Attention deficit/hyperactivity disorder (ADHD) is a common disorder of school age children (although adults can also be affected). Estimates vary but the prevalence of ADHD is thought to be in the range of 2 – 7% of children 11. As the name suggest ADHD comprises hyperactivity and a range of attentional deficits including problems listening, paying attention and finishing tasks, as well as interrupting others 12. The illness is also associated with social withdrawal, shyness and anxiety and around one quarter of children with ADHD may also show learning difficulties including problems with reading and writing 13. Such behavioural problems can affect academic attainment as well as relationships with family and peers.

Over 80% of children with ADHD in the US are treated with stimulants such as methylphenidate (Ritalin). While efficacious in some patients, these medications have significant side effects including decreased appetite, insomnia, impaired growth and irritability 13. Although the aetiology of ADHD is unclear, one suggested contributory factor is diet including the abnormal intake and abundance of various types of PUFA 1415. Reduced PUFA levels have been reported in both plasma and erythrocyte membranes of children with ADHD 16171819, while a preliminary study suggests that omega-3 fatty acid breakdown occurring consequent to oxidative stress is increased 20. Such findings have led to the hypothesis that lack of sufficient amounts of specific fatty acids affects brain function in such a way as to cause or worsen the symptoms of ADHD 14. Early studies examining the effects of essential fatty acid supplementation focused exclusively on omega-6 fatty acids. In double-blind placebo-controlled trials of mixtures of gamma linoleic acid and LA in children with ADHD both Aman and colleagues 21 and Arnold and colleagues 22 reported no significant improvement in symptoms. Despite such negative results, the encouraging data emanating from early trials of omega-3 fatty acids in depression and schizophrenia (described later in this review) prompted investigation of these fatty acids in ADHD and related disorders.

Interest in the interaction between diet and attentional disorders is currently high with Joshi and colleagues 23 reporting decreased hyperactivity in children with ADHD receiving flax oil (an oil rich in the 18 carbon omega-3 fatty acid ALA) in a non-placebo-controlled trial. Furthermore, Fontani and colleagues 24 reporting that omega-3 fatty acid supplementation enhances measures of attention in healthy adults. In addition, five double-blind placebo-controlled trials have been carried out that examine how omega-3 PUFA supplementation affects attention and hyperactivity (Table 1). The trials used a variety of outcome measures. We have summarized a small subset of the results with a focus on two aspects of ADHD, attention and hyperactivity (Table 1). The first ADHD study was conducted by Voigt and colleagues 25. These researchers tested the effect of 345 mg/day DHA for 4 months upon 63 children with the disorder. Although blood DHA levels were increased in the active treatment group, no significant difference in symptoms was observed compared to placebo and assessed using the Child Behaviour Checklist 26 and the Conners' rating scale 27 (Conner's scale data is not shown in the report). No significant benefit of a DHA/EPA mixture compared to placebo was also reported by Hirayama and colleagues 28. Rather than being in capsule form, the DHA supplementation was administered through DHA fortification of food stuffs. As such, the daily dose can only be estimated but was approximately 100 mg EPA and 500 mg DHA/day. The authors report that the number of different symptoms present which comprise an ADHD diagnosis (as described in the Diagnostic and Statistical Manual for Mental Disorders Version IV abbreviated to DSM-IV 12), was not changed compared to placebo by omega-3 PUFA administration. It is important to note, however, that the authors did not assess the severity of symptoms, merely their presence. Such a measure may not possess sufficient sensitivity to detect smaller improvements in the condition however.

The three other trials differed from the others in that they did not utilize children with formally diagnosed ADHD but rather ADHD-related symptoms, as determined using one or more rating scales. As such the subject groups are likely to be more heterogeneous than found in the trials conducted by Voigt and colleagues 25 and by Hirayama and colleagues 28, and likely contain participants who would not meet the DSM-IV criteria for clinical ADHD. Richardson and Puri 29 tested the effects of a supplement containing a mixture of omega-3 and omega-6 fatty acids in children with learning difficulties (mainly dyslexia) who also exhibited ADHD-like features assessed using the Conner's Teacher Rating Scale. Since the Conner's scale scores are influenced both age and gender, scores are routinely transformed using standard population values which convert the raw scores into standardised t-scores with mean = 50 and standard deviation of 10. A score greater than two standard deviations from the mean (> 70) correlates well with a clinical diagnosis of ADHD 27. It is notable that the participants in the Richardson and Puri trial 29 have a mean t-score of less than 70, indicating that most of the participants likely would not meet the criteria for clinical ADHD. In the trial, subjects were treated with placebo or 186 mg EPA, 480 mg DHA, 96 mg GLA, 864 mg LA and 42 mg AA/day for 12 weeks. It is unclear why the authors chose to include the omega-6 PUFA GLA in the formulation given earlier negative findings 2122, however, as noted below, the inclusion of AA and GLA, a precursor of AA, may be beneficial. The authors report statistically significant improvements upon a range of ADHD-like symptoms assessed using the Conner's scale including psychosomatic symptoms and inattention, with cognitive problems and anxiety approaching statistical significance. Examination of the difference between placebo and omega-3 PUFA groups indicates, however, that the beneficial effect of the omega-3 PUFA treatment was, at most, modest (Table 1). The small number of study participants in this trial is also a significant weakness. A comparable study conducted by Stevens and colleagues 30 examined fatty acid supplementation in children with ADHD-related symptoms, such as inattention, hyperactivity, and other disruptive behaviours. Subjects received either placebo or 480 mg DHA, 80 mg EPA, 40 mg AA and 96 mg GLA/day for 4 months. No statistically significant difference between placebo and active groups was observed for any rating scale when those who completed the trial were compared (Table 1). Using an intent-to-treat analysis did however indicate a significant benefit of fatty acids upon attention assessed by teachers, and conduct assessed by parents using the Disruptive Behaviours Scale 31. An intent-to-treat analysis is considered more valid since it includes participants who withdrew from the trial (who are likely to be more be severely ill) by carrying forward their baseline score (intake score) to the end of the trial even though they have not participated fully, or at all, in the study treatment protocol. Notably, the authors also report that by the end of the trial a significantly greater proportion of children had moved out of the clinically significant range for oppositional/defiant behaviour than in the treatment group. While these improvements are interesting, the magnitude of the effects described are relatively small and the trial, like that by Richardson and Puri 29, is at best suggestive of a small effect upon attentional deficit and/or hyperactivity.

A further trial 32 used a substantially larger sample size to investigate the effects of mixed omega-3 and omega-6 supplementation in 117 children with Developmental Coordination Disorder (DCD) 33. DCD is characterised by specific impairments of motor function and shows substantial overlap with ADHD in terms of difficulties with organizational skills and attention. Similar to the author's earlier study 29, the Conner's rating scale values at entry into are indicative of a study population in which the majority of participants would likely not meet the criteria for ADHD (quoted in the report as 69% of participants). Using a double blind, placebo controlled high quality design (Jadad score = 5) children received either 558 mg EPA, 174 mg DHA and 60 mg GLA/day or placebo for 12 weeks. The fatty acid supplementation had no significant benefit over placebo upon motor function, but, notably, resulted in statistically significant improvements in reading age, spelling age and on all except one Conner's'subscale (opposition, cognitive problems, hyperactivity, anxiety, perfectionism, social problems, impulsivity, and inattention). A concern arises, however, from the fact that while the p-values for the difference between omega-3 PUFA and placebo groups reported by the authors appear impressive, the actual magnitude of the difference between the groups is much less so. For example, the change in normalised t-scores for DSM-IV Attention scales in the PUFA group was better than the placebo group by only 3.8 points (or 38% of 1 standard deviation) while the quoted statistical significance is p < 0.00001. Information provided in the report suggests two possible explanations. Firstly, the authors state 32 that they used non-parametric tests which, depending on how the data ranks in each group, could produce such an outcome although this is unlikely to occur. Secondly, they state 32 that "group comparisons were therefore performed by using the raw scores obtained by summing across all items." This suggests that the statistical significance quoted is for comparison of raw scores, rather than the t-scores presented in the paper. Whatever the explanation, it appears that the magnitude of difference between placebo and PUFA groups is not as striking as is suggested by the very small p-values. Furthermore, since most of the participants (69%) did not have clinically significant inattention and/or hyperactivity, it is unclear what the clinical relevance of the authors observations are, if any. On the other hand, the authors did find an effect and it will be of great interest to utilise the same formulation in children who have clinically significant symptoms as defined using either the Conner's scale or by psychiatric assessment.

The most recent trial 34 assessing the effect of omega-3 PUFA upon hyperactivity (but not inattention) involved a group of children with autism. Autism is chiefly characterised by limited behaviour patterns, reduced social interaction and delayed language, however hyperactivity is also frequently observed 12. Whether there is an aetiological overlap between hyperactivity in ADHD and in autism is unclear. The authors administered a supplement delivery a daily dose of 800 mg of EPA and 700 mg of DHA or a coconut oil placebo for 6 weeks (a considerably shorter duration than most trials), and assessed psychopathology using the Aberrant Behaviours Checklist 35. Omega-3 PUFA showed no statistically significant benefit over placebo on any of the ABC scales including irritability, social withdrawal, stereotypy, inappropriate speech or hyperactivity. The authors highlight the fact that hyperactivity showed the greatest difference relative to the placebo group although much of the inter-group difference was due to a worsening of hyperactivity during the trial in the placebo group. The small size and short duration of the trial are problematical and further trials will be required to confirm or reject a previous observation obtained using and open-label trial that omega-3 PUFA supplementation is beneficial in autism 36.

The variety of disorders and outcome measures used in the ADHD-related trials made direct comparison amongst them difficult. Three trials 293032 utilised comparable measures of hyperactivity and inattention, however, which allowed us to provide preliminary estimates of the effect of omega-3 fatty acid supplementation on inattention and hyperactivity as assessed by parents and teachers (Figure 1). These estimates are exploratory since the grouping into separate parent-teacher and inattention-hyperactivity categories was based on the available data, not on any a priori hypothesis. Furthermore, there was not sufficient comparable data to attempt to calculate an overall estimate of effect. From these limited data it appears that teachers may tend to report a greater beneficial effect than do parents, and that there may be a greater effect on inattention than on hyperactivity.

In summary, omega-3 containing PUFA supplements did not perform better than placebo in children with clinically diagnosed ADHD, but may have had a modest effect on attention and hyperactivity symptoms in children with DCD. The data are, however, inconclusive at this time. A trial of a similarly formulated supplement to that used in the DCD trial 32 in clinically defined ADHD has not yet been published. Such an experiment is needed to resolve the question of whether omega-3 PUFA supplementation is beneficial in ADHD, as are trials which take place over longer time intervals. Finally, because the trials used a variety of PUFA formulations, no conclusion can currently be drawn regarding which omega-3 PUFA, if any, is most effective.

The investigation of the efficacy of omega-3 PUFA in anxiety disorders is a field in its infancy. Anxiety disorders comprise a variety of disorders characterised by abnormal fears and phobias such as panic disorder, generalised anxiety disorder, obsessive compulsive disorder and social phobia 12. To date only 2 placebo controlled trials have been performed (Table 2). Omega-3 fatty acid supplementation has been assessed using double blind, placebo controlled trial in obsessive compulsive disorder (OCD), as well as anxiety associated with substance use. Using a crossover design Fux and colleagues 37 administered placebo or 2 g/day ethyl EPA for 6 weeks followed by a liquid paraffin placebo or EPA for a further 6 weeks to 11 patients with OCD. Symptoms were assessed using the Yale-Brown Obsessive Compulsive Scale 38, the Hamilton Depression Rating Scale (HDRS 39) and the Hamilton Anxiety Rating Scale 40. The authors found no significant difference compared to placebo treatment on any of the scales and concluded that omega-3 fatty acids were not efficacious (it is worth noting that depression and anxiety symptoms in the patient groups were mild). The study, however, utilized a very small sample size and administered fatty acids for a much shorter time period than used in the most other trials. As such, although this trial reports a negative finding, its limitations leave open the question of whether omega-3 PUFA have any efficacy in OCD. A second recent trial has generated more positive results although the findings should be considered as very preliminary. In a double-blinded randomised trial Buydens-Branchley and Branchley 41 administered either a vegetable oil placebo or an omega-3 supplement providing 2.2 g EPA and 0.5 g DHA/day to 24 men being treated for substance use. Using a self-administered test scale which assessed anger, tension and anxiety, and mood (Profiles of Mood states scale 42) the authors report a significantly better improvement in the tension and anxiety subscale compared to placebo. The use of patients who do not have a clinically defined anxiety disorder is a limiting factor of the trial, as is the small size and use of a self-rating scale. Thus, while these trials are not conclusive with regard to the potential efficacy of omega-3 PUFA supplementation, they do provide a rationale for conducting further trials in populations with clinically well defined anxiety disorders. Interestingly, anxiety was also reduced in an open-label trial (i.e. a non-blinded trial having with no placebo) of an omega-3/omega-6 PUFA mixture is students writing their examinations 43 whereas supplementation with 443 mg EPA and 319 mg/day DHA for 2 months reduced plasma catecholamine levels (adrenaline, noradrenaline and dopamine) relative to those receiving a soybean lecithin placebo 44. Such an observation increases the biological plausibility of omega-3 PUFA reducing the symptoms of anxiety given the central role that the hypothalamic-pituitary-adrenal axis (the major control mechanism for catecholamine synthesis) in these disorders 6. It is also of note that reduced omega-3 PUFA abundance has recently been reported in non-depressed patients with social phobia, another form of anxiety disorder, opening up a further avenue for clinical investigation 45.

Fatty acids have also been the focus of intense study in the psychotic disorder schizophrenia 12. Schizophrenia is a severe mental illness with a prevalence of 1 – 2% 46 that, like depression, has a complex and poorly understood aetiology. The disease is episodic and is characterised by two classes of symptoms: positive, which include hallucinations, delusions, disorganized thought and behaviour, and negative, such as flattened mood, poverty of speech, and deficits in goal directed behaviours which account for most of the morbidity of the illness 47. The disorder is treated with a variety of anti-psychotic medications all of which have limited efficacy (treatment of the debilitating negative symptoms is poor) and significant side effects including motor function, obesity and, more controversially, diabetes 6. More effective treatments are needed for schizophrenia and a variety of different approaches have been tried including one that postulates that schizophrenia is associated with an abnormality in the cell membrane, termed the phospholipid hypothesis 47. A large number of studies have examined fatty acid abundance in the disorder 48 including reports of decreased PUFA abundance of a variety of body tissues 49. The PUFA affected vary between studies leading to the recent proposal that fatty acid alterations in the disorder are secondary to altered dietary intake occurring as a consequence of the disease process 48.

Despite the inconsistent nature of the fatty acid abundance data, a number of clinical trials utilising fatty acid supplementation in schizophrenia defined according to DSM criteria have been carried out. The earliest trials utilized n-6 fatty acids, mainly gamma linoleic acid. The outcome of these small studies was largely negative 49. More recently, the efficacy of omega-3 fatty acids was examined in a series of double blind trials. All the trials utilised the Positive and Negative Syndrome Scale (PANSS) 50 to monitor disease severity in patients with similar baseline psychopathology (Table 3). Using a double-blind placebo-controlled design, Peet and colleagues 3 compared the effect of administering an EPA-enriched oil containing 2 g/day EPA, a DHA-enriched oil containing 2 g/day DHA or a corn-oil placebo for 3 months upon schizophrenic symptom onset in 45 patients who were in receipt of conventional anti-psychotic medications. The authors reported that at the end of the trial the PANSS score in the EPA groups was significantly lower than in the placebo group although the difference was not large (Table 3). A comparison of change from baseline values for omega-3 and placebo groups was not performed. In addition, a significantly greater proportion of participants in the EPA group had PANSS scores that improved by over 25% compared to that in the placebo and DHA groups. This success criterion was not an a priori outcome measure, however, and, in any case, the clinical significance of a 25% improvement in symptoms is unclear 51. The authors also conducted a second double-blind placebo-controlled trial in which 26 unmedicated patients with schizophrenia were treated with an EPA-enriched oil providing an equivalent of 2 g/day EPA for 3 months 3. The trial was unusual in that patients received conventional antipsychotic medications if they required them during the EPA treatment period, and as such the level and type of medication of subjects tended to vary during the trial, an important confound which hinders interpretation of the findings. At the end of the trial the EPA treated group had significantly lower PANSS scores than the corn-oil placebo group, although again a change from baseline comparison was not performed. Moreover, the difference between active and placebo groups was not large (Table 3). The authors also report significantly fewer days on antipsychotic treatment during the trial in the EPA group and that at the end of the trial 4 out of 15 EPA-treated subjects had not received any additional medication throughout the trial, while all placebo-treated patients were medicated with conventional drugs. While an interesting finding, the short duration of the trial combined with the episodic nature of the disorder makes it difficult to assess the clinical relevance of such an observation.

Peet and Horrobin 52 followed up these trials with a dose-ranging placebo-controlled double-blind study of 1, 2, or 4 g/day ethyl-EPA or a liquid paraffin placebo for 12 weeks in a group of 115 medicated patients with schizophrenia. They report that 2 g/day EPA (but not 1 or 4 g/day) improved change-from-baseline scores in patients treated with the atypical antipsychotic clozapine, but not in those treated with typical or non-clozapine atypical antipsychotics 52. Indeed, in those treated with typical and non-clozapine atypical neuroleptics all doses of EPA except one actually performed less well than placebo (mean difference scores were positive). A clozapine-treatment specific effect of EPA in schizophrenia seems unlikely and instead may be due to chance alone. The authors do not state the effect of EPA when all the medication groups are combined. Using the data presented in the paper the change-from-baseline values for EPA and placebo groups can be calculated (Table 3). Assuming a normal distribution of the data it is also possible to calculate 95% confidence intervals for the difference between placebo EPA-treated groups these being for 1 g/day EPA: -4.7 to + 6.7; 2 g/day EPA: -12.7 to +1.8; 4 g/day EPA: -2.7 to +10.2. Since all of these intervals contain the value zero i.e. no difference between active and placebo groups, it is likely that none of the EPA doses significantly improved symptoms compared to placebo when subjects are analysed as a whole.

Besides the researchers lead by Peet, two other groups have investigated the use of EPA in schizophrenia using double-blind placebo controlled trials. Fenton and colleagues 53 administered either 3 g/day ethyl-EPA or a mineral oil placebo to 87 medicated patients with schizophrenia for 16 weeks. They observed no significant difference in PANSS scores between the EPA and placebo groups at any of the time points reported (1, 2, 4, 8, 12 or 16 weeks). It has been argued that erythrocyte EPA levels rose significantly in the placebo group, suggesting that the informed consent procedure lead to participants consuming omega-3 fatty acid rich foods or taking fish oils supplements thereby defeating the placebo element 54. It is unlikely that such an explanation explains the lack of effect given that the change from baseline symptom scores in both placebo and omega-3 groups were low compared to other trials, and that change in EPA abundance in the placebo group was not correlated to clinical improvement 55. Another trial 56 used a higher dose of ethyl-EPA (3 g/day for 12 weeks) which was compared to a liquid paraffin placebo administered to 40 medicated patients with schizophrenia. These authors reported a significant positive difference in symptom scores in the placebo and EPA groups after 3, 9 and 12 weeks. Moreover, in contrast to Peet and Horrobin 52, these researchers report that the largest reduction in PANSS scores is observed in those patients taking typical antipsychotics, not the atypical drug clozapine, although the difference did not reach statistical significance. It should be noted, however, that despite the fact that the authors' main a priori outcome measure was intended to be scores at 12 weeks, the difference between the two groups had in fact diminished by this time point. Unfortunately, the statistical analysis and trials outcomes were only reported in detail for the 9 week scores, although the authors do not highlight this point in their analysis. The failure to use the a priori outcome measure, along with deficits in other reporting aspects of the trial, diminishes our confidence in the robustness of this trial's findings.

In general, clinical trials of omega-3 fatty acids in schizophrenia, despite being mostly of high quality, have produced inconsistent results and small effects sizes of doubtful clinical significance. Although the trial by Peet and Horrobin 52 does report a significant improvement, this only occurs at one dose in a group of patients having a specific background treatment. Taken as a whole, the evidence suggests that omega-3 fatty acids little or no effect upon the symptoms of schizophrenia, and that even if a true effect exists, that it is unlikely to be clinically relevant.

Personality disorders (also known as axis-2 disorders) are a type of mental illness in which patients form inflexible patterns of actions and thoughts 12. They are generally treated using various forms of psychotherapy although pharmacological treatments are commonly used for attending symptoms such as depression or anxiety. To date the efficacy of omega-3 PUFA has only been tested in one type of personality disorder, borderline personality disorder (BPD). Zanarini and Frankenburg 57 administered 1 g/day ethyl EPA or placebo to 30 subjects with the disorder for 8 weeks and assessed aggression and depression using the Modified Overt Aggression Scale (MOAS 58) and the Montgomery-Asberg Depression Rating Scale (MADRS 59) respectively. The authors' conclusion that "ethyl EPA was superior to placebo in diminishing aggression as well as the severity of depressive symptoms" is surprising given the data presented in the research report. For the MOAS the difference between change in baseline values between placebo and omega-3 PUFA groups was only -0.8 and for MADRS -1.5 which does not support the authors conclusions. Based on the published data we find that there is little evidence to support the use of omega-3 fatty acids in the treatment of BPD.

Major depressive disorder (MDD) is a serious affective illness 12 with a lifetime prevalence estimated to be between 5 and 11% of the population 60. It is characterized by depressed mood, a loss of interest in pleasurable activities, changes in sleep patterns and weight, and reduced cognitive abilities and concentration. A significant proportion of persons (approximately 15%) with severe depression eventually commit suicide making it the seventh most frequent cause of death in the US 61. Episodes can last up to several years and the illness has a high recurrence rate ranging from 50% after one episode to 90% for those with 3 or more occurrences 61. Depression is most commonly treated with a variety of antidepressant drugs such as the selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants. Most treatments have a response rate, defined as a 50% improvement in symptoms, of approximately 66%, and around 80–90% of patients eventually respond to some treatment 60. However, a significant proportion (10 – 20%) of patients are treatment refractive i.e. they do not respond at all or respond poorly to therapy. Moreover, the proportion of successfully treated patients who stay well for even 18 months is disappointingly low, being around 70% 60. These statistics indicate that there is much room for improvement in the treatment and prevention of depression. Such advances are difficult because the disease has a complex biological, psychological and sociological aetiology. Diet has been postulated to be involved and it has been argued that the rising rates of MDD 62 are at least partly due to a decreased consumption of omega-3 fatty acids, these having been replaced in the diet by omega-6 fatty acids 6364. In support of this hypothesis, studies of patients with major depressive disorder have shown a striking and consistent deficit in omega-3 fatty acid abundance, while omega-6 PUFA levels are largely unaffected 65. These findings do not appear to be easily explained by such potentially confounding factors as antidepressant medication or smoking 48. Epidemiological studies have suggested that omega-3 PUFA deficits may be due to decreased dietary intake, although metabolic dysfunction has also been postulated 65.

Such studies have lead several investigators to conduct clinical trials of omega-3 fatty acids in patients with depressive disorders (Table 4). The trials were not of a uniform quality, however, as assessed by Jadad scores which ranged from 2 to 5. Peet and Horrobin 66 carried out the first double-blind placebo-controlled trial testing omega-3 fatty acids in MDD. They administered 1, 2 or 4 g/day ethyl-EPA or a liquid paraffin placebo for 12 weeks to 70 patients with MDD who had persistent symptoms of depression despite the use of conventional anti-depressant drugs. They report that 1 g/day, but not 2 or 4 g/day ethyl-EPA, was significantly more likely than placebo to improve symptoms rated using the HDRS, the MADRS and the Beck Depression Inventory 67, with the effect being apparent at the earliest time point recorded, 4 weeks. The magnitude of the difference between omega-3 and placebo groups was, however, small. For example, ethyl EPA reduced the HDRS score by 3.8 points more than placebo. Peet and Horrobin 66 also report that a higher proportion of patients receiving 1 g/day achieved a 50% improvement in their symptoms (considered to be clinically significant) compared to the placebo group (9/17 vs. 5/17). The statistical significance of this difference was not reported, but can be calculated as being not significant (p = 0.163 for a two-sided test of proportions; p = 0.082 for the one-sided test).