or so in a separate bottle that you open every day. 

Conclusions (reviewed as of 3/2006; still seem to hold):  

• the evidence is piling up that omega-3 fatty acids do something, at least in some people; 
• the dose to use is not at all clear, as some studies suggest you can go too high and lose benefits (Nevets, Sagduyu), whereas many of the individual glowing results come with the higher doses; 
• even at higher doses, the risks seem minimal, and there may actually be additional benefits (on cholesterol, perhaps arthritis); 
• however, it's a large number of pills, though a minimal-moderate expense; 
• fish burps can be managed easily 
• it's not clear how long you have to wait to see benefits, but especially with the smaller doses they may take 1-2 months to show up, so if you take them, prepare yourself for a period of taking a lot of pills with no benefits. 

Do I recommend them to my patients? Yes, rather commonly, especially when we're looking for all possible anti-depression tools to use, rather than have to use a typical antidepressant.  I still have yet to see a clear-cut stunning improvement like those case reports in the table above, but because the risk appears to be so minimal, in many cases it seems like it's worth a try.  

For more on omega-3's generally, here's a 2001 summary, including an extensive explanation of omega-3 physiology.  For small details including , pill type, flaxseed oil and any other tidbits I accumulate, here are more of my fish (oil) stories.