Evidence-Based Reviews

Omega-3 fatty acids: Do ‘fish oils’ have a therapeutic role in psychiatry?

Current Psychiatry. 2004 January;3(1):25-52

References

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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.

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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 depression^1,2 and suicidal ideation³ decrease in populations as fish consumption increases. Some studies^4,5 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) neurotransmission^6,7
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).

Box

What are the omega-3 fatty acids?

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 neurotransmission^6,7 and signal transduction pathways^9,10 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: mean HRSD scores (-9.9) compared with placebo group (-6.1) secondary outcome measures (MADRS and BDI)
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