The results of the trial did not support the hypothesis that co-administration of 2 g/day of omega-3 FA improves the efficacy of 50 mg/day of sertraline in patients with major depression and heart disease. These results are inconsistent with previous studies of depressed psychiatric patients that found omega-3 supplements to substantially improve the efficacy of standard antidepressants. However, there are other studies of depressed psychiatric patients that have also failed to find a beneficial effect for omega-3 taken alone or in combination with antidepressants.31
Lin and Su completed a meta-analysis of ten studies of omega-3 treatment for patients with either unipolar or bipolar depression.19
They found a significant antidepressant effect for omega-3, but noted that there was considerable heterogeneity among the studies. No reliable moderators of the antidepressant effect of omega-3 have emerged from this literature.
The participants in this study received 50 mg per day of sertraline for the ten-week duration of the trial. It is possible that omega-3 augmentation would have been more effective at higher doses of the antidepressant. However, previous studies found little additional improvement in response rates with higher doses of sertraline (100–200 mg per day), whereas they did find a significant increase in side effects.25, 26
Furthermore, increasing the dose of sertraline for participants who did not respond to 50 mg could have resulted in an imbalance in dosage between the groups. This would have likely occurred if the hypothesized omega-3 effect had been observed. Nevertheless, whether omega-3 is more effective in combination with higher doses of sertraline is unknown.
The choice of the omega 3 dosage was based on a study by Peet and Horribon21
who found that higher doses of EPA omega-3 (> 1 gram/day) resulted in more reported side effects without any additional improvement in depression. Nevertheless, it is possible that higher doses of omega-3 would have had a beneficial effect in the present study. Two capsules of Lovaza contain just below one gram of EPA (930 mg). Both the pill counts and RBC levels of EPA and DHA indicated a very high adherence rate, suggesting that nearly all patients took at least this amount daily. In order to ingest one gram or more of EPA per day, three or more pills of any formulation available at the time the study began would have been required. Increasing the number of pills per day or the total amount of EPA received could have decreased adherence to the treatment regimen and worsened the depression outcomes by increasing both the complexity of the medication regimen and drug-related side effects. The meta-analysis by Lin and Su found larger effect sizes for studies that used higher doses of EPA, but the differences were not statistically significant and not every study using a higher dose of EPA found it to be effective.e.g.32
Nevertheless, it remains unknown whether higher doses of omega-3 can improve depression in patients with CHD.
It is also possible that DHA may be more important than EPA for treating depression in patients with CHD. An earlier study5
, later confirmed4, 6
, found that blood levels of DHA but not EPA were lower in depressed cardiac patients. Although patients in the present trial received a daily dose of 750 mg of DHA, that may not be enough to produce an effect on depression in cardiac patients.
The trial was limited to 10 weeks, which may not have been long enough to observe an effect for omega-3. However, there is no indication that a longer treatment period would have resulted in an outcome favoring the omega-3 group. Although both groups showed improvement, the between-group difference in weekly BDI-II scores remained nearly identical throughout the trial (). Furthermore, earlier positive studies found effects within ten weeks.e.g.20
We proposed to enroll 175 patients and expected to randomize 150 after the two week run-in phase during which patients received 25 mg of sertraline and placebo capsules. We actually enrolled 178 patients with a major depression episode who met all of the inclusion and exclusion criteria. However, 58 instead of the expected 28 patients were excluded or dropped out before randomization. In most cases, this was due to improvement in depression which placed the patient below the eligibility threshold (n=22); a decision by the patient to avoid possible randomization to a placebo and to seek omega-3 and antidepressants elsewhere (n=15); or new or previously unidentified medical or psychiatric exclusions (n=12). Although the enrolled sample was smaller than planned, it is unlikely that a different outcome would have been observed if the proposed 150 or even 200 patients had been randomized. The mean BDI-II between-group difference was negligible.
Although some trials of omega-3 for depression have been strongly positive, others, including the present study, have failed to demonstrate a benefit of omega-3, either alone or combined with conventional antidepressants. These contradictory findings mirror those of studies that have examined the efficacy of omega-3 supplements in reducing cardiac morbidity and mortality.33, 34
Some studies have found that omega-3 supplements greatly reduce the incidence of sudden cardiac death.15–17
Others have failed to find a benefit, and still others have reported that omega-3 supplements increase the risk of cardiac death.35
These confusing results have led to speculation about the clinical characteristics of cardiac patient subsets who may either benefit or be harmed by increased intake of omega-3.34, 36, 37
Similar attempts should be made to identify the characteristics of the depressed patients who benefit from omega-3 depression monotherapy or augmentation of standard antidepressants. Confirmatory prospective clinical trials should then be undertaken in these subgroups. To this end, secondary and exploratory analyses are currently being conducted to determine whether any subgroups benefited from omega-3 in this study.
In conclusion, this randomized, double-blind, placebo-controlled trial found no evidence that omega-3 augmentation of sertraline is superior to sertraline plus placebo capsules for depression in patients with major depression and established CHD. Whether higher doses of EPA and/or DHA, higher doses of sertraline, a longer duration of treatment, or the use of omega-3 as a monotherapy, can improve depression in patients with stable heart disease remains to be determined.