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Drugs 2005; 65 (8): 1051-1059

Drugs 2005; 65 (8): 1051-1059  2005 Adis Data Information BV. All rights reserved.
Omega-3 Fatty Acids in the Treatment
of Psychiatric Disorders
Malcolm Peet and Caroline Stokes
Swallownest Court Hospital, Doncaster and South Humber Healthcare NHS Trust, Sheffield, UK
The importance of omega-3 fatty acids for physical health is now well recognised and there is increasing evidence that omega-3 fatty acids may also beimportant to mental health. The two main omega-3 fatty acids in fish oil,eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have importantbiological functions in the CNS. DHA is a major structural component of neuronalmembranes, and changing the fatty acid composition of neuronal membranesleads to functional changes in the activity of receptors and other proteins embed-ded in the membrane phospholipid. EPA has important physiological functionsthat can affect neuronal activity. Epidemiological studies indicate an associationbetween depression and low dietary intake of omega-3 fatty acids, and biochemi-cal studies have shown reduced levels of omega-3 fatty acids in red blood cellmembranes in both depressive and schizophrenic patients.
Five of six double-blind, placebo-controlled trials in schizophrenia, and four of six such trials in depression, have reported therapeutic benefit from omega-3 fattyacids in either the primary or secondary statistical analysis, particularly when EPAis added on to existing psychotropic medication. Individual clinical trials havesuggested benefits of EPA treatment in borderline personality disorder and ofcombined omega-3 and omega-6 fatty acid treatment for attention-deficit hyperac-tivity disorder. The evidence to date supports the adjunctive use of omega-3 fattyacids in the management of treatment unresponsive depression and schizophrenia.
As these conditions are associated with increased risk of coronary heart diseaseand diabetes mellitus, omega-3 fatty acids should also benefit the physical state ofthese patients. However, as the clinical research evidence is preliminary, large,and definitive randomised controlled trials similar to those required for thelicensing of any new pharmacological treatment are needed.
The importance of omega-3 fatty acids for physi- arthritis.[3] Homo sapiens evolved in an omega-3- cal well-being has been recognised for several de- rich nutritional environment.[4] Over the last centu- cades.[1] Amongst other health benefits, omega-3 ry, dietary intake of omega-3 fatty acids has de- fatty acids have anti-inflammatory, antithrombotic, clined, whereas there has been an increase in the antiarrhythmic and hypolipidaemic effects.[1] Be- amount of omega-6 fatty acids. This altered balance cause of this, these fatty acids are beneficial in the of fatty acids is regarded as detrimental to the health prevention and treatment of physical illnesses rang-ing from coronary heart disease[2] to rheumatoid of the population.[1] Peet & Stokes More recently, there has been increasing evi- it can be obtained only from the diet. Other omega-3 dence that omega-3 fatty acids are important not fatty acids, including EPA and DHA, can be only for physical health but also for brain develop- metabolised from ALA by a process of desaturation, ment and function.[5-7] As a result, there has been elongation and β-oxidation.[1] However, this process increasing interest in the use of omega-3 fatty acids is very inefficient[8] and in practice most EPA and for the treatment of mental health problems. This DHA comes from food sources. The main food review summarises the background, rationale, pub- providing EPA and DHA is fish, and the fish in turn lished double-blind clinical trials and clinical impli- obtain these omega-3 fatty acids by eating algae.
cations relating to omega-3 fatty acids in the treat- Fish oil contains a mixture of EPA, DHA and other ment of psychiatric disorders.
fatty acids. Highly purified EPA and DHA are nowavailable.
1. Background and Rationale
Omega-3 fatty acids have important effects on brain function. DHA is a major structural compo- Eicosapentaenoic acid (EPA) and docosahexae- nent of phospholipid in neuronal cell membranes.[9] noic acid (DHA), are considered to be the most Altering the lipid environment of the phospholipid important omega-3 fatty acids in relation to brain bilayer leads to functional changes in the activity of function. The parent fatty acid for the omega-3 receptors and other proteins embedded in the mem- series is α-linolenic acid (ALA) [see figure 1], brane phospholipid.[10] EPA is not present in neu- which is regarded as an essential fatty acid because ronal cell membranes, but has other important phys-iological functions, including a role as precursor foreicosanoids and modulator of cytokines that have α-Linolenic acid neurotransmitter and neuromodulatory activity.[10] Thus, there are many potential mechanisms wherebyomega-3 fatty acids can modulate brain function.
The first suggestion that omega-3 fatty acids might be helpful for the treatment of mental disorderwas made by Rudin,[11] who suggested that mental Eicosapentaenoic acid(20:5n-3) health problems were caused by omega-3 fatty aciddeficiency and reported successful treatment of a number of patients with flax oil, which is a rich source of ALA. However, this work was largely ignored. The modern resurgence of interest in thetherapeutic benefits of omega-3 fatty acids was the Tetrahexaenoic acid (24:6n-3) direct result of observations that levels of omega-3 Acyl coenzyme-A desaturase fatty acids are reduced in the cell membranes of erythrocytes of patients with schizophrenia and de-pression.[12-14] The first studies with fish oil deriva-tives were carried out in schizophrenic patients, andthis was closely followed by studies in patients withmood disorders. Studies in patients with depression Docosahexaenoic acid were further supported by epidemiological evidence showing that international variations in the preva-lence of depression correlated closely with fish con- Fig. 1. Pathway for the synthesis of eicosapentaenoic acid and
docosahexaenoic acid from the parent essential fatty acid, α-li-
sumption in the national diet.[15] This early finding nolenic acid.
has been supported by further studies showing fish  2005 Adis Data Information BV. All rights reserved.
Drugs 2005; 65 (8) Omega-3 Fatty Acids in Psychiatry Table I. Omega-3 fatty acids in the treatment of schizophrenia: double-blind, placebo-controlled trials
Add-on; EPA 2 g/day EPA > DHA = placebo Mono; EPA 2 g/day Peet and Horrobin[21] Add-on; ethyl EPA 1, 2 and 4 g/day EPA > placeboIn clozapine subgroup only, 2g most effective Emsley et al.[20] Add-on; ethyl EPA 3 g/day EPA > placebo for schizophrenic symptoms and also tardive dyskinesia Berger et al.[23] Add-on; ethyl EPA 2 g/day EPA > placebo for dose of antipsychotic Fenton et al.[22] Add-on; ethyl EPA 3 g/day Add-on = added to existing medication; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; mono = monotherapy.
consumption correlates not only with rates of de- ment in schizophrenic symptoms resulting from pression, but also with rates of bipolar disorder,[16] treatment with 2 g/day of ethyl EPA was seen in the homicide[17] and postnatal depression.[18] subgroup of patients who were receiving clozapinetreatment. This differential benefit of EPA in clozapine-treated patients was not replicated byEmsley et al.,[20] though their findings may have The first pilot study compared an EPA-enriched been confounded by a strong beneficial effect of oil, a DHA-enriched oil and a corn oil (high omega- EPA on tardive dyskinesia, which is found less 6) placebo formulation, added to existing antip- amongst patients treated with clozapine. A fourth sychotic medication for 3 months in a group of study[22] found no benefit from adding 3 g/day of symptomatic schizophrenic patients.[19] It was foundthat patients on the high EPA treatment all showed ethyl EPA to existing antipsychotic medication.
clinical improvement, whereas those treated with Two studies[19,23] have suggested that EPA may have DHA did not differ from placebo in their therapeutic an ‘antipsychotic sparing' effect in patients under- response. Subsequently, all studies in schizophrenia going their first treatment for schizophrenia. In the have focussed on EPA or a mixture of EPA and first of these studies[19] schizophrenic patients were DHA, with no studies using pure DHA.
treated with either EPA or placebo as a monother- A summary of all available placebo-controlled apy. The primary endpoint of the study was the trials of EPA in schizophrenia is shown in table I.
requirement for standard antipsychotic medication.
Several themes arise from these findings. First, all By the end of the 3-month study period all 12 but one of the studies has reported benefits from patients in the placebo group required treatment EPA treatment in either the primary or the seconda- with antipsychotic drugs, whereas only 6 of the 14 ry statistical analysis, however, the results are not patients given EPA required such treatment. Despite consistent across the studies. In two studies[19,20] the the difference in antipsychotic drug usage, symptom addition of EPA to the existing antipsychotic medi- ratings were significantly lower at the end of the cation led to an overall improvement in symptoms.
study in the EPA group relative to the placebo One of these studies[20] found improvement after 12 group. In the second study,[23] first-episode schizo- weeks of treatment, not only in schizophrenia symp- phrenic patients were given ethyl EPA or placebo in toms but also in tardive dyskinesia, which is a addition to standard treatment with risperidone. At movement disorder seen particularly in schizo- the end of treatment it was found that patients given phrenic patients treated long-term with older antip- ethyl EPA required significantly lower dosages of sychotic drugs. A third study[21] which compared 1, antipsychotic medication to produce the same 2 or 4 g/day of highly purified ethyl EPA added toexisting antipsychotic medication for 12 weeks re- clinical benefit, and they also experienced substan- ported no overall improvement in schizophrenic tially less cognitive decline than those given place- symptoms at any dose. However, a marked improve-  2005 Adis Data Information BV. All rights reserved.
Drugs 2005; 65 (8) Peet & Stokes Table II. Omega-3 fatty acids in the treatment of depression: double-blind, placebo-controlled trials
Nemets et al.[24] Add-on; EPA 2 g/day Peet and Horrobin[25] Add-on; EPA 1, 2 and 4 g/day EPA 1 g/day > placebo Add-on; fish oil 9.6 g/day Fish oil > placebo Marangell et al.[27] Mono; DHA 2 g/day Add-on; EPA 6 g/day Frangou and Lewis[30] Add-on; EPA 1 or 2 g/day Add-on = added to existing medication; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; mono = monotherapy.
Whilst these results are encouraging, it is clear fit from a very high daily dose of EPA (6g) added to that further large-scale studies are required in order existing treatment, whereas Frangou and Lewis[30] to establish the potential role for EPA in the treat- reported significant benefit from 1 or 2 g/day of ment of schizophrenia. Current evidence suggests EPA relative to placebo as an add-on treatment.
that these studies might be best focused on treatment There have been two studies investigating the role of early in the first episode, and on the possible en- omega-3 fatty acids in the prevention of mood sw- hancement of the efficacy of clozapine.
ings for patients with bipolar disorder. The first ofthese studies, in which fish oil was given in addition 3. Mood Disorders
to existing treatment with mood stabilisers, reportedmarked improvement over a 6-month period in pa- Treatment studies in depression have produced tients with bipolar mood disorder.[31] Patients treated more consistent results. The available studies are with omega-3 fatty acids had a significantly longer summarised in table II. In three of the reported period of remission than the placebo group, mainly studies, EPA or fish oil was given in addition to because of an effect on depression. A second study existing antidepressant treatment to patients who using 6 g/day of ethyl EPA as adjunctive treatment were treatment nonresponders.[24-26] All three stud- was negative.[32] Therefore, the possible efficacy of ies in unipolar depression gave strongly positive omega-3 fatty acids as mood stabilisers in bipolar results; two using ethyl EPA[24,25] and one using fish disorder is unresolved.
oil.[26] In a dose-finding study using EPA 1, 2 or 4 g/day an effect was seen at a 1 g/day dosage but not at 4. Other Psychiatric Disorders
higher dosages.[25] Although this may seem counter-intuitive, there is evidence that high doses of EPA, Double-blind, placebo-controlled trials on ome- which go well beyond normal dietary intake, can ga-3 fatty acid treatment have been conducted in have a deleterious effect on cell membrane fatty acid borderline personality disorder, obsessive-compul- profiles by displacing other fatty acids.[21] In con- sive disorder and attention-deficit hyperactivity dis- trast with the broadly positive findings with EPA, a order (ADHD).
study using DHA monotherapy showed no thera- In borderline personality disorder, it was reported peutic benefit.[27] This is consistent with an early that ethyl EPA 1 g/day was superior to placebo in pilot study in which EPA or DHA were given as diminishing aggression as well as the severity of monotherapy to a small number of patients with depressive symptoms.[33] This is consistent with depression. The four patients treated with EPA findings from two double-blind, placebo-controlled showed an average 56% improvement on a standard trials in healthy subjects, which demonstrated an depression rating scale, compared with an 18% im- anti-aggressive effect of DHA.[34,35] provement in the five patients given DHA.[28] Studies in ADHD have given mixed results. Two Two studies in bipolar depression, so far pub- double-blind, placebo-controlled studies of DHA in lished only as abstracts, have produced conflicting the treatment of ADHD found no significant differ- findings. Keck et al.[29] reported no significant bene- ence between the effects of DHA and placebo.[36,37]  2005 Adis Data Information BV. All rights reserved.
Drugs 2005; 65 (8) Omega-3 Fatty Acids in Psychiatry Other studies using combinations of fish oil and group of schizophrenic patients correlates with diet- evening primrose oil (containing both omega-3 and ary consumption of omega-3 fatty acids,[51] or with omega-6 fatty acids) have shown a significant treat- polyunsaturated fatty acids more generally.[52] Tak- ment effect relative to placebo on ADHD symp- en together with evidence of efficacy of EPA in the toms.[38,39] A single study of adjunctive EPA in the treatment of schizophrenia, this would indicate that treatment of obsessive-compulsive disorder reported omega-3 fatty acids are capable of modulating the no clinical benefit.[40] severity of schizophrenia, but that dietary lack of Epidemiological studies have indicated that con- omega-3 fatty acids does not have the same central sumption of one fish meal a week is associated with aetiological importance as they may have in depres- a reduced risk of Alzheimer's disease,[41] although this may be confounded by educational level as In treatment studies for both schizophrenia and better educated people eat more fish.[42] However, depression, current evidence suggests that EPA rath- there are no published controlled trials of omega-3fatty acids in the treatment of Alzheimer's disease.
er than DHA is the effective agent. Whilst thisstatement must be qualified by the relative paucityof studies using pure DHA, it does raise questions 5. Mode of Action
about mode of action. Most investigators initiallyassumed that DHA would be the primary effective Studies of omega-3 fatty acids in mental disor- agent, because it is of such considerable structural ders such as schizophrenia and depression were and functional importance in the brain. If EPA is stimulated by observations that levels of omega-3 indeed the active agent, then this would indicate a fatty acids were reduced in cell membranes of pa- more indirect effect based on the other biological tients with these conditions. Therefore, it was postu- actions of EPA. Thus, EPA is an eicosanoid precur- lated that supplementation of omega-3 fatty acids sor,[53] acts at the peroxisome proliferator-activated may be of therapeutic benefit. In the case of depres- receptor[54] and (like DHA) can modulate gene ex- sion this simple relationship might still hold true.
pression.[55] It has been suggested that EPA is work- Epidemiological studies support a relationship be-tween dietary intake of fish and national prevalence ing as an inhibitor of phospholipase A2, which is of depression.[15,43] Several, though not all, studies known to be elevated in patients with schizophre- within populations have supported this relation- nia.[56] Others have suggested that omega-3 fatty ship.[44-47] In depressed patients, a correlation be- acids may act as mood stabilisers by inhibiting pro- tween dietary intake of omega-3 fatty acids and tein kinase C, in a similar way to lithium and valpro- severity of depression has been demonstrated.[48] In ic acid, which are used as mood stabilisers.[57] It has schizophrenia, the situation appears to be more com- also been suggested that schizophrenia is a proin- plex. Some of the earlier findings of reduced cell flammatory condition, which is supported by in- membrane levels of both omega-3 and omega-6 creased risk of autoimmune disorders in first-degree fatty acids were confounded by extraneous factors relatives of schizophrenic patients, and increased including smoking, medication and storage artefact.
levels of proinflammatory cytokines in schizophren- More recent studies have given less consistent re- ic patients.[58] Thus, EPA could be acting through an sults.[49] International variations in the long-term anti-inflammatory effect. In support of this concept outcome of schizophrenia (which has a better out- a recent study has shown that celecoxib, a cyclo- come in developing countries than in the Western oxygenase-2 inhibitor, is of therapeutic benefit in developed world) show correlations with dietaryconsumption of saturated fat and sugar but not ome- schizophrenia.[59] However, at the present time the ga-3 fatty acids.[43,50] Separate studies have shown true mode of action of omega-3 fatty acids is un- that variations in severity of symptoms within a  2005 Adis Data Information BV. All rights reserved.
Drugs 2005; 65 (8) Peet & Stokes 6. Side Effects
ent. Epidemiological studies in depression suggestthat one or two fish meals a week might confer The more common adverse effects of fish oil protection against subsequent development of de- preparations, particularly in higher dosages, include pressive illness.[44] This is similar to the recom- nausea, fishy belching and looseness of the mended level of fish intake for the prevention of stools.[60] Because of these effects, the blinding of cardiovascular disease. There are concerns about some of the earlier studies of fish oils in the treat- contamination of fish with dioxins, dioxin-like com- ment of mental health problems has been question- pounds and methyl mercury.[69] For this reason ed.[61] These problems are much less apparent with many countries have issued advice about the maxi- purified ethyl ester preparations of omega-3 fatty mum quantities of fish that should be consumed, acids. The safety of omega-3 fatty acids is evident which in some cases includes advice about different from their acceptance by the regulatory authorities types of fish as well as particular cautions for wo- of several countries. For example, the US FDA men who are pregnant or of childbearing potential.
recognises the safety of menhaden oil up to a dose of As this advice varies somewhat between countries, 3 g/day of EPA plus DHA,[62] the ethyl esters of local sources should be consulted.
EPA plus DHA are registered for prescription in the The evidence suggests that dosages of 1–2 g/day, UK in doses up to 4 g/day[60] and pure ethyl EPA has particularly of EPA, are required. This level cannot been marketed in Japan in doses up to 2.7 g/day be safely attained by diet alone. Fish oil preparations available from health food stores and pharmacists Most of the other associated effects of omega-3 are of variable quality and composition, and are fatty acids are beneficial, particularly in relation to potentially unsafe in high dosage because of con- cardiovascular disease. This is important in a popu- taminants that vary between products. Pharmaceuti- lation with mental health problems; patients with cal grade omega-3 fatty acid preparations will deliv- both depression and schizophrenia have been shown er the necessary quantity of omega-3 fatty acids to be at substantially increased risk of coronary within the dosages that are already prescribed for artery disease.[64,65] Furthermore, some of the com- lipid and cardiovascular disorders.
monly used antipsychotic medications, such asclozapine and olanzapine, are associated with ele- 8. Clinical Implications
vated plasma triglyceride levels, which are normal-ised during treatment with omega-3 fatty acids.[21] The potential role of omega-3 fatty acids for Omega-3 fatty acids generally do not appear to mental health is just one aspect of a huge body of have clinically significant effects on bleeding evidence suggesting abnormalities of phospholipid time,[66] but caution has been urged when using and fatty acid metabolism in schizophrenia.[70] The these preparations in high dosages, or for patients use of omega-3 fatty acids in the treatment of mental with pre-existing haemorrhagic disorders or those health problems is the first therapeutic approach to on anticoagulant treatment. There have been con- emerge from this body of evidence. Most research cerns that omega-3 fatty acid treatment might wors- has been performed on omega-3 fatty acids in the en glycaemic control in patients with diabetes mel- treatment of depression and schizophrenia. These litus, but this has not been substantiated in two meta- are best described as pilot studies and in most cases they have produced encouraging positive findings,although with some discrepancies. There is no long- 7. Diet, Health Supplements or
er any point in conducting further small pilot studies in mood disorders and schizophrenia. Very large, The available evidence supporting the benefits of definitive randomised controlled trials similar to omega-3 fatty acids for mental health raises the those required for the licensing of any new pharma- question of how best to increase intake of this nutri- cological treatment are needed.
 2005 Adis Data Information BV. All rights reserved.
Drugs 2005; 65 (8) Omega-3 Fatty Acids in Psychiatry 2. Hu FB, Willet WC. Optimal diets for prevention of coronary There remains the question of whether the availa- heart disease. JAMA 2002; 288: 2569-78 ble information should be applied clinically in the 3. Cleland LG, James MJ, Proudman SM. The role of fish oils in current state of knowledge. It is well recognised that the treatment of rheumatoid arthritis. Drugs 2003; 63 (9):845-53 depression and schizophrenia are associated with 4. Crawford MA, Bloom M, Cunnane S, et al. Docosahexaenoic very high rates of coronary heart disease.[64,65] It is acid and cerebral evolution. World Rev Nutr Diet 2001; 88:6-17 accepted that changes in nutrition, including the 5. Uauy R, Peirano P, Hoffman D, et al. Role of essential fatty consumption of one or two meals of fish per week, acids in the function of the developing nervous system. Lipids will significantly reduce the rate of coronary heart 1996; 31 Suppl.: S167-76 disease.[2] It is noteworthy that a number of other 6. Wainwright PE. Dietary essential fatty acids and brain function: a developmental perspective on mechanisms. Proc Nutr Soc nutrients that are beneficial to cardiac health, such as folic acid,[71] also have some evidence of benefit as 7. Salem Jr N, Litman B, Kim HY, et al. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 2001; 36: adjunctive treatments in depression and schizophre- nia.[72,73] Therefore, it is the opinion of these review- 8. Burdge G. Alpha-linolenic acid metabolism in men and women: ers that nutritional advice, including advice on con- nutritional and biological implications. Curr Opin Clin NutrMetab Care 2004; 7: 137-44 sumption of fish, should form part of the holistic 9. Horrobin DF, Manku MS, Hillman H, et al. Fatty acid levels in management of all patients with mood disorders and the brains of schizophrenic and normal controls. Biol Psychia- schizophrenia. If that advice also helps to improve try 1991; 30: 795-805 10. Fenton WS, Hibbeln J, Knable M. Essential fatty acids, lipid the mental state, then that is an added bonus.
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11. Rudin DO. The major psychosis and neuroses as omega-3 essential fatty acid deficiency syndrome: substrate pellagra.
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Schizophr Res 1994; 13: 217-26 However, it is worth noting that most treatment 14. Glen AL, Glen EM, Horrobin DF, et al. A red cell membrane abnormality in a subgroup of schizophrenic patients: evidence guidelines will include some recommendations that for two diseases. Schizophr Res 1994; 12: 53-61 are based more on opinion than on conclusive evi- 15. Hibbeln JR. Fish consumption and major depression [letter].
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mother's milk, and prevalence rates of postpartum depression:a cross-national ecological analysis. J Affect Disord 2002; 69:15-29 19. Peet M, Brind J, Ramchand CN, et al. Two double-blind place- bo-controlled pilot studies of eicosapentaenoic acid in the Dr Peet has received research funding from Laxdale Ltd.
treatment of schizophrenia. Schizophr Res 2001; 49: 243-51 He is a scientific advisor to Laxdale Ltd and Minami Nutri- 20. Emsley R, Myburgh C, Ousthuizen P, et al. Randomised, place- tion, and has received speaking honoraria from Eli Lilly, bo-controlled study of ethyl-eicosapentaenoic acid as supple- Janssen, Novartis and Organon. Ms Stokes has no conflicts of mental treatment in schizophrenia. Am J Psychiatry 2002; 159: interest that are directly relevant to the content of this review.
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