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Fourteen clinical trials in the past 3 years have examined the potential of omega-3 fatty acids in treating psychiatric disorders. Preliminary findings in at least 700 patients suggest that:
- omega-3 fatty acids used as adjuncts or monotherapy appear well-tolerated and safe in psychiatric disorders
- efficacy data vary by disorder
- the two marine omega-3 fatty acids may differ in efficacy.
Although we cannot offer specific guidance for using omega-3 fatty acids at this time, we can update you on recent trials of these “fish oils” in depression, bipolar disorder, schizophrenia, and other psychiatric disorders.
Treating depression
Prevalence rates of major depression1,2 and suicidal ideation3 decrease in populations as fish consumption increases. Some studies4,5 have shown omega-3 fatty acid deficiency in erythrocyte membranes and serum of depressed patients. This putative deficiency has been hypothesized to lead to:
- alterations in membrane fluidity, which affect monoamine (particularly serotonin) neurotransmission6,7
- an imbalance between omega-6 and omega-3 fatty acids, which affects the inflammatory response system (Box).5-12
- Nemets et al. 13 Twenty patients with recurrent major depression taking maintenance antidepressants were randomly assigned to adjunctive ethyl-EPA, 2 grams/d, or placebo for 4 weeks. Patients given ethyl-EPA showed significantly greater improvement than the placebo group in depressive symptoms, as measured by the Hamilton Rating Scale for Depression (HRSD).13
- Peet and Horrobin. 14 Seventy depressed patients taking antidepressants were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo for 12 weeks. Only the group taking ethyl-EPA, 1 gram/d, showed significantly greater improvement than the placebo group.
- Su et al. 15 Twenty-eight patients taking antidepressants for major depression were randomly assigned to adjunctive omega-3 fatty acids (4.4 grams/d of EPA plus 2.2 grams/d of DHA) or placebo. After 8 weeks, depressive symptoms improved significantly more in the adjunctive treatment group.
- Marangell et al. 16 Thirty-six patients with mild to moderate depression (defined as a score of 17 on the 28-item HRSD) were randomly assigned to monotherapy with DHA, 2 grams/d, or placebo. Response rates after 6 weeks were comparable (27.8% with DHA versus 23.5% with placebo).
Polyunsaturated fatty acids contain a hydrocarbon chain with two or more double bonds. They are divided into families based on the location of their first double bond relative to the methyl end carbon—the “omega” carbon. Polyunsaturated fatty acids of interest in psychiatry include:
- omega-6 fatty acids—arachidonic acid (AA) and linoleic acid (LA)
- omega-3 fatty acids—eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA).
Omega-3 and omega-6 fatty acids are called “essential” because they must be obtained from dietary sources. EPA and DHA are derived largely from wild—not farm-raised—fish, including sea bass, mackerel, pike, sardines, salmon, trout, herring, and cod liver oil.8 ALA, a precursor to both EPA and DHA, is derived from plant sources such as flaxseed oil, canola oil, walnuts, and soybean oil.
Polyunsaturated fatty acids, particularly AA and DHA, are important components of the phospholipid bilayer of neuronal cell membranes.They increase the ability of phospholipids to move “fluidly” within the membrane and modulate neurotransmission6,7 and signal transduction pathways9,10 thought to be important in psychiatric disorders. They also are precursors for eicosanoid molecules (such as prostaglandins and leukotrienes) and cytokines. Thus, an imbalance favoring omega-6 fatty acids over omega-3 fatty acids may lead to overproduction of pro-inflammatory cytokines.11
Omega-3 fatty acids are thought to be beneficial in numerous inflammatory and cardiovascular diseases. The American Heart Association’s dietary guidelines include dietary sources of omega-3 fatty acids as part of a healthy diet.12 Unfortunately, typical Western culture diets disproportionately favor foods rich in cholesterol and omega-6 fatty acids instead.
Table 1
Controlled trials of omega-3 fatty acids in treating major depression
| Author, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Adjunctive therapy | |||
| Nemets et al, 2002 13 | 4 weeks, 2 grams/d of ethyl-EPA in recurrent depression | 20 | Significantly greater reduction in mean HRSD scores in ethyl-EPA group(-12.4) compared with placebo group (-1.6) 6 of 10 patients in ethyl-EPA group achieved 50% reduction in HRSD scores, compared with 1 in 10 patients in placebo group |
| Peet and Horrobin, 2002 14 | 12 weeks, 1, 2, or 4 grams/d of ethyl-EPA | 70 | Patients receiving 1 gram/d of ethyl-EPA showed significantly greater reduction in:
|
| Su et al, 2003 15 | 8 weeks, 4.4 grams/d of EPA and 2.2 grams/d of DHA | 28 | Treatment group showed significantly greater reduction in HRSD scores from baseline at weeks 4, 6, and 8 than placebo group |
| Monotherapy | |||
| Marangell et al, 2003 16 | 6 weeks, 2 grams/d of DHA | 36 | Little difference between response rates in DHA group (27.8%) and placebo group (23.5%) |
| BDI: Beck Depression Inventory | |||
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
| HRSD: Hamilton Rating Scale for Depression | |||
| MADRS: Montgomery-Åsberg Depression Rating Scale | |||
Analysis. For patients with unipolar depression who were treated with omega-3 fatty acids:
- the most promisingresults have been seen with adjunctive EPA
- safety and tolerability have been good across studies.
No positive monotherapy studies have been published. Studies are needed to confirm EPA’s efficacy in unipolar depression and to determine the most effective dosage.
Treating bipolar disorder
EPA and DHA have been studied in bipolar disorder (Table 2) because their actions in modulating signal transduction pathways resemble those of lithium and valproate.10,17 Biochemical studies also have shown decreased AA and DHA in erythrocyte membranes of manic patients compared with controls.18
- Stoll et al. 19 Thirty patients receiving usual treatment for bipolar disorder were randomly assigned to adjunctive omega-3 fatty acids (6.2 grams/d of EPA plus 3.4 grams/d of DHA) or placebo for 4 months. Results were promising; patients receiving the omega-3 fatty acids remained in remission significantly longer than the placebo group.
- Keck et al. 20,21 On the other hand, two more-recent studies were disappointing. Both were 4-month, randomized, controlled trials in which patients received adjunctive EPA, 6 grams/d, or placebo. One study enrolled 59 patients with acute bipolar depression;20 the other enrolled 62 patients with rapid-cycling bipolar disorder.21 EPA was well-tolerated, but both studies found little difference in effectiveness between EPA and placebo.
Table 2
Controlled trials of adjunctive omega-3 fatty acids in treating bipolar disorder
| Author, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Stoll et al, 1999 19 | 4 months, maintenance therapy (6.2 grams/d of EPA and 3.4 grams/d of DHA) in patients with bipolar I or II disorder | 30 | Significantly longer remission in omega-3 fatty acid group compared with placebo group |
| Keck et al, 2003 20 | 4 months, 6 grams/d of EPA in patients with acute bipolar depression | 59 | No significant difference in mean change from baseline to endpoint between EPA and placebo groups |
| Keck et al, 2003 21 | 4 months, 6 grams/d of EPA in patients with rapid-cycling bipolar disorder | 62 | Little difference in mean change from baseline to endpoint between EPA and placebo groups |
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
Analysis. Further studies are needed to determine omega-3 fatty acids’ usefulness in treating bipolar illness.
Treating schizophrenia
Essential fatty acid deficiency and resulting lipid membrane abnormalities have been hypothesized to play a role in schizophrenia onset.22 Moreover, epidemiologic data suggest an association between high fish consumption and positive outcomes in patients with schizophrenia.23
Open-label trials, adjunctive therapy
- Mellor et al. 24 Twenty patients receiving antipsychotics for schizophrenia were treated for 6 weeks with 10 grams/d of a fish oil formulation containing 1.7 grams of EPA and 1.1 grams of DHA (Table 3). Psychotic symptoms improved significantly and were correlated with increased omega-3 fatty acid levels in erythrocyte membranes. Tardive dyskinesia also improved significantly, as measured by Abnormal Involuntary Movement Scale (AIMS) scores.
- Arvindakshan et al. 25 Thirty-three patients receiving antipsychotics for schizophrenia were given omega-3 fatty acids (360 mg/d of EPA and 240 mg/d of DHA) plus antioxidants (800 IU vitamin E and 1,000 IU vitamin C) for 4 months. Symptom and quality-of-life measures improved significantly, and clinical improvement was retained after 4 months of supplement washout.
Table 3
Clinical trials of omega-3 fatty acids in treating schizophrenia
| Authors, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Open-label trials, adjunctive therapy | |||
| Mellor et al, 1995 24 | 6 weeks, 10 grams/d of fish oil (1.7 grams EPA and 1.1 grams DHA) | 20 | Significant improvement on PANSS and AIMS scores from baseline to endpoint |
| Arvindakshan et al, 2003 25 | 4 months, 360 mg/d of EPA and 240 mg/d of DHA, plus antioxidants (1,000 IU of vitamin C and 800 IU of vitamin E) | 33 | Significant improvements on total BPRS, PANSS, and Henrich’s Quality of Life Scale scores; improvements sustained after 4 months of supplementation washout |
| Controlled trials, adjunctive therapy | |||
| Peet et al, 2001 26 | 3 months, 2 grams/d of EPA or DHA | 45 | Greater improvement in total PANSS scores with EPA compared with DHA and placebo; EPA more effective than DHA in treating positive symptoms |
| Fenton et al, 2001 27 | 16 weeks, 3 grams/d of ethyl-EPA in patients with schizophrenia or schizoaffective disorder | 87 | No difference between ethyl-EPA and placebo groups in positive or negative symptoms, cognition, mood, or EPS |
| Peet et al, 2002 28 | 12 weeks, 1, 2, or 4 grams/d of ethyl-EPA with typical and atypical antipsychotics, including clozapine | 115 | Significantly greater improvement in mean total PANSS scores in clozapine-treated patients taking ethyl-EPA, 2 grams/d, compared with placebo; no difference between ethyl-EPAand placebo in patients taking typical or atypical antipsychotics |
| Emsley et al, 2002 29 | 12 weeks, 3 grams/d of ethyl-EPA | 40 | Significantly greater reduction in total PANSS and EPS Rating Scale dyskinesia scores in ethyl-EPA group compared with placebo |
| Controlled trial, monotherapy | |||
| Peet et al, 2001 26 | 3 months, 2 grams/d of EPA | 26 | EPA-treated patients had significantly lower PANSS scores at endpoint, compared with placebo; significantly more patients on placebo required antipsychotics (12 of 12) than did those on EPA (8 of 14) |
| AIMS: Abnormal Involuntary Movement Scale | |||
| BPRS: Brief Psychiatric Rating Scale | |||
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
| EPS: extrapyramidal symptoms | |||
| PANSS: Positive and Negative Syndrome Scale | |||
Controlled trials, adjunctive therapy
- Peet et al. 26 In a 3-month study, 45 patients with schizophrenia were randomly assigned to adjunctive EPA or DHA (2 grams/d) or placebo. Those receiving EPA showed significantly greater improvement as measured by the Positive and Negative Syndrome Scale (PANSS), compared with DHA or placebo.
- Fenton et al. 27 In a 16-week study, 87 patients with schizophrenia or schizoaffective disorder were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo. Little difference was noted in outcome measures of psychotic symptoms, mood, cognition, or extrapyramidal symptoms.
- Peet et al. 28 In a 12-week study. 115 patients with schizophrenia receiving typical antipsychotics, clozapine, or other atypical antipsychotics were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo. Those taking clozapine improved significantly more with 2 grams/d of ethyl-EPA compared with patients receiving placebo. Little difference was noted between ethyl-EPA and placebo among patients taking typical or atypical antipsychotics.
- Emsley et al. 29 Forty patients with schizophrenia were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo across 12 weeks. The ethyl-EPA group showed greater improvement in total PANSS scores and reduced dyskinesia, compared with placebo. Further analysis suggested, however, that the reduced dyskinesia scores at least partially accounted for the PANSS changes.
Controlled trial, monotherapy
- Peet et al. 26 Twenty-six patients with schizophrenia were randomly assigned to EPA, 2 grams/d, or placebo. After 3 months, those receiving EPA had significantly lower PANSS scores, and fewer (8 of 14) required antipsychotics than did those receiving placebo (12 of 12).
Analysis. Adjunctive ethyl-EPA (and perhaps combinations of EPA and DHA) may help patients with schizophrenia who are taking typical or atypical antipsychotics. EPA monotherapy also may be useful. Data are limited, however, and studies are needed before such use could be recommended.
Treating other disorders
Postpartum depression. The developing fetus and neonate require DHA from maternal stores for neurologic development. Maternal DHA depletion30 has been hypothesized to put mothers at risk for postpartum depression.31 An ecological study with data from 23 countries found that higher concentrations of DHA in maternal breast milk and greater seafood consumption predicted lower postpartum depression rates.32
In a randomized, controlled trial, giving DHA, 200 mg/d, to breastfeeding women during the first 4 months postpartum increased maternal plasma phospholipid content by 8%, compared with a 31% decrease in women given placebo.33
Data from randomized, controlled trials are needed to assess whether omega-3 fatty acid supplementation during pregnancy and the postpartum protects against postpartum depression.
Borderline personality disorder. In an 8-week controlled trial, Zanarini and Frankenburg34 randomly assigned 20 subjects with borderline personality disorder to monotherapy with ethyl-EPA, 1 gram/d, or placebo. Depressive symptoms improved and aggression decreased significantly in the ethyl-EPA group, suggesting the need for further research.
ADHD. Low DHA levels have been found in serum35 and erythrocytes36 of hyperactive children when compared with controls. Limited data in boys ages 6 to 12 also suggest an inverse relationship between plasma omega-3 fatty acids and behavior problems, as measured by the Connors’ Rating Scale.37
More research is needed into omega-3 fatty acids’ potential role in treating attention-deficit/hyperactivity disorder (ADHD), even though results of one controlled trial of adjunctive DHA in ADHD were disappointing.38
Dementia. Some large, prospective, epidemiologic studies39-41—but not others42—found an inverse relationship between dietary intake of omega-3 fatty acids and risk of cognitive decline or dementia.
Related resources
- USDA Nutrient Data Laboratory. http://www.nalusda.gov/fnic/foodcomp (accessed Dec. 1, 2003)
- Stoll AL. The omega-3 connection: the groundbreaking omega-3 antidepression diet and brain program. New York: Simon and Schuster, 2001.
Drug brand names
- Clozapine • Clozaril
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Hibbeln JR. Fish consumption and major depression. Lancet 1998;351(9110):1213.-
2. Tanskanen A, Hibbeln JR, Tuomilehto J, et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv 2001;52(4):529-31.
3. Tanskanen A, Hibelln JR, Hintikka J, et al. Fish consumption, depression, and suicidality in a general population. Arch Gen Psychiatry 2001;58(5):512-3.
4. Edwards R, Peet M, Shay J, Horrobin D. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998;48(2-3):149-55.
5. Maes M, Christophe A, Delanghe J, et al. Lowered omega-3 polyunsaturated fatty acids in serum phospholipids and cholesterol esters of depressed patients. Psychiatry Res 1999;85(3):275-91.
6. Lundbaek JA, Andersen OS. Lysophospholipids modulate channel function by altering the mechanical properties of lipid bilayers. J Gen Physiol 1994;104(4):645-73.
7. Delion S, Chalon S, Guilloteau D, et al. Alpha-linolenic acid dietary deficiency alters age-related changes of dopaminergic and serotonergic neurotransmission in the rat frontal cortex. J Neurochem 1996;66(4):1582-91.
8. Passi S, Cataudella S, Di Marco P, et al. Fatty acid composition and antioxidant levels in muscle tissue of different Mediterranean marine species of fish and shellfish. J Agric Food Chem 2002;50(25):7314-22.
9. Hudson CJ, Young LT, Li PP, Warsh JJ. CNS signal transduction in the pathophysiology and pharmacology of affective disorders and schizophrenia. Synapse 1993;13(3):278-93.
10. Sperling RI, Benincaso AI, Knoell CT, et al. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 1993;91(2):651-60.
11. Endres S. Messengers and mediators: interactions among lipids, eicosanoids and cytokines. Am J Clin Nutr 1993;57(5 suppl):798S-800S.
12. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003;23(2):e20-e30.
13. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159(3):477-9.
14. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002;59(10):913-9.
15. Su K-P, Huang S-Y, Chiu C-C, Shen WW. Omega-3 fatty acids in major depressive disorder: a preliminary double-blind, placebo-con-trolled trial. Eur Neuropsychopharmacol 2003;13(4):267-71.
16. Marangell LB, Martinez JM, Zboyan HA, et al. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 2003;160(5):996-8.
17. Stoll AL, Severus WE. Mood stabilizers: shared mechanisms of action at postsynaptic signal transduction and kindling processes. Harv Rev Psychiatry 1996;4(2):77-89.
18. Chiu CC, Huang SY, Su KP, et al. Polyunsaturated fatty acid deficit in patients with bipolar disorder. Eur Neuropsychopharmacol 2003;13(2):99-103.
19. Stoll AL, Severus WE, Freeman MP, et al. Omega-3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56(5):407-12.
20. Keck PE, Jr, McElroy SL, Freeman MP, et al. Randomized, placebo-controlled trial of eicosapentaenoic acid in bipolar depression. Bipolar Disord 2003;5(suppl 1):58.-
21. Keck PE, Jr, McElroy SL, Freeman MP, et al. Randomized, placebo-controlled trial of eicosapentaenoic acid in rapid cycling bipolar disorder. Bipolar Disord 2003;5(suppl 1):58.-
22. Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 1998;30(3):193-208.
23. Christensen O, Christensen E. Fat consumption and schizophrenia. Acta Psychiatr Scand 1988;78(5):587-591
24. Mellor JE, Laugharne JD, Peet M. Schizophrenic symptoms and dietary intake of n-3 fatty acids. Schizophr Res 1995;18(1):85-6.
25. Arvindakshan M, Ghate M, Ranjekar PK, et al. Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr Res 2003;62(3):195-204.
26. Peet M, Brind J, Ramchand CN, et al. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 2001;49(3):243-51.
27. Fenton WS, Dickerson F, Boronow J, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 2001;158(12):2071-4.
28. Peet M, Horrobin DF. E-E Multicentre Study Group. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 2002;36(1):7-18.
29. Emsley R, Myburgh C, Oosthuizen P, Van Rensburg SJ. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 2002;159(9):1596-8.
30. Al MD, van Houwelingen AC, Kester AD, et al. Maternal essential fatty acid patterns during normal pregnancy and their relationship to neonatal essential fatty acid status. Br J Nutr 1995;74(1):55-68.
31. Hibbeln JR, Salem N, Jr. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr 1995;62(1):1-9.
32. Hibbeln JR. Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord 2002;69(1-3):15-29.
33. Llorente AM, Jensen CL, Voigt RG, et al. Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing. Am J Obstet Gynecol 2003;188(5):1348-53.
34. Zanarini MC, Frankenburg FR. Omega-3 fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry 2003;160(1):167-9.
35. Mitchell EA, Aman MG, Turbott SH, Manku M. Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clin Pediatr 1987;26(8):406-11.
36. Stevens LJ, Zentall SS, Deck JL, et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995;62(4):761-8.
37. Stevens LJ, Zentall SS, Abate ML, et al. Omega-3 fatty acids in boys with behavior, learning, and health problems. Physiol Behav 1996;59(4-5):915-20.
38. Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001;139(2):189-96.
39. Kalmijn S, Launer LJ, Ott A, et al. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 1997;42(5):776-82.
40. Barberger-Gateau P, Letenneur L, Deschamps V, et al. Fish, meat, and risk of dementia: cohort study. BMJ 2002;325(7370):932-3.
41. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 2003;60(7):940-6.
42. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Diet and risk of dementia: does fat matter? The Rotterdam Study. Neurology 2002;59(12):1915-21.
Fourteen clinical trials in the past 3 years have examined the potential of omega-3 fatty acids in treating psychiatric disorders. Preliminary findings in at least 700 patients suggest that:
- omega-3 fatty acids used as adjuncts or monotherapy appear well-tolerated and safe in psychiatric disorders
- efficacy data vary by disorder
- the two marine omega-3 fatty acids may differ in efficacy.
Although we cannot offer specific guidance for using omega-3 fatty acids at this time, we can update you on recent trials of these “fish oils” in depression, bipolar disorder, schizophrenia, and other psychiatric disorders.
Treating depression
Prevalence rates of major depression1,2 and suicidal ideation3 decrease in populations as fish consumption increases. Some studies4,5 have shown omega-3 fatty acid deficiency in erythrocyte membranes and serum of depressed patients. This putative deficiency has been hypothesized to lead to:
- alterations in membrane fluidity, which affect monoamine (particularly serotonin) neurotransmission6,7
- an imbalance between omega-6 and omega-3 fatty acids, which affects the inflammatory response system (Box).5-12
- Nemets et al. 13 Twenty patients with recurrent major depression taking maintenance antidepressants were randomly assigned to adjunctive ethyl-EPA, 2 grams/d, or placebo for 4 weeks. Patients given ethyl-EPA showed significantly greater improvement than the placebo group in depressive symptoms, as measured by the Hamilton Rating Scale for Depression (HRSD).13
- Peet and Horrobin. 14 Seventy depressed patients taking antidepressants were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo for 12 weeks. Only the group taking ethyl-EPA, 1 gram/d, showed significantly greater improvement than the placebo group.
- Su et al. 15 Twenty-eight patients taking antidepressants for major depression were randomly assigned to adjunctive omega-3 fatty acids (4.4 grams/d of EPA plus 2.2 grams/d of DHA) or placebo. After 8 weeks, depressive symptoms improved significantly more in the adjunctive treatment group.
- Marangell et al. 16 Thirty-six patients with mild to moderate depression (defined as a score of 17 on the 28-item HRSD) were randomly assigned to monotherapy with DHA, 2 grams/d, or placebo. Response rates after 6 weeks were comparable (27.8% with DHA versus 23.5% with placebo).
Polyunsaturated fatty acids contain a hydrocarbon chain with two or more double bonds. They are divided into families based on the location of their first double bond relative to the methyl end carbon—the “omega” carbon. Polyunsaturated fatty acids of interest in psychiatry include:
- omega-6 fatty acids—arachidonic acid (AA) and linoleic acid (LA)
- omega-3 fatty acids—eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA).
Omega-3 and omega-6 fatty acids are called “essential” because they must be obtained from dietary sources. EPA and DHA are derived largely from wild—not farm-raised—fish, including sea bass, mackerel, pike, sardines, salmon, trout, herring, and cod liver oil.8 ALA, a precursor to both EPA and DHA, is derived from plant sources such as flaxseed oil, canola oil, walnuts, and soybean oil.
Polyunsaturated fatty acids, particularly AA and DHA, are important components of the phospholipid bilayer of neuronal cell membranes.They increase the ability of phospholipids to move “fluidly” within the membrane and modulate neurotransmission6,7 and signal transduction pathways9,10 thought to be important in psychiatric disorders. They also are precursors for eicosanoid molecules (such as prostaglandins and leukotrienes) and cytokines. Thus, an imbalance favoring omega-6 fatty acids over omega-3 fatty acids may lead to overproduction of pro-inflammatory cytokines.11
Omega-3 fatty acids are thought to be beneficial in numerous inflammatory and cardiovascular diseases. The American Heart Association’s dietary guidelines include dietary sources of omega-3 fatty acids as part of a healthy diet.12 Unfortunately, typical Western culture diets disproportionately favor foods rich in cholesterol and omega-6 fatty acids instead.
Table 1
Controlled trials of omega-3 fatty acids in treating major depression
| Author, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Adjunctive therapy | |||
| Nemets et al, 2002 13 | 4 weeks, 2 grams/d of ethyl-EPA in recurrent depression | 20 | Significantly greater reduction in mean HRSD scores in ethyl-EPA group(-12.4) compared with placebo group (-1.6) 6 of 10 patients in ethyl-EPA group achieved 50% reduction in HRSD scores, compared with 1 in 10 patients in placebo group |
| Peet and Horrobin, 2002 14 | 12 weeks, 1, 2, or 4 grams/d of ethyl-EPA | 70 | Patients receiving 1 gram/d of ethyl-EPA showed significantly greater reduction in:
|
| Su et al, 2003 15 | 8 weeks, 4.4 grams/d of EPA and 2.2 grams/d of DHA | 28 | Treatment group showed significantly greater reduction in HRSD scores from baseline at weeks 4, 6, and 8 than placebo group |
| Monotherapy | |||
| Marangell et al, 2003 16 | 6 weeks, 2 grams/d of DHA | 36 | Little difference between response rates in DHA group (27.8%) and placebo group (23.5%) |
| BDI: Beck Depression Inventory | |||
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
| HRSD: Hamilton Rating Scale for Depression | |||
| MADRS: Montgomery-Åsberg Depression Rating Scale | |||
Analysis. For patients with unipolar depression who were treated with omega-3 fatty acids:
- the most promisingresults have been seen with adjunctive EPA
- safety and tolerability have been good across studies.
No positive monotherapy studies have been published. Studies are needed to confirm EPA’s efficacy in unipolar depression and to determine the most effective dosage.
Treating bipolar disorder
EPA and DHA have been studied in bipolar disorder (Table 2) because their actions in modulating signal transduction pathways resemble those of lithium and valproate.10,17 Biochemical studies also have shown decreased AA and DHA in erythrocyte membranes of manic patients compared with controls.18
- Stoll et al. 19 Thirty patients receiving usual treatment for bipolar disorder were randomly assigned to adjunctive omega-3 fatty acids (6.2 grams/d of EPA plus 3.4 grams/d of DHA) or placebo for 4 months. Results were promising; patients receiving the omega-3 fatty acids remained in remission significantly longer than the placebo group.
- Keck et al. 20,21 On the other hand, two more-recent studies were disappointing. Both were 4-month, randomized, controlled trials in which patients received adjunctive EPA, 6 grams/d, or placebo. One study enrolled 59 patients with acute bipolar depression;20 the other enrolled 62 patients with rapid-cycling bipolar disorder.21 EPA was well-tolerated, but both studies found little difference in effectiveness between EPA and placebo.
Table 2
Controlled trials of adjunctive omega-3 fatty acids in treating bipolar disorder
| Author, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Stoll et al, 1999 19 | 4 months, maintenance therapy (6.2 grams/d of EPA and 3.4 grams/d of DHA) in patients with bipolar I or II disorder | 30 | Significantly longer remission in omega-3 fatty acid group compared with placebo group |
| Keck et al, 2003 20 | 4 months, 6 grams/d of EPA in patients with acute bipolar depression | 59 | No significant difference in mean change from baseline to endpoint between EPA and placebo groups |
| Keck et al, 2003 21 | 4 months, 6 grams/d of EPA in patients with rapid-cycling bipolar disorder | 62 | Little difference in mean change from baseline to endpoint between EPA and placebo groups |
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
Analysis. Further studies are needed to determine omega-3 fatty acids’ usefulness in treating bipolar illness.
Treating schizophrenia
Essential fatty acid deficiency and resulting lipid membrane abnormalities have been hypothesized to play a role in schizophrenia onset.22 Moreover, epidemiologic data suggest an association between high fish consumption and positive outcomes in patients with schizophrenia.23
Open-label trials, adjunctive therapy
- Mellor et al. 24 Twenty patients receiving antipsychotics for schizophrenia were treated for 6 weeks with 10 grams/d of a fish oil formulation containing 1.7 grams of EPA and 1.1 grams of DHA (Table 3). Psychotic symptoms improved significantly and were correlated with increased omega-3 fatty acid levels in erythrocyte membranes. Tardive dyskinesia also improved significantly, as measured by Abnormal Involuntary Movement Scale (AIMS) scores.
- Arvindakshan et al. 25 Thirty-three patients receiving antipsychotics for schizophrenia were given omega-3 fatty acids (360 mg/d of EPA and 240 mg/d of DHA) plus antioxidants (800 IU vitamin E and 1,000 IU vitamin C) for 4 months. Symptom and quality-of-life measures improved significantly, and clinical improvement was retained after 4 months of supplement washout.
Table 3
Clinical trials of omega-3 fatty acids in treating schizophrenia
| Authors, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Open-label trials, adjunctive therapy | |||
| Mellor et al, 1995 24 | 6 weeks, 10 grams/d of fish oil (1.7 grams EPA and 1.1 grams DHA) | 20 | Significant improvement on PANSS and AIMS scores from baseline to endpoint |
| Arvindakshan et al, 2003 25 | 4 months, 360 mg/d of EPA and 240 mg/d of DHA, plus antioxidants (1,000 IU of vitamin C and 800 IU of vitamin E) | 33 | Significant improvements on total BPRS, PANSS, and Henrich’s Quality of Life Scale scores; improvements sustained after 4 months of supplementation washout |
| Controlled trials, adjunctive therapy | |||
| Peet et al, 2001 26 | 3 months, 2 grams/d of EPA or DHA | 45 | Greater improvement in total PANSS scores with EPA compared with DHA and placebo; EPA more effective than DHA in treating positive symptoms |
| Fenton et al, 2001 27 | 16 weeks, 3 grams/d of ethyl-EPA in patients with schizophrenia or schizoaffective disorder | 87 | No difference between ethyl-EPA and placebo groups in positive or negative symptoms, cognition, mood, or EPS |
| Peet et al, 2002 28 | 12 weeks, 1, 2, or 4 grams/d of ethyl-EPA with typical and atypical antipsychotics, including clozapine | 115 | Significantly greater improvement in mean total PANSS scores in clozapine-treated patients taking ethyl-EPA, 2 grams/d, compared with placebo; no difference between ethyl-EPAand placebo in patients taking typical or atypical antipsychotics |
| Emsley et al, 2002 29 | 12 weeks, 3 grams/d of ethyl-EPA | 40 | Significantly greater reduction in total PANSS and EPS Rating Scale dyskinesia scores in ethyl-EPA group compared with placebo |
| Controlled trial, monotherapy | |||
| Peet et al, 2001 26 | 3 months, 2 grams/d of EPA | 26 | EPA-treated patients had significantly lower PANSS scores at endpoint, compared with placebo; significantly more patients on placebo required antipsychotics (12 of 12) than did those on EPA (8 of 14) |
| AIMS: Abnormal Involuntary Movement Scale | |||
| BPRS: Brief Psychiatric Rating Scale | |||
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
| EPS: extrapyramidal symptoms | |||
| PANSS: Positive and Negative Syndrome Scale | |||
Controlled trials, adjunctive therapy
- Peet et al. 26 In a 3-month study, 45 patients with schizophrenia were randomly assigned to adjunctive EPA or DHA (2 grams/d) or placebo. Those receiving EPA showed significantly greater improvement as measured by the Positive and Negative Syndrome Scale (PANSS), compared with DHA or placebo.
- Fenton et al. 27 In a 16-week study, 87 patients with schizophrenia or schizoaffective disorder were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo. Little difference was noted in outcome measures of psychotic symptoms, mood, cognition, or extrapyramidal symptoms.
- Peet et al. 28 In a 12-week study. 115 patients with schizophrenia receiving typical antipsychotics, clozapine, or other atypical antipsychotics were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo. Those taking clozapine improved significantly more with 2 grams/d of ethyl-EPA compared with patients receiving placebo. Little difference was noted between ethyl-EPA and placebo among patients taking typical or atypical antipsychotics.
- Emsley et al. 29 Forty patients with schizophrenia were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo across 12 weeks. The ethyl-EPA group showed greater improvement in total PANSS scores and reduced dyskinesia, compared with placebo. Further analysis suggested, however, that the reduced dyskinesia scores at least partially accounted for the PANSS changes.
Controlled trial, monotherapy
- Peet et al. 26 Twenty-six patients with schizophrenia were randomly assigned to EPA, 2 grams/d, or placebo. After 3 months, those receiving EPA had significantly lower PANSS scores, and fewer (8 of 14) required antipsychotics than did those receiving placebo (12 of 12).
Analysis. Adjunctive ethyl-EPA (and perhaps combinations of EPA and DHA) may help patients with schizophrenia who are taking typical or atypical antipsychotics. EPA monotherapy also may be useful. Data are limited, however, and studies are needed before such use could be recommended.
Treating other disorders
Postpartum depression. The developing fetus and neonate require DHA from maternal stores for neurologic development. Maternal DHA depletion30 has been hypothesized to put mothers at risk for postpartum depression.31 An ecological study with data from 23 countries found that higher concentrations of DHA in maternal breast milk and greater seafood consumption predicted lower postpartum depression rates.32
In a randomized, controlled trial, giving DHA, 200 mg/d, to breastfeeding women during the first 4 months postpartum increased maternal plasma phospholipid content by 8%, compared with a 31% decrease in women given placebo.33
Data from randomized, controlled trials are needed to assess whether omega-3 fatty acid supplementation during pregnancy and the postpartum protects against postpartum depression.
Borderline personality disorder. In an 8-week controlled trial, Zanarini and Frankenburg34 randomly assigned 20 subjects with borderline personality disorder to monotherapy with ethyl-EPA, 1 gram/d, or placebo. Depressive symptoms improved and aggression decreased significantly in the ethyl-EPA group, suggesting the need for further research.
ADHD. Low DHA levels have been found in serum35 and erythrocytes36 of hyperactive children when compared with controls. Limited data in boys ages 6 to 12 also suggest an inverse relationship between plasma omega-3 fatty acids and behavior problems, as measured by the Connors’ Rating Scale.37
More research is needed into omega-3 fatty acids’ potential role in treating attention-deficit/hyperactivity disorder (ADHD), even though results of one controlled trial of adjunctive DHA in ADHD were disappointing.38
Dementia. Some large, prospective, epidemiologic studies39-41—but not others42—found an inverse relationship between dietary intake of omega-3 fatty acids and risk of cognitive decline or dementia.
Related resources
- USDA Nutrient Data Laboratory. http://www.nalusda.gov/fnic/foodcomp (accessed Dec. 1, 2003)
- Stoll AL. The omega-3 connection: the groundbreaking omega-3 antidepression diet and brain program. New York: Simon and Schuster, 2001.
Drug brand names
- Clozapine • Clozaril
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Fourteen clinical trials in the past 3 years have examined the potential of omega-3 fatty acids in treating psychiatric disorders. Preliminary findings in at least 700 patients suggest that:
- omega-3 fatty acids used as adjuncts or monotherapy appear well-tolerated and safe in psychiatric disorders
- efficacy data vary by disorder
- the two marine omega-3 fatty acids may differ in efficacy.
Although we cannot offer specific guidance for using omega-3 fatty acids at this time, we can update you on recent trials of these “fish oils” in depression, bipolar disorder, schizophrenia, and other psychiatric disorders.
Treating depression
Prevalence rates of major depression1,2 and suicidal ideation3 decrease in populations as fish consumption increases. Some studies4,5 have shown omega-3 fatty acid deficiency in erythrocyte membranes and serum of depressed patients. This putative deficiency has been hypothesized to lead to:
- alterations in membrane fluidity, which affect monoamine (particularly serotonin) neurotransmission6,7
- an imbalance between omega-6 and omega-3 fatty acids, which affects the inflammatory response system (Box).5-12
- Nemets et al. 13 Twenty patients with recurrent major depression taking maintenance antidepressants were randomly assigned to adjunctive ethyl-EPA, 2 grams/d, or placebo for 4 weeks. Patients given ethyl-EPA showed significantly greater improvement than the placebo group in depressive symptoms, as measured by the Hamilton Rating Scale for Depression (HRSD).13
- Peet and Horrobin. 14 Seventy depressed patients taking antidepressants were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo for 12 weeks. Only the group taking ethyl-EPA, 1 gram/d, showed significantly greater improvement than the placebo group.
- Su et al. 15 Twenty-eight patients taking antidepressants for major depression were randomly assigned to adjunctive omega-3 fatty acids (4.4 grams/d of EPA plus 2.2 grams/d of DHA) or placebo. After 8 weeks, depressive symptoms improved significantly more in the adjunctive treatment group.
- Marangell et al. 16 Thirty-six patients with mild to moderate depression (defined as a score of 17 on the 28-item HRSD) were randomly assigned to monotherapy with DHA, 2 grams/d, or placebo. Response rates after 6 weeks were comparable (27.8% with DHA versus 23.5% with placebo).
Polyunsaturated fatty acids contain a hydrocarbon chain with two or more double bonds. They are divided into families based on the location of their first double bond relative to the methyl end carbon—the “omega” carbon. Polyunsaturated fatty acids of interest in psychiatry include:
- omega-6 fatty acids—arachidonic acid (AA) and linoleic acid (LA)
- omega-3 fatty acids—eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA).
Omega-3 and omega-6 fatty acids are called “essential” because they must be obtained from dietary sources. EPA and DHA are derived largely from wild—not farm-raised—fish, including sea bass, mackerel, pike, sardines, salmon, trout, herring, and cod liver oil.8 ALA, a precursor to both EPA and DHA, is derived from plant sources such as flaxseed oil, canola oil, walnuts, and soybean oil.
Polyunsaturated fatty acids, particularly AA and DHA, are important components of the phospholipid bilayer of neuronal cell membranes.They increase the ability of phospholipids to move “fluidly” within the membrane and modulate neurotransmission6,7 and signal transduction pathways9,10 thought to be important in psychiatric disorders. They also are precursors for eicosanoid molecules (such as prostaglandins and leukotrienes) and cytokines. Thus, an imbalance favoring omega-6 fatty acids over omega-3 fatty acids may lead to overproduction of pro-inflammatory cytokines.11
Omega-3 fatty acids are thought to be beneficial in numerous inflammatory and cardiovascular diseases. The American Heart Association’s dietary guidelines include dietary sources of omega-3 fatty acids as part of a healthy diet.12 Unfortunately, typical Western culture diets disproportionately favor foods rich in cholesterol and omega-6 fatty acids instead.
Table 1
Controlled trials of omega-3 fatty acids in treating major depression
| Author, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Adjunctive therapy | |||
| Nemets et al, 2002 13 | 4 weeks, 2 grams/d of ethyl-EPA in recurrent depression | 20 | Significantly greater reduction in mean HRSD scores in ethyl-EPA group(-12.4) compared with placebo group (-1.6) 6 of 10 patients in ethyl-EPA group achieved 50% reduction in HRSD scores, compared with 1 in 10 patients in placebo group |
| Peet and Horrobin, 2002 14 | 12 weeks, 1, 2, or 4 grams/d of ethyl-EPA | 70 | Patients receiving 1 gram/d of ethyl-EPA showed significantly greater reduction in:
|
| Su et al, 2003 15 | 8 weeks, 4.4 grams/d of EPA and 2.2 grams/d of DHA | 28 | Treatment group showed significantly greater reduction in HRSD scores from baseline at weeks 4, 6, and 8 than placebo group |
| Monotherapy | |||
| Marangell et al, 2003 16 | 6 weeks, 2 grams/d of DHA | 36 | Little difference between response rates in DHA group (27.8%) and placebo group (23.5%) |
| BDI: Beck Depression Inventory | |||
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
| HRSD: Hamilton Rating Scale for Depression | |||
| MADRS: Montgomery-Åsberg Depression Rating Scale | |||
Analysis. For patients with unipolar depression who were treated with omega-3 fatty acids:
- the most promisingresults have been seen with adjunctive EPA
- safety and tolerability have been good across studies.
No positive monotherapy studies have been published. Studies are needed to confirm EPA’s efficacy in unipolar depression and to determine the most effective dosage.
Treating bipolar disorder
EPA and DHA have been studied in bipolar disorder (Table 2) because their actions in modulating signal transduction pathways resemble those of lithium and valproate.10,17 Biochemical studies also have shown decreased AA and DHA in erythrocyte membranes of manic patients compared with controls.18
- Stoll et al. 19 Thirty patients receiving usual treatment for bipolar disorder were randomly assigned to adjunctive omega-3 fatty acids (6.2 grams/d of EPA plus 3.4 grams/d of DHA) or placebo for 4 months. Results were promising; patients receiving the omega-3 fatty acids remained in remission significantly longer than the placebo group.
- Keck et al. 20,21 On the other hand, two more-recent studies were disappointing. Both were 4-month, randomized, controlled trials in which patients received adjunctive EPA, 6 grams/d, or placebo. One study enrolled 59 patients with acute bipolar depression;20 the other enrolled 62 patients with rapid-cycling bipolar disorder.21 EPA was well-tolerated, but both studies found little difference in effectiveness between EPA and placebo.
Table 2
Controlled trials of adjunctive omega-3 fatty acids in treating bipolar disorder
| Author, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Stoll et al, 1999 19 | 4 months, maintenance therapy (6.2 grams/d of EPA and 3.4 grams/d of DHA) in patients with bipolar I or II disorder | 30 | Significantly longer remission in omega-3 fatty acid group compared with placebo group |
| Keck et al, 2003 20 | 4 months, 6 grams/d of EPA in patients with acute bipolar depression | 59 | No significant difference in mean change from baseline to endpoint between EPA and placebo groups |
| Keck et al, 2003 21 | 4 months, 6 grams/d of EPA in patients with rapid-cycling bipolar disorder | 62 | Little difference in mean change from baseline to endpoint between EPA and placebo groups |
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
Analysis. Further studies are needed to determine omega-3 fatty acids’ usefulness in treating bipolar illness.
Treating schizophrenia
Essential fatty acid deficiency and resulting lipid membrane abnormalities have been hypothesized to play a role in schizophrenia onset.22 Moreover, epidemiologic data suggest an association between high fish consumption and positive outcomes in patients with schizophrenia.23
Open-label trials, adjunctive therapy
- Mellor et al. 24 Twenty patients receiving antipsychotics for schizophrenia were treated for 6 weeks with 10 grams/d of a fish oil formulation containing 1.7 grams of EPA and 1.1 grams of DHA (Table 3). Psychotic symptoms improved significantly and were correlated with increased omega-3 fatty acid levels in erythrocyte membranes. Tardive dyskinesia also improved significantly, as measured by Abnormal Involuntary Movement Scale (AIMS) scores.
- Arvindakshan et al. 25 Thirty-three patients receiving antipsychotics for schizophrenia were given omega-3 fatty acids (360 mg/d of EPA and 240 mg/d of DHA) plus antioxidants (800 IU vitamin E and 1,000 IU vitamin C) for 4 months. Symptom and quality-of-life measures improved significantly, and clinical improvement was retained after 4 months of supplement washout.
Table 3
Clinical trials of omega-3 fatty acids in treating schizophrenia
| Authors, year of publication | Duration and dosages | Number of patients | Results |
|---|---|---|---|
| Open-label trials, adjunctive therapy | |||
| Mellor et al, 1995 24 | 6 weeks, 10 grams/d of fish oil (1.7 grams EPA and 1.1 grams DHA) | 20 | Significant improvement on PANSS and AIMS scores from baseline to endpoint |
| Arvindakshan et al, 2003 25 | 4 months, 360 mg/d of EPA and 240 mg/d of DHA, plus antioxidants (1,000 IU of vitamin C and 800 IU of vitamin E) | 33 | Significant improvements on total BPRS, PANSS, and Henrich’s Quality of Life Scale scores; improvements sustained after 4 months of supplementation washout |
| Controlled trials, adjunctive therapy | |||
| Peet et al, 2001 26 | 3 months, 2 grams/d of EPA or DHA | 45 | Greater improvement in total PANSS scores with EPA compared with DHA and placebo; EPA more effective than DHA in treating positive symptoms |
| Fenton et al, 2001 27 | 16 weeks, 3 grams/d of ethyl-EPA in patients with schizophrenia or schizoaffective disorder | 87 | No difference between ethyl-EPA and placebo groups in positive or negative symptoms, cognition, mood, or EPS |
| Peet et al, 2002 28 | 12 weeks, 1, 2, or 4 grams/d of ethyl-EPA with typical and atypical antipsychotics, including clozapine | 115 | Significantly greater improvement in mean total PANSS scores in clozapine-treated patients taking ethyl-EPA, 2 grams/d, compared with placebo; no difference between ethyl-EPAand placebo in patients taking typical or atypical antipsychotics |
| Emsley et al, 2002 29 | 12 weeks, 3 grams/d of ethyl-EPA | 40 | Significantly greater reduction in total PANSS and EPS Rating Scale dyskinesia scores in ethyl-EPA group compared with placebo |
| Controlled trial, monotherapy | |||
| Peet et al, 2001 26 | 3 months, 2 grams/d of EPA | 26 | EPA-treated patients had significantly lower PANSS scores at endpoint, compared with placebo; significantly more patients on placebo required antipsychotics (12 of 12) than did those on EPA (8 of 14) |
| AIMS: Abnormal Involuntary Movement Scale | |||
| BPRS: Brief Psychiatric Rating Scale | |||
| DHA: docosahexaenoic acid | |||
| EPA: eicosapentaenoic acid | |||
| EPS: extrapyramidal symptoms | |||
| PANSS: Positive and Negative Syndrome Scale | |||
Controlled trials, adjunctive therapy
- Peet et al. 26 In a 3-month study, 45 patients with schizophrenia were randomly assigned to adjunctive EPA or DHA (2 grams/d) or placebo. Those receiving EPA showed significantly greater improvement as measured by the Positive and Negative Syndrome Scale (PANSS), compared with DHA or placebo.
- Fenton et al. 27 In a 16-week study, 87 patients with schizophrenia or schizoaffective disorder were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo. Little difference was noted in outcome measures of psychotic symptoms, mood, cognition, or extrapyramidal symptoms.
- Peet et al. 28 In a 12-week study. 115 patients with schizophrenia receiving typical antipsychotics, clozapine, or other atypical antipsychotics were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo. Those taking clozapine improved significantly more with 2 grams/d of ethyl-EPA compared with patients receiving placebo. Little difference was noted between ethyl-EPA and placebo among patients taking typical or atypical antipsychotics.
- Emsley et al. 29 Forty patients with schizophrenia were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo across 12 weeks. The ethyl-EPA group showed greater improvement in total PANSS scores and reduced dyskinesia, compared with placebo. Further analysis suggested, however, that the reduced dyskinesia scores at least partially accounted for the PANSS changes.
Controlled trial, monotherapy
- Peet et al. 26 Twenty-six patients with schizophrenia were randomly assigned to EPA, 2 grams/d, or placebo. After 3 months, those receiving EPA had significantly lower PANSS scores, and fewer (8 of 14) required antipsychotics than did those receiving placebo (12 of 12).
Analysis. Adjunctive ethyl-EPA (and perhaps combinations of EPA and DHA) may help patients with schizophrenia who are taking typical or atypical antipsychotics. EPA monotherapy also may be useful. Data are limited, however, and studies are needed before such use could be recommended.
Treating other disorders
Postpartum depression. The developing fetus and neonate require DHA from maternal stores for neurologic development. Maternal DHA depletion30 has been hypothesized to put mothers at risk for postpartum depression.31 An ecological study with data from 23 countries found that higher concentrations of DHA in maternal breast milk and greater seafood consumption predicted lower postpartum depression rates.32
In a randomized, controlled trial, giving DHA, 200 mg/d, to breastfeeding women during the first 4 months postpartum increased maternal plasma phospholipid content by 8%, compared with a 31% decrease in women given placebo.33
Data from randomized, controlled trials are needed to assess whether omega-3 fatty acid supplementation during pregnancy and the postpartum protects against postpartum depression.
Borderline personality disorder. In an 8-week controlled trial, Zanarini and Frankenburg34 randomly assigned 20 subjects with borderline personality disorder to monotherapy with ethyl-EPA, 1 gram/d, or placebo. Depressive symptoms improved and aggression decreased significantly in the ethyl-EPA group, suggesting the need for further research.
ADHD. Low DHA levels have been found in serum35 and erythrocytes36 of hyperactive children when compared with controls. Limited data in boys ages 6 to 12 also suggest an inverse relationship between plasma omega-3 fatty acids and behavior problems, as measured by the Connors’ Rating Scale.37
More research is needed into omega-3 fatty acids’ potential role in treating attention-deficit/hyperactivity disorder (ADHD), even though results of one controlled trial of adjunctive DHA in ADHD were disappointing.38
Dementia. Some large, prospective, epidemiologic studies39-41—but not others42—found an inverse relationship between dietary intake of omega-3 fatty acids and risk of cognitive decline or dementia.
Related resources
- USDA Nutrient Data Laboratory. http://www.nalusda.gov/fnic/foodcomp (accessed Dec. 1, 2003)
- Stoll AL. The omega-3 connection: the groundbreaking omega-3 antidepression diet and brain program. New York: Simon and Schuster, 2001.
Drug brand names
- Clozapine • Clozaril
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Hibbeln JR. Fish consumption and major depression. Lancet 1998;351(9110):1213.-
2. Tanskanen A, Hibbeln JR, Tuomilehto J, et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv 2001;52(4):529-31.
3. Tanskanen A, Hibelln JR, Hintikka J, et al. Fish consumption, depression, and suicidality in a general population. Arch Gen Psychiatry 2001;58(5):512-3.
4. Edwards R, Peet M, Shay J, Horrobin D. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998;48(2-3):149-55.
5. Maes M, Christophe A, Delanghe J, et al. Lowered omega-3 polyunsaturated fatty acids in serum phospholipids and cholesterol esters of depressed patients. Psychiatry Res 1999;85(3):275-91.
6. Lundbaek JA, Andersen OS. Lysophospholipids modulate channel function by altering the mechanical properties of lipid bilayers. J Gen Physiol 1994;104(4):645-73.
7. Delion S, Chalon S, Guilloteau D, et al. Alpha-linolenic acid dietary deficiency alters age-related changes of dopaminergic and serotonergic neurotransmission in the rat frontal cortex. J Neurochem 1996;66(4):1582-91.
8. Passi S, Cataudella S, Di Marco P, et al. Fatty acid composition and antioxidant levels in muscle tissue of different Mediterranean marine species of fish and shellfish. J Agric Food Chem 2002;50(25):7314-22.
9. Hudson CJ, Young LT, Li PP, Warsh JJ. CNS signal transduction in the pathophysiology and pharmacology of affective disorders and schizophrenia. Synapse 1993;13(3):278-93.
10. Sperling RI, Benincaso AI, Knoell CT, et al. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 1993;91(2):651-60.
11. Endres S. Messengers and mediators: interactions among lipids, eicosanoids and cytokines. Am J Clin Nutr 1993;57(5 suppl):798S-800S.
12. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003;23(2):e20-e30.
13. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159(3):477-9.
14. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002;59(10):913-9.
15. Su K-P, Huang S-Y, Chiu C-C, Shen WW. Omega-3 fatty acids in major depressive disorder: a preliminary double-blind, placebo-con-trolled trial. Eur Neuropsychopharmacol 2003;13(4):267-71.
16. Marangell LB, Martinez JM, Zboyan HA, et al. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 2003;160(5):996-8.
17. Stoll AL, Severus WE. Mood stabilizers: shared mechanisms of action at postsynaptic signal transduction and kindling processes. Harv Rev Psychiatry 1996;4(2):77-89.
18. Chiu CC, Huang SY, Su KP, et al. Polyunsaturated fatty acid deficit in patients with bipolar disorder. Eur Neuropsychopharmacol 2003;13(2):99-103.
19. Stoll AL, Severus WE, Freeman MP, et al. Omega-3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56(5):407-12.
20. Keck PE, Jr, McElroy SL, Freeman MP, et al. Randomized, placebo-controlled trial of eicosapentaenoic acid in bipolar depression. Bipolar Disord 2003;5(suppl 1):58.-
21. Keck PE, Jr, McElroy SL, Freeman MP, et al. Randomized, placebo-controlled trial of eicosapentaenoic acid in rapid cycling bipolar disorder. Bipolar Disord 2003;5(suppl 1):58.-
22. Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 1998;30(3):193-208.
23. Christensen O, Christensen E. Fat consumption and schizophrenia. Acta Psychiatr Scand 1988;78(5):587-591
24. Mellor JE, Laugharne JD, Peet M. Schizophrenic symptoms and dietary intake of n-3 fatty acids. Schizophr Res 1995;18(1):85-6.
25. Arvindakshan M, Ghate M, Ranjekar PK, et al. Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr Res 2003;62(3):195-204.
26. Peet M, Brind J, Ramchand CN, et al. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 2001;49(3):243-51.
27. Fenton WS, Dickerson F, Boronow J, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 2001;158(12):2071-4.
28. Peet M, Horrobin DF. E-E Multicentre Study Group. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 2002;36(1):7-18.
29. Emsley R, Myburgh C, Oosthuizen P, Van Rensburg SJ. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 2002;159(9):1596-8.
30. Al MD, van Houwelingen AC, Kester AD, et al. Maternal essential fatty acid patterns during normal pregnancy and their relationship to neonatal essential fatty acid status. Br J Nutr 1995;74(1):55-68.
31. Hibbeln JR, Salem N, Jr. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr 1995;62(1):1-9.
32. Hibbeln JR. Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord 2002;69(1-3):15-29.
33. Llorente AM, Jensen CL, Voigt RG, et al. Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing. Am J Obstet Gynecol 2003;188(5):1348-53.
34. Zanarini MC, Frankenburg FR. Omega-3 fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry 2003;160(1):167-9.
35. Mitchell EA, Aman MG, Turbott SH, Manku M. Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clin Pediatr 1987;26(8):406-11.
36. Stevens LJ, Zentall SS, Deck JL, et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995;62(4):761-8.
37. Stevens LJ, Zentall SS, Abate ML, et al. Omega-3 fatty acids in boys with behavior, learning, and health problems. Physiol Behav 1996;59(4-5):915-20.
38. Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 2001;139(2):189-96.
39. Kalmijn S, Launer LJ, Ott A, et al. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 1997;42(5):776-82.
40. Barberger-Gateau P, Letenneur L, Deschamps V, et al. Fish, meat, and risk of dementia: cohort study. BMJ 2002;325(7370):932-3.
41. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 2003;60(7):940-6.
42. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Diet and risk of dementia: does fat matter? The Rotterdam Study. Neurology 2002;59(12):1915-21.
1. Hibbeln JR. Fish consumption and major depression. Lancet 1998;351(9110):1213.-
2. Tanskanen A, Hibbeln JR, Tuomilehto J, et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv 2001;52(4):529-31.
3. Tanskanen A, Hibelln JR, Hintikka J, et al. Fish consumption, depression, and suicidality in a general population. Arch Gen Psychiatry 2001;58(5):512-3.
4. Edwards R, Peet M, Shay J, Horrobin D. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998;48(2-3):149-55.
5. Maes M, Christophe A, Delanghe J, et al. Lowered omega-3 polyunsaturated fatty acids in serum phospholipids and cholesterol esters of depressed patients. Psychiatry Res 1999;85(3):275-91.
6. Lundbaek JA, Andersen OS. Lysophospholipids modulate channel function by altering the mechanical properties of lipid bilayers. J Gen Physiol 1994;104(4):645-73.
7. Delion S, Chalon S, Guilloteau D, et al. Alpha-linolenic acid dietary deficiency alters age-related changes of dopaminergic and serotonergic neurotransmission in the rat frontal cortex. J Neurochem 1996;66(4):1582-91.
8. Passi S, Cataudella S, Di Marco P, et al. Fatty acid composition and antioxidant levels in muscle tissue of different Mediterranean marine species of fish and shellfish. J Agric Food Chem 2002;50(25):7314-22.
9. Hudson CJ, Young LT, Li PP, Warsh JJ. CNS signal transduction in the pathophysiology and pharmacology of affective disorders and schizophrenia. Synapse 1993;13(3):278-93.
10. Sperling RI, Benincaso AI, Knoell CT, et al. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 1993;91(2):651-60.
11. Endres S. Messengers and mediators: interactions among lipids, eicosanoids and cytokines. Am J Clin Nutr 1993;57(5 suppl):798S-800S.
12. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003;23(2):e20-e30.
13. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159(3):477-9.
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