This project examines the question of whether a low nutritional status of essential fatty acids increases the predisposition to psychiatric disorders including depression and schizophrenia or to pathological behaviors such as homicide and suicide from several perspectives. Clinical interventional trials are currently being conducted in adult populations among aggressive alcoholics, women with depression during pregnancy and schizophrenics. These studies have, in part, been designed after discovering large differences in the prevalence rates of several psychiatric disorders when comparing populations with high or low measure of seafood consumption and omega-3 fatty acid tissue concentrations in epidemiological studies. The residual effects of these nutritional inadequacies in early development may also contribute to an increased predisposition toward psychiatric disorders. Three developmental outcome studies are discussed below. Mothers can become depleted of omega-3 essential fatty acids during pregnancy when their dietary intake is inadequate. Dietary deficiencies may increase the risk of depressive symptoms for the mothers. 1) A cross-national comparison of 23 countries indicated that low consumption of seafood strongly predicted a 50-fold increased risk for postpartum depression. Low concentrations of DHA in mothers' breast milk were also associated with a similar increase in risk. 2) The dietary intake of omega-3 fatty acids during pregnancy was examined among nearly 14,000 women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). In clear dose response relationships deficient intakes was associated with nearly a doubling of the risk of depressive symptoms (EPDS >12) at 32 weeks gestation (p<1.4 X 10 -17) and 18 weeks gestation and at both 8 weeks and 8 months postpartum. Findings were robust after rigorous examination of potential confounding factors. 3) Two intervention trials, of omega-3 fatty acids among women with depression during pregnancy and in the postpartum, are being currently conducted in collaboration with Marlene Freeman, MD at the University of Arizona. Deficient intake of omega-3 essential fatty acids during early development may also have adverse residual effects on the behaviors of children. 1) In collaboration with the ALSPAC study, we found that deficient intake of omega-3 fatty acids during pregnancy were related to a doubling of the risk of adverse behavioral disorders among children at both 3.5 and 7 years of age. A dose response relationship, similar to the increased risk of postpartum depression, predicted such parameters as increased risk of conduct disorders: fighting, lying, stealing, disobedience, which are well recognized risk factors for future sociopathic and criminal behaviors. These data are still being evaluated to determine the contribution of other variables such as socioeconomic status. 2) In an animal model we have documented long-term adverse residual effects of infant formulas, which are deficient in DHA and another essential fatty acid, arachidonic acid. Supplementing the formulas of infant rhesus monkeys with DHA and AA produced improvements in motor and visual development in as little as 5 days. After 6 months, all these animals received diets rich in these nutrients to restore their body stores. Despite up to 3.5 years of nutritional repletion these animals had residual deficits in the ability to regulate their autonomic nervous system as measured by differences in heart rate variability. A poor capacity to regulate autonomic nervous system reactivity, and measures of low heart rate variability, have been reported to predict future sociopathy. 3) In order to determine if these findings are applicable to human populations we are following up children, who are now 10 years old who had been fed either standard infant formulas or formulas supplemented with DHA and AA as part of a controlled intervention trial. This study in being conducted in collaboration with Dr. Peter Willats at the University of Dundee, Scotland, who has been funded for the study with an Independent Investigators Award from NARSAD, the National Association for Research in Schizophrenia and Depression. Earlier studies conducted by our group had indicated that low plasma concentrations of omega-3 fatty acids predicted low concentrations of cerebrospinal fluid 5-HIAA, a marker of serotonin concentrations in the brain. Since low concentrations of 5-HIAA have been linked to impulsive violence and homicide, we have examined the role of omega-3 intake as a mediating risk factor for aggression and violence. 1) In a cross-national analysis across 26 countries, we found higher rates of homicide mortality were correlated to lower rates of seafood consumption. The diagnosis of death due to homicide is subject to fewer cross-national cultural differences than are other behavioral outcomes. These data also are consistent with observational and interventional data for violence and hostility published by other investigators. 2) In collaboration with Dr. Carlos Iribarren, we examined the dietary intake of omega-3 fatty acids and behavioral correlates among the 4,000 subjects in the CARDIA trial. We found that among all categories of subjects, white men, white women, black men and black women, lower intake of DHA and other omega-3 fatty acids predicted a doubling of the risk of reporting clinically significant measures of hostility. These findings were robust after evaluation of confounding factors. 3) In an interventional trial conducted in collaboration with Dr. Muldoon at the University of Pittsburgh, subjects with hypercholesterolemia were given either Simvistatin, (a cholesterol lowering drug) or a placebo for 8 weeks. We quantified changes in mood, cognition and plasma concentrations of essential fatty acids. Treatment with Simvistatin lowered total fatty acid concentrations, but spared DHA and AA. The relationship between the sparing of these essential fatty acids and improvements or decrements in mood and cognition are still under examination. 4) In an interventional trial conducted in collaboration with Jay Kaplan at Bowman Grey University, adult Rhesus monkeys were fed each of four different diets for 6 months. Initial analyses indicate that there is a dose-dependent increase in aggression closely related to lower concentrations of the omega-3 fatty acids eicosapentaenoic acid and DHA as measured in plasma. 5) An interventional trial in collaboration with a Fulbright scholar has received a high priority for funding as an R0-1 grant. A randomized trial of omega-3 fatty acids to reduce aggression among Thai school children will be conducted. The key questions our ongoing clinical trial are to assess if treatment of aggressive alcoholics with 2.8 g/d of omega-3 fatty acids will reduce 1) aggressive behaviors, 2) improve neurochemical measures of serotonergic function 3) improve cardiovascular measures thought to be associated with depressive and violent behaviors.
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