Hostname: page-component-7c8c6479df-24hb2 Total loading time: 0 Render date: 2024-03-27T01:04:28.581Z Has data issue: false hasContentIssue false

Effects of omega 3 fatty acids supplementation in behavior and non-neurodegenerative neuropsychiatric disorders

Published online by Cambridge University Press:  17 May 2012

R. M. Ortega*
Affiliation:
Departamento de Nutrición, Facultad de Farmacia, Universidad Complutense, 28040Madrid, Spain Research group UCM-920030, Departamento de Nutrición, Facultad de Farmacia, Universidad Complutense, 28040Madrid, Spain
E. Rodríguez-Rodríguez
Affiliation:
Research group UCM-920030, Departamento de Nutrición, Facultad de Farmacia, Universidad Complutense, 28040Madrid, Spain Sección Departamental de Química Analítica, Facultad de Farmacia, Universidad Complutense, 28040Madrid, Spain
A. M. López-Sobaler
Affiliation:
Departamento de Nutrición, Facultad de Farmacia, Universidad Complutense, 28040Madrid, Spain Research group UCM-920030, Departamento de Nutrición, Facultad de Farmacia, Universidad Complutense, 28040Madrid, Spain
*
*Corresponding author: R. M. Ortega, fax +34 91 394 18 10, email rortega@farm.ucm.es
Rights & Permissions [Opens in a new window]

Abstract

This work provides a systematic review of all published randomised, controlled clinical trials (RCT) investigating the effects of n-3 PUFA intake on the prevention and treatment of non-neurodegenerative neuropsychiatric disorders. Five databases (PubMed, EMBASE, LILACS, CINAHL and The Cochrane Database) were searched for RCT in this area published up to April 2011. The selected studies all involved human participants and included a comparison group. Thirty eight studies were identified, which examined the influence of n-3 PUFA supplementation on the prevention/treatment of depression (non-perinatal) (n 23), perinatal depression (n 6) and attention deficit hyperactivity disorder (ADHD) (n 9). Great heterogeneity was noticed in terms of study design, the doses of n-3 PUFA administered, and study duration. Some benefit was noted with respect to the treatment of hyperactivity and depression in over half the examined studies, although the evidence was not conclusive. For any firm conclusions to be drawn, further studies will be needed that take into account the initial n-3 PUFA status of the subjects. Excessive n-3 PUFA intakes might be associated with a greater risk of peroxidation events and therefore neuropsychiatric deterioration. Indeed, some studies only recorded benefits when lower doses were administered. It is therefore important that the dose required to achieve any potential benefit be determined.

Type
Full Papers
Copyright
Copyright © The Authors 2012

There is biochemical evidence that n-3 polyunsaturated fatty acids (n-3 PUFA) play an important role in neural structure and function. The brain and central nervous system contain high concentrations of n-3 PUFA and several studies suggest a role for them in nervous system activity, the neuroplasticity of nerve membranes, synaptogenesis, synaptic transmission and neurotransmitter uptake(Reference Chang, Ke and Chen1). In fact, reduced blood levels of n-3 PUFA have been associated with a number of neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, schizophrenia and depression(Reference Horrobin, Chiu E and Katona2, Reference Young and Conquer3).

n-3 PUFA are available from dietary sources only; an insufficient intake may therefore be associated with psychiatric effects(Reference Freeman, Hibbeln and Wisner4). Some evidence exists that suggests supplementation with individual n-3 PUFA or their combinations can reduced the intensity of the symptoms associated with certain neuropsychiatric conditions(Reference Bourre5).

Nevertheless, although some studies find positive effects associated with supplementation, others do not find this benefit(Reference Silvers, Woolley and Hamilton6Reference Raz, Carasso and Yehuda8). It is worth mentioning that messages which recommend the use of n-3 PUFA supplements to prevent and reduce the risk of various diseases such as depression have spread rapidly among the population based on studies that find positive results(Reference Appleton, Rogers and Ness9). However, some aspects must be taken into account before releasing a general recommendation: if the effects are valid for both healthy and sick subjects and what doses and time of treatment are required to achieve the effects.

The aim of the present systematic review was to examine all published RCT investigating the effects of dietary supplementation with n-3 PUFA on the prevention and treatment of non-neurodegenerative neuropsychiatric conditions.

Experimental method

A computerized search was conducted for clinical trials in the Medlars Online International Literature (MEDLINE, via PubMed), the EMBASE®, the Latin American and Caribbean Heath Sciences Literature (LILACS), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane databases. The search terms and equations used for the PubMed search were: “Fatty Acids, Omega-3”[Mesh] AND (“Depression”[Mesh] OR “Mood disorders” [Mesh] OR “Attention Deficit Disorder with Hyperactivity”[Mesh]), limited to ‘clinical trials’ and ‘humans’ (Fig. 1). Similar equations were used with the other databases. The references in these returned articles were checked manually for further studies.

Fig. 1 Literature search flow chart.

Report inclusion and data extraction

The titles and abstracts of the articles detected (n 182 detected by the 1st April 2011) were inspected independently by two researchers (AMLS and ERR) to select those relevant to the present work. Initial discrepancies between these researchers' decisions were either resolved or a third reviewer (RMO) was called to make a judgement. Duplicates, review articles and non-relevant articles were excluded (n 122). Twenty two of the remaining 60 articles were rejected for the reasons shown in Fig. 1, which summarizes the inclusion/exclusion criteria of the work. The data of the 38 remaining articles were tabulated by all three of the above researchers. When data were incomplete, the corresponding authors were contacted and asked to provide the missing information. Tables 1–3 summarise the design of and the results provided by the 38 articles finally selected.

Table 1 Randomised controlled clinical trials of supplementation with n-3 PUFA in subjects with depression and related disorders

MDD =  major depression disorder; BD =  bipolar disorder; PD =  psychological distress; NR =  not reported

Table 2 -Randomized controlled clinical trials of supplementation with n-3 PUFA in patients with perinatal depression

MDD =  major depression disorder; NR =  not reported

Table 3 Randomised controlled clinical trials of supplementation with n-3 PUFA in children with ADHD

GLA: gamma linolenic acid

Because pregnancy is a specific physiological situation, data from studies about perinatal depression are presented separately from studies examining the effect of n-3 PUFA supplementation in depression at other stages of life (Table 2).

Results

Twenty three RCT (published since May 1999) examined the effect of n-3 PUFA supplementation on the prevention and treatment of non-perinatal depression (Table 1). The studies were heterogeneous in terms of sample size (which ranged from 14(Reference Chiu, Huang and Chen10) to 302 subjects(Reference van de Rest, Geleijnse and Kok11)). Two studies involved only women(Reference Lucas, Asselin and Merette12, Reference Rondanelli, Giacosa and Opizzi13), and two only children(Reference Gracious, Chirieac and Costescu14, Reference Nemets, Nemets and Apter15). The diagnosis of the study subjects also varied, from major depressive disorder (MDD)(Reference Rondanelli, Giacosa and Opizzi13, Reference Nemets, Nemets and Apter15Reference Su, Huang and Chiu23), to bipolar disorder (BD)(Reference Chiu, Huang and Chen10, Reference Gracious, Chirieac and Costescu14, Reference Frangou, Lewis and McCrone24Reference Stoll, Severus and Freeman26), depression but not MDD(Reference Lucas, Asselin and Merette12, Reference Rogers, Appleton and Kessler27), depression with other pathologies(Reference Bot, Pouwer and Assies28Reference Freund-Levi, Basun and Cederholm31) and healthy volunteers(Reference van de Rest, Geleijnse and Kok11, Reference Antypa, Van der Does and Smelt32). The type and quantity of n-3 PUFA administered varied too, from 0·4 g/d(Reference van de Rest, Geleijnse and Kok11) to 9·6 g/d(Reference Stoll, Severus and Freeman26). Six studies involved the administration of EPA (20 : 5n-3) only, employing doses of 1 g/d(Reference Jazayeri, Tehrani-Doost and Keshavarz16, Reference Mischoulon, Papakostas and Dording19, Reference Peet and Horrobin21, Reference Frangou, Lewis and McCrone24, Reference Bot, Pouwer and Assies28) to 6·6 g/d(Reference Gracious, Chirieac and Costescu14). Two studies involved the administration of DHA (22 : 6n-3) only(Reference Marangell, Martinez and Zboyan17, Reference Mischoulon, Best-Popescu and Laposata18). The remaining studies involved the administration of both EPA and DHA in varying quantities, with the EPA/DHA ratio ranging from 0·25(Reference Silvers, Woolley and Hamilton22) to 7(Reference Lucas, Asselin and Merette12, Reference Antypa, Van der Does and Smelt32). In some studies the subjects received no pharmacological treatment as part of the study(Reference van de Rest, Geleijnse and Kok11Reference Gracious, Chirieac and Costescu14, Reference Jazayeri, Tehrani-Doost and Keshavarz16, Reference Mischoulon, Best-Popescu and Laposata18, Reference Mischoulon, Papakostas and Dording19, Reference Rogers, Appleton and Kessler27, Reference Antypa, Van der Does and Smelt32), while in others(Reference Chiu, Huang and Chen10, Reference Carney, Freedland and Rubin29) some drug was administered. In the majority of studies(Reference Nemets, Nemets and Apter15, Reference Nemets, Stahl and Belmaker20Reference Stoll, Severus and Freeman26, Reference Bot, Pouwer and Assies28, Reference da Silva, Munhoz and Alvarez30, Reference Freund-Levi, Basun and Cederholm31), however, the subjects continued with their normal treatment.

Six RCT (published since May 2003) examined the effect of n-3 PUFA supplementation on the prevention and treatment of perinatal depression (Table 2). Again, these were heterogeneous in terms of sample size, which ranged from 26(Reference Rees, Austin and Parker33) to 2399 subjects(Reference Makrides, Gibson and McPhee34). Three studies were performed on pregnant women with MDD(Reference Freeman, Hibbeln and Wisner4, Reference Rees, Austin and Parker33, Reference Su, Huang and Chiu35), analysing the effect of n-3 PUFA supplementation on the course of disease. The remaining trials all examined healthy women to determine the preventive effects of supplementation when given post-partum(Reference Llorente, Jensen and Voigt36), pre-partum(Reference Makrides, Gibson and McPhee34) and over both periods(Reference Doornbos, van Goor and Dijck-Brouwer37). The type and quantity of n-3 PUFA administered also differed widely. In one study only DHA(Reference Llorente, Jensen and Voigt36) was given, in three studies different quantities of DHA+EPA(Reference Makrides, Gibson and McPhee34, Reference Su, Huang and Chiu35, Reference Freeman, Davis and Sinha38) were given, in one(Reference Rees, Austin and Parker33) DHA+EPA and an n-6 PUFA were given, and in one(Reference Doornbos, van Goor and Dijck-Brouwer37) DHA+AA (20 : 4n-6) or DHA alone was given. The doses of n-3 PUFA given ranged from 0·2 g/d(Reference Llorente, Jensen and Voigt36) to 3·4 g/d(Reference Su, Huang and Chiu35).

Nine RCT (published since August 2001) examined the effect of n-3 PUFA supplementation on the prevention and treatment of ADHD (Table 3). Again, the sample size was heterogeneous, with a range of 37(Reference Belanger, Vanasse and Spahis39) to 129(Reference Sinn and Bryan40) subjects. Five studies involved supplementation with n-3 and n-6 PUFA. Generally, supplementation with EPA and/or DHA was provided, except in one study(Reference Raz, Carasso and Yehuda41) that involved supplementation with LA (18 : 2n-6) and ALA (18 : 3n-3). The dose of n-3 PUFA administered ranged from 0·345 g/d(Reference Voigt, Llorente and Jensen42) to 1·4 g/d(Reference Belanger, Vanasse and Spahis39). In five studies(Reference Belanger, Vanasse and Spahis39Reference Raz, Carasso and Yehuda41, Reference Gustafsson, Birberg-Thornberg and Duchen43, Reference Johnson, Ostlund and Fransson44) the subjects received no pharmacological treatment, in one a stimulant medication(Reference Voigt, Llorente and Jensen42) was provided, and in two(Reference Hirayama, Hamazaki and Terasawa45, Reference Richardson and Puri46) the subjects continued with their normal medication.

Discussion

n-3 PUFA and depression disorders

Depression is very common – one in five people become depressed at some point in their lives(Reference Olfson, Shea and Feder47). A significant proportion (10–20 %) of patients do not respond at all or respond poorly to therapy(Reference McIntyre and O'Donovan48); useful prevention and treatment strategies are therefore a priority.

Although observational studies have indicated that depression is associated with lower levels of total n-3 PUFA and those of both EPA and DHA(Reference Lin and Su49), only two studies were found that analysed the role of n-3 PUFA supplements in healthy persons, the results of which were not conclusive.

Van de Rest et al. (Reference van de Rest, Geleijnse and Kok11) reported no effect on mental well-being for either of two doses of n-3 PUFA administered (0·4 g/d and 2·0 g/d) compared to a placebo. In contrast, Antipa et al. (Reference Antypa, Van der Does and Smelt32) reported a positive effect of supplementation on cognitive reactivity, risky decision-making and control/perfectionism score. The dose of n-3 PUFA used in the latter work was also 2 g/d, although the EPA/DHA ration was higher (7·0 compared to 1·3).

The majority of studies, which employed doses of up to 2·5 g/d, performed on patients with depression, MDD or BD who received no pharmacological treatment, recorded a positive effect for EPA supplementation(Reference Chiu, Huang and Chen10, Reference Lucas, Asselin and Merette12), DHA supplementation, (Reference Mischoulon, Best-Popescu and Laposata18) and their combination(Reference Lucas, Asselin and Merette12, Reference Rondanelli, Giacosa and Opizzi13). Gracious et al. (Reference Gracious, Chirieac and Costescu14) also reported a positive effect, but for a dose of 6·6 g/d EPA. Those studies that found no difference in effect between the administration of n-3 PUFA and placebo also employed low/moderate doses of n-3 PUFA(Reference Marangell, Martinez and Zboyan17, Reference Mischoulon, Papakostas and Dording19, Reference Rogers, Appleton and Kessler27) (up to 2 g/d). However, the EPA/DHA ratio was much higher in those that found positive effects (EPA/DHA = 2·0(Reference Rondanelli, Giacosa and Opizzi13)-7·0(Reference Lucas, Asselin and Merette12)) compared to those that found no effect (EPA/DHA = 0·70)(Reference Rogers, Appleton and Kessler27).

More trials report a positive effect for n-3 PUFA supplementation as an adjunct therapy(Reference Nemets, Nemets and Apter15, Reference Nemets, Stahl and Belmaker20, Reference Peet and Horrobin21, Reference Su, Huang and Chiu23, Reference Frangou, Lewis and McCrone24, Reference Stoll, Severus and Freeman26) than those that found no effect(Reference Silvers, Woolley and Hamilton22, Reference Keck, Mintz and McElroy25). As in those studies that involved n-3 PUFA supplementation only, those that found this positive effect involved lower doses of EPA ( < 2·0 g/d(Reference Silvers, Woolley and Hamilton22, Reference Keck, Mintz and McElroy25)) or a higher EPA/DHA ratio(Reference Nemets, Nemets and Apter15, Reference Su, Huang and Chiu23, Reference Stoll, Severus and Freeman26) (2·0 vs. 0·25(Reference Silvers, Woolley and Hamilton22) in positive and negative trials respectively). Carney et al. (Reference Carney, Freedland and Rubin29) (who administered sertraline) and Chiu et al. (Reference Chiu, Huang and Chen10) (who used valproate) found no evidence that n-3 PUFA increased the effect of medication on depression or manic phase BD symptoms.

The trials that involved n-3 PUFA administration with and without pharmacological treatment found EPA to produce more promising results with respect to the improvement of depression symptoms than DHA monotherapy(Reference Pouwer, Nijpels and Beekman50, Reference Martins51). A specific ratio of EPA/DHA might be the most effective(Reference Bot, Pouwer and Assies28). However, whereas increased n-3 PUFA intake might alleviate depressive symptoms, there is little evidence it is of any benefit in the treatment of mania(Reference Chiu, Huang and Chen10, Reference Hegarty and Parker52).

Depression is a common co-morbid disorder in both type 1 and type 2 diabetes mellitus(Reference Bot, Pouwer and Assies28), but a considerable percentage of diabetic subjects receiving antidepressant drugs does not achieve full remission(Reference Lustman and Clouse53). Depression is also frequent in patients with Parkinson Disease(Reference Nuyen, Schellevis and Satariano54, Reference Wichowicz, Slawek and Derejko55), but antidepressant treatment given in addition to Parkinson's medication can often result in collateral effects and adverse reactions(Reference Vajda and Solinas56). Depression may also occur in the early stages of Alzheimer disease(Reference McKeith and Cummings57). However, very few studies have been performed in such patients. Bot et al. (Reference Bot, Pouwer and Assies28) found no evidence of a therapeutic effect of 1·0 g/d ethyl–EPA as an add-on to antidepressant medication compared to placebo in diabetic patients with depression, and Freund-Levi et al. (Reference Freund-Levi, Basun and Cederholm31) observed no positive effect on depression symptoms in patients with Alzheimer disease. However, in these trials, patients continued with their usual treatment for depression, and this may have masked small effects of treatment with n-3 PUFA. Certainly, da Silva et al. (Reference da Silva, Munhoz and Alvarez30) found that an EPA/DHA ratio of 1·5 improved depressive symptoms in patients with Parkinson disease, even in those who had already been taking antidepressant medication for over a year but still suffered major depression diagnosis.

n-3 PUFA supplementation and perinatal depression

Pregnancy leads to several changes in n-3 PUFA status, including a depletion of maternal plasma DHA under normal dietary conditions, that persist after delivery(Reference Al, van Houwelingen and Hornstra58). Mothers may be at higher risk of post-partum depression when they become depleted in n-3 PUFA, especially DHA, and certainly, depression is quite common in the post-partum period(Reference Jans, Giltay and Van der Does59). The studies described in Table 2 all investigate the possible effects of n-3 PUFA supplementation on the prevention and treatment of perinatal depression.

In studies involving healthy women, supplementation was found not to be associated with any effect on the prevention of depression during(Reference Doornbos, van Goor and Dijck-Brouwer37) or after(Reference Makrides, Gibson and McPhee34, Reference Llorente, Jensen and Voigt36, Reference Doornbos, van Goor and Dijck-Brouwer37) pregnancy. Llorente et al. (Reference Llorente, Jensen and Voigt36) used supplements of DHA at a dose of 200 mg/d with no other treatment, and observed no effect on the incidence of postpartum depression, while Doornbos et al. (Reference Doornbos, van Goor and Dijck-Brouwer37) used supplements of DHA (220 mg/d) or DHA+AA (220 mg/d each), and found them to have no effect either (Table 2). This may have been because no EPA was provided in these studies, or simply because of their small sample sizes. Makrides et al. (Reference Makrides, Gibson and McPhee34) overcame some of the limitations of these studies, such as the low dose of DHA given, the absence of EPA in supplements, and small sample size. However, even when 800 mg/d DHA were provided, along with 100 mg/d EPA, no reduction in the prevention of postpartum depression was seen.

In pregnant women diagnosed with perinatal depression, supplementation was associated with no improvement in symptoms in some studies(Reference Rees, Austin and Parker33, Reference Su, Huang and Chiu35, Reference Freeman, Davis and Sinha38)(Table 2). For example, Freeman et al. (Reference Freeman, Davis and Sinha38) reported no improvements with a dose of EPA+DHA of 1·9 g/d, and Rees et al. (Reference Rees, Austin and Parker33) observed none after providing 6 g/d of fish oil (414 mg EPA+1638 mg DHA). The only study to report some improvement in symptoms was that of Su et al. (Reference Su, Huang and Chiu35). The main difference between this and the previous two studies was that the dose of n-3 PUFA administered and the EPA/DHA ratio (1·8) were higher, and that the Hawthorn effect (a high response in the control group)(Reference Walsh, Seidman and Sysko60) was avoided by not including those individuals in the randomisation procedure who, after a single-blind placebo run-in of 1 week, showed a strong placebo response.

Although the use of n-3 PUFA supplements in depressed pregnant women at the above doses does not appear to improve symptoms, there is insufficient evidence to confirm this at present. New trials should be undertaken in which the consumption of fish is controlled since this has the potential to confound the results. In such trials, depressed pregnant women should be provided an n-3 PUFA supplement with an adequate EPA/DHA ratio, and an adequate control group should be present. The involvement of depressed pregnant women with an inadequate n-3 PUFA status might also be useful. Certainly, future studies should examine the improvement in gestational diabetes since, in the general population, diabetes is associated with a greater risk of depression(Reference Bot, Pouwer and Assies28).

n-3 PUFA supplementation and ADHD

The link between ADHD and n-3 PUFA deficiency was first proposed by Colquhoun & Bunday(Reference Colquhoun and Bunday61). Since then, a number of researchers have reported lower n-3 PUFA levels in children with ADHD than in healthy controls(Reference Stevens, Zhang and Peck62Reference Chen, Hsu and Hsu66), and different studies have been carried out to determine whether n-3 PUFA supplementation can improve symptoms.

Some authors have reported improvements with n-3 PUFA supplements(Reference Sinn and Bryan40, Reference Gustafsson, Birberg-Thornberg and Duchen43, Reference Johnson, Ostlund and Fransson44, Reference Richardson and Puri46, Reference Stevens, Zhang and Peck62), although even the best have been modest. Further, the applicability of these studies to children with ADHD is questionable since some of studies focused on children not properly diagnosed with ADHD (DSM-IV)(Reference Sinn and Bryan40, Reference Richardson and Puri46, Reference Stevens, Zhang and Peck62), others were unable to demonstrate clinical improvements in more than one setting(Reference Sinn and Bryan40, Reference Richardson and Puri46, Reference Stevens, Zhang and Peck62), and some found positive results only when comparing certain subgroups of children(Reference Gustafsson, Birberg-Thornberg and Duchen43, Reference Johnson, Ostlund and Fransson44, Reference Richardson and Puri46).

A number of studies report no effect of supplementation on ADHD(Reference Belanger, Vanasse and Spahis39, Reference Raz, Carasso and Yehuda41, Reference Voigt, Llorente and Jensen42, Reference Hirayama, Hamazaki and Terasawa45); in all these studies the children had been properly diagnosed with ADHD (DSM-IV).

A number of limitations could have conditioned the results obtained in these studies on children with ADHD. The majority had a small sample size as a result of a high dropout rate. Although some studies found that children with ADHD had a less adequate n-3 PUFA status than the controls(Reference Belanger, Vanasse and Spahis39, Reference Gustafsson, Birberg-Thornberg and Duchen43, Reference Stevens, Zhang and Peck62), virtually none tried to determine whether the baseline status was adequate and none indicated, when effects of supplementation on ADHD were seen, whether the children involved had any starting deficiency. This poor design quality might explain the results obtained in many of these studies: while the initial status of a subject might be improved by supplementation, if a deficiency remains uncorrected no improvement in symptoms might occur.

The lack of positive results observed in the examined studies might also be due to their short-term nature (none lasted longer than four months) and the low n-3 PUFA doses employed. Although the fatty acid composition of the plasma and erythrocytes could change over such short periods, the turnover of fatty acids in the brain is likely to be quite low in children. Longer periods of supplementation and/or larger supplements might be required for any change in the fatty acid content of the central nervous system to be seen.

Given the above, and in agreement with that stated in a recent review by Raz & Gabis(Reference Raz and Gabis67), support for the use of essential fatty acids (EFA) supplements in children with ADHD will require further studies with more rigorous methodologies, proper ADHD diagnosis, known baseline fatty acid status, behavioural assessment in more than one setting, to be blinded (unfortunately problematic with fish oil supplements), and to involve adequate sample sizes and supplementation periods.

Omega 3 and other neuropsychiatric and behavioral disorders

Although initially 3 papers were excluded because they did not fit the inclusion criteria, we find interesting the topics addressed and deserve to be mentioned. The first study is a research conducted in 30 women with borderline personality disorder(Reference Zanarini and Frankenburg68). The main finding is that those women who received 1 g of ethyl-EPA (E-EPA) daily for 8 weeks experienced a greater decrease in depressive and aggressive symptoms than those receiving placebo (mineral oil). In other study, the effect of n-3 PUFA was analyzed in eleven patients with current obsessive-compulsive disorder, who were randomly allocated to 6 weeks of placebo (2 g/day of liquid paraffin) followed by 6 weeks of 2 g/day of EPA, or to EPA followed by placebo(Reference Fux, Benjamin and Nemets69). The authors didn't find significant effect of the supplement. According with the author's conclusion, one of the reasons for its ineffectiveness could be a low EPA dose. The last work studied the effect of n-3 on the Developmental Coordination Disorder(Reference Richardson and Montgomery70). In this study, 117 children aged 5 to 12 years were given a supplement with an omega 3:6 ratio of 4:1 or a placebo for 3 months, followed by a period for 3 months in which all participants received the supplement. Although there were not improvements on motor skills, improvements for active treatment versus placebo were found in reading, spelling, and behaviour over the 3 months of treatment. After the crossover, similar changes were seen in the placebo-active group, whereas children continuing with active treatment maintained or improved their progress. In view of these results is interesting to note the possible use of n-3 in the treatment of some neuropsychiatric and behavioural disorders, yet little studied.

Conclusions

In conclusion, the results of the articles examined in the present work regarding the effect of n-3 PUFA supplementation on the prevention and treatment of non-neurodegenerative neuropsychiatric disorders are inconclusive, although it would seem plausible that such supplementation could provide some benefit.

Having in mind the data of the present review, most of the existing studies do not meet important requirements to elucidate the effect of n-3 PUFA on the prevention and treatment of non-neurodegenerative neuropsychiatric disorders. Future studies should include: a sample size justified by an adequate sample size predetermination (specific to the group under study); the assessment of basal situation in n-3 PUFA in order to include only those patients with a status that could be improved; an appropriate selection criteria (healthy or sick subjects, with or without drug treatment..); control of dietary intake during the intervention, since changes in other nutrients may modify the results of the intervention; and the study of changes in erythrocytes n-3 PUFA levels in order to determine whether dietary intervention corresponds with changes in biochemical parameters. In addition, according with the studies included in the present review, the ratio EPA/DHA should be higher than 1·5-2 and future studies should be long enough to ensure that biochemical changes lead to a functional change (in both behavior or neuropsychiatric disorders). Thus, improving the design of future studies is essential to reach conclusive results.

Acknowledgements

R. M. O. and A. M. L. S. contributed to the planning of the search of this review, A. M. L. S. and E. R. R. decided the analysis and presentation of the results and created the quality assessment tool of the articles. All authors were involved in the analyses of the articles. A. M. L. S. and E. R. R. wrote the introduction and methodology of the first manuscript. All authors wrote the results section and revised and discussed all drafts and approved the final manuscript. There are no conflicts of interest to report. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

References

1 Chang, CY, Ke, DS & Chen, JY (2009) Essential fatty acids and human brain. Acta Neurol Taiwan 18, 231241.Google Scholar
2 Horrobin, D (2002) Cardiovascular disease, affective disorders and impaired fatty acid and phosopholipid metabolism. In Vascular disease and affective disorders, pp. 332352 [Chiu E, AD and Katona, C, editors]. London: United Kingdom.Google Scholar
3 Young, G & Conquer, J (2005) Omega-3 fatty acids and neuropsychiatric disorders. Reprod Nutr Dev 45, 128.Google Scholar
4 Freeman, MP, Hibbeln, JR, Wisner, KL, et al. (2006) Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 67, 19541967.CrossRefGoogle ScholarPubMed
5 Bourre, JM (2005) Dietary omega-3 Fatty acids and psychiatry: mood, behaviour, stress, depression, dementia and aging. J Nutr Health Aging 9, 3138.Google Scholar
6 Silvers, KM, Woolley, CC, Hamilton, FC, et al. (2005) Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids 72, 211218.Google Scholar
7 Grenyer, BF, Crowe, T, Meyer, B, et al. (2007) Fish oil supplementation in the treatment of major depression: a randomised double-blind placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 31, 13931396.CrossRefGoogle ScholarPubMed
8 Raz, R, Carasso, RL & Yehuda, S (2009) The influence of short-chain essential fatty acids on children with attention-deficit/hyperactivity disorder: a double-blind placebo-controlled study. J Child Adolesc Psychopharmacol 19, 167177.Google Scholar
9 Appleton, KM, Rogers, PJ & Ness, AR (2010) Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr 91, 757770.CrossRefGoogle ScholarPubMed
10 Chiu, CC, Huang, SY, Chen, CC, et al. (2005) Omega-3 fatty acids are more beneficial in the depressive phase than in the manic phase in patients with bipolar I disorder. J Clin Psychiatry 66, 16131614.Google Scholar
11 van de Rest, O, Geleijnse, JM, Kok, FJ, et al. (2008) Effect of fish-oil supplementation on mental well-being in older subjects: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 88, 706713.Google Scholar
12 Lucas, M, Asselin, G, Merette, C, et al. (2009) Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial. Am J Clin Nutr 89, 641651.Google Scholar
13 Rondanelli, M, Giacosa, A, Opizzi, A, et al. (2010) Effect of omega-3 fatty acids supplementation on depressive symptoms and on health-related quality of life in the treatment of elderly women with depression: a double-blind, placebo-controlled, randomized clinical trial. J Am Coll Nutr 29, 5564.Google Scholar
14 Gracious, BL, Chirieac, MC, Costescu, S, et al. (2010) Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder. Bipolar Disord 12, 142154.CrossRefGoogle ScholarPubMed
15 Nemets, H, Nemets, B, Apter, A, et al. (2006) Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry 163, 10981100.CrossRefGoogle ScholarPubMed
16 Jazayeri, S, Tehrani-Doost, M, Keshavarz, SA, et al. (2008) Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry 42, 192198.Google Scholar
17 Marangell, LB, Martinez, JM, Zboyan, HA, et al. (2003) A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 160, 996998.CrossRefGoogle ScholarPubMed
18 Mischoulon, D, Best-Popescu, C, Laposata, M, et al. (2008) A double-blind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder. Eur Neuropsychopharmacol 18, 639645.CrossRefGoogle ScholarPubMed
19 Mischoulon, D, Papakostas, GI, Dording, CM, et al. (2009) A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder. J Clin Psychiatry 70, 16361644.CrossRefGoogle ScholarPubMed
20 Nemets, B, Stahl, Z & Belmaker, RH (2002) Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 159, 477479.CrossRefGoogle ScholarPubMed
21 Peet, M & Horrobin, DF (2002) 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 59, 913919.CrossRefGoogle ScholarPubMed
22 Silvers, KM, Woolley, CC, Hamilton, FC, et al. (2005) Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids 72, 211218.Google Scholar
23 Su, KP, Huang, SY, Chiu, CC, et al. (2003) Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 13, 267271.Google Scholar
24 Frangou, S, Lewis, M & McCrone, P (2006) Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry 188, 4650.Google Scholar
25 Keck, PE Jr, Mintz, J, McElroy, SL, et al. (2006) Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry 60, 10201022.Google Scholar
26 Stoll, AL, Severus, WE, Freeman, MP, et al. (1999) Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 56, 407412.Google Scholar
27 Rogers, PJ, Appleton, KM, Kessler, D, et al. (2008) No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. Br J Nutr 99, 421431.CrossRefGoogle ScholarPubMed
28 Bot, M, Pouwer, F, Assies, J, et al. (2010) Eicosapentaenoic acid as an add-on to antidepressant medication for co-morbid major depression in patients with diabetes mellitus: a randomized, double-blind placebo-controlled study. J Affect Disord 126, 282286.CrossRefGoogle ScholarPubMed
29 Carney, RM, Freedland, KE, Rubin, EH, et al. (2009) Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: a randomized controlled trial. JAMA 302, 16511657.CrossRefGoogle ScholarPubMed
30 da Silva, TM, Munhoz, RP, Alvarez, C, et al. (2008) Depression in Parkinson's disease: a double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. J Affect Disord 111, 351359.CrossRefGoogle ScholarPubMed
31 Freund-Levi, Y, Basun, H, Cederholm, T, et al. (2008) Omega-3 supplementation in mild to moderate Alzheimer's disease: effects on neuropsychiatric symptoms. Int J Geriatr Psychiatry 23, 161169.Google Scholar
32 Antypa, N, Van der Does, AJ, Smelt, AH, et al. (2009) Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers. J Psychopharmacol 23, 831840.CrossRefGoogle ScholarPubMed
33 Rees, AM, Austin, MP & Parker, GB (2008) Omega-3 fatty acids as a treatment for perinatal depression: randomized double-blind placebo-controlled trial. Aust N Z J Psychiatry 42, 199205.Google Scholar
34 Makrides, M, Gibson, RA, McPhee, AJ, et al. (2010) Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA 304, 16751683.CrossRefGoogle ScholarPubMed
35 Su, KP, Huang, SY, Chiu, TH, et al. (2008) Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 69, 644651.CrossRefGoogle ScholarPubMed
36 Llorente, AM, Jensen, CL, Voigt, RG, et al. (2003) Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing. Am J Obstet Gynecol 188, 13481353.CrossRefGoogle ScholarPubMed
37 Doornbos, B, van Goor, SA, Dijck-Brouwer, DA, et al. (2009) Supplementation of a low dose of DHA or DHA+AA does not prevent peripartum depressive symptoms in a small population based sample. Prog Neuropsychopharmacol Biol Psychiatry 33, 4952.CrossRefGoogle ScholarPubMed
38 Freeman, MP, Davis, M, Sinha, P, et al. (2008) Omega-3 fatty acids and supportive psychotherapy for perinatal depression: a randomized placebo-controlled study. J Affect Disord 110, 142148.Google Scholar
39 Belanger, SA, Vanasse, M, Spahis, S, et al. (2009) Omega-3 fatty acid treatment of children with attention-deficit hyperactivity disorder: A randomized, double-blind, placebo-controlled study. Paediatr Child Health 14, 8998.CrossRefGoogle ScholarPubMed
40 Sinn, N & Bryan, J (2007) Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. J Dev Behav Pediatr 28, 8291.CrossRefGoogle ScholarPubMed
41 Raz, R, Carasso, RL & Yehuda, S (2009) The influence of short-chain essential fatty acids on children with attention-deficit/hyperactivity disorder: a double-blind placebo-controlled study. J Child Adolesc Psychopharmacol 19, 167177.CrossRefGoogle ScholarPubMed
42 Voigt, RG, Llorente, AM, Jensen, CL, et al. (2001) A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr 139, 189196.Google Scholar
43 Gustafsson, PA, Birberg-Thornberg, U, Duchen, K, et al. (2010) EPA supplementation improves teacher-rated behaviour and oppositional symptoms in children with ADHD. Acta Paediatr 99, 15401549.CrossRefGoogle ScholarPubMed
44 Johnson, M, Ostlund, S, Fransson, G, et al. (2009) Omega-3/omega-6 fatty acids for attention deficit hyperactivity disorder: a randomized placebo-controlled trial in children and adolescents. J Atten Disord 12, 394401.Google Scholar
45 Hirayama, S, Hamazaki, T & Terasawa, K (2004) Effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder - a placebo-controlled double-blind study. Eur J Clin Nutr 58, 467473.CrossRefGoogle ScholarPubMed
46 Richardson, AJ & Puri, BK (2002) A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog Neuropsychopharmacol Biol Psychiatry 26, 233239.Google Scholar
47 Olfson, M, Shea, S, Feder, A, et al. (2000) Prevalence of anxiety, depression, and substance use disorders in an urban general medicine practice. Arch Fam Med 9, 876883.CrossRefGoogle Scholar
48 McIntyre, RS & O'Donovan, C (2004) The human cost of not achieving full remission in depression. Can J Psychiatry 49, 10S16S.Google Scholar
49 Lin, PY & Su, KP (2007) A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry 68, 10561061.CrossRefGoogle ScholarPubMed
50 Pouwer, F, Nijpels, G, Beekman, AT, et al. (2005) Fat food for a bad mood. Could we treat and prevent depression in Type 2 diabetes by means of omega-3 polyunsaturated fatty acids? A review of the evidence. Diabet Med 22, 14651475.Google Scholar
51 Martins, JG (2009) EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr 28, 525542.CrossRefGoogle Scholar
52 Hegarty, BD & Parker, GB (2011) Marine omega-3 fatty acids and mood disorders - linking the sea and the soul: 'Food for Thought' I. Acta Psychiatr Scand 124, 4251.Google Scholar
53 Lustman, PJ & Clouse, RE (2002) Treatment of depression in diabetes: impact on mood and medical outcome. J Psychosom Res 53, 917924.CrossRefGoogle ScholarPubMed
54 Nuyen, J, Schellevis, FG, Satariano, WA, et al. (2006) Comorbidity was associated with neurologic and psychiatric diseases: a general practice-based controlled study. J Clin Epidemiol 59, 12741284.Google Scholar
55 Wichowicz, HM, Slawek, J, Derejko, M, et al. (2006) Factors associated with depression in Parkinson's disease: a cross-sectional study in a Polish population. Eur Psychiatry 21, 516520.Google Scholar
56 Vajda, FJ & Solinas, C (2005) Current approaches to management of depression in Parkinson's Disease. J Clin Neurosci 12, 739743.Google Scholar
57 McKeith, I & Cummings, J (2005) Behavioural changes and psychological symptoms in dementia disorders. Lancet Neurol 4, 735742.CrossRefGoogle ScholarPubMed
58 Al, MD, van Houwelingen, AC & Hornstra, G (2000) Long-chain polyunsaturated fatty acids, pregnancy, and pregnancy outcome. Am J Clin Nutr 71, 285S291S.Google Scholar
59 Jans, LA, Giltay, EJ & Van der Does, AJ (2010) The efficacy of n-3 fatty acids DHA and EPA (fish oil) for perinatal depression. Br J Nutr 104, 15771585.Google Scholar
60 Walsh, BT, Seidman, SN, Sysko, R, et al. (2002) Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287, 18401847.Google Scholar
61 Colquhoun, I & Bunday, S (1981) A lack of essential fatty acids as a possible cause of hyperactivity in children. Med Hypotheses 7, 673679.Google Scholar
62 Stevens, L, Zhang, W, Peck, L, et al. (2003) EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors. Lipids 38, 10071021.Google Scholar
63 Mitchell, EA, Aman, MG, Turbott, SH, et al. (1987) Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clin Pediatr (Phila) 26, 406411.Google Scholar
64 Arnold, LE, Kleykamp, D, Votolato, NA, et al. (1989) Gamma-linolenic acid for attention-deficit hyperactivity disorder: placebo-controlled comparison to D-amphetamine. Biol Psychiatry 25, 222228.Google Scholar
65 Burgess, JR, Stevens, L, Zhang, W, et al. (2000) Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder. Am J Clin Nutr 71, 327S330S.CrossRefGoogle ScholarPubMed
66 Chen, JR, Hsu, SF, Hsu, CD, et al. (2004) Dietary patterns and blood fatty acid composition in children with attention-deficit hyperactivity disorder in Taiwan. J Nutr Biochem 15, 467472.CrossRefGoogle ScholarPubMed
67 Raz, R & Gabis, L (2009) Essential fatty acids and attention-deficit-hyperactivity disorder: a systematic review. Dev Med Child Neurol 51, 580592.Google Scholar
68 Zanarini, MC & Frankenburg, FR (2003) Omega-3 Fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry 160, 167169.CrossRefGoogle ScholarPubMed
69 Fux, M, Benjamin, J & Nemets, B (2004) A placebo-controlled cross-over trial of adjunctive EPA in OCD. J Psychiatr Res 38, 323325.CrossRefGoogle ScholarPubMed
70 Richardson, AJ & Montgomery, P (2005) The Oxford-Durham study: a randomized, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder. Pediatrics 115, 13601366.Google Scholar
Figure 0

Fig. 1 Literature search flow chart.

Figure 1

Table 1 Randomised controlled clinical trials of supplementation with n-3 PUFA in subjects with depression and related disorders

Figure 2

Table 2 -Randomized controlled clinical trials of supplementation with n-3 PUFA in patients with perinatal depression

Figure 3

Table 3 Randomised controlled clinical trials of supplementation with n-3 PUFA in children with ADHD