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 Hamilton6–Reference 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.
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.
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
-Randomized controlled clinical trials of supplementation with n-3 PUFA in patients with perinatal depression
MDD = major depression disorder; NR = not reported
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 Apter15–Reference Su, Huang and Chiu23), to bipolar disorder (BD)(Reference Chiu, Huang and Chen10, Reference Gracious, Chirieac and Costescu14, Reference Frangou, Lewis and McCrone24–Reference 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 Assies28–Reference 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 Kok11–Reference 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 Belmaker20–Reference 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 Spahis39–Reference 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 Peck62–Reference 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.
