Research Article

Omega-3 Fatty Acids and Psychiatric Disorders

From Alternative Therapies in Women's Health | December 1999
By Jerry Cott, PhD

It has been suggested that depletion of omega-3 polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), impairs membrane function and may be of etiological importance in depression, aggression, schizophrenia, and other mental and neurological disorders.1-4 The American diet is low in omega-3 fatty acids, which are long-chain PUFAs found in plant and marine sources. Fish oil is very high in the PUFAs, DHA, and eicosapentaenoic acid (EPA). DHA can also be extracted from golden algae (Schizochytrium sp.). Alpha linolenic acid and other omega-3 fatty acids can be found in the seed oil of flax (Linum), black currant (Ribes), and Cannabis. Neuronal membranes contain high concentrations of DHA as well as arachidonic acid (AA); both of these essential fatty acids are crucial components of the phospholipid bilayer (each comprises approximately 25% of the phospholipid content).5 Neurotransmitter receptors lie embedded in the matrix of this membrane and their three-dimensional conformation is dependent on the fatty acids which give structure to the membrane.6

There is intriguing indirect evidence to support the possibility that lowered blood levels of certain fats may result in behavioral disturbances. Rapid lowering of blood lipids by HMG-CoA reductase inhibitors is associated with a large number of psychiatric disorders; 15% of psychiatric drug reactions were attributed to statins in a national Norwegian database.7 Reactions included aggression, nervousness, depression, anxiety, and sleeping disorders. Additional data are accumulating that suggest an association between PUFAs and serotonin, a neurotransmitter important in determining mood. Severely depressed patients have lower levels of the serotonin metabolite 5HIAA in CSF. Both cholesterol lowering therapies and low cholesterol levels have been associated with an increased risk of suicide;8-10 the prevailing theory holds that low cholesterol levels lower serotonin turnover. However, drug and diet therapies to lower cholesterol also alter essential fatty acid levels. Since essential fatty acid levels predict CSF 5-HIAA levels, and cholesterol does not,11,12 cholesterol levels may be a surrogate marker for changes in essential fatty acids.

Depression
It has been theorized that adequate long-chain PUFAs, particularly DHA, may reduce the development of depression just as they may reduce coronary artery disease.2 There appears to be an inverse relationship between the prevalence of major depression and the amount of fish consumed per capita worldwide.13 Patients with major depression have an increased ratio of AA to EPA in their plasma14,15 and erythrocytes.14-16 It was recently reported that fatty acid composition of phospholipid in erythrocyte membranes (thought to mirror neuronal membranes) of depressive patients showed significant depletion of total omega-3 PUFA, particularly DHA.17

Postpartum Depression
Depletion of maternal omega-3 fatty acids has been noted during pregnancy.18 The physiology of pregnancy involves the mobilization of PUFAs from maternal stores to the fetus, and supplementation with essential fatty acids may ensure adequate supplies for the needs of the mother and the developing fetus.19,20 Hornstra et al demonstrated that maternal essential fatty acids, especially DHA, progressively decrease during pregnancy.21 These decreased levels of DHA in plasma and erythrocytes may remain low for some time postpartum, particularly in lactating women. Thus it is possible that brain levels also are low during late pregnancy and the early postpartum period and that this maternal DHA depletion may contribute to postpartum depression.

Breast Milk and Infant Formula
Breast milk, unlike infant formula, has relatively high concentrations of DHA and EPA.22 The World Health Organization recommends that DHA and EPA be added to infant formulas. European infant formulas are routinely fortified with these fatty acids, but to date the FDA has not allowed the addition of either DHA or EPA to infant formulas sold in the United States. These omega-3 fatty acids are crucial in the development of the fetal and neonatal brain and nervous system.19 Intellectual development may also suffer in infants deprived of these fatty acids. A recent study found that infants who received formula supplemented with long chain PUFAs during their first four months performed better at 10 months of age on a problem-solving test than infants given the unsupplemented formula.23

Bipolar Disorder
Bipolar disorder, or manic-depressive illness, is a common neuropsychiatric illness with a high morbidity and mortality. Despite available mood-stabilizing drugs, including lithium and valproate, there are high rates of recurrence. All of the currently available mood-stabilizing drugs appear to inhibit neuronal signal transduction (or second messenger) systems, supporting the hypothesis that overactive cell-signaling pathways are involved in the pathological process underlying bipolar disorder.24-27 Biochemical studies have shown that high-dose therapy with omega-3 fatty acids leads to the incorporation of these compounds into the membrane phospholipids crucial for cell signaling.28,29 Phosphatidylinositol-associated second messenger activity is also suppressed. This mechanism is similar to the putative actions of lithium and valproate.30 The ingestion of large amounts of omega-3 fatty acids is associated with a general dampening of signal transduction pathways associated with phosphatidylinositol, AA, and other systems.29,31

A recent study by Andrew Stoll et al found that dietary supplementation with DHA and EPA showed marked mood-stabilizing activity in bipolar disorder.32 A four-month, double-blind, placebo-controlled study compared 15 one-gram capsules of fish oil daily (containing 9.6 g/d omega-3 fatty acids) to an olive oil placebo, as an adjunct to usual treatment in 30 patients with bipolar disorder. Participating subjects were men and women, 18 to 65 years old, who met DSM-IV criteria for bipolar disorder (types I or II), and were free of other medical and psychiatric illnesses. Patients were required to have had at least one manic or hypomanic episode within the past year, in order to enhance the power of the study to detect a difference between the two treatment groups within the study period. Forty percent of the study cohort had rapid-cycling symptoms, defined as four or more mood episodes in the year before enrollment in the study. Patients were permitted to continue with their outpatient psychiatrist or psychotherapist, but no new psychotherapeutic or pharmaceutical interventions were permitted. Subjects receiving other medications at entry continued to receive these medications at constant dosages (whether or not they were considered to be in the therapeutic range).

The 15 patients receiving 15 g/d of fish oil had mild dose-related gastrointestinal distress (nausea and loose stools) as the primary complaint. Also, "fishy" breath was occasionally noted. The omega-3 fatty acid-treated group had a significantly longer period of remission than the placebo group (P = 0.002). During the four-month trial, two of 14 patients relapsed in the fish oil group while nine of 16 relapsed in the placebo-treated group. Significant group differences in favor of fish oil were seen on the Hamilton depression scale, the Global Assessment Scale, and the Clinical Global Impression. No differences were seen on the Young Mania Rating Scale. The authors concluded that omega-3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

Schizophrenia
There is increasing evidence that oxidative stress injury contributes to the pathophysiology of schizophrenia, as indicated by increased lipid peroxidation products in plasma and CSF, and altered levels of antioxidants in chronic and drug-naive first-episode schizophrenic patients.33-35 An increase of plasma lipid peroxidation is also consistent with lower levels of polyunsaturated essential fatty acids of erythrocyte plasma membrane phospholipids36 as well as in the brain.37 Considerable effort has been directed toward determining the respective roles of increased oxidative stress (increased breakdown) vs. dietary deficiencies or defective metabolic pathways (reduced synthesis) on membrane fatty acid concentrations.5

AA and DHA levels are relatively depleted in the RBC membranes of chronic schizophrenic patients, compared to normal controls.38 In an uncontrolled study with 20 chronic patients showing primarily negative symptomatology, dietary supplementation for six weeks with 10 g per day of concentrated fish oil (MaxEPA) led to significant improvement in negative (alogia, flat affect, anhedonia, apathy, motor retardation) but not positive symptoms (hallucinations, disorganized thought) as rated by the Positive and Negative Syndrome Scale (PANSS). Improvement in clinical symptoms was related to increased levels of omega-3 fatty acids in RBC.39

Because membrane phospholipids play a critical role in neuronal signal transduction, oxidative damage of these lipids may contribute to the proposed altered neurotransmitter receptor-mediated signal transduction and thereby alter information processing in schizophrenia. This depletion is believed to result from an increased breakdown of these fatty acids rather than by impaired incorporation into membranes.40 It is conceivable that dietary supplementation with antioxidants (e.g., vitamins E and C, beta-carotene), and omega-3 fatty acids at the initial stages of illness may prevent further oxidative injury and thereby prevent further possible deterioration of associated neurological and behavioral deficits in schizophrenia.41

Additional studies with essential fatty acids are required for confirmation that dietary supplementation can affect the outcome of chronic and severe mental disorders. The National Institute of Mental Health has recently funded a larger study by Dr. Andrew Stoll at Harvard of fish oil supplementation in bipolar disorder, and the Stanley Foundation has recently initiated three separate clinical trials of fish oil in major depression, bipolar disorder, and schizophrenia. Although current evidence is preliminary, fish oil may have a promising future as a safe and effective treatment for psychiatric disorders.

Dr. Cott is a pharmacologist at the National Institute of Mental Health.

References:
1. Hibbeln JR, et al. Are disturbances in lipid-protein interactions by phospholipase-A2 a predisposing factor in affective illness? Biol Psychiatry 1989;25:945-961.

2. Hibbeln JR, Salem N Jr. Dietary polyunsaturated fatty acids and depression: When cholesterol does not satisfy. Am J Clin Nutr 1995;62:1-9.

3. Hillbrand M, et al. Investigating the role of lipids in mood, aggression, and schizophrenia. Psychiatr Serv 1997;48:875-876.

4. Hibbeln JR, et al. Do plasma polyunsaturates predict hostility and depression? World Rev Nutr Diet 1997;82:175-186.

5. Mahadik SP, Evans DR. Essential fatty acids in the treatment of schizophrenia. Drugs Today 1997;33:5-17.

6. Mitchell DC, et al. Why is docosahexaenoic acid essential for nervous system function? Biochem Soc Trans 1998;26:365-370.

7. Buajordet I, et al. Statins—the pattern of adverse effects with emphasis on mental reactions. Data from a national and an international database. Tidsskr Nor Laegeforen 1997;117:3210-3213.

8. Muldoon MF, et al. Lowering cholesterol concentrations and mortality: A quantitative review of primary prevention trials. BMJ 1990;301:309-314.

9. Neaton JD, et al. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med 1992;152:1490-1500.

10. Golomb BA. Cholesterol and violence: Is there a connection? Ann Intern Med 1998;128:478-487.

11. Hibbeln JR, et al. Essential fatty acids predict metabolites of serotonin and dopamine in CSF among healthy controls, early and late onset alcoholics. Biol Psychiatry 1998;44:235-242.

12. Hibbeln JR, et al. A replication study of violent and non-violent subjects: CSF metabolites of serotonin and dopamine are predicted by plasma essential fatty acids. Biol Psychiatry 1998;44:243-249.

13. Hibbeln JR. Fish consumption and major depression. Lancet 1998;351:1213.

14. Maes M, et al. Fatty acid composition in major depression: Decreased omega-3 fractions in cholesteryl esters and increased C20:4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids. J Affect Disord 1996;38:35-46.

15. Adams PB, et al. Arachadonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 1996;31(suppl): S157-S161.

16. Edwards R, et al. Omega-3 polyunsaturated fatty acids in the diet and in the red blood cell membranes of depressed patients. J Affect Disord 1998;48:149-155.

17. Peet M, et al. Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry 1998;43:315-319.

18. Otto SJ, et al. Maternal and neonatal essential fatty acid status in phospholipids: An international comparative study. Eur J Clin Nutr 1997;51:232-242.

19. Holman RT, et al. Deficiency of essential fatty acids and membrane fluidity during pregnancy and lactation. Proc Natl Acad Sci 1991;88:4835-4839.

20. Al MD, et al. Maternal essential fatty acid patterns during normal pregnancy and their relationship to the neonatal essential fatty acid status. Br J Nutr 1995;74:55-68.

21. Hornstra G, et al. Essential fatty acids in pregnancy and early human development. Eur J Obstet Gyn Reprod Biol 1995;61:57-62.

22. Willatts P, et al. Effect of long-chain polyunsaturated fatty acids in infant formula on problem solving at 10 months of age. Lancet 1998;352:688-691.

23. Stoll AL, Severus E. Mood stabilizers: Shared mechanisms of action at post-synaptic signal transduction and kindling processes. Harvard Rev Psychiatry 1996;4:77-89.

24. Berridge MJ, et al. Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J 1982;206:587-595.

25. Chen G, et al. Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. J Neurochem 1994;63:2361-2364.

26. Manji HK, et al. Modulation of protein kinase C isozymes and substrates by lithium: The role of myo-inositol. Neuropsychopharmacology 1996;15:370-381.

27. Medini L, et al. Diets rich in n-9, n-6 and n-3 fatty acids differentially affect the generation of inositol phosphates and of thromboxane by stimulated platelets, in the rabbit. Biochem Pharmacol 1990;39:129-133.

28. Sperling RI, et al. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 1993;91:651-660.

29. Kinsella JE. Lipids, membrane receptors, and enzymes: Effects of dietary fatty acids. J Parenteral Enteral Nutrition 1990;14:200s-217s.

30. Tappia PS, et al. The influence of membrane fluidity, TNF receptor binding, cAMP production and GTPase activity on macrophage cytokine production in rats fed a variety of fat diets. Mol Cell Biochem 1997;166:135-143.

31. Stoll AL, et al. Omega-3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-412.

32. Salem N. Omega-3 fatty acids: Molecular and biochemical aspects. In: New Protective Roles for Selected Nutrients. New York: Alan E. Liss, Inc.; 1989; 109-228.

33. Mahadik SP, Mukherjee S. Free radical pathology and antioxidant defense in schizophrenia: A review. Schizophr Res 1996;19:1-17.

34. Mukerjee S, et al. Impaired antioxidant defense at the onset of psychosis. Schizophr Res 1996;19:19-26.

35. Mahadik SP, et al. Elevated plasma lipid peroxides at the onset of nonaffective psychosis. Biol Psychiatry 1998;43:674-679.

36. Rotrosen J, Wolkin A. Phospholipid and prostaglandin hypothesis of schizophrenia. In: Psychopharmacology: The Third Generation of Progress. Meltzer HY, ed. New York: Raven Press; 1987:759-764.

37. Horrobin DF, et al. Fatty acid levels in the brains of schizophrenics and normal controls. Biol Psychiatry 1991;30:795-805.

38. Peet M, et al. Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical effects of dietary supplementation. Prostaglandins Leukot Essent Fatty Acids 1996;55:71-75.

39. Laugharne JD, et al. Fatty acids and schizophrenia. Lipids 1996;31(Suppl):S163-S165.

40. Peet M, et al. Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients. J Psychiatr Res 1995;29:227-232.

41. Mahadik SP, Scheffer RE. Oxidative injury and potential use of antioxidants in schizophrenia. Prostaglandins Leukot Essent Fatty Acids 1996;55: 45-54.

*These statements have not been evaluated by the Food and Drug Administration.

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