Trial Of Omega-3 Fatty Acids Research Articles

The Impact of Omega-3 Fatty Acid Use on the Risk of Atrial Fibrillation in Patients with Cardiovascular Disease

Fish oils containing omega-3 fatty acids (OM3FA) are widely prescribed in the management of dyslipidemia. An asso-ciation between OM3FA and reduced risk of atrial fibrillation (AF) has been proposed. We examined the impact of OM3FA exposure on the risk of developing AF in patients with cardiovascular disease. Data was obtained from elec-tronic medical records of patients seen by our cardiology service between 2005 and 2007. Patients were excluded if AF developed prior to, or on the day of, OM3FA exposure. A total of 11,360 subjects were eligible for analyses. Subjects exposed to OM3FA were at higher risk for AF. Nearly all AF risk factors were significantly more prevalent in the OM3FA exposed group. As expected, those prescribed OM3FA were also more likely to be prescribed statins, ACE in-hibitors, aspirin, and beta blockers. AF occurred in 8.5% (221/2600) of OM3FA exposed subjects and 23.5% (2054/8760) of those not exposed. After controlling for AF risk factors, OM3FA exposed subjects were 74% less likely to develop AF than those not exposed to OM3FA (odds ratio 0.26, 95%CI 0.22-0.30, p < 0.0001). After controlling for risk factors for AF, OM3FA use is significantly associated with a reduced risk for AF in patients with cardiovascular disease. Potential mechanisms which may explain the ability of OM3FAs to reduce AF include its anti-inflammatory and anti-arrhythmic properties. The optimal dose of OM3FA to prevent AF is unknown and warrants prospective as-sessment in a randomized controlled trial of OM3FAs powered to detect significant differences in AF.

A Pilot Randomized Controlled Trial of Omega-3 Fatty Acids for Autism Spectrum Disorder

We conducted a pilot randomized controlled trial to determine the feasibility and initial safety and efficacy of omega-3 fatty acids (1.3 g/day) for the treatment of hyperactivity in 27 children ages 3–8 with autism spectrum disorder (ASD). After 12 weeks, hyperactivity, as measured by the Aberrant Behavior Checklist, improved 2.7 (±4.8) points in the omega-3 group compared to 0.3 (±7.2) points in the placebo group (p = 0.40; effect size = 0.38). Correlations were found between decreases in five fatty acid levels and decreases in hyperactivity, and the treatment was well tolerated. Although this pilot study did not find a statistically significant benefit from omega-3 fatty acids, the small sample size does not rule out small to moderate beneficial effects.

RMSSD, a measure of vagus-mediated heart rate variability, is associated with risk factors for SUDEP: The SUDEP-7 Inventory

Objective The goal of this study was to determine if specific measures of heart rate variability (HRV) are associated with the total score on a new seven-item inventory for sudden unexplained death in epilepsy (SUDEP). Methods Nineteen subjects with intractable partial seizures, at least three per month, were enrolled in a randomized clinical trial of omega-3 fatty acids in epilepsy. At study entry, subjects underwent a 1-hour ECG recording for the determination of HRV. To estimate the risk of SUDEP, we assembled a seven-item inventory (the SUDEP-7 Inventory) from risk factors prospectively validated by T.S. Walczak, I.E. Leppik, M. D'Amelio M, et al. (Neurology 2001;56:519–25). The SUDEP-7 score was then correlated with measures of HRV using the Pearson correlation and other parametric and nonparametric methods. Results Subjects had highly drug-resistant seizures, with a mean seizure frequency of 22.8 seizures per month. Scores on the SUDEP-7 inventory ranged from 1 to 7 of a maximum possible score of 12. RMSSD, a measure of high-frequency HRV, was inversely correlated with the SUDEP-7 score, r = –0.64, P = 0.004. Subjects with higher SUDEP-7 scores had reduced levels of HRV (RMSSD). Other time-dependent measures of HRV (SDNN, SDANN) were not significantly correlated with SUDEP risk scores. Conclusions RMSSD, a measure of HRV, which reflects the integrity of vagus nerve-mediated autonomic control of the heart, is highly associated with the total score on a new seven-item SUDEP risk inventory. Lower RMSSD values were associated with higher risk scores on the new SUDEP risk inventory. This provides new evidence that HRV (specifically RMSSD) is a marker of SUDEP risk.

Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials

BackgroundMultiple randomized controlled trials (RCTs) have examined the cardiovascular effects of omega-3 fatty acids and have provided unexplained conflicting results. A meta-analysis of these RCTs to estimate efficacy and safety and potential sources of heterogeneity may be helpful.MethodsThe Cochrane library, MEDLINE, and EMBASE were systematically searched to identify all interventional trials of omega-3 fatty acids compared to placebo or usual diet in high-risk cardiovascular patients. The primary outcome was all-cause mortality and secondary outcomes were coronary restenosis following percutaneous coronary intervention and safety. Meta-analyses were carried out using Bayesian random-effects models, and heterogeneity was examined using meta-regression.ResultsA total of 29 RCTs (n = 35,144) met our inclusion criteria, with 25 reporting mortality and 14 reporting restenosis. Omega-3 fatty acids were not associated with a statistically significant decreased mortality (relative risk [RR] = 0.88, 95% Credible Interval [CrI] = 0.64, 1.03) or with restenosis prevention (RR = 0.89, 95% CrI = 0.72, 1.06), though the probability of some benefit remains high (0.93 and 0.90, respectively). However in meta-regressions, there was a >90% probability that larger studies and those with longer follow-up were associated with smaller benefits. No serious safety issues were identified.ConclusionsAlthough not reaching conventional statistical significance, the evidence to date suggests that omega-3 fatty acids may result in a modest reduction in mortality and restenosis. However, caution must be exercised in interpreting these benefits as results were attenuated in higher quality studies, suggesting that bias may be at least partially responsible. Additional high quality studies are required to clarify the role of omega-3 fatty acid supplementation for the secondary prevention of cardiovascular disease.

Oiling the brain: a review of randomized controlled trials of omega-3 fatty acids in psychopathology across the lifespan.

Around one in four people suffer from mental illness at some stage in their lifetime. There is increasing awareness of the importance of nutrition, particularly omega-3 polyunsaturated fatty acids (n-3 PUFA), for optimal brain development and function. Hence in recent decades, researchers have explored effects of n-3 PUFA on mental health problems over the lifespan, from developmental disorders in childhood, to depression, aggression, and schizophrenia in adulthood, and cognitive decline, dementia and Alzheimer’s disease in late adulthood. This review provides an updated overview of the published and the registered clinical trials that investigate effects of n-3 PUFA supplementation on mental health and behavior, highlighting methodological differences and issues.

Role of Omega‐3 Fatty Acids for Prevention or Treatment of Perinatal Depression

Perinatal depression is a complex mental health disorder that can manifest during pregnancy or after childbirth. Women with perinatal depression may not receive proper medical treatment because of concerns over teratogenic effects related to drug therapy. Evidence suggests that low levels of omega-3 fatty acids are correlated with depressive symptoms during pregnancy and after delivery. Omega-3 fatty acids may produce antidepressant effects due to their role in serotonin functioning. A literature search identified seven clinical trials of omega-3 fatty acids for the prevention or treatment of perinatal depression. Depression rating scale scores used in the studies improved, but results were statistically significant in only three trials. Four studies were randomized and placebo controlled, and three were open label. One study evaluating the prevention of postpartum depression in women with a history of depression was discontinued early due to relapse of depressive symptoms. In the trials we evaluated, the most common adverse effects were foul breath and/or unpleasant taste, and gastrointestinal complaints; no serious adverse events were reported. The seven studies were limited by small sample sizes and variable dosing and study durations. In the studies that demonstrated statistical significance, improvement in depression rating scale scores for omega-3 fatty acids was comparable to placebo. Overall, results have been inconclusive, but further investigation of omega-3 fatty acids is warranted because they did improve depression scores and appeared to be safe during pregnancy.

Supportive psychotherapy for perinatal depression: preliminary data for adherence and response

We sought to determine patient factors associated with adherence and response to a manualized supportive psychotherapy designed for pregnant and postpartum women with major depressive disorder (MDD). Supportive psychotherapy was provided to all participants in parallel to a placebo-controlled trial of omega-3 fatty acids. The supportive psychotherapy was a six-session, manualized intervention. Clinicians recorded participation and adherence. Symptom rating scales were completed at baseline and every 2 weeks and included the Hamilton Depression Rating Scale (HAM-D) as the primary outcome. N=59 participants were enrolled. Subjects were referred by obstetrical and pediatric health-care providers. Descriptive statistics and general linear models were used to assess the study outcomes. The mean number of completed sessions was 4.4 out of a full course of 6. There were no significant differences found between omega-3 fatty acid and placebo groups in the parallel assessments. We found significantly lower adherence to the psychotherapy sessions for women who were not married, were unemployed, and those with higher scores on the HAM-D at baseline. Completion of a greater number of psychotherapy sessions, lower baseline depression scores, and postpartum status (compared with pregnant status) were associated with lower final HAM-D scores. Overall, the response rate was 52.9% (> or =50% decrease on HAM-D scores), and the remission rate (final score<8) was 31.4%. Study limitations included small sample size, and possible nonspecific and placebo effects. Adherence appears important in response to supportive psychotherapy in women with perinatal MDD, and future efforts to improve adherence in perinatal women with MDD are warranted.

The Effect Of Omega-3 Fatty Acid Supplementation On The Inflammatory Response To Eccentric Strength Exercise

Omega-3 fatty acids (omega-3) have anti-inflammatory properties. Although dietary omega-3 supplementation has been shown to be beneficial for inflammatory conditions such as coronary heart disease, Crohn's disease, ulcerative colitis and rheumatoid arthritis, it is not known if omega-3 supplementation attenuates exercise-induced inflammation. PURPOSE: To determine if omega-3 supplementation reduces inflammation as measured at 48-hours after eccentric arm curl exercise. METHODS: Eleven healthy adult men and women (age: 35 ± 10 y; BMI: 22.9 ± 2.0 kg/m2) underwent eccentric biceps curl exercise to induce inflammation on two occasions, once after 14 days on a omega-3 restricted diet (control trial) and then again after 7 days of 3000 mg/d omega-3 supplementation (omega-3 trial). Immediately before and 48h after eccentric exercise, inflammation was assessed by measuring soreness ratings (visual analog scale), swelling (arm circumference and arm volume), and temperature (infrared skin sensor). RESULTS: Arm volume and skin temperature did not change in response to eccentric exercise in either trial. Arm soreness increased (p<0.0001) in response to eccentric exercise; however, the magnitude of increase in soreness was 15% less in the omega-3 trial (p= 0.004). Although arm circumference increased after eccentric exercise in the control trial (p= 0.01) but not in the omega-3 trial (p= 0.15), the difference between trials was not significant (p= 0.45). CONCLUSIONS: These findings suggest that omega-3 supplementation decreases soreness after eccentric exercise. However further research needs to be done using more sensitive objective measures of inflammation, as most of the objective measures in the present study were not sensitive enough to pick up an inflammatory response.

Tolerability of omega-3 fatty acid supplements in perinatal women

Background Benefits of omega-3 fatty acids in perinatal women are well documented, although fish intake has declined among perinatal women. Objective To determine the tolerability of omega-3 fatty acid supplementation in perinatal women. Design Pregnant and postpartum women with major depressive disorder (MDD) entered an 8-week double-blind, placebo-controlled trial of omega-3 fatty acids. Four capsules provided 1.84 g/day of eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), or matching placebo (corn oil with 1% fish oil to maintain blind). Tolerability was assessed by clinician interview biweekly. Results Fifty-nine women enrolled. Thirteen (22%) reported mainly transient side effects including dizziness, diarrhea, nausea, burping, heartburn/reflux, difficulty swallowing capsules, unpleasant breath/bad taste or feeling tired. The most common were unpleasant breath/bad taste and heartburn/reflux. Six reporting side effects received omega-3 fatty acids; seven received placebo. Neither pregnant nor postpartum women discontinued due to intolerability. Conclusions Omega-3 fatty acid supplements were well tolerated by perinatal women.

Antenatal Depression: Navigating the Treatment Dilemmas

“Ms. A” was a 35-year-old married Caucasian health care professional with a history of recurrent major depressive disorder that responded well to treatment with a selective serotonin reuptake inhibitor (SSRI). She discontinued her antidepressant prior to conception for a planned pregnancy because she did not want to expose her baby to medication. She soon relapsed, and by the first trimester of her pregnancy, she was in a major depressive episode. Her symptoms included anhedonia, tearfulness, irritability, insomnia, and diminished appetite. She presented for participation in an open-label pilot trial of omega-3 fatty acids for antenatal major depressive disorder (1). At intake, after hearing the risks and benefits of available treatment options, Ms. A declined antidepressant medication and a referral for psychotherapy and consented to participate in the study of omega-3 fatty acids, which she started at 16 weeks’ gestation. She was assessed every 2 weeks throughout pregnancy. At 8 weeks she had not responded to omega-3 fatty acids and was again presented with other treatment options, including medication and psychotherapy. She again declined these treatments and continued to do so throughout the remainder of her pregnancy. She was concerned about the safety of medications in pregnancy and believed that taking medication would make her a bad mother. She also declined referral for psychotherapy, stating that she was “too busy.”

Fatty Acids as Modulators of the Immune Response

Research describing fatty acids as modulators of inflammation and immune responses abounds. Many of these studies have focused on one particular group of fatty acids, omega-3. The data from animal studies have shown that these fatty acids can have powerful anti-inflammatory and immunomodulatory activities in a wide array of diseases (e.g., autoimmunity, arthritis, and infection). However, the evidence from human trials is more equivocal. In this review, a historical framework for understanding how and why fatty acids may affect the immune system is provided. Second, highlights of two recent landmark reports from the Agency for Healthcare Research and Quality are presented. These reports critically evaluate the evidence from human clinical trials of omega-3 fatty acids and rheumatoid arthritis, asthma, and a few other immune-mediated diseases. Third, the data from human clinical trials investigating the impact of various bioactive fatty acids on ex vivo and in vivo immune response are reviewed. Limitations in experimental design and immune assays commonly used are discussed. The discordance between expectation and evidence in this field has been a disappointment. Recommendations for improving both animal-based and human studies are provided.

An open trial of Omega-3 fatty acids for depression in pregnancy.

In this flexible-dose, open-label trial, we examined the efficacy of omega-3 fatty acids for the treatment of depression during pregnancy. Fifteen pregnant women with major depressive episodes participated. Subjects initially received two capsules per day [0.93 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]; the dose could be increased by one capsule per day every 2 weeks to a maximal dose of 2.8 g. Subjects were assessed with the Edinburgh Postnatal Depression Scale (EPDS) and Hamilton Rating Scale for Depression (HRSD). Average duration of participation in this treatment trial was 8.3 weeks (SD ± 7.1). Average final dose of EPA + DHA in this flexible dose trial was 1.9 g per day (±0.5). The mean reduction in EPDS scores was 40.9% (SD ± 21.9); the mean decrease in HRSD score was 34.1% (SD ± 27.1). This open trial provides data to support the need for randomized controlled dose-finding trials of omega-3 fatty acids in major depressive episodes during pregnancy.

P.2.009 Mirtazapine orally disintegrating tablet (ODT) for the treatment of depressive patients with insomnia and anxiety symptoms

None of the clinical trials of omega-3 fatty acids using combinations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were able to show any effect on cardiovascular outcomes, despite reductions in triglyceride levels. In contrast, the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT), which employed high-dose (4 g) purified EPA, demonstrated a 25% reduction in atherosclerotic cardiovascular disease–related events compared with placebo (hazard ratio 0.75; 95% confidence interval 0.68–0.83; P < 0.001). Moreover, REDUCE-IT is the first clinical trial using a lipid-lowering agent as adjuvant therapy to a statin to show a significant reduction in cardiovascular mortality. Significant reductions in stroke, need for revascularization, and myocardial infarction were also observed. The pharmacology of EPA is distinct from that of DHA, with a differential effect on membrane structure, lipoprotein oxidation, and the production of downstream metabolites that promote the resolution of inflammation. Attained plasma levels of EPA may be an important determinant of efficacy, with a substudy of REDUCE-IT suggesting that the threshold for clinical benefit of EPA is approximately 100 μg/mL, a level achieved in only a minority of patients in other studies. No similar clinical trials of DHA monotherapy have been conducted, so no such threshold has been established. The results of the REDUCE-IT and the Japan EPA Lipid Intervention Study (JELIS) together affirm the efficacy of EPA therapy for cardiovascular disease risk reduction in certain patient populations.

A trial of omega-3 fatty acids for prevention of hypertension

Although ω-3 polyunsaturated fatty acid supplements reduce blood pressure (BP), the typical doses cause untoward side effects. A novel fatty acid supplement was tested in a randomized trial of patients with high normal diastolic BP. The novel fatty acid supplement did not significantly reduce BP in patients with high normal diastolic blood pressure.

Omega-3 fatty acids for intermittent claudication.

Omega-3 fatty acids are established as being effective in the treatment and prevention of coronary artery disease. It is possible that they may also benefit people with peripheral arterial disease, since the pathogenesis of the two conditions is similar. To determine the effects of omega-3 supplementation in people with intermittent claudication. Trials were identified from the Cochrane Peripheral Vascular Diseases Group trials register (last searched April 2004), and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 1, 2004). In addition, literature from pharmaceutical companies (Roche Pharmaceuticals and Seven Seas), manufacturers of omega-3 rich foods (Columbus Eggs) and web sites of nutritional organisations dedicated to omega-3 fatty acids (Omega-3 information and the Fish Foundation) were searched. Randomised controlled trials of omega-3 fatty acids versus placebo or non-omega-3 fatty acids in people with intermittent claudication. One reviewer (TS) identified potential trials, assessed study quality and extracted data. The other reviewer (WH) assessed study quality and checked data extraction. Four studies were included involving a total of 203 participants. The overall methodological quality of studies was good. All studies compared omega-3 fatty acid supplementation with placebo. Two studies used an omega-6 fatty acid as the placebo preparation, one used a monounsaturated fatty acid and one used a combination of omega-6 and monounsaturated fatty acids.Omega-3 fatty acid supplementation reduced triglyceride levels (weighted mean difference (WMD) -0.66 mmol/litre; 95% confidence interval (CI) -1.24 to -0.09) and diastolic blood pressure (WMD -1.94 mmHg; 95% CI -3.58 to -0.29) in the treatment group, but increased total cholesterol levels (WMD 0.41 mmol/litre; 95% CI 0.03 to 0.80) and LDL cholesterol levels (WMD 0.43 mmol/litre; 95% CI 0.12 to 0.74). Gastrointestinal side-effects were observed in one study. No significant changes were observed in pain-free walking distance (WMD -17 m; 95% CI -51 to 17 m), maximal walking distance (WMD -21 m; 95% CI -59 to 17 m) or ankle brachial pressure index (WMD -0.03; 95% CI -0.1 to 0.04). Omega-3 fatty acids appear to have some beneficial biochemical and haemodynamic effects in people with intermittent claudication but there is no evidence of improved clinical outcomes. It should be noted that no consistent effect on primary outcome measures was detected. Further research is needed in this area, to evaluate short- and long-term effects on more clinically relevant outcomes.

Cross-National Comparisons of Seafood Consumption and Rates of Bipolar Disorders

The authors sought to determine if greater seafood consumption, a measure of omega-3 fatty acid intake, is associated with lower prevalence rates of bipolar disorder in community samples. Lifetime prevalence rates in various countries for bipolar I disorder, bipolar II disorder, bipolar spectrum disorder, and schizophrenia were identified from population-based epidemiological studies that used similar methods. These epidemiological studies used structured diagnostic interviews with similar diagnostic criteria and were population based with large sample sizes. Simple linear and nonlinear regression analyses were used to compare these prevalence data to differences in apparent seafood consumption, an economic measure of disappearance of seafood from the economy. Simple exponential decay regressions showed that greater seafood consumption predicted lower lifetime prevalence rates of bipolar I disorder, bipolar II disorder, and bipolar spectrum disorder. Bipolar II disorder and bipolar spectrum disorder had an apparent vulnerability threshold below 50 lb of seafood/person/year. The absence of a correlation between lifetime prevalence rates of schizophrenia and seafood consumption suggests a specificity to affective disorders. These data describe a robust correlational relationship between greater seafood consumption and lower prevalence rates of bipolar disorders. These data provide a cross-national context for understanding ongoing clinical intervention trials of omega-3 fatty acids in bipolar disorders.

Prevention of postcoronary angioplasty restenosis by omega-3 fatty acids: Main results of the Esapent for Prevention of Restenosis ITalian Study (ESPRIT)

Background and Objective Previous trials of omega-3 fatty acids (ω-3 FA) for restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA) have yielded conflicting results. We tested the hypothesis that long-term administration of ω-3 FA before PTCA may have significant effects on restenosis. Methods We randomized 339 patients in a double-blind, placebo-controlled study of ω-3 FA (as an ethyl ester preparation given as 6 1-g capsules providing 3 g eicosapentaenoic acid and 2.1 g docosahexaenoic acid/d started 1 month before PTCA and given for 1 month thereafter, then continued at half-dose for 6 months) versus an olive oil placebo. Of these, 257 patients (125 on ω-3 FA, 132 on placebo) well matched for risk factors underwent successful balloon-only PTCA (280 total lesions) and were evaluable at 6 months with repeat angiography. Restenosis was defined at quantitative angiography as a recurrence of >50% diameter stenosis in the dilated vessel (Definition I) and as >50% loss of the short-term gain immediately after PTCA (Definition II). Results Restenosis rates per vessel were 29.4% and 31.6% in the ω-3 FA group, and 39.6% and 35.4% in the placebo group according to Definitions I (P =.04) and II (P = not significant), respectively. Restenosis rates per patient were 31.2% and 33.6% in the ω-3 FA group, and 40.9% and 37.1% in the placebo group according to Definitions I (P =.05) and II (P = not significant), respectively. Conclusions With a long treatment before PTCA, ω-3 FA produced a small but significant decrease in the restenosis rate compared with placebo. (Am Heart J 2002;143:e5.)

How blind is double-blind? A study of fish oil versus placebo

The distinctive aftertaste associated with fish oil preparations used in clinical trials of omega-3 fatty acids may weaken the double-blind. This double-blind pilot study was designed to examine whether normal subjects could correctly ‘guess’ if they were receiving capsules containing concentrated fish oil or capsules of pure olive oil. The informed consent was designed to give subjects ambiguous expectations about what oil they might be receiving to examine whether this would influence their guess. Despite a marked difference in taste experience, there was no significant difference in correct guesses between the two groups. The results suggest that altering subjects' expectations could further improve the validity of the double-blind.