Insufficient intake of essential fatty acids (EFAs) may contribute to the pathogenesis of mental diseases, while their supplementation may relieve some symptoms, according to researchers who attended the National Institutes of Health (NIH) Workshop on Omega-3 Essential Fatty Acids and Psychiatric Disorders held in Bethesda, Md., in September 1998.
"This is the first time researchers in this field have been brought together," said Joseph Hibbeln, M.D., National Institute on Alcohol(Drug information on alcohol) Abuse and Alcoholism (NIAAA), who organized the workshop. Other organizers were Jerry Cott, Ph.D., National Institute of Mental Health (NIMH), Sahebarao Mahadik, Ph.D., Medical College of Georgia, Augusta, and the NIH Offices of Dietary Supplements and Research on Women's Health.
Despite having long established that omega-3 fatty acids are highly concentrated in neurosynaptic membranes, Hibbeln said that researchers have only recently considered the physiologic effects of these brain-specific nutrients. These include the pathologic effects of their deficiency on neural and mental functioning.
The EFAs, essential components of the diet that are not synthesized in the body, are ubiquitous in immune and anti-inflammatory response mechanisms and in oxidative cell injury defense. It is in these roles, Cott posited, that EFA deficiency might contribute to the well-known association of depression with coronary artery disease. Depression can follow from the emotional stress of myocardial injury and can exacerbate cardiac illness (Frasure-Smith et al., 1995). However, Cott suggested that lowered EFA levels could predispose an individual to both the myocardial injury and the depression.
"Epidemiological studies in various countries and in the United States in the last century suggest that decreased omega-3 fatty acid consumption correlates with increasing rates of depression," Cott wrote in the initial proposal of the workshop. "There is evidence that deficiency of long-chain, omega-3 polyunsaturate may contribute to symptoms of schizophrenia, alcoholism, multiple sclerosis and postpartum depression. Adequate long-chain polyunsaturated fatty acid [LC-PUFA], particularly docosahexaenoic acid(Drug information on docosahexaenoic acid) [DHA], may reduce the development of depression and schizophrenia just as omega-3 polyunsaturated fatty acids may reduce coronary artery disease."
Mahadik has examined the possibility of oxidative cell injury underlying the pathology of first-episode psychosis; noting such injury involves "predominately and selectively" the neuronal membrane phospholipids that are highly enriched in EFAs, particularly arachidonic acid [AA] and DHA, which are most sensitive to free radical-mediated peroxidation.
"Since AA and DHA are critical for brain and behavioral development and for maintenance and neurotransmitter function throughout life," Mahadik reasoned, "their levels may play critical roles in etiogenesis as well as pathogenesis of several neurological and major mental disorders, particularly bipolar disorder and schizophrenia, both of which seem to involve abnormal neurodevelopment."
Michael Maes, M.D., Ph.D., of the Clinical Research Centre for Mental Healthcare, Antwerp, Belgium, was a presenter at this workshop. He and Ronald Smith, M.D., described in a Biological Psychiatry editorial how EFA deficiency could lead to depression through effects on immune function and production of cytokines (Maes and Smith, 1998).
Maes and Smith point to evidence that depression is accompanied by, and possibly follows from, an "acute phase" response in which there is an increased secretion of eicosanoids such as prostaglandins, and of proinflammatory cytokines.
"Inflammatory cytokines or lipopolysaccharide given to animals or humans provoke an extensive set of symptoms and signs similar to, if not identical to, those found in major depression," wrote Maes and Smith. They added, "Cytokines may be common mediators of external stressors [that is, psychosocial stressors such as adverse life events] and internal stressors [that is, organic disorders] that are known to play a role in the etiology of depression."
One of the indicators of cytokine involvement in the pathogenesis of depression offered by Maes and Smith is the suppression of cytokine release from human blood monocytes by antidepressants. This suggests, they wrote, "that these drugs have potent anti-inflammatory activities."
A more fundamental method of countering the proinflammatory cytokine effects proposed by Maes and others at this workshop, however, is to increase the omega-3 PUFA from sources such as fish oil in relation to the consumption of omega-6 PUFA from vegetable oils (Table). "The increased incidence rate of major depression since 1913 may be explained by a sharp increase in the rate of omega-6/omega-3 PUFAs in the diet," wrote Maes and Smith.
Smith has previously suggested that the increased omega-6/omega-3 PUFA ratio of the Western diet, replacing omega-3 fatty acids from fish, wild game and leaves with omega-6 fatty acids from seeds, has contributed to the increased incidence of cardiovascular and inflammatory disorders (Smith, 1991).Clinical Effects of Diet
Hibbeln reported investigating a possible correlation of EFA status with occurrence of suicide in 50 patients hospitalized for suicide attempts. Thirty of the patients had a primary diagnosis of depression, 20 had another primary diagnosis. Hibbeln found that for those not having a primary diagnosis of depression, a higher plasma concentration of eicosapentaenoic acid (EPA) predicted "strikingly" lower scores, indicating less suicidal risk across six different psychological rating scales. No similar correlation was found with other fatty acids, including DHA. Although this was not a prospective study of dietary intervention, Hibbeln concluded, "These data do suggest that some subgroups of suicidal patients may reduce their suicidal risk with the consumption of EPA."
In a previous investigation, Hibbeln and Norman Salem Jr., Ph.D., acting scientific director of NIAAA, had implicated the depletion of DHA as a probable etiologic factor for major depression (Hibbeln and Salem, 1995). Their study was the basis for Rhian Edwards, Ph.D. candidate, department of psychiatry, University of Sheffield, England, comparing measurements of red blood cell membrane (RBCM) fatty acid levels in 10 depressed patients and 14 matched healthy controls. Edwards reported finding that the patients with depression had significantly lower RBCM levels of both DHA and EPA. This correlated, he indicated, with a lower mean dietary intake of DHA and, generally, of other omega-3 EFAs and a higher omega-6 EFA intake than those patients without depression.
Edwards acknowledged that the insidious onset of depression and the limitations in assessing diet make it difficult to establish a causal relationship. He concluded, however, "the role of diet and DHA/EPA supplementation in major depression warrants further investigation, as the findings raise the possibility that depressive symptoms may be alleviated by omega-3 EFA supplements."
Jeffrey Yao, Ph.D., Veterans Administration Medical Center, Pittsburgh, described recent evidence that altered membrane structure and function of red blood cells and platelets are "unequivocally" present in patients with schizophrenia. Specifically, according to Yao, there are decreased amounts of linoleic acid and AA in the RBCM of patients with schizophrenia during treatment with antipsychotic medication and in drug-free periods.
Malcolm Peet, M.D., University of Sheffield, added that epidemiologic evidence suggests a correlation between national outcome figures for schizophrenia and the proportion of polyunsaturated to saturated fat in the national diet. Peet previously correlated dietary omega-3 fatty acid levels with the severity of schizophrenic symptoms, and now related two new studies of omega-3 EFA supplementation as an adjunct to antipsychotic medication. The dietary supplementation, Peet said, "led to significant clinical improvement in treatment-resistant patients." In one of the two double-blind studies, Peet recounted, EPA-but not DHA-was found to be a useful adjunct to antipsychotic medication.
Andrew Stoll, M.D., department of psychiatry, Harvard University, reported finding high-dose omega-3 fatty acid supplementation to be helpful in treating patients with unstable bipolar disorder. Stoll previously investigated the utility of choline to attenuate cell signaling through the phosphatidylcholine system (Stoll et al., 1996), which he hypothesized can become heightened in lithium(Drug information on lithium)-resistant patients after lithium inhibits the phosphatidylinositol second messenger system (Berridge et al., 1982).
With evidence that omega-3 fatty acids can also inhibit hydrolysis of membrane phospholipids such as phosphatidylinositol, and may thus inhibit receptor-linked G-protein signal transduction, Stoll's group undertook a four-month controlled trial comparing high-dose omega-3 fatty acids (9 gms daily) with olive oil(Drug information on olive oil) placebo in 30 patients with bipolar disorder.
Stoll reported that in contrast to the recurrence of symptoms in seven of 15 patients (46.7%) receiving placebo, only one of the 15 patients (6.7%) receiving the omega-3 fatty acids supplementation had breakthrough mood symptoms. His data analysis indicated, further, that the patients receiving the omega-3 fatty acids had a significantly longer period of remission than those receiving placebo; and, by the end of the study period, demonstrated greater improvement on both the Clinical Global Impression and the Hamilton Depression Scales scores.
"Omega-3 fatty acids represent a new class of membrane-active agents capable of altering signal transduction pathways," Stoll concluded. "This study provides additional evidence of aberrant postsynaptic signal transduction mechanisms in the pathophysiology of bipolar disorder, and may herald the advent of a new class of rationally designed mood-stabilizing drugs."
Stoll's assessment was supported by evidence presented by Burton J. Litman, Ph.D., NIAAA, in the workshop section examining EFAs and cellular signal transduction. Litman described DHA-containing phospholipids potentiating receptor activation through G-protein signaling pathways. "Many neurotransmitter receptors implicated in the pathophysiology of affective disorders are members of the superfamily of G-protein-coupled receptors," he explained; and so modulation of G-protein mediated signal transduction may underlie mechanisms of antidepressants as well as mood stabilizers.Additional EFA Investigations
Other presentations at the workshop included investigations of effects of EFA supplementation on attention and cognition, and assessments of the importance of EFAs in early development. Anton Llorente, Ph.D., of Baylor University, administered 200 mg DHA or placebo daily to 140 women in late-stage pregnancy to ascertain the effect on postpartum depression. This population did not present sufficient depression to distinguish severity of symptoms between groups. However, Llorente did demonstrate with the Stroop Interference Test, a measure of alterations in formation processing, that the supplement improved cognitive capacity in postpartum women without depression.
Two separate evaluations of EFA intervention for attention-deficit/hyperactivity disorder (ADHD) failed to show therapeutic effect for this condition. Jay Burgess, Ph.D., of Purdue University, compared LC-PUFA supplementation to an olive oil placebo in 50 children with ADHD. He found an indication of benefit on some behavioral assessments, but not across all measures. Robert Voigt, M.D., of the Mayo Clinic, provided DHA supplements (345 mg daily) or placebo to 63 children with ADHD who had been successfully treated with stimulant medication. After four months of supplementation, the stimulant dosage was halved. Although Voigt found the DHA to be no more useful than placebo in sustaining clinical effect with reduced dosage of stimulants, his group is now assessing whether there was benefit demonstrated in any subpopulation.
Martha Neuringer, Ph.D., from the Oregon Health Sciences University, in Portland, Ore., and the Oregon Regional Primate Research Center, reported that in rhesus monkeys as well as human infants, diets low in omega-3 EFAs result in lowered DHA levels in the cerebral cortex and retina. Although it has been difficult to assess whether the lower omega-3 EFA status correlates with cognitive development, Neuringer indicated that it has been associated with changes in visual development, including abnormalities in retinal function, slower development of visual acuity and a longer visual fixation that relates to slower visual processing.
Neuringer said that the effects of early omega-3 EFA status on other behavioral domains such as sleep patterns, temperament, emotional reactivity and response to stress remain largely unexplored. "There is a need for more comprehensive and long-term studies in both humans and animal models to understand the influence of dietary fatty acids on development as well as on later behavior," she concluded.
A note of caution was expressed by Richard Nakamura, Ph.D., acting deputy director, NIMH, who presented an introduction to the workshop and later discussed the findings with Psychiatric Times. Nakamura said that while NIMH is interested in new ideas about causes and treatments of mental disorders, "the information being provided at this conference could not be interpreted as more than suggestive."
Nakamura indicated that NIMH is receptive to applications for further research into the role of EFAs in psychiatric disorders, but is not now setting aside funding specifically for this area. He emphasized that with only preliminary studies, psychiatric patients should be cautioned against interrupting treatment with proven medications; and, if they choose to take EFA supplements, should be advised that the quality of purity in these dietary supplements is not regulated in the same manner as medication products.