New Perspectives on Treatment of Depression in Coronary Heart Disease.

ABSTRACT: It has been 35 years since we published a study in Psychosomatic Medicine showing that patients with coronary heart disease (CHD) and major depression were at twice the risk of having a cardiac event as were nondepressed patients (Carney et al. Psychosom Med. 1988;50:627-33). This small study was followed a few years later by a larger, more convincing report from Frasure-Smith et al. (JAMA. 1993;270:1819-25) showing that depression increased the rate of mortality in patients with a recent acute myocardial infarction. Since the 1990s, there have been many more studies of depression as a risk factor for cardiac events and cardiac-related mortality from all over the world, and many clinical trials designed to determine whether treating depression improves medical outcomes in these patients. Unfortunately, the effects of depression treatment in patients with CHD remain unclear. This article considers why it has been difficult to determine whether treatment of depression improves survival in these patients. It also proposes several lines of research to address this question, with the goal of definitively establishing whether treating depression can extend cardiac event-free survival and enhance quality of life in patients with CHD.

Predicting the effects of supplemental EPA and DHA on the omega-3 index.

BACKGROUND: Supplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear. OBJECTIVE: The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I. METHODS: Deidentified data from 1422 individuals from 14 published n-3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion. RESULTS: Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products. CONCLUSIONS: Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.

A Randomized Placebo-Controlled Trial of Omega-3 and Sertraline in Depressed Patients With or at Risk for Coronary Heart Disease.

OBJECTIVE: Studies of depressed psychiatric patients have suggested that antidepressant efficacy can be increased by adding eicosapentaenoic acid (EPA), one of the omega-3 fatty acids found in fish oils. The purpose of this study was to determine whether the addition of EPA improves the response to sertraline in depressed patients with or at high risk for coronary heart disease (CHD). METHODS: Between May 2014 and June 2018, 144 patients with DSM-5 major depressive disorder seen at the Washington University School of Medicine with or at high risk for CHD were randomized to receive either 50 mg/d of sertraline and 2 g/d of EPA or 50 mg/d of sertraline and corn oil placebo capsules for 10 weeks. The Beck Depression Inventory II (BDI-II) was the primary outcome measure. RESULTS: After 10 weeks of treatment, there were no differences between the arms on the mean baseline-adjusted BDI-II (placebo, 10.3; EPA, 12.1; P = .22), the 17-item Hamilton Depression Rating Scale (placebo, 7.2; EPA, 8.0; P = .40), or the 10-week remission rate (BDI-II score ≤ 8: placebo, 50.6%; EPA, 46.7%; odds ratio = 0.85; 95% CI, 0.43 to 1.68; P = .63). CONCLUSIONS: Augmentation of sertraline with 2 g/d of EPA for 10 weeks did not result in greater improvement in depressive symptoms compared to sertraline and corn oil placebo in patients with major depressive disorder and CHD or CHD risk factors. Identifying the characteristics of cardiac patients whose depression may benefit from omega-3 and clarifying the pathways linking omega-3 to improvement in depression symptoms are important directions for future research. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02021669; FDA IND registration number: 121107.

Baseline blood levels of omega-3 and depression remission: a secondary analysis of data from a placebo-controlled trial of omega-3 supplements.

OBJECTIVE: Depression is associated with low red blood cell (RBC) levels of 2 omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), suggesting that omega-3 supplements might improve depression. However, clinical trials have produced mixed results. The purpose of this secondary analysis of data from a randomized controlled trial was to determine whether baseline blood levels of omega-3, which are known to vary widely among individuals, predict depression outcomes. METHOD: The percentages of EPA, DHA, and the omega-6 arachidonic acid (AA) were measured in RBCs at baseline and posttreatment in 122 participants with DSM-IV major depression who were randomly assigned between May 2005 and December 2008 to receive either 50 mg/d of sertraline and a daily dosage of 930 mg EPA/750 mg DHA or sertraline plus placebo. Associations between baseline omega-3 RBC levels and remission of depression (17-item Hamilton Depression Rating Scale score ≤ 7) were analyzed by treatment arm. RESULTS: Among participants in the omega-3 arm, baseline RBC levels of EPA + DHA (P = .002) and the EPA + DHA:AA ratio (P = .003) were significantly higher among those whose depression subsequently remitted compared with those whose depression did not remit. No associations were detected in the sertraline plus placebo arm. Baseline levels of EPA (P = .03) and the EPA + DHA:AA ratio (P = .04) moderated the relationship between treatment arm and depression outcomes. CONCLUSIONS: High baseline RBC levels of EPA and DHA and a high EPA + DHA:AA ratio predict favorable depression outcomes in patients receiving omega-3 supplements. Omega-3 supplementation may be an effective treatment for depression, but the requisite dosage and duration of treatment may depend on the patient's baseline level of omega-3 fatty acids. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00116857.

The efficacy of auriculotherapy for smoking cessation: a randomized, placebo-controlled trial.

BACKGROUND: Quitting smoking remains a challenge for almost one-third of the military veteran population. Alternatives to pharmacological therapies such as acupuncture, acupressure, and electrical stimulation have received minimal attention in research but have been widely reported to be popular and safe interventions for smoking cessation. METHODS: This randomized, double-blind, placebo-controlled clinical trial of 125 veterans was conducted to determine whether aural electrical stimulation (auriculotherapy) once a week for 5 consecutive weeks is associated with a higher rate of smoking abstinence are than observed with sham stimulation. RESULTS: Auriculotherapy was found to be safe and largely free from significant side effects. However, there was no difference in the rate of smoking cessation between those participants who received true auriculotherapy and those who received sham auriculotherapy. The auriculotherapy group achieved a rate of 20.9% abstinence versus 17.9% for the placebo arm after 6 weeks. CONCLUSION: The results of this randomized, controlled clinical trial do not support the use of auriculotherapy to assist with smoking cessation. It is possible that a longer treatment duration, more frequent sessions, or other modifications of the intervention protocol used in this study may result in a different outcome. However, based on the results of this study, there is no evidence that auriculotherapy is superior to placebo when offered once a week for 5 weeks, as described in previous uncontrolled studies.

Obstructive sleep apnea/hypopnea syndrome and poor response to sertraline in patients with coronary heart disease.

OBJECTIVE: Evidence from several clinical trials in patients with coronary heart disease suggests that depression that does not respond to treatment is associated with a particularly high risk of adverse cardiac outcomes. The purpose of this study was to determine whether obstructive sleep apnea/hypopnea syndrome (OSAHS) is associated with a poor response to antidepressant medication in patients with coronary heart disease. METHOD: This was a secondary analysis of data from a randomized, double-blind, placebo-controlled clinical trial of omega-3 fatty-acid augmentation of sertraline for depression in patients with coronary heart disease. Patients with documented coronary heart disease were recruited between May 2005 and December 2008 from cardiology practices in St Louis, Missouri, and through cardiac diagnostic laboratories affiliated with Washington University School of Medicine, St Louis, Missouri. One hundred five patients (mean age = 58 years) with coronary heart disease and current major depressive disorder (DSM-IV) were randomized to receive sertraline plus either omega-3 or placebo for 10 weeks. Cyclical heart-rate patterns associated with OSAHS were detected via ambulatory electrocardiography prior to treatment. Symptoms of depression were measured at baseline and follow-up with the Beck Depression Inventory-II (BDI-II) and the 17-item Hamilton Depression Rating Scale (HDRS-17). The primary endpoint was the BDI-II score at 10 weeks. RESULTS: Thirty of the 105 patients (29%) were classified as having probable moderate to severe OSAHS on the basis of nighttime heart-rate patterns. These OSAHS patients had significantly higher scores on both the BDI-II (t = -2.78, P = .01) and the HDRS-17 (t = -2.33, P = .02) at follow-up as compared to the reference group. Adjustment for baseline depression score, treatment arm (omega-3 vs placebo), body mass index, and inflammatory markers did not change the results. Patients with OSAHS reported higher item scores at follow-up on all depressive symptoms measured with the BDI-II compared to those without OSAHS. CONCLUSIONS: Obstructive sleep apnea/hypopnea syndrome is associated with a relatively poor response to sertraline treatment for depression. Future research should determine the contribution of OSAHS to the increased risk of adverse cardiac outcome associated with treatment-resistant depression.

Inflammation and treatment response to sertraline in patients with coronary heart disease and comorbid major depression.

OBJECTIVE: Treatment-resistant depression has recently emerged as a marker of increased risk for morbidity and mortality in patients with coronary heart disease (CHD). Studies in depressed patients without CHD suggest that elevated markers of inflammation predict poor response to treatment. This may help to explain the increased risk of cardiac events associated with depression. We therefore studied the relationship between pretreatment markers of inflammation and treatment response in patients with CHD and major depression. METHODS: This was a planned, secondary analysis of a clinical trial in which 122 patients with CHD and comorbid major depression were randomly assigned to 50 mg of sertraline plus 2 g/day omega-3 fatty acids or to 50 mg of sertraline plus 2 g/day corn oil placebo capsules for ten weeks. Depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II). Blood samples were collected at baseline to determine levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). The primary outcome was the post-treatment BDI-II depression score. RESULTS: Baseline levels of hs-CRP, IL-6, and TNF-α were not associated with the 10-week post-treatment depression score (P=.89, P=.88, and P=.31, respectively). Treatment responders (>50% reduction from baseline BDI-II score) did not differ from non-responders in either baseline hs-CRP, IL-6, or TNF-α (P=.83, P=.93, and P=.24, respectively). Similarly, depression remitters (BDI-II ≤8 at post-treatment) did not differ from non-remitters on the three baseline inflammation markers. CONCLUSION: These findings do not support the hypothesis that elevated baseline inflammatory markers predict poor response to sertraline in patients with CHD and major depression. The explanation for the increased risk of cardiac events associated with poor response to depression treatment remains unclear.

Effect of omega-3 fatty acids on heart rate variability in depressed patients with coronary heart disease.

OBJECTIVE: To determine whether omega-3 fatty acid (FA) increases the natural log of very low frequency (lnVLF) power, an index of heart rate variability (HRV), and reduces 24-hour heart rate (HR) in depressed patients with coronary heart disease (CHD). Low intake of omega-3 FAs is associated with depression and with low HRV, and all three are associated with an increased risk of death in patients with CHD. METHODS: Thirty-six depressed patients with CHD randomized to receive 50 mg of sertraline and 2 g of omega-3/day, and 36 randomized to sertraline and a placebo, had 24-hour HRV measured at baseline and after 10 weeks of treatment. RESULTS: There was a significant treatment × time interaction for covariate adjusted lnVLF (p = .009), for mean 24-hour HR (p = .03), and for 1-minute resting HR (p = .02). The interaction was not significant for three other measures of HRV. LnVLF did not change over time in the omega-3 arm but decreased in the placebo arm (p = .002), suggesting that omega-3 may have prevented or slowed deterioration in cardiac autonomic function. CONCLUSIONS: The effects of omega-3 FAs on lnVLF and HR, although modest, were detected after only 10 weeks of treatment with 2 g per day of omega-3. Whether a longer course of treatment or a higher dose of omega-3 would further decrease HR, improve other indices of HRV, or reduce mortality in depressed CHD patients should be investigated.

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 x time interaction = 0.02; 95% confidence interval [CI], -0.33 to 0.36; t(112) = 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; t(116) = -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; t(115) = 0.12; P = .90). The groups did not differ on predefined indicators of depression remission (BDI-II < or = 8: placebo, 27.4% vs omega-3, 28.3%; odds ratio [OR], 0.96; 95% CI, 0.43-2.15; t(113) = -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; t(112) = 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.

Pathways linking depression, adiposity, and inflammatory markers in healthy young adults.

Despite mounting evidence that depression increases risk for cardiovascular morbidity and mortality, little is known about the mechanisms responsible for this association. The current study examined the inter-relationships between depression, adiposity, and inflammatory molecules implicated in the pathogenesis of coronary heart disease. One hundred adults were enrolled. Half were clinically depressed; the others were matched controls with no history of psychiatric illness. All subjects were in excellent health, defined as having no acute infectious disease, chronic medical illness, or prescribed medication regimen. Structural equation modeling yielded support for a model in which depressive symptoms promote weight accumulation, which in turn activates an inflammatory response through two distinct pathways: expanded adipose tissue release of interleukin-6 and leptin-induced upregulation of interleukin-6 release by white blood cells (CFI =.99; NNFI =.99; RMSEA =.05). It did not support a sickness behavior model in which the inflammatory molecules arising from expanded adipose tissue promote depressive symptoms.