From Medscape Medical News
Deborah Brauser
June 24, 2010 — Omega-3 fatty acid supplements significantly reduce symptoms of major depressive episodes (MDEs) for patients without comorbid anxiety disorders (ADs) compared with those taking placebo, according to a new study of more than 400 patients from 8 Canadian clinics.
However, patients with both MDE and AD showed only a trend toward major symptom reduction after taking the omega-3 supplements.
"To our knowledge, this [trial] is the largest ever conducted testing the efficacy of omega-3 supplements for treating MDE," write lead study author François Lespérance, MD, from the Department of Psychiatry and Centre de Recherché du Centre Hospitalier at the Université de Montréal (CRCHUM), Quebec, Canada, and colleagues.
They note that in designing the most inclusive trial possible, over 80% of their study participants "would have been excluded from the usual type of phase 3 trial (27% chronic depression, 53% comorbid ADs, 40% taking at least 1 antidepressant, and approximately 15% undergoing some form of psychotherapy). This approach resulted in a heterogeneous sample of patients with depression that included many difficult-to-treat individuals."
"While caution is warranted in interpreting most subgroup analysis, the current results of our planned subgroup analysis could lead many unipolar patients with depression without significant anxiety to conclude that omega-3 supplements are worth trying," Dr. Lespérance told Medscape Psychiatry.
The study is published online in the Journal of Clinical Psychiatry.
Antidepressant Alternatives Needed
"Despite the availability of several newer antidepressants over the last 20 years, a substantial proportion of patients experiencing [an MDE] do not respond sufficiently to antidepressant treatment, are unable to tolerate antidepressants in order to obtain or maintain a clinical response, or refuse to take antidepressants despite substantial psychological suffering and disability," write the study authors.
They note that almost 54% of people with depression in the United States use some form of complementary treatment.
"It is clear that there is a need for additional therapeutic options that represent alternatives to standard antidepressants," the study authors write. Although past research has suggested a role for omega-3 in treating depression, "the level of evidence is still insufficient."
For this study, 432 adult outpatients (mean age, 46 years; 68.5% female) with an MDE lasting at least 4 weeks were enrolled at 1 of 8 Canadian academic and psychiatric clinics between October 2005 and January 2009.
All patients were randomized to receive 8 weeks of either omega-3 supplements (including 1050 mg of eicosapentaenoic acid and 150 mg of docosahexaenoic acid daily, n = 218) or matched doses of sunflower oil placebo (n = 214). To strengthen the double-blind and limit the potential bias of a fishy aftertaste often reported by those taking omega-3, 2% fish oil was added to the placebo.
Antidepressants were also used at baseline by 40.3% of the patients, and clinic visits were made by all at weeks 1, 2, 4, and 8.
The study's primary outcome measure was the self-report score from the 30-item Inventory of Depressive Symptomatology (IDS-SR30), whereas the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) was the secondary efficacy outcome measure.
Subgroup analysis was also conducted based on the presence or absence of comorbid AD at baseline, use of antidepressants, patient sex, and number of portions of fish per week during the month before the study's initiation.
Only MDE Patients Without ADs Had Significant Improvements
Results showed that the adjusted mean difference between the omega-3 treatment and the placebo treatment was 1.32 points (95% confidence interval [CI], −0.20 to 2.84; P = .088) on the IDS-SR30 and 0.97 points (95% CI, −0.012 to 1.95; P = .053) on the MADRS, neither of which was statistically significant.
"This could have been due in part to including patients with [ADs], who tend to be more difficult to treat," explained Dr. Lespérance. "The neurobiology of anxiety disorders or the combination of conditions may have reduced the capacity to distinguish the effect between placebo and active treatment. Whereas if we had a more pure group of depressed patients, such as those most often included in these types of trials, we could possibly have gotten the same sort of effect we find with other antidepressants."
In the subgroup analyses, no evidence of interactions was found for antidepressant use at baseline, patient sex, or fish intake before the study. However, "the interaction of comorbid [ADs] and study group was significant (P = .035), suggesting heterogeneity of the [treatment] efficacy," report the study authors. A total of 52.8% of the total patients were found to have comorbid ADs.
For the 204 patients without comorbid ADs, those taking the omega-3 supplements had significantly fewer depressive symptoms compared with those taking placebo — shown by an adjusted mean difference of 3.17 points on the IDS-SR30 (95% CI, 0.89 − 5.45; P = .007) and 1.93 points on the MADRS (95% CI, 0.50 − 3.36; P = .008).
In addition, the omega-3 supplements "seemed to be more efficacious for patients as a stand-alone treatment in comparison to adjuvant treatment," reported Dr. Lespérance.
A total of 46.2% of the patients treated with omega-3 and 53.4% of those treated with placebo reported no medication-attributed adverse effects. There were 7 serious adverse events in the omega-3 group and 4 reported in the placebo group.
"I think this study should and will trigger more interest in doing trials with less conventional treatments for depression, such as those looking at exercise and yoga, as well as looking more at the link between omega-3 and inflammation," said Dr. Lespérance.
He notes that his team hopes to next look at a head-to-head comparison trial between omega-3 supplements and antidepressant medications. "With this, we'd like to see if we can find out what the predictors are for a better response from either omega-3 or commercial antidepressants."
Efficacy Despite Obstacles
"When I look at this trial, I see that despite setting themselves up for failure, [the investigators] reported a treatment efficacy comparable to other antidepressants," CAPT Joseph R. Hibbeln, MD, acting chief of the Section on Nutritional Neurosciences at the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, in Bethesda, Maryland, told Medscape Psychiatry.
Dr. Hibbeln, who was not involved with this study, explained that he has 20 years of experience in this field and "originated the hypothesis" about omega-3 in depression in 1995. "So I've seen many studies and watched the development of this field. Overall, this is quite an expected result, and it has to be taken in comparison to other trials of antidepressants in similar populations to really appreciate the effectiveness demonstrated here."
He noted that in 2002 the US Food and Drug Administration (FDA) recognized that the likelihood of seeing a benefit in an antidepressant trial depends on how depressed the patients are at baseline. "For example, trials of fluoxetine will show effects in severe and moderately severe patients but not in mild or moderate patients. And that's because of scoring and the statistics of depression.
"However, in this study, the patients had moderate severity, it's a population of exceptionally difficult to treat patients, and it was a very heterogeneous sample," added Dr. Hibbeln. "Statistically, in comparison with other antidepressant trials of similar populations, this is exactly what we would expect to see for a successful antidepressant. It demonstrated efficacy despite these factors and despite — and this is the critical piece — absolutely no biological validation of compliance."
When asked what he would recommend to clinicians, Dr. Hibbeln said that he would urge a "paradigm shift." Instead of treating with medicine first and then correcting the nutritional deficiency only after the medicine failed, he recommends correcting the deficiency first and then, if it is not successful, turning to medicine.
In addition, he reported that in 2006, the treatment recommendation committee for the American Psychiatric Association (APA), of which he was a member, issued recommendations that all psychiatric patients should take at least 1 g per day of omega-3 fatty acids. "The rationale was that psychiatric patients are at a much higher risk for cardiovascular disease and metabolic problems. And we have clear and unequivocal evidence that omega-3 fatty acids improve these factors.
"Plus, one of the major complications noted in second-generation antipsychotics is hypertriglyceridemia, and the most effective FDA-approved and insurance-reimbursable treatment for this is omega-3 fatty acids," he added. "And as recently as 2 weeks ago, the US dietary guidelines recommended eating fish 2 to 3 times a week for the general population.
"So should clinicians follow the guidelines from the FDA, the USDA [US Department of Agriculture], and the American Heart Association about fish intake and omega-3? And should they follow the [APA] treatment recommendations to prevent comorbid problems? Yes! And, oh by the way, correcting this nutritional deficiency is as effective as antidepressants," said Dr. Hibbeln. "It really is a no-brainer."
He also noted that patients "don't have to guess as to what their omega-3 fatty acid status is" because finger-prick blood tests are now readily available. "With this, physicians and patients can get direct assessment of fatty acid levels and psychiatric and cardiovascular risk."
This study was supported by the Fondation du Centre Hospitalier de l'Université de Montréal and the CRCHUM and by an unrestricted grant from Isodis Natura. Although Dr. Lespérance has disclosed no relevant financial relationships, 3 of the other study authors reported several potential conflicts. The full list of disclosures is listed in the original article. Dr. Hibbeln has reported no relevant financial relationships.
J Clin Psychiatry. Published online June 15, 2010.
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