BRAVO Study: The Better Resiliency Among Veterans with Omega-3s: A Double Blind, Placebo-Controlled Trial of Omega-3 Fatty Acid Supplementation among Military Veterans A large well designed RCT is needed to definitively determine if elevating n-3 HUFAs reduce risk of suicidal behaviors, major depressive symptoms and reduce substance abuse among a population representative of the US Military. We have recently been notified that the Department of Defense has approved $10 million to definitively evaluate if restoring adequate omega-3 fatty acid nutritional status can prevent severe suicidal behaviors and reduce addictive behaviors among US military veterans. This study will be conducted in close collaboration with Bernadette Marriott, Ph.D. at the Medical College of South Carolina. The BRAVO study seeks to determine if dietary supplementation with 3 g/d of n-3 HUFAs reduces the risk for serious suicidal behaviors, suicidal thinking, negative emotions, and symptoms associated with suicide risk, in a veteran population (n=350) at risk for suicidal behaviors. Changes in cognitive processes specific to suicide risk will be evaluated, including implicit associations, response inhibition and sustained attention. Sub-studies will evaluate efficacy in reducing depressive symptoms, alcohol and nicotine use among veterans with concomitant significant depressive symptoms, and alcohol and nicotine use disorders. In addition, a sub-study will utilize functional magnetic resonance imaging (fMRI) to evaluate the neuropsychological and neurophysiological effects. This study seeks to evaluate the efficacy of n-3 HUFAs among a representative population of US Veterans already receiving appropriate medical care so that if successful, these results can be readily applied to broader populations. The BRAVO study was conducted based upon two prior findings. First we recently evaluated the serum fatty acid status from n=800 Military suicide deaths and n=800 matched controls. We found that that all US Military personnel studied had low levels of docosahexaenoic acid and with-in this narrow range, the lowest levels were associated with a75% increase in the risk of suicide death. Second, in a previously conducted study, we found that 2 g/d of n-3 HUFAs reduced suicidal thinking by 40% among subjects with episodes of self-harm. Major depression is a risk factor for suicide. We sought to investigate sources of the heterogeneous findings reported in trials evaluating treatment efficacy of n-3 HUFAs for depressed mood. In a hierarchical meta-analysis we found that EPA predominant formulations (>50% EPA) demonstrated considerable clinical benefits (Hedges g = 0.34;p = 10-7), but DHA predominant formulations (>50% DHA) displayed no clinical benefits. Study populations with a significant clinical depression demonstrated a considerable benefit over placebo (Hedges g = 0.86;p = 10-8);unlike non-clinical populations. Identifying these factors clarified presumed inconsistencies. In previous publications we reported that lower intake of seafood and lower levels of DHA in breast milk were associated with markedly increased risks of depression during pregnancy and in the postpartum. Mothers selectively transfer DHA to their fetuses to support optimal neurological development during pregnancy. Without sufficient dietary intake, mothers can become depleted of DHA relative to n-6 HUFAs and may increase their risk of suffering major depressive symptoms and manifesting risk factors for suicide. Cross-sectional analyses were performed on data from 234 pregnant women enrolled in a prospective cohort study in Rio de Janeiro, Brazil. We found a higher likelihood of suicide risk was observed among women with higher arachidonic acid levels AA (20:4, n-6): OR=1.45, 95% CI 1.02-2.07 and adrenic acid levels AdA (22:4, n-6): OR=1.43, 95% CI 1.01-2.04. A higher likelihood of major depressive episode was also observed among women with higher AA levels OR=1.47, 95% CI 1.03-2.10 and AdA levels OR=1.59, 95% CI 1.09-2.32. Thus, higher serum levels of AA and AdA were associated with a greater likelihood of suicide risk and major depressive episode among pregnant Brazilian women. Previously we found that the 2004 FDA and EPA advisory for women to limit seafood consumption during pregnancy inadvertently creates risk of neurodevelopmental harm to the children. The children of mothers who ate seafood below the limit advised had greater risks of peer problems, poor prosocial behaviors and low verbal IQ. The work was conducted in collaboration with the ALSPAC study and examined nearly 9,000 children. These data have formed the core of an FDA model that reevaluates both the risks and benefits of seafood consumption in pregnancy, issued 15 JAN 2009. One goal has been to quantify the contribution of components of maternal diet to prenatal blood mercury level. Whole blood samples and information on diet and sociodemographic factors were col-lected from pregnant women (n = 4,484) enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). The blood samples were assayed for total mercury using inductively coupled plasma dynamic reaction cell mass spectrometry. Linear regression was used to estimate the relative contributions of 103 dietary variables and 6 sociodemographic characteristics to whole blood total mercury levels. We estimated that maternal diet accounted for 19.8% of the total variation in total blood mercury, with 44% of diet-associated variability (8.75% of the total variation) associated with seafood consumption (white fish, oily fish, and shellfish). Other dietary components positively associated with total blood mercury included wine and herbal teas, and components with significant negative associations included white bread, meat pies or pasties, and French fries. Thus although seafood is a source of dietary mercury, seafood appeared to explain a relatively small proportion of the variation in total blood mercury in our UK study population. Our findings suggest that limiting seafood intake during pregnancy may have a limited impact on prenatal blood mercury levels. Chronic excessive alcohol consumption depletes brain stores of omega-3 fatty acids which are necessary for optimal neural function. In our ongoing clinical trial of aggressive alcoholics, we determine if treatment with 2.8 g/d of omega-3 fatty acids will reduce 1) aggressive behaviors, 2) improve neurochemical measures of serotonergic function as well as other neurotransmitters associated with impulsivity and alcohol use 3) reduce measures of craving 4) reduce risk of relapse. This protocol enrolled 96 subjects with 100% tracking of data. Preliminary results indicate that anger is reduced by 33% (p<0.0008) in 12 weeks. An unexpected finding was the substantial reduction of heavy drinking days among recovering alcoholics. Those compliant with the protocol in the active group drank 3.2 days/90 while those compliant in the placebo group drank 17 days/ 90. This indicates that treatment with omega-3 fatty acids may have an effect size of 8.4. In comparison the effect size of Naltrexone, also used for relapse prevention is 0.2. These findings complement a placebo controlled clinical trial conducted with collaboration with Laure Buydens-Branchey, M.D., among polysubstance dependent subjects where omega-3 fatty acids reduced anger scores by 50% over 4 months. .

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