Ever since an international panel of scientists agreed 12 years ago that omega-3 fatty acids might help prevent depression, health and nutrition companies have touted the mood benefits of consuming omega-3 rich oil from salmon, sardines, and other cold-water fish.

Yet doctors have been slow to follow suit, perhaps because studies provide mixed results on omega-3 fatty acids’ antidepressant potential.

Now a team of scientists from Argentina reports that fish oil exhibits marked antidepressant activity in rats when combined with low doses of prescription antidepressants. The findings, if also true for humans, could help patients decrease their antidepressant dose and avoid side effects while remaining in remission from depression.

In the new study, researchers tested rats with salmon oil and one of two different antidepressants — fluoxetine (also known as Prozac) and mirtazapine (sold under the brand name Remeron). Although low doses of these antidepressants were ineffective by themselves, combining them with omega-3 fatty acids produced antidepressant-like activity that was similar to full-strength doses of the drugs. The results are published electronically ahead of print this month in the European Journal of Pharmacology.

“Combining omega-3 fatty acids with low ineffective doses of antidepressants might represent benefits in the treatment of depression,” the authors conclude, adding that patients may be more likely to keep taking their antidepressants if they have fewer dose-dependent side effects.Investigators from the University of Buenos Aires and the University of the Rioja added salmon oil to the rats’ food, either alone or in combination with a full-strength or a low-dose injection of fluoxetine or mirtazapine.

Comparison groups of rats received full-strength or low-dose injections of fluoxetine only, mirtazapine only, or a saline solution.

After 16 weeks of treatment, each group of rats underwent the forced-swim test, which is used in rodents to identify drugs that have antidepressant effects in humans. Investigators placed rats in Plexiglas tanks of water for five minutes and measured the amount of time the rats spent swimming, attempting to climb the sides of the tank, and not moving. Studies have shown that antidepressants cause decreased immobility during the forced-swim test.

Rats given only low doses of mirtazapine or fluoxetine spent about the same amount of time in each activity as those given saline solution, indicating that the antidepressant dosages were too low to cause an effect. However, animals that were also given salmon oil behaved similarly to those that received full-strength doses of fluoxetine or mirtazapine.

Based on these results, said Dr. Analia Reines, the study’s lead author, patients troubled by side effects from fluoxetine or mirtazapine might be able to add omega-3 fatty acid supplements in order to decrease their dose while still benefiting from the drugs’ antidepressant action.However, Reines cautioned that the results needed confirmation.

“Before extrapolating these results to patients with depression, clinical trials are mandatory,” she said. “Our findings could represent the pre-clinical basis for that to happen.”

“This is a single study in rats,” agreed Dr. Michael Peterson, a psychiatrist at the University of Wisconsin Psychiatric Institute and Clinic in Madison. “But it does pose some testable questions to look at in humans.”

Peterson says that although most of his patients take antidepressants, and some have told him that omega-3 fatty acids helped their mood, none have reported that adding omega-3 fatty acids enabled them to lower their antidepressant dose. Peterson does not often recommend omega-3 supplements in his practice.

“Often in psychiatry, we see people who have more of a refractory depression to begin with,” he said. “And this can bias the treatments that we use.”However, Peterson added, a number of non-pharmaceutical interventions have been shown to be effective for depression, either alone or in combination with antidepressants.

These include psychotherapy, the nutritional supplement S-adenosyl methionine (or SAMe), light therapy, and exercise.“In particular, exercise is under-utilized and has clearly shown benefit,” he said.

Dr. Adam Rindfleisch, a family practitioner in the University of Wisconsin Department of Family Medicine’s Integrative Medicine Program, had a different perspective.“While I realize there is some debate as far as research findings, I frequently recommend omega-3's in my practice for mood disorders,” he said. “Not only is it clear that most people are deficient in them, and that deficiencies can lead to myriad different health problems, but they are incredibly safe to take.”

However, Rindfleisch said, he does not recommend that patients treat their depression solely with omega-3 fatty acids.

“I use drug and supplement interventions, exercise therapy, counseling, and any other approaches that might have promise for the person as an individual,” he said. “Mood disorders have many different potential causes. And that seems to equate with needing to approach them from a variety of angles.”

To date, studies on omega-3 fatty acids mirror physicians’ lack of agreement as to their benefits.
“There have been 25 to 30 clinical trials looking at omega-3 as a single treatment or as an augmentation therapy for depression, and it’s a mixed story,” explained Dr. Robert Carney, a professor of psychiatry at Washington University in St. Louis, Missouri. “About half of these studies are finding an effect, and about half are not.” Carney was lead author last year on a study on the antidepressant effect of omega-3 fatty acids combined with sertraline (or Zoloft). The research, published in 2009 in the Journal of the American Medical Association, did not find a stronger effect from combined therapy than from giving sertraline alone.

Carney said that the type of omega-3 fatty acid used — that is, eicosapentaenoic versus docosahexaenoic acid — seems to make a difference in study outcome. He said that EPA seems to be more effective than DHA, although the reason is unclear.

“Studies looking at omega-3 levels in red blood cells found both forms to be deficient, with a statistical association with depression,” he said. “So why EPA is more effective against depression than DHA is not known.”

Carney explained that so far, studies indicate that an omega-3 supplement should contain at least 1.3 to 1.4 times more EPA than DHA in order to work against depression.

“It doesn’t matter how much EPA you’re getting — if the ratio of EPA to DHA is close to 1:1, you won’t see a treatment effect,” he said.The EPA-to-DHA ratio in Reines’ study neared 1.4, while in Carney’s it was about 1.2.