Long chain omega-3 polyunsaturated fatty acids in the treatment of psychiatric illnesses in children and adolescents

Authors

  • Edward H. Clayton,

    Corresponding author
    1. Nutraceuticals Research Group, University of Newcastle, Callaghan, NSW, Australia
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  • Tanya L. Hanstock,

    1. The Bipolar Program, Hunter New England Area Health Service, Newcastle, NSW, Australia
    2. Department of Psychology, University of Newcastle, Callaghan, NSW, Australia
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  • Manohar L. Garg,

    1. Nutraceuticals Research Group, University of Newcastle, Callaghan, NSW, Australia
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  • Philip L. Hazell

    1. Central Clinical School, University of Sydney, NSW, Australia
    2. Discipline of Psychiatry, School of Medical Practice and Population Health, University of Newcastle, Callaghan, NSW, Australia
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Dr Edward Clayton, Research Fellow, Nutraceuticals
Research Group, Room 305B, Medical Sciences
Building, University of Newcastle, Callaghan,
NSW 2305, Australia.
Tel: +61 249 215 343;
Fax: +61 249 212 028;
E-mail: edward.clayton@newcastle.edu.au

Abstract

Objective:  Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) are in increasing use in the general population to treat health problems. The objective of the current article is to review the evidence for the rationale and benefit of LCn-3PUFA in the treatment of common psychiatric disorders in children and adolescents.

Methods:  A search of Psychlit, PubMed and Cochrane Databases was conducted using the terms child, adolescent, bipolar, depression, psychosis, first-episode psychosis, schizophrenia, attention deficit hyperactivity disorder (ADHD), autism, psychiatric, omega-3, n-3, docosahexaenoic acid and eicosapentaenoic acid. Further studies were identified from the bibliographies of published reviews.

Results:  One small randomized controlled trial with LCn-3PUFA supplementation in depression in children found a small beneficial effect over placebo. Four placebo-controlled trials showed uncertain benefit of LCn-3PUFA for ADHD. Single placebo-controlled trials showed no benefit in autism or bipolar disorder. There is an absence of studies examining benefit for first-episode psychosis or schizophrenia in children and adolescents.

Conclusions:  While children and adolescents are receiving LCn-3PUFA for a range of psychiatric indications, there is only evidence of likely benefit for unipolar depression.

Introduction

Omega-3 fatty acids (long chain omega-3 polyunsaturated fatty acids, LCn-3PUFA) is becoming an increasingly used term in the lay public and media as well as in the health profession. LCn-3PUFA are long chain fatty acids with more than one double bond in their structure, with the first double bond occurring three bonds from the methyl end of the chain. LCn-6PUFA contains more than one double bond with the first double bond occurring six bonds from the methyl end (Fig. 1). LCn-3PUFAs are consumed from two main dietary sources, plants and marine life.

Figure 1.

Structure of EPA and DHA LCn-3PUFA and AA LCn-6PUFAs showing the position of the first double bond either three or six bonds from the methyl end.

The plant form of omega-3, α-linolenic acid (C18:3n-3), found in high quantities in linseed oil for example, is an essential fatty acid that can be converted to eicosapentaenoic acid (C20:5n-3; EPA) and docosahexaenoic acid (C22:6n-3; DHA) (1) (Fig. 2). The conversion from α-linolenic acid to EPA and DHA is very inefficient though with estimates of only 0.2% (2) to 6% (3) of consumed α-linolenic acid being converted to EPA and only approximately 63% of EPA being converted to DHA (3). Furthermore, increased intake of linoleic acid (C18:2n-6) also decreases the conversion of α-linolenic acid to EPA (3) through competitive inhibition.

Figure 2.

Summary of the metabolism of omega-3 and omega-6 fatty acids. Sources: Parker et al. (47), Wang and Anderson (106) and Moore et al. (107).

The highest concentrations of EPA and DHA LCn-3PUFA are found in seafood, which contributes around 70% of LCn-3PUFA intake in the Australian diet (4). Beef, lamb, pork and chicken also contain relatively high concentrations of DPA (5,6), which is readily converted to DHA. There are several other sources of EPA and DHA that contribute to overall LCn-3PUFA intake, including eggs and a range of omega-3 enriched foods such as bread, milk, margarines and spreads, eggs, yoghurt and, even surprisingly, fish (4).

There are several different recommendations for intakes of omega-3 fatty acids [mainly given as recommended intake of EPA + DHA (4)]. Recently released Australian Nutrient Reference Values indicate that at least 190 mg/day EPA + DHA should be consumed by the general population. The United States National Institute of Health recommends 300 mg/day, while people at risk of cardiovascular disease are recommended to consume at least 1000 mg/day of EPA+DHA by several health organizations.

Omega-3 polyunsaturated fatty acids have received substantial public attention as candidate treatments for many medical and psychiatric health problems. Alternative therapies such as nutritional supplementation are increasingly administered by parents to their children as an adjunct to mainstream treatment (7,8), of which the LCn-3PUFA supplements appear to be the most popular. Many brands of omega-3 supplements are promoted in the media, and these supplements are readily available from retail outlets and through the Internet. Advertisements claim benefits for a wide range of symptoms and disorders. LCn-3PUFA supplements have been used in the treatment of childhood medical conditions such as asthma (9), Crohn’s disease (10,11) and eczema [for review, see Horrobin (12)], and one study has reported the benefits of omega-3 supplementation in reducing the frequency of seizures in epilepsy (13).

Clinicians in the field of child and adolescent mental health will likely encounter patients who are receiving LCn-3PUFA supplements and may be asked questions about efficacy and safety in psychiatric conditions. The following paper will examine the rationale for treating psychiatric problems with LCn-3PUFA supplementation and review the evidence for efficacy in common psychiatric disorders affecting children and adolescents.

Background evidence linking LCn-3PUFA to psychiatric illness

There are several lines of evidence that suggest that LCn-3PUFA may be involved with the aetiology of psychiatric illness in adults. First, epidemiological studies linking fish consumption with rates of psychiatric disease, second, comparative studies examining deficiencies of LCn-3PUFA in the plasma of people with psychiatric conditions compared with healthy controls and, last, evidence from intervention studies examining the effectiveness of LCn-3PUFA either as monotherapy or as adjunct therapy in several illnesses.

Early evidence of the role of LCn-3PUFA came from the treatment of mental disorders with flax-seed oil (14). Since that time, Western European diets have often been referred to as being largely deficient in LCn-3PUFA (15), which may be associated with increasing rates of several psychiatric illnesses, including affective disorders (16). There is epidemiological evidence relating fish consumption to the incidence of several psychiatric diseases including depression (17,18), post-natal depression (19), bipolar disorder (20) and schizophrenia (21).

Many studies have been conducted examining both deficiencies of LCn-3PUFA in the blood of individuals with psychiatric illness compared with healthy controls and supplementation studies in several diseases. This evidence will be examined in detail in relation to psychiatric illness of children and adolescents throughout this review.

Omega-3 in brain development

LCn-3PUFA plays a vital role in brain development. DHA is a major structural component of cell membranes throughout the body, particularly in brain neurones (22). DHA is predominantly found in phospholipids, while EPA is found primarily in cholesterol esters, triglycerides and phospholipids. DHA is the most abundant unsaturated fatty acid found in the brain (23), particularly in the cerebral cortex accounting for approximately 14% of total fatty acids (24). DHA is also found in large concentrations in the retina, testes and sperm (25). Normal brain growth and development in infants and children require dietary intake of LCn-3PUFA as the major structural components of neural cell membranes (26,27), and DHA, in particular, appears to be involved in the development of cognition in infants [for review, see Willatts and Forsyth (28)].

Proposed mechanisms of action of omega-3 fatty acids

A number of possible mechanisms may link improvement in psychiatric illness symptoms with LCn-3PUFA supplementation. LCn-3PUFA supplementation is associated with increased membrane fluidity in patients with bipolar disorder (29), which is believed to be associated with a general dampening of signal transduction pathways associated with phosphatidylinositol, arachidonic acid (AA) and other systems (30).

Increased EPA and DHA concentrations also inhibit the activity of rat protein kinase C in vitro (31,32), similar to the actions of lithium and valproate. Altering the ratio of LCn-6PUFA to LCn-3PUFA by supplementation, in conjunction with standard pharmacotherapy (33), may further improve membrane function. It is recommended, therefore, that LCn-3PUFAs are used as an adjunct to standard pharmacotherapy for the treatment of bipolar disorder (34).

LCn-3PUFA and LCn-6PUFA are believed to have opposing biological effects (34), and, in general, the LCn-6PUFA AA (20:4 n-6) is believed to be proinflammatory and associated with upregulation of cytokines, while the LCn-3PUFAs EPA and DHA are anti-inflammatory (35). While EPA is not found in neuronal cell membranes, it is an important precursor for eicosanoids and is a modulator of inflammation [for review, see Peet and Stokes (36)]. Increased circulating proinflammatory cytokines have been proposed to be involved with the aetiology of depression [for review, see Charlton (37) and Raison et al. (38)]. Higher concentrations of LCn-3PUFA in brain may lead to decreased cytokine production (and inflammation) via alterations to the tumour necrosis factor-α receptor for example (30), thereby providing a further possible link between LCn-3PUFA and the treatment of depression.

Further evidence linking LCn-3PUFA to psychiatric disorders comes from the effect of commonly used psychiatric medications on fatty acid metabolism. Lithium and valproate treatment decrease the turnover of brain AA, without altering concentrations of DHA (39,40) or increasing the turnover of DHA in brain phospholipids in rats (41).

Low intakes of DHA are associated with lower concentrations of dopamine and serotonin in the frontal cortex of pigs (42) and rats (43). Low omega-3 is also associated with reduced serotonergic transmission in rats (44).

LCn-3PUFA in child and adolescent psychiatry

Several comprehensive reviews have been conducted over recent years relating LCn-3PUFA to psychiatric illness in adults (24,36,45–48). The current review will not try to re-present much of the information contained in these reviews but rather examine what evidence from psychiatric research indicates the effectiveness of LCn-3PUFA, particularly in children and adolescents.

Depression

Studies of adult patients with major depression have found a depletion in LCn-3PUFA, including α-linolenic acid (C18:3 n-3), EPA (C20:5n-3) and DHA (C22:6 n-3), in plasma cholesteryl esters (49) and DHA compared with AA in red blood cell (RBC) membrane phospholipids (50) than healthy controls. Plasma total DHA is also found to be reduced in depressed patients who attempt suicide compared with those who do not attempt suicide (51). LCn-3PUFAs are depleted and monounsaturated fatty acids increased in plasma phospholipids of adult patients with major depression compared with non-psychiatric controls (52,53). Preliminary clinical studies, however, suggest that supplementation with LCn-3PUFA is of equivocal benefit for depression in adults (54–56).

There are no studies comparing blood LCn-3PUFA concentrations between patients with depression compared with controls in children or adolescents. A negative relationship between symptoms of depression and adipose tissue fatty acid ratios in an adolescent population (57) has been reported; however, there is no relationship between adipose LCn-3PUFA concentration and depression severity, and no studies have been conducted examining whether there is a deficiency in adipose tissue LCn-3PUFA concentrations in adolescent patients diagnosed with depression compared with controls.

Nemets et al. (58) conducted a controlled, double-blind pilot study investigating LCn-3PUFA supplementation in the treatment of children aged 8–12 years with a first episode of depression. Ratings were performed at baseline as well as at 2, 4, 8, 12 and 16 weeks using the Children’s Depression Ratings Scale (CDRS), Children’s Depression Inventory (CDI) and Clinical Global Impressions (CGI). Subjects were randomized to receive LCn-3PUFA (380 mg EPA and 180 mg DHA/day) or placebo (olive oil or safflower oil) as monotherapy. Twenty-eight subjects were randomized to the treatment, of whom 20 returned ratings for at least 1 month. Seven of 10 children receiving active treatment achieved response criteria (50% reduction from baseline score on the CDRS) compared with none of 10 children receiving placebo (P < 0.01, Fischer’s exact test). More children receiving active treatment (4 of 10) achieved remission (defined as a score of 29 or less on the CDRS) than did children receiving placebo (0 of 10), but the difference was not statistically significant.

Conclusions that may be drawn from the study by Nemets et al. (58) are limited by the lack of intention to treat analyses that should be conducted for all randomized controlled trials (59). Participant disposition at least should be shown using a flow diagram as outlined in the CONSORT guidelines (60). In addition, blood LCn-3PUFA concentrations were not measured and, therefore, changes in blood LCn-3PUFA could not be correlated to severity or improvement in symptoms. Finally, the placebo capsule contained either olive or safflower depending on whether participants could swallow 500 or 1000 mg capsules, respectively. This highlights the importance of choosing a placebo, as safflower oil contains approximately 74% linoleic acid (C18:2n-6), which is known to compete with conversion of α-linolenic acid to EPA.

In summary, there is evidence that LCn-3PUFA may be involved with the aetiology of depression in adults, but to date, there are no large controlled studies examining this relationship in children or adolescents. One small randomized control trial has shown LCn-3PUFA to be of likely benefit in reducing depressive symptoms in pre-pubertal children with major depression but not in achieving remission. The study warrants replication.

Bipolar disorder

There is typically a 10–15 year delay from first onset of symptoms of bipolar disorder until diagnosis, such that many affected individuals will have active but untreated disorder through adolescence (61). Early treatment is warranted, as each manic episode is associated with an incremental decrease in cognitive functioning (62), and there is a 20% lifetime risk of mortality because of suicide (63,64). Bipolar disorder is associated with a high level of impairment, ranking as the 6th most debilitating disorder in the world (65).

The percentage of DHA in erythrocyte membrane phospholipids is depleted in adults with bipolar disorder compared with healthy controls (66). Some authors (67) have reported a beneficial effect of LCn-3PUFA supplementation in treating symptoms of bipolar disorder in adults, whereas other authors have not found any benefit of supplementation, particularly when using ethyl EPA alone as the supplement [for example, see Keck et al. (68), Post et al. (69)]. No published studies have examined the LCn-3PUFA status of children or adolescents with bipolar disorder compared with healthy controls.

In a pilot study, children and adolescents aged 6–17 years with currently symptomatic bipolar I or II disorder were randomized to either flax-seed oil or an olive oil placebo adjunctively or as monotherapy (70). Primary outcome measures including Kaplan-Meier survival analysis, Young Mania Rating Scale, Children’s Depression Rating Scale-Revised (CDRS-R) and Clinical Global Impressions-Bipolar (CGI-BP) ratings were not significantly different between treatment groups. The lack of treatment effect could have been because of low conversion of α-linolenic acid to EPA and DHA (Fig. 2), the main active forms of LCn-3PUFA. Analysis of RBC membrane LCn-3PUFA would be necessary to confirm any proposed changes. To date, no studies examining the effectiveness of EPA or DHA LCn-3PUFA in child and adolescent bipolar disorder have been published. Evidence from studies in adults, however, suggests that studies with EPA and DHA may be warranted in this patient population.

Attention-deficit hyperactivity disorder

Fatty acid deficiency was first proposed as a possible cause for the development of attention deficit hyperactivity disorder (ADHD) more than 25 years ago (71). Results from a number of studies indicate lower concentrations of LCn-3PUFA in the blood of children with hyperactive difficulties compared with matched healthy controls (72–75).

Five randomized control trials have examined the efficacy of LCn-3PUFA supplementation for ADHD (Table 1). Voigt et al. (76) randomized 63 children aged 6–12 years with ADHD to receive LCn-3PUFA capsules containing 345 mg DHA/day (n = 32) or placebo (type not specified, n = 31) for 12 weeks as an adjunct to established treatment with stimulant medication. Stimulant medication was withheld from participants for 24 h prior to completing pre- and post-laboratory measures for inattention and impulsivity using the Test of Variables of Attention and the Children’s Color Trails. Secondary outcome measures were parent ratings of ADHD symptoms using the Child Behavior Checklist and the Conners Parent Rating Scale. Blood samples were also collected for the measurement of long chain fatty acid concentrations.

Table 1.  Clinical randomized controlled trials examining the effectiveness of LCn-3PUFA supplementation in psychiatric illnesses in children and adolescents
Psychiatric illnessPopulation age*Clinical trialSupplementNumber of participants analysedSymptom improvement with PUFAs
  • CDI, Child Depression Inventory (patient self-administered); CDRS, Children’s Depression Rating Scale (clinician administered); MN, micronutrients.

  • *

    Children, 5–12 years and adolescents, 12–17 years.

  • GLA (C18:3n-6).

Bipolar disorderChildren and adolescentsGracious (70)α-linolenic (flax-seed – plant)22, placebo, 22 flax-seed oilNo significant improvement
DepressionChildrenNemets et al. (58)EPA = 380 mg/day, DHA = 180 mg/day10, placebo; 10, PUFASignificant improvement on CDRS and CDI
AdolescentsNone reported 
Schizophrenia or first-episode psychosisChildren or adolescentsNone reported 
ADHDChildrenVoigt et al. (76)DHA = 345 mg/day31, placebo; 32, DHANo improvement
Richardson and Puri (77)EPA = 186 mg/day, DHA = 480 mg/day, GLA= 96 mg/day14, placebo; 15, PUFASignificant improvement on two of seven ADHD measures only compared with placebo
Stevens et al. (79)EPA = 80 mg/day, DHA = 480 mg/day, GLA = 96 mg/day25, placebo; 25, PUFASignificant improvement on 1 of 16 ADHD measures only compared with placebo
Hirayama et al. (80)EPA = 100 mg/day, DHA = 514 mg/day20, placebo; 20 PUFANo improvement. Controls higher in visual short-term memory
Sinn and Bryan (81)EPA = 558 mg/day, DHA = 174 mg/day, GLA = 60 mg/day27 placebo; 36, PUFA; 41, PUFA + MNSignificant improvement in 9 of 14 Conners’ Parent ratings but not in teacher ratings
AdolescentsNone Reported 
AutismChildren and adolescentsAmminger et al. (92)EPA = 840 mg/day, DHA = 700 mg/day7, fish oil; 5, placeboNo significant effect

Twenty-seven participants from each treatment arm completed the study. Plasma phospholipid DHA percentage of total fatty acids increased significantly (1.89 ± 0.45% to 4.85 ± 1.35%) over the treatment period in children receiving DHA compared with those receiving the placebo; however, there were no significant correlations between plasma phospholipid DHA concentrations and any behavioural measures. There were no statistically significant improvements in any measures (laboratory measures or parent ratings of ADHD symptoms) in children receiving DHA compared with children receiving placebo. An important limitation of the study was continuation of stimulant treatment, which may have caused a ceiling effect. In addition, one of the behavioural rating scales used in the study is not sensitive to treatment effects.

Richardson and Puri (77) randomized 41 children aged 8–12 years with specific learning disorder and ADHD symptoms to receive capsules containing 186 mg EPA, 480 mg DHA, 96 mg γ-linolenic acid (GLA), 864 mg linoleic acid and 42 mg AA/day (n = 22) or placebo capsules (containing olive oil, n = 19) for 12 weeks. Analysable data from the Conners Parent Rating Scale were available for 17 participants in the active treatment arm and 14 participants in the placebo arm. Improvements in parent-reported symptoms (change in score over 12 weeks) were significantly greater for children receiving active treatment than for those receiving placebo for only two of seven ADHD subscales [Cognitive Problems: mean ± standard deviation (SD) = 62.1 ± 9.6 to 57.0 ± 10.4 for active treatment vs. 63.4 ± 7.6 to 63.5 ± 9.3 for placebo, P = 0.01; and Anxious/Shy: mean ± SD = 61.1 ± 13.1 to 53.9 ± 14.6 for active treatment vs. 61.9 ± 13.6 to 62.1 ± 11.8 for placebo, P = 0.04] and for one of seven Global subscales (Global Conners Index: mean ± SD = 64.9 ± 10.2 to 59.7 ± 6.9 for active treatment vs. 65.1 ± 10.7 to 65.2 ± 10.51 for placebo, P = 0.02). Overall, this study failed to show any clear advantage of the LCn-3PUFA supplement over placebo for symptoms of ADHD in this participant population. Limitations of the study include that the supplements contained high doses of LCn-6PUFA as well as LCn-3PUFA and the absence of an intent-to-treat analysis. Additionally, the statistical methods do not allow an accurate comparison of the change in symptoms between treatment groups over time and a MIXED model repeated measures analysis using the SAS statistical program for example, could be used to show the interaction between treatment and time for each treatment (78).

Stevens et al. (79) randomized 50 children with ADHD-like symptoms to receive either placebo (olive oil, n = 25) or 480 mg DHA, 80 mg EPA, 96 mg GLA, 40 mg AA and 24 mg vitamin E/day (n = 25) for 4 months. Using an intent-to-treat analysis, only attention symptoms rated by teachers were significantly improved in children receiving LCn-3PUFA supplements compared with placebo (−14.8 vs. +3.4% respectively, P = 0.03). Changes in RBC membrane EPA as a percentage of total fatty acids were significantly and negatively correlated with changes in disruptive behaviour as assessed by the Abbreviated Symptom Questionnaire rated by parents and teachers and Disruptive Behavior Disorders (DBD) Rating Scale, subscale for Attention rated by teachers. Changes in RBC membrane vitamin E concentrations were also significantly negatively correlated with changes in hyperactivity, attention, conduct and oppositional defiant disorder subscales of the teachers DBD Rating Scale. Although the children in this study had symptoms of ADHD, they did not have a formal diagnosis of ADHD. Therefore, these results should be treated with caution and need replication in a clinical population.

Hirayama et al. (80) randomized 32 children with a definite ADHD diagnosis and 8 with a probable ADHD diagnosis to receive whole foods fortified with fish oil containing 514 mg DHA and 100 mg EPA/day (n = 20) or whole foods containing placebo (olive oil; n = 20). Two children receiving LCn-3PUFA and four children receiving placebo were receiving concurrent stimulant medication. The study measured the mean number of attention deficit, hyperactivity and impulsivity symptoms according to the DSM-IV and performance on a continuous performance task (CPT). No ADHD-related measures were significantly improved in participants receiving LCn-3PUFA compared with participants receiving placebo. Performance was significantly improved in children receiving the placebo compared with those receiving active treatment for two measures including visual short-term memory (median, 25th–75th percentile = 0 (0–2) to 0 (0–0.3) for placebo vs. 0.5 (0–1) to 1 (0–2) for active treatment, P = 0.001) and commission errors on the CPT [median (25th–75th percentile) = 3.5 (2–6) to 5 (3–7) for placebo vs. 2.5 (1–6) to 3 (2–4) for active treatment, P = 0.02]. In summary, supplementation with LCn-3PUFA did not improve symptoms of ADHD in this study population. A limitation of the study was the absence of an objective measure of compliance with the study diet.

Sinn and Bryan (81) randomized 167 children aged 7–12 years using Conners ADHD Index scores greater than 2 SDs from the population average to receive capsules containing LCn-3PUFA including 558 mg EPA, 174 mg DHA and 60 mg GLA/day or capsules containing LCn-3PUFA and a range of micronutrients or placebo (palm oil) for 15 weeks. Data were available for 104 children over the first 15 weeks of treatment (placebo, n = 27; LCn-3PUFA, n = 36 and LCn-3PUFA + micronutrients, n = 41). Improvements were reported for 9 of 14 subscales on the Connors Parent Rating Scale, mostly in the inattention and hyperactivity/impulsivity subscales in both treatment groups receiving LCn-3PUFA compared with placebo after 15 weeks of treatment (P < 0.01 for Cognitive Problems/Inattention, ADHD index, Global:Restless/Impulsive, Global Total, DSM-IV Inattentive, DSM-IV Hyperactive/Impulsive, DSM-IV Total and Oppositional, and P < 0.05 for Hyperactivity). No significant differences were reported for ratings from children receiving the LCn-3PUFA alone compared with those receiving LCn-3PUFA and micronutrients. Limitations of the study include a high drop out rate, no assessment of dietary intake of LCn-3PUFA or supplement compliance and no clinical confirmation of the ADHD diagnosis.

In summary, clinical trials demonstrate uncertain benefit of LCn-3PUFA supplementation in children with ADHD. As other authors have highlighted (81,82), the inconsistent findings may be because of the variation in the design of these studies such as in sample sizes, inclusion/exclusion criteria, dosage levels of PUFAs, period of supplementation, baseline PUFA status, type of outcome measures, lack of measurement of compliance and a lack of control of comorbid diagnoses or medications. While several studies have been conducted with children, no studies have yet been published examining the effects of LCn-3PUFA in adolescents.

Schizophrenia and first-episode psychosis

Epidemiology studies have indicated that adult patients with schizophrenia have a better outcome if they live in countries where people consume a diet rich in fats from vegetable and marine sources that are rich in LCn-3PUFA (83). Lower concentrations of LCn-3PUFA are reported in RBC membranes of patients with schizophrenia [for example, see Reddy et al. (84)] and first-episode psychosis (85,86) and in cultured skin fibroblasts of patients with first-episode psychosis (87) compared with healthy controls. Although a confirmed diagnosis of schizophrenia is difficult to make in child and adolescent patients, first-episode psychosis often occurs in the adolescent population. No studies have been conducted examining deficiencies of LCn-3PUFA or the efficacy of supplementation with LCn-3PUFA in children and adolescents with schizophrenia or first-episode psychosis.

One of the difficulties in determining why patients with schizophrenia or first-episode psychosis have lower levels of essential fatty acids is that RBC membrane concentrations of LCn-3PUFA are significantly affected by cigarette smoking, poor diet and even the long-term effect of taking psychiatric medications (88,89). These factors are very common in people with mental illness, especially schizophrenia and first-episode psychosis. Only one clinical trial examining the effectiveness of LCn-3PUFA in schizophrenia reports to participants who have included were aged 18 years (88); however, no studies have been published including participants younger than 18 years.

Autism

Bell et al. (90) reported lower percentages of DHA and AA in erythrocyte membrane phospholipids in a patient with autism compared with controls but gave no information about the patient’s age, gender or dietary intake. The percentage of LCn-3PUFA in plasma phospholipids was reported to be lower in 15 children and adolescents with autism compared with 15 children and adolescents with intellectual delay without autism (91).

Amminger et al. (92) randomized 13 children and adolescents diagnosed with autism according to the Autism Diagnostic Interview Revised and the Autism Diagnosis Observational Schedule, with high baseline scores on the Aberrant Behaviour Checklist (ABC), to receive capsules containing either 840 mg EPA and 700 mg DHA/day (n = 7) or placebo (coconut oil; n = 6) for 6 weeks. Data were analysed by repeated measures analysis of variance for seven children receiving LCn-3PUFA and five children receiving placebo after drop outs. In the primary analysis, no significant differences in any subscale scores on the ABC between participants receiving either LCn-3PUFA or placebo were reported. In a secondary intent-to-treat analysis using hot-deck imputation to replace missing scores, there was a significant interaction between treatment and time (P = 0.046). Limitations of the study include no assessment of compliance and the small sample size. In conclusion, LCn-3PUFA supplementation is of uncertain benefit in children and adolescents with autism.

Safety of omega-3 use

LCn-3PUFAs have been shown to be very safe even when used in relatively high doses (67). LCn-3PUFAs do not generally affect bleeding time; however, LCn-3PUFA may reduce platelet activation (93–95) and should be used cautiously in patients with pre-existing haematological conditions and, when high doses are used, any unusual symptoms of bleeding should be carefully monitored and reported.

Side-effects of omega-3 include nausea, fishy eructation and loose stools [for review, see Peet and Stokes (36)], which may mean that patients are not blind to treatment. There are currently no validated questionnaires suitable for the assessment of gastrointestinal symptoms in the context of treatment with LCn-3PUFA. Most questionnaires measuring abnormal gastrointestinal symptoms have been designed for use in Inflammatory Bowel Disease or Irritable Bowel Syndrome (96). A gastrointestinal symptom evaluation record designed specifically for the monitoring of symptoms before and following treatment with LCn-3PUFA is needed.

Discussion

There are few well-designed studies that show positive results for using LCn-3PUFA as adjunct or monotherapy treatments for children and adolescents with psychiatric illness. One study in children with unipolar depression has shown promising results (58); however, studies in ADHD, the area in which the majority of research has been conducted and autism, have shown equivocal benefit. There is no published evidence for the effectiveness of LCn-3PUFA in the treatment of bipolar disorder, schizophrenia or first-episode psychosis. The lack of large randomized controlled studies is a problem that has been previously highlighted in the adult population (97). Based on available evidence, claims for the benefit of LCn-3PUFA for psychiatric disorders in children and adolescents are currently overstated.

Parents and children and adolescents are often interested in using alternative therapies in the treatment of their psychiatric illness, either as adjunct treatment or as monotherapy (7). LCn-3PUFA supplements are commonly used in a range of psychiatric illnesses in young people; however, it appears as though many people may be taking these supplements without knowing which is the best source (marine vs. plant) and what doses to take and may not know what improvements to look for. For some individuals, LCn-3PUFA supplements may provide effective treatment, with less harmful side-effects than pharmacological treatments. In particular, the effectiveness of LCn-3PUFA in unipolar depression in children and adolescents should be further explored.

Methodological issues in omega-3 research

The media coverage of LCn-3PUFA has led to many parents encouraging their children to take these supplements. Studying the efficacy of LCn-3PUFA is, therefore, difficult because of the young people already receiving different strengths and types of LCn-3PUFA supplements and for varying duration.

Studies need to investigate more clearly the reason as to why people with psychiatric illness have lower plasma levels of LCn-3PUFA. This includes investigating whether the reduced level of LCn-3PUFA in psychiatric illness is a state or trait problem (such as because of a specific metabolic problem). Studies need to take into account socio-economic status and dietary intake of foods high in LCn-3PUFA such as fish, meat and vegetables. Epidemiological studies linking diet, blood LCn-3PUFA status and incidence of psychiatric illness in children and adolescents are also needed.

A Food Frequency Questionnaire specific for LCn-3PUFA in children and adolescents is needed in order to estimate the intake of LCn-3PUFA to allow an examination of whether differences in intake or metabolism underlie the relationship between LCn-3PUFA and severity of illness or response to treatment. Additionally, owing to the known effects alcohol and nicotine on LCn-3PUFA metabolism (89), the effects of comorbid substance/alcohol abuse and cigarette smoking in people with a mental illness on LCn-3PUFA need to be addressed.

As mentioned above, the importance of choosing an effective placebo that enables patients and researchers to be blind to treatment in randomised controlled trials studies is very important. The choice of placebo is also important, as olive oil, which is high in oleic acid, may affect eicosanoid production for example (98). The choice of LCn-3PUFA is also important, with EPA and DHA offering most promise of benefit compared with the shorter chain α-linoleic acid.

Treatment studies testing the efficacy of LCn-3PUFA should also be conducted according to the International Committee for Harmonisation Good Clinical Practice guidelines (99,100), thereby treating LCn-3PUFA in the same way as any other pharmacotherapy. Studies of these types are harder to conduct than those normally conducted in nutrition; however, the benefits of these well-designed, conducted, recorded and reported studies would outweigh the initial cost of conducting the study.

Future directions

Research with LCn-3PUFA in psychiatric illnesses in younger populations may help in determining whether abnormalities in LCn-3PUFA metabolism are associated with the onset and progression of these illnesses. Long-term studies of effective supplementation will also determine whether the severity of these illnesses can be reduced over time.

While the studies reviewed have examined single axis I diagnoses in children and adolescents, it is more common for young people to have comorbid axis I diagnoses than a single axis I diagnoses. Future studies would be helpful in examining children and adolescents with comorbid axis I disorders such as ADHD and bipolar disorder, ADHD and depression as well as schizoaffective disorder.

The efficacy of LCn-3PUFA supplementation has not been studied in number of child and adolescent psychiatric populations (Table 1). If future studies show more convincing evidence for the effectiveness of LCn-3PUFA supplementation in children and adolescent psychiatric illness, then preventative studies with at risk populations should be undertaken.

LCn-3PUFA may also be helpful in reducing side-effects of medications in certain psychiatric conditions. Some commonly prescribed antipsychotic medication such as clozapine and olanzapine are associated with increased plasma triglycerides (101). Omega-3 fatty acids are known to reduce plasma triglyceride concentrations (4) and may, therefore, also be beneficial when used as an adjunct therapy even without concomitant reduction in psychotic symptoms.

While measuring the plasma and RBC levels of LCn-3PUFA and symptoms before and after treatment is important, there is also a need to investigate cognitive and brain changes because of LCn-3PUFA adjunctive or monotherapy treatment. Pre- and post-cognitive testing would be useful in studies examining LCn-3PUFA supplementation in children and adolescent psychiatric illness to determine whether abilities such as attention and concentration can improve. Richardson and Montgomery (102) included assessments of academic abilities in their study of supplementation with EPA and DHA on improvements in reading, spelling and symptoms of behaviour in children with developmental coordination disorder. Further studies combining neuropsychological testing with blood levels of LCn-3PUFA and behaviour and symptom ratings may be beneficial to use in children and psychiatric patient populations.

Finally, neuroimaging has been used to study changes in brain size and function in adults [for example, see Drevets et al. (103)], children and adolescents [for reviews, see Biederman and James (104), Kowatch et al. (105)] experiencing several disorders including bipolar disorder. Similar studies examining changes in brain function following supplementation with LCn-3PUFA would provide improved insight into the possible mechanisms of action of LCn-3PUFA in psychiatric illness.

Conclusions

Omega-3 from fish oil is a common supplement used for children and adolescents, especially those suffering from a psychiatric illness. However, the published evidence to date for its effectiveness in this population does not match its commercial popularity. There is growing evidence that LCn-3PUFA may be effective in the treatment and, possibly, in the prevention of child and adolescent psychiatric illness; however, good quality, well-controlled research is greatly needed in this area.

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