OMEGA 3 ESSENTIAL FATTY ACIDS
Excerpt from:
Lake, J. Omega 3 Essential Fatty Acids. In Lake, J and Spiegel, D (ed.),
Clinical Manual of Complementary and Alternative Treatments in Mental Health.
Washington, DC: American Psychiatric Press, Inc. 2006.
It has been established since the 1930s that certain fatty acids are required for normal human fetal and neonatal development (Uauy et al), and that an inadequate supply of these “essential” fatty acids during critical developmental periods results in pathological changes in immune function, degenerative changes in the lungs, liver and kidneys, and abnormalities in CNS maturation. It has been hypothesized that chronic deficiencies in dietary essential fatty acids may result in an increased incidence of multiple sclerosis, arthritis, enteritis, immune system dysfunction, heart disease, cancer, schizophrenia, bipolar disorder, diabetes and many other diseases (Rudin 1982).
Mechanism of Action of Essential Fatty Acids in Normal Brain Development and Function
To clearly understand the role of EFAs in brain structure and function, it is important to briefly review phosopholipid metabolism. Phosopholipids are comprised of a 3-carbon glycerol backbone with a terminal phosphorus group. The final step in the synthesis of phosophlipids in nerve cell membranes is the attachment of highly unsaturated fatty acids by phospholipases to the glycerol molecule. The four essential fatty acids that are the normal structural elements of brain phospholipids are DGLA, and arachidonic acid (the n-6 EFAs), and ecosapentanoic acid (EPA) and docosahexanoic acid (DHA) (the n-3 EFAs).
DHA is an n-3 fatty acid that is essential to normal fetal and neonatal maturation of the brain where it is synthesized into phospholipids that are fundamental components of nerve cell membranes. Infants who are not provided adequate amounts of necessary EFAs in utero or during the neonatal period are at risk for numerous medical complications including peripheral neuropathy, abnormal visual development, and reduced slow-wave sleep if the deficiency is not corrected early. If the required EFAs are not present in adequate amounts, other fatty acids will be incorporated into nerve cell membranes, possibly predisposing the infant to a range of medical and psychiatric disorders. Pre-term infants are especially at risk, as they do not receive intrauterine DHA during the third trimester, and if they are not breast-fed or provided formula containing DHA, they will be susceptible to many disorders. The other n-3 fatty acid, EPA, is also essential for normal brain functioning. EPA plays a central role in maintenance of nerve cell membranes from early development through adulthood.
Fatty acids are precursors of prostaglandins-the body's principle regulatory molecules. A consequence of this fact is that a diet comprised of relatively more n-6 versus n-3 EFAs will adversely affect the balance of opposing processes in normal human physiology. The n-6 EFAs are crucial to synthesis of cytokines that mediate inflammation, including several interleukins, tumor necrosis factor alpha (TNF-alpha), and interferon-gamma (Maes, 1997). In contrast, diets high in the n-3 EFAs are correlated with reduced production of pro-inflammatory cytokines (Caughey et al, 1996). Other factors that increase levels of pro-inflammatory cytokines include infection, trauma, allergens, and toxins (Logan 2003). The anti-inflammatory role of n-3 PUFAs is well documented and research findings suggest that both DHA and EPA suppress cell-mediated immune responses (Logan 2003; Simpoulos 2002) The potent immunomodulatory activities of n-3 PUFAs affect the type and amount of eicosanoids (inflammatory precursors) manufactured in the body, in addition to acting upon intracellular signaling pathways and influencing transcription factor activity and gene expression (Simopoulos 2002). In this context n-3 fatty acids obtained from fish oil are believed to be more biologically potent than n-3 PUFAs obtained from flaxseed oil and other plant sources (Simopoulos 2002).
The Phospholipid Deficiency Hypothesis-A Model for the Pathogenesis of Schizophrenia and Other Psychiatric Disorders
It has been suggested (Rudin 1982) that widespread deficiencies of n-3 PUFAs in industrialized countries have resulted from trends in dietary preferences and food processing methods starting in the early 1900s, and that increased prevalence rates of numerous medical and psychiatric disorders in industrialized countries are a result. The phospholipid deficiency hypothesis states that increases in the ratio of n-6 to n-3 EFAs in the average industrialized diet have resulted from increased consumption of plant-derived products high in n-6 EFAs concurrent with reduced consumption of food sources rich in n-3 EFAs. According to the hypothesis, the relative shift in fatty acid consumption has resulted in the increased prevalence of medical and psychiatric disorders mediated by chronic inflammatory changes including heart disease and major depressive disorder (Severus et al 1999). The pathophysiology of depression, schizophrenia and possibly other psychiatric disorders, may be associated with excessive production of pro-inflammatory cytokines including interleukin-1B, -2, -6, interferon-, and tumor necrosis factor alpha (see above). These cytokines have both direct and indirect effects on the CNS by lowering the availability of neurotransmitter precursors and altering biosynthetic pathways of neurotransmitters implicated in psychiatric disorders (Logan 2003; Simopoulos 2002). Epidemiological findings suggest that many disorders result from pathological effects of chronic EFA deficiencies on phospholipid metabolism that affect cell membrane function in the brain and other major organs (Severus 1999; Rudin 1982; Horrobin 1996). The hypothesis asserts that disorders resulting from deficiencies of dietary essential fatty acids mimic a general deficiency in the B vitamins (especially B-6, pyridoxine) because many B vitamins are essential cofactors required for conversion of essential fatty acids into prostaglandins. Thus, the same medical and psychiatric symptoms that potentially result from chronic vitamin B deficiencies are postulated consequences of chronic essential fatty acid deficiencies. Disorders associated with B vitamin deficiencies include neuropathies, dermatoses, enteritis, diabetes, immune system dysfunction, and numerous psychiatric syndromes including schizophrenia and depressed mood.
The Membrane Phospholipid Model May Help Explain the Pathogenesis of Many Psychiatric Disorders
Horrobin (Horrobin, 1996; 1998) has proposed a “membrane phosopholipid” model of schizophrenia, which argues that abnormal metabolism of phosopholipids resulting from both genetic and environmental factors manifests as symptoms of chronic psychosis, and possibly other severe psychiatric disorders. The membrane phosopholipid model may provide a unifying conceptual framework for understanding not only schizophrenia, but also bipolar disorder, and possibly dyslexia, schizotypal personality disorder, other schizophrenia-like syndromes, and possibly other psychiatric disorders. The membrane phosopholipid hypothesis is compatible with the dominant paradigm in contemporary biological psychiatry, which ascribes the etiology of psychiatric disorders to dysfunction at the level of neurotransmitters and their receptors. The synthesis and breakdown of phosopholipids in the brain is integral to normal growth of axons and dendrites, as well as the formation of new synapses and the pruning of old ones. Phospholipids comprise approximately 25% of the dry weight of the human brain, and together, arachidonic acid (AA) and docosahexanoic acid (DHA) account for roughly half of total brain phospholipids. Brain phospholipids are essential for fluidity of nerve cell membranes and provide the physicochemical environment in which cell-membrane associated proteins are embedded, influencing their tertiary structure and therefore their capacity to function as neurotransmitter receptors. Abnormal phospholipid metabolism in nerve cell membranes indirectly affects the functional integrity of neurotransmitter receptors and intra-neuronal signaling systems that are believed to be centrally involved in the pathogenesis of schizophrenia, bipolar disorder and other psychiatric disorders. According to the membrane phospholipid hypothesis, an inadequate dietary supply of EFAs, or metabolic factors interfering with the normal conversion of parent EFAs (LA or ALA) into DHA or EPA, has the end effect of restricting the supply of n-3 EFAs to the brain for incorporation into nerve cell membranes resulting in abnormal phospholipid composition and sub-optimal functioning of a range of membrane-based neurotransmitter systems.
According to the hypothesis a “spectrum” of psychiatric syndromes is associated with structural and functional abnormalities in neuronal membranes, and the specific symptoms and their severity are expressions of the magnitude and type of metabolic errors leading to abnormal phospholipid metabolism. Severe psychiatric syndromes like schizophrenia develop when genetic errors of metabolism resulting in chronic brain deficiencies of dietary EFAs are combined with other metabolic abnormalities that result in errors of EFA incorporation into phosopholipid membranes or abnormally high rates of removal of EFAs from nerve cell membranes by phospholipases. Less severe psychiatric syndromes may result from chronic dietary EFA deficiencies or metabolic errors interfering with the normal biosynthetic pathways that incorporate EFAs into nerve cell membranes. Examples of the latter include dyslexia, which is often associated with schizotypal personality-a mild schizophrenia-like syndrome-and possibly attention-deficit disorder (Stevens et al, 1995). In contrast to disorders resulting from abnormalities of phospholipid synthesis, bipolar disorder may result from an abnormally high rate of remodeling of nerve cell membranes affecting the functional integrity of specific neurotransmitter receptors or cell signaling systems. According to the hypothesis, remodeling errors are mediated by excess activity of phosopholipase A2, the enzyme that removes EFAs from nerve cell membranes. The following research findings are consistent with the membrane phospholipid hypothesis (Horrobin 1996; 1998):
Review of research on n-3 fatty acids in mental health care: Bipolar Disorder
Case reports and the findings of one small double-blind trial suggest that n-3 EFAs improve both depressive and manic symptoms in bipolar patients, possibly by inhibiting the activity of CNS phospholipases, thereby reducing the release of unsaturated EFAs from nerve cell phospholipids, and limiting the production of specific prostaglandins (eg, PGE1) that are known to be associated with mania or depression. It has been postulated that lithium, dopamine antagonists and serotonin blocking agents are effective treatments of mania through a similar mechanism of action that corrects “over-activity” in cell membrane signal transduction processes.
Until now there have been no large studies on the efficacy of n-3 PUFAs in the treatment of bipolar disorder, and all studies done to date have been designed to assess the efficacy of n-3 EFAs in combination with mood stabilizing medications but not n-3 fatty acids alone. However, findings from one small double-blind study (Stoll et al, 1999) suggest that Bipolar patients taking n-3 fatty acids alone remain in remission significantly longer than matched patients receiving a placebo. In this 4-month placebo-controlled double blind study, 30 bipolar patients were treated with a combination of n-3 EFAs (6.16 g EPA plus 3.36 g DHA for a total dose of 9.6gm/d) or placebo (olive oil) in combination with their usual mood stabilizing medications (including lithium, valproic acid, carbamazepine, and others). Significantly, post-hoc analysis determined that four out of eight patients who took only n-3 fatty acids remained in remission significantly longer than three patients who received only placebo. Further, among the remaining 22 patients taking mood stabilizing drugs, those treated with n-3 EFAs performed significantly better on all outcome measures compared to patients in the placebo arm. In a 4 month double-blind placebo-controlled study, 120 Bipolar patients were randomized to n-3 EFAs (ethyl ester EPA) 6g/day versus placebo in combination with their conventional mood stabilizers (Keck et al 2002). The response rates in the n-3 EFA and placebo groups were not significantly different.
Review of research on n-3 fatty acids in mental health care: Schizophrenia
Case reports (Puri et al 2002; Su 2001) and small double-blind trials (Laugharne et al, 1996; Mellor et al1995; Peet et al1997) have demonstrated sustained improvements of both positive and negative symptoms in chronic schizophrenic patients who consume certain n-3 EFAs and who are not being treated with conventional antipsychotic medications. Findings of a small 4-month open study suggest that combining EPA and DHA with antioxidant vitamins reduces the severity of both positive and negative symptoms and improves overall quality of life (Arvindakshan 2003). Findings of studies evaluating the putative antipsychotic efficacy of n-3 EFAs as an adjunctive treatment of schizophrenia have been inconsistent. In a 12 week controlled trial schizophrenic patients randomized to adjunctive EPA experienced greater reductions in psychotic symptoms compared to those who received only DHA or placebo while continuing on a conventional antipsychotic (Peet et al 1997). All patients remained on conventional antipsychotics throughout the study. In a large 3 month controlled study (N=115) schizophrenics who had been refractory to conventional antipsychotics were randomized to 1, 2 or 4 g/day of ethyl-EPA versus placebo while remaining on conventional drugs (Peet et al 2002). Schizophrenics taking EPA concurrently with clozapine experienced the most significant and sustained improvements at doses of 2g/day, however a differential effect was not observed in patients who combined EPA with other antipsychotic drugs. The finding of a specific augmentation effect with clozapine is consistent with Horrobin's membrane phospholipid hypothesis (see above). In another controlled study sustained reductions in psychotic symptoms and tardive dyskinesia were observed after 3 months of augmentation with purified EPA (ethyl EPA 3g/day) (Emsley 2002). However, another double-blind placebo-controlled study found no differences in response between EPA (3gm/day) and placebo in a group of 87 schizophrenics concurrently taking antipsychotic medications (Fenton et al, 2001). In contrast to earlier studies, those patients were treated for residual psychotic symptoms, and were not treated while in the early acute phase of illness.