Special Feature

More on Omega-3 Fatty Acids and Psychiatric Disorders

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 depletions 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 (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.