Omega-3 Augmentation of Sertraline in Treatment of Depression in Patients With Coronary Heart Disease: A Randomized Controlled Trial

Context Studies of depressed psychiatric patients have shown that antidepressant efficacy can be increased by augmentation with omega-3 fatty acids.

Objective To determine whether omega-3 improves the response to sertraline in patients with major depression and coronary heart disease (CHD).

Design, Setting, and Participants Randomized controlled trial. Between May 2005 and December 2008, 122 patients in St Louis, Missouri, with major depression and CHD were randomized.

Interventions After a 2-week run-in period, all patients were given 50 mg/d of sertraline and randomized in double-blind fashion to receive 2 g/d of omega-3 acid ethyl esters (930 mg of eicosapentaenoic acid [EPA] and 750 mg of docosahexaenoic acid [DHA]) (n=62) or to corn oil placebo capsules (n=60) for 10 weeks.

Main Outcome Measures Scores on the Beck Depression Inventory (BDI-II) and the Hamilton Rating Scale for Depression (HAM-D).

Results Adherence to the medication regimen was 97% or more in both groups for both medications. There were no differences in weekly BDI-II scores (treatment × time interaction = 0.02; 95% confidence interval [CI], −0.33 to 0.36; t₁₁₂ = 0.11; P = .91), pre-post BDI-II scores (placebo, 14.8 vs omega-3, 16.1; 95% difference-in-means CI, −4.5 to 2.0; t₁₁₆ = −0.77; P = .44), or HAM-D scores (placebo, 9.4 vs omega-3, 9.3; 95% difference-in-means CI, −2.2 to 2.4; t₁₁₅ = 0.12; P = .90). The groups did not differ on predefined indicators of depression remission (BDI-II ≤8: placebo, 27.4% vs omega-3, 28.3%; odds ratio [OR], 0.96; 95% CI, 0.43-2.15; t₁₁₃ = −0.11; P = .91) or response (>50% reduction in BDI-II from baseline: placebo, 49.0% vs omega-3, 47.7%; OR, 1.06; 95% CI, 0.51-2.19; t₁₁₂ = 0.15; P = .88).

Conclusions Treatment of patients with CHD and major depression with sertraline and omega-3 fatty acids did not result in superior depression outcomes at 10 weeks, compared with sertraline and placebo. Whether higher doses of omega-3 or sertraline, a different ratio of EPA to DHA, longer treatment, or omega-3 monotherapy can improve depression in patients with CHD remains to be determined.

Trial Registration clinicaltrials.gov Identifier: NCT00116857

Depression is a risk factor for coronary heart disease (CHD) morbidity and mortality.^1-3 Low dietary intake and low serum or red blood cell levels of omega-3 fatty acids are associated with depression in patients with^4-6 and without^7-10 CHD and with an increased risk for cardiac mortality.^11,12 Two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), concentrate at synapses in the human brain and are essential for neuronal functioning.^11,13,14 Eating foods or taking dietary supplements containing DHA and EPA may reduce sudden cardiac deaths in high-risk patients,^15-18 improve depression, and enhance the efficacy of antidepressants.^19-21

In depressed psychiatric patients who are otherwise medically well, some studies have indicated that augmentation with omega-3 fatty acids dramatically improves the efficacy of antidepressants. In 20 patients with major depression who were taking antidepressants, Nemets and colleagues²⁰ reported an 11.5-point greater improvement on the Hamilton Rating Scale for Depression (HAM-D) in patients randomly assigned to receive 2 g/d of EPA compared with those taking a placebo. Peet and Horrobin²¹ found a greater improvement on the HAM-D (4 points) and on the Beck Depression Inventory (BDI) (6 points) in patients taking antidepressants who received 1 g/d of EPA compared with patients given a placebo.

This randomized, double-blind, placebo-controlled superiority trial was conducted to determine whether omega-3 augmentation improves the efficacy of sertraline for comorbid major depression in CHD.

Patients were recruited between May 2005 and December 2008 from cardiology practices in St Louis, Missouri, and from cardiac diagnostic laboratories affiliated with Washington University School of Medicine. Patients were informed about the study by their physicians, study staff, or pamphlets placed in cardiology offices and diagnostic laboratories. Patients who provided written informed consent and who had CHD as documented by at least 50% stenosis in at least 1 major coronary artery, a history of revascularization, or hospitalization for an acute coronary syndrome completed the Patient Health Questionnaire 9 for depression.²²

Exclusions were (1) cognitive impairment, comorbid psychiatric disorders, psychosis, high risk of suicide, or current substance abuse; (2) an acute coronary syndrome within the previous 2 months, a left ventricular ejection fraction of less than 30%, advanced malignancy, or physical inability to participate; (3) use of antidepressants, anticonvulsants, lithium, or omega-3 supplements; (4) sensitivity to sertraline or omega-3; and (5) physician or patient refusal.

Patients who scored 10 or higher on the Patient Health Questionnaire 9 were scheduled for a structured clinical interview.²³ Those who met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) criteria for a current major depressive episode and who scored 16 or higher on the BDI-II²⁴ were enrolled. Their self-described race and ethnicity were recorded for preplanned analyses of possible moderators of the primary outcome. The study was approved by the Human Research Protection Office at Washington University.

This study was a randomized, double-blind, placebo-controlled superiority trial to determine the efficacy of 50 mg/d of sertraline plus 2 g/d of omega-3 vs sertraline plus corn oil placebo capsules. Doses higher than 50 mg only marginally increase response rates but increase adverse effects.^25,26 All patients maintained 50 mg/d of sertraline for 10 weeks.

The 930-mg dose of EPA was based on the finding of Peet and Horrobin²¹ that greater than 1 g/d of EPA produced more adverse effects and less of an augmentation effect. The choice of an omega-3 product containing both EPA and DHA was based on the finding of Frasure-Smith et al⁵ of low serum levels of DHA but not EPA in depressed cardiac patients.

Participants were given a 2.5- to 3.5-week supply of sertraline, 25 mg/d, and a placebo resembling the omega-3 capsules. They returned 2 weeks later for a second diagnostic interview. The remaining pills and capsules were counted, and medication adverse effects were assessed. Patients who continued to meet the DSM-IV criteria for major depression, scored at least 16 on the BDI-II, reported no serious adverse effects, took both drugs on at least 85% of days, and were not otherwise excluded were invited to remain in the study.

The Beck Anxiety Inventory (BAI),²⁷ a 21-item questionnaire with scores ranging from 0 to 64 and established reliability and validity,^27,28 was administered to assess the severity of anxiety symptoms. Five mL of blood was drawn for measurement of omega-3 levels in red blood cells, and the patient was fitted with an ambulatory electrocardiogram monitor for a 24-hour recording.

A SAS (SAS Institute, Cary, North Carolina) permuted-block random allocation program randomly assigned participants to receive 10 weeks of sertraline, 50 mg/d, plus 2 capsules per day of omega-3, or sertraline, 50 mg/d, plus 2 g of a corn oil placebo. The group assignments were concealed in sealed envelopes and opened at enrollment by a clinical trial pharmacist who was blinded to all baseline assessments.

Only the study pharmacist and the chair of the data and safety monitoring committee were unblinded to group assignment during the trial. Depression symptoms were monitored weekly.

The participants were evaluated by the study psychiatrist (E.H.R.) or a psychiatric nurse at baseline and at 4 and 10 weeks after randomization. These 30-minute sessions included a review of symptoms, protocol adherence, and medication adverse effects. Weekly telephone contacts were made to encourage adherence, identify new depressive symptoms or suicidal ideation, and answer study-related questions. Adverse effects, adverse events, and medical status were recorded at each contact. After 10 weeks of treatment, the participants again provided a blood sample and completed the same assessments that were administered at baseline. Participants were compensated $100 for the baseline and the posttreatment assessments.

At each visit, participants were given enough sertraline and omega-3 or placebo capsules to last 5 to 8 days after their next scheduled visit and were instructed to return all unused medications at each visit. The remaining medications were counted and subtracted from the number provided to determine the number taken. The participants were asked to confirm that all pills removed were actually taken as prescribed. Red blood cell membrane EPA+DHA was assessed before and after treatment. It was measured by capillary gas chromatography as previously described²⁹ and expressed as a percentage of total RBC fatty acids.

The BDI-II is a 21-item depression symptom questionnaire with scores ranging from 0 to 64. The 17-item HAM-D measures interviewer-rated symptom severity. Both are widely used for assessing depression outcomes in clinical trials, and both have established reliability and validity.^30,31 The weekly BDI-II score is the primary outcome measure. Secondary outcomes include pre-post test scores on the BDI-II, HAM-D, and BAI and response and remission rates based on BDI-II scores.

An independent cardiologist, the study investigators, and the study nurses met quarterly to review adverse events. The study pharmacist and the independent cardiologist were informed immediately about serious adverse events and quarterly about routine adverse events. At each meeting, they advised the investigators whether to continue the study based on the latest adverse event data.

χ² Tests and analysis-of-variance models were used to compare the groups' demographic, psychiatric, and medical characteristics and to identify differences in protocol completion, adverse events, and adverse effects. Model diagnostics, including residual, influence, and outlier analyses, were performed for each statistical model.

Study discontinuation for any reason counted as a treatment failure. Efficacy analyses were conducted according to the intention-to-treat principle.³² Some of the data were plausibly missing at random, so a multiple imputation model was used to create 5 data sets. Analysis models were fitted to each imputed data set and then aggregated.

A mixed-effects linear regression model with an autoregressive covariance structure tested the primary hypothesis that the course of depression, as measured by weekly BDI-II scores, differs between conditions (treatment×time interaction).

Secondary analysis-of-covariance models were fitted to the week 10 BDI-II, HAM-D, and BAI scores. These scores were regressed on the treatment group and the baseline level.

Additional secondary analyses compared the groups' remission (BDI-II score ≤8) and response (≥50% reduction from the baseline BDI-II score) at 10 weeks. These artificially dichotomized outcomes were regressed on the treatment group parameter in a logistic regression model. Planned comparisons tested for age, sex, and minority moderation of the primary outcome by adding interaction terms to the model. A completers analyses were also conducted. All hypothesis tests were 2-tailed, with P < .05 denoting statistical significance. No major violations of model assumptions and no influential observations were identified for any of the statistical models. SAS version 9.1 was used for all statistical analyses.

Studies published before 2004, when this study was planned, reported a 4- to 10-point greater improvement on the HAM-D and 6 points more on the BDI for those receiving an antidepressant plus omega-3 vs an antidepressant plus placebo.^20,21,33 We conservatively projected a difference of 4 points or more on both the BDI-II and HAM-D with a within-group standard deviation of 5.0 and a 2-sided α level of .05 per comparison. Given these assumptions, the sample size needed to detect a treatment effect with 90% power is 49 patients per group. However, we aimed for 75 per group to provide 85% power to detect a 3-point difference, as a hedge against attrition.

Nine hundred forty-one patients expressed interest in the study (Figure 1), and 178 met the eligibility criteria and were enrolled. After 2 weeks taking sertraline, 25 mg/d, plus 2 placebo capsules per day, 122 (69%) continued to meet the eligibility criteria. Sixty of these patients were randomly assigned to the placebo group and 62 to the omega-3 group. Four patients in the placebo group and 3 in the omega-3 group dropped out of treatment. Two withdrew to try a different antidepressant, 2 had symptoms possibly related to sertraline (insomnia, dizziness), 2 refused to return without explanation, and 1 was hospitalized after experiencing worsening of a preexisting medical condition. Fifty-nine (95%) of the patients assigned to the omega-3 group and 56 (93%) of those assigned to the placebo group completed all phases of the study.

Baseline medical, demographic, and depression history data are presented in Table 1. There were no significant differences between the groups except for a higher proportion of aspirin use in the placebo group (88%) than in the omega-3 group (73%) (χ21 = 4.79; P = .03). Baseline omega-3 index levels were in the expected range.³⁴ Most participants had a history of depression and depression treatment. The mean baseline BDI-II score did not differ between the omega-3 group (28.1; 95% confidence interval [CI], 25.8-30.3) and placebo group (29.0; 95% CI, 26.7-31.3) at baseline (F_1,120 = 0.29; P = .59). However, the mean HAM-D score at baseline was significantly higher in the omega-3 group than in the placebo group (21.2 [95% CI, 19.8-22.6] vs 19.2 [95% CI, 17.9-20.5]; t₁₁₈ = −2.06; P = .04) (Table 2).

Adherence to the medication regimen was at least 97% in both groups for both medications (Table 2). Mean omega-3 red blood cell levels were nearly identical between the groups at baseline (4.6% [95% CI, 4.3%-5.0%] vs 4.6% [95% CI, 4.3%-5.0%]; F_1,119 = 0.0; P = .95). At 10 weeks, mean omega-3 levels in the placebo group were unchanged from baseline, whereas in the mean omega-3 group increased to 7.6% (95% CI, 7.2%-8.0%; F_1,112 = 113.2; P < .001), as expected (Table 2).²⁹ There was no difference in the mean weekly number of servings of fish consumed by the placebo group (0.70; 95% CI, 0.47-0.94) and omega-3 group (0.63; 95% CI, 0.36-0.91) during the 10 weeks of the trial (t₁₁₉=0.39; P=.69).

Primary Outcome. There was no differential improvement between groups on the BDI-II (treatment×time interaction = 0.02; 95% CI, −0.33 to 0.36; t₁₁₂ = 0.11; P = .91) (Table 3). Estimated weekly BDI-II scores show that depressive symptoms improved over time in both groups at comparable rates (Figure 2).

Secondary Outcomes. The placebo and omega-3 groups did not differ at 10 weeks in regard to depression (mean BDI-II scores: 14.8 [95% CI, 12.5-17.1] vs 16.1 [95% CI, 13.8-18.3]; t₁₁₆ = −0.77; P = .44; mean HAM-D scores: 9.4 [95% CI, 7.8-11.1] vs 9.3 [95% CI, 7.7-10.9; t₁₁₅ = 0.12; P = .90) or anxiety (mean BAI scores: 11.2 [95% CI, 12.5-17.1] vs 10.7 [95% CI, 13.8-18.3]; t₁₁₃ = 0.40; P = .69). The groups did not differ in rates of remission (27.4% vs 28.3%; estimated ψ_R = 0.96 [95% CI, 0.43-2.15]; t₁₁₃ = −0.11; P = .91) or treatment response (49.0% vs 47.7%; estimated ψ_I = 1.06 [95% CI, 0.51-2.19]; t₁₁₂ = 0.15; P = .88) (Table 3). Two-way interaction terms (group×moderator) were added to the primary outcome model but provided no evidence for treatment moderation by sex (−2.37; 95% CI, −7.87 to 3.12; t₁₁₂ = −0.86; P = .39), minority status (−1.31; 95% CI, −7.73 to 5.11; t₁₁₃ = −0.40; P = .69), age (−0.25; 95% CI, −0.54 to 0.04; t₁₁₃ = −1.72; P = .09), or aspirin use (0.95; 95% CI, −5.97 to 7.86; t₁₁₂ = 27; P = .79).

The preceding analyses were repeated for the subgroup of study completers (n = 115). No significant differences were found from the intention-to-treat analyses.

Overall, 22% of the placebo and 19% of the omega-3 group participants (χ21 = 0.13;P = .72) reported symptoms that have been associated in previous studies with high doses of omega-3, including gastrointestinal problems and prolonged bleeding. Prolonged bleeding was reported by 1 patient in the placebo group. There was only 1 between-group difference of 5% or more for any reported symptom. Stomach upset was reported by 10% of placebo and 3% of omega-3 participants. Thus, most patients tolerated 2 g/d of omega-3 very well.

There were no differences between the groups in the frequency of any other symptoms or in adverse effects commonly reported by patients taking sertraline. Overall, 73% of the placebo group and 63% of the omega-3 group reported at least 1 new symptom during the 10 weeks of the study (χ21 = 0.38; P = .24).

Fourteen adverse events resulted in either a visit to an emergency department or hospitalization. There were 4 cardiac and 4 noncardiac hospitalizations per group. One patient in the placebo group had an acute myocardial infarction, 2 omega-3 patients and 1 placebo patient underwent coronary angioplasty, 1 omega-3 patient was hospitalized for syncope, 1 placebo patient received an automatic implantable cardioverter-defibrillator, and 1 placebo patient had ablation for atrial flutter. All of the noncardiac hospitalizations were for non–life-threatening conditions. Each group had 3 emergency department visits. The reasons for these visits were for the omega-3 group, worsening heart failure, injury from a fall, and kidney stones and for the placebo group, severe influenza, allergic reaction to a nonstudy medication, and injury from a fall. None of these events were thought to be study-related.

The results of this trial do not support the hypothesis that coadministration of 2 g/d of omega-3 fatty acids improves the efficacy of 50 mg/d of sertraline in patients with major depression and CHD. This is inconsistent with 2 previous studies of depressed psychiatric patients in which omega-3 supplements substantially augmented the efficacy of standard antidepressants.^20,21 However, other studies of depressed psychiatric patients have failed to find beneficial effects of omega-3 alone or in combination with antidepressants.³⁶ A meta-analysis of 10 studies of patients with either unipolar or bipolar depression¹⁹ found a significant antidepressant effect for omega-3, but 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/d of sertraline for 10 weeks. 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 dosages of sertraline (100-200 mg/d), despite a significant increase in adverse effects.^25,26 Furthermore, increasing the dosage of sertraline for participants who did not respond to 50 mg could have resulted in an imbalance in dosage between the groups.

The choice of the omega-3 dosage was based on a study²¹ in which higher dosages of EPA omega-3 (>1 g/d) yielded more adverse effects without any additional improvement in depression. Nevertheless, higher dosages of omega-3 might have had beneficial effects. Two Lovaza (GlaxoSmithKline, Middlesex, England) capsules contain a little less than 1 g of EPA. Both the pill counts and red blood cell levels of EPA and DHA indicated a very high adherence rate, suggesting that nearly all patients took at least this amount daily. The meta-analysis by Lin and Su¹⁹ found larger effect sizes for studies that used higher dosages of EPA, but the differences were not statistically significant and not every study using a higher dosage of EPA found it to be effective.³⁷ Nevertheless, whether higher dosages of omega-3 can improve depression in patients with CHD remains unknown.

It is also possible that DHA may be more effective than EPA for depression in patients with CHD. An earlier study,⁵ later confirmed,^4,6 found lower serum levels of DHA but not EPA in depressed cardiac patients. Although patients in the present trial received 750 mg/d of DHA, that may not be enough to reduce depression in cardiac patients. It is possible that EPA alone or a higher ratio of EPA to DHA would have produced better depression outcomes.

The trial was limited to 10 weeks, which may not have been long enough to observe an effect. However, there is no indication that longer treatment would have favored the omega-3 group. Although both groups showed improvement, the between-group difference in weekly BDI-II scores remained nearly identical throughout the trial (Figure 2). Furthermore, earlier positive studies found effects within 10 weeks.²⁰

We proposed to enroll 175 patients and expected to randomize 150 after the 2-week run-in phase during which patients received 25 mg/d of sertraline plus placebo capsules. We actually enrolled 178 patients, but 58 were excluded or dropped out before randomization, instead of the expected 28. In most cases, this was because of improvement in depression prior to randomization, 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 was large enough to detect the expected 4-point differences on the BDI-II and HAM-D. Furthermore, 670 patients would have been required to detect an effect for the observed 1.4-point difference on the BDI-II, and this difference favored the placebo group.

Although some trials of omega-3 for depression have been strongly positive, others, including the present study, have failed to demonstrate a benefit, 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.^38,39 Some 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.⁴⁰ These conflicting results have led to speculation about the clinical characteristics of cardiac patient subsets who may either benefit or be harmed by omega-3 supplements.^39,41,42 Efforts should be made to identify the characteristics of depressed patients who may 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, exploratory analyses are currently being conducted to determine whether any subgroups in this study benefited from omega-3.

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 the treatment of depression in patients with major depression and established CHD. Whether higher doses of EPA, DHA, or sertraline, a longer duration of treatment, or the use of omega-3 as monotherapy can improve depression in patients with stable heart disease remains to be determined.

Corresponding Author: Robert M. Carney, PhD, Behavioral Medicine Center, Department of Psychiatry, Washington University School of Medicine, 4320 Forest Park Ave, Ste 301, St Louis, MO 63108 (carneyr@bmc.wustl.edu).

Author Contributions: Dr Carney had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Carney, Freedland, Rubin, Rich.

Acquisition of data: Carney, Freedland, Rubin, Harris.

Analysis and interpretation of data: Carney, Freedland, Rubin, Rich, Steinmeyer, Harris.

Drafting of the manuscript: Carney, Freedland, Steinmeyer, Harris.

Critical revision of the manuscript for important intellectual content: Carney, Freedland, Rubin, Rich.

Statistical analysis: Freedland, Steinmeyer.

Obtained funding: Carney, Freedland.

Administrative, technical, or material support: Carney, Rubin.

Study supervision: Carney, Rubin.

Funding/Support: This study was supported by grant RO1 HL076808-01A1 from the National Heart, Lung, and Blood Institute. GlaxoSmithKline Inc supplied omega-3 and placebo capsules and Pfizer Inc supplied sertraline.

Role of the Sponsor: The peer review process of the National Institutes of Health resulted in some changes in the original design of the study prior to funding. The National Institutes of Health had no further role in study design and no role in data collection, data analysis, data interpretation, or writing of the manuscript. Glaxo-Smith-Kline Inc and Pfizer Inc had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. Dr Carney had final responsibility for the decision to submit the manuscript for publication after funding.

Additional Contributions: We thank Ronald Krone, MD, for his service on the data and safety monitoring committee and Judith Skala, PhD, Stephanie Porto, PharmD, Julie Nobbe, PharmD, Patricia Herzing, RN, Cathi Klinger, RN, Carol Sparks, LPN, Tiffany Bonds, and Kim Metze (Washington University, St Louis, Missouri) for their contributions to the conduct of the trial. We also thank Nancy Frasure-Smith, PhD, and Francois Lespérance, MD (University of Montreal, Montreal, Quebec, Canada) for providing valuable advice during the planning of the study. Drs Frasure-Smith and Lespérance received payment for consultation services.