NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

AHRQ Evidence Report Summaries. Rockville (MD): Agency for Healthcare Research and Quality (US); 1998-2005.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of AHRQ Evidence Report Summaries

AHRQ Evidence Report Summaries.

Show details

116Effects of Omega-3 Fatty Acids on Mental Health: Summary

, , , , , and .

Current as of .

Introduction

The purpose of this study was to conduct a systematic review of the scientific-medical literature to identify, appraise, and synthesize the human evidence for the effects of omega-3 fatty acids on mental health. The review was requested and funded by the Office of Dietary Supplements, National Institutes of Health. It was undertaken as part of a consortium involving three Evidence-based Practice Centers (EPCs), which investigated the value of omega-3 fatty acid supplementation across eleven health/disease areas. The three EPCs are Southern California-RAND, Tufts-New England Medical Center, and, the University of Ottawa. To ensure consistency of approach, the three EPCs collaborated on selected methodologic elements, including literature search strategies, rating of evidence, and data table design.

While the intention was to evaluate the spectrum of psychiatric disorders or conditions (i.e., behavior or symptoms which, while their consequences could be serious, do not warrant receipt of a formal psychiatric diagnosis), certain foci were beyond the scope of the review (go to Methods). At the same time, a mental health disorder or condition did not require extant animal or basic science data or models to justify the investigation of their evidence. Nevertheless, justification for the study of two disorders exists in the literature.

The mechanism by which diet may affect health, including depression or cardiovascular disease, has been thought to involve low levels of omega-3 fatty acid content in biomarkers (e.g., red blood cells [RBCs]).1, 2 An omega-3 fatty acid deficiency hypothesis of depression has been put forward, which has helped justify treatment with omega-3 fatty acid supplementation.3 The membrane phospholipid hypothesis of schizophrenia has been proposed in an attempt to develop a model explaining its etiology.4 It describes the presumed biochemical dynamics underpinning a neurodevelopmental theory. Some of the evidence used to support this perspective suggests the existence of phospholipid and PUFA metabolic abnormalities in schizophrenia.46 It has been posited that modifications to diet could mitigate or even aggravate an underlying abnormality of phospholipid metabolism.4

However, the present review was not conducted to test these hypotheses. Rather, the rationale for this two-year project investigating the possible health benefits of omega-3 fatty acids was to systematically review the evidence to aid in the development of a research agenda. Nevertheless, these emerging models regarding depression and schizophrenia do suggest plausible bases for the use of omega-3 fatty acids to treat or prevent these psychiatric disorders.

Key Questions

Four basic questions were investigated with respect to each psychiatric disorder or condition for which evidence meeting eligibility criteria could be identified. To illustrate, the questions pertaining to depression were:

  • Are omega-3 fatty acids efficacious as (primary or supplemental) treatment for depression?
  • Is omega-3 fatty acid intake, including diet and/or supplementation, associated with the onset, continuation or recurrence of depression? (i.e., primary or secondary prevention)
  • Is the onset, continuation or recurrence of depression associated with omega-3 or omega-6/omega-3 fatty acid content of biomarkers? (i.e., primary or secondary prevention)
  • What is the evidence that, in review-relevant studies concerning mental health, adverse events (e.g., side effects) or contraindications are associated with the intake of omega-3 fatty acids?

Where data permitted, the impact of effect modifiers (e.g., covariates) was investigated with respect to the following study characteristics:

  • Population (e.g., primary diagnosis; disorder severity; smoker status; alcohol consumption).
  • Intervention/exposure (e.g., source, type, dose or serving size, and method to deliver the omega-3 fatty acids; intervention length; dietary omega-6/omega-3 fatty acid content).
  • Comparator/control (e.g., type of placebo material; a “gold standard” medication).
  • Cointerventions (e.g., concurrent psychotropic medication; other supplement use).

Methods

A Technical Expert Panel (TEP) consisting of nine members was convened to provide advisory support to the project, including refining the questions and highlighting key variables requiring consideration in the evidence synthesis.

Study Identification

Several electronic databases were searched: MEDLINE®, Embase®, the Cochrane Library including the Cochrane Central Register of Controlled Trials, PsycInfo, and CAB Health. Searches were not restricted by language of publication, publication type, or study design, except with respect to the MeSH term “dietary fats,” which was limited by study design to increase its specificity. Search elements included: scientific terms, with acronyms, as well as generic and trade names relating to the exposure and its sources (e.g., eicosapentaenoic acid [EPA]; omega-3 fatty acids; MaxEPA®); and, relevant population terms (e.g., depression). Additional published or unpublished literature was sought through manual searches of reference lists of included studies and key review articles, and from the files of content experts. A final set of 1,212 unique references was identified and posted to an internet-based software system for review.

Studies were considered relevant if they described live human populations of any age, which exhibited the psychiatric status consistent with one of the above-noted research questions concerning treatment or prevention (i.e., with or without [a known elevated risk to develop] a psychiatric diagnosis or condition) in addition to any or no comorbidity, and investigated at least one pertinent clinical outcome (e.g., symptom improvement; incidence of a disorder). As markers of omega-3 fatty acid metabolism, the following fatty acid compositions or concentrations, from any source (e.g., plasma phospholipids), were considered relevant as possible predictors of the onset, continuation or recurrence of psychiatric disorders or conditions: EPA, DHA, AA/EPA, AA/DHA, AA/EPA+DHA. Studies exclusively evaluating the role of other biomarkers (e.g., cytokine production, eicosanoid levels) were not included. Excluded populations were those with degenerative (e.g., Alzheimer's) and peroxisomal (e.g., Zellweger's) disorders since each was addressed in SC-RAND's year-2 review of the evidence concerning omega-3 fatty acids in neurology.

Treatment studies, as well as those investigating the possible association between omega-3 fatty acid intake and the onset, continuation or recurrence of psychiatric disorders or conditions, had to investigate foods or supplements known to contain omega-3 fatty acids of any type (e.g., EPA), from any source (e.g., walnuts), any serving size or dose, delivered in any fashion (e.g., capsules, PUFA-rich diet), and for any length of time. In all studies, some method had to have been employed to suggest the presence of omega-3 fatty acid content in the exposure, if not its actual amount (e.g., g/d). Studies investigating “PUFAs” or “LC PUFAs,” or even types of diet one might presume would contain marine or land sources of omega-3 fatty acids (e.g., “Mediterranean diet”) at minimum had to highlight at least one source of the omega-3 fatty acid content (e.g., oily fish servings). No restrictions were placed on the types or doses of pre- or on-study cointerventions (e.g., psychotropic medication, omega-6 fatty acid intake).

Controlled studies employing any control were required to address questions of intervention efficacy (or effectiveness), with randomized controlled trials (RCTs) being the gold standard method to investigate these questions.7 Any type of research design other than noncomparative case series or case studies was deemed appropriate for questions concerning the possible association between the intake of omega-3 fatty acids and the onset, continuation or recurrence of psychiatric disorders or conditions. A special interpretative emphasis was placed on results from prevention RCTs and other controlled prospective designs. Controlled studies involving any control were required to address the questions of the possible association between the fatty acid content of biomarkers and the onset, continuation or recurrence of psychiatric disorders or conditions. A special interpretative emphasis was placed on results from controlled prospective designs. These decisions were made with the assistance of our TEP.

Two initial levels of screening for relevance, and two reviewers per level, were employed (directed at bibliographic records, then full articles). A third dual-assessor relevance screening identified and thereby excluded uncontrolled studies with respect to questions of intervention efficacy or the possible protective role of lipid biomarker content. Calibration exercises preceded each step of the screening process. Excluded studies were noted as to the reason for their ineligibility using a modified QUOROM format.8 Disagreements were resolved by forced consensus and, if necessary, third party intervention.

Data Abstraction

Following a calibration exercise, seven reviewers independently abstracted the contents of each included study using an electronic Data Abstraction form. A second reviewer verified these data. Data included the characteristics of the report (e.g., publication status), study (e.g., research design), population (e.g., diagnosis), intervention/exposure (e.g., omega-3 fatty acid type), comparator group(s), cointerventions (e.g., medications), withdrawals or dropouts, and outcomes (i.e., symptom improvement; biomarker status; adverse events).

After calibration exercises, each study's quality (internal validity) and applicability (external validity) were formally assessed. Dual-review appraised RCTs' quality while only single-assessor evaluations could be conducted for other research designs. For the RCTs, disagreements were resolved by forced consensus and, if necessary, third party intervention. RCTs' reporting of randomization, double blinding, withdrawals and dropouts, and the concealment of allocation, were evaluated using Jadad's 9 and Schulz's validated instruments.10 The validated Newcastle-Ottawa Scale (NOS) assessed case-control and cohort study designs,11 while all other designs were evaluated using modifications of the NOS,11 Jadad's instrument,9 or items from Downs and Black's validated 27-item tool.12 Applicability was defined as the extent to which a given study's sample population was representative of a “typical” North American population. The method of diagnosis and the omega-6/omega-3 fatty acid ratio in the background diet were the key variables defining the reference population of North Americans identified with a psychiatric disorder. The omega-6/omega-3 fatty acid ratio in the background diet defined the reference population of North Americans who did not exhibit a psychiatric disorder.

Data Synthesis

A summary table provided a question-specific overview of included studies' relevant data presented in greater detail in evidence tables. A question-specific summary matrix situated each study in terms of its quality and applicability ratings. Question-specific qualitative syntheses of the evidence were derived. A dearth of studies best suited to address a particular kind of question (i.e., RCTs; prospective and controlled observational studies), as well as limitations on, or the strong clinical heterogeneity of, available studies (e.g., divergent intervention-comparator contrasts; use of complex interventions where it was impossible to tease out the possible specific benefit of omega-3 fatty acids; failure to control for key confounders), made it impossible to perform meta-analysis for any question other than the supplemental treatment for schizophrenia.

Results

Literature Search

Of 1,212 records entered into the initial screening for relevance, 955 were excluded. All but 7 of the remaining 257 reports were then retrieved, and subjected to a more detailed relevance assessment.1321 A second relevance screening then excluded 137 reports. A third screening excluded 27 reports of uncontrolled studies. In total, 86 reports, describing 79 unique studies, were deemed relevant for the systematic review, with six studies each described by more than one report. To simplify matters, only one report per study is referred to in this summary. Yet, data from all of a study's documents were included in qualitative and quantitative syntheses. Some studies addressed more than one question.

Of the included studies, only one failed to be described by at least one published report.22 Of the 16 relevant studies identified by manual search, only this abstract was disseminated in a format other than a journal publication.22 All but one of the included reports (all published), which required translation from Chinese,23 were written in English.

Overall, depression (n=22 studies) and schizophrenia (n=28) were the most frequently studied disorders. Only the 10 studies investigating attention-deficit/hyperactivity disorder (AD/HD) enrolled pediatric populations. Many of the studies exhibited poor quality or weak applicability to North American populations. Synopses of evidence are presented according to seven cross-cutting topics:

Adverse Events

A number of study reports explicitly stated that no exposure-related adverse events had been observed.2432 Ten RCTs described at least one mild adverse event associated with an omega-3 fatty acid intervention/exposure.2, 3341 Results from these studies suggest that the exposures were well tolerated. In spite of a small number of discontinuations presumed to have been instigated by an adverse event, it is unlikely that moderate or severe side effects were ever observed in relation to an omega-3 fatty acid exposure. Reported difficulties tended to be mild and transient, often involving gastrointestinal upset or nausea. Occasionally, adverse events were linked to the intake of oily substances, rather than to the omega-3 fatty acid contents in the oils. Aside from the mild adverse effects associated with Stoll, et al.'s very high dose of 9.6 g/d EPA+DHA (i.e., three patients had to decrease the number of capsules swallowed per day, yet none were required to discontinue),38 no other patterns were discerned regarding the impact of dose, type (e.g., DHA, EPA) or source (e.g., marine, plant) of omega-3 fatty acids on safety. In one study, a child with AD/HD in the active treatment group had to leave the study due to problems swallowing the capsules.41 Few of the events described in two trials by Hamazaki, et al., which enrolled healthy volunteers, suggested that the adverse effects had been directly related to the exposure.39, 40

Primary Treatment

One RCT examined omega-3 fatty acids as primary treatment for depression.34 It found no benefit for 2 g/d DHA as primary treatment despite an increase in the absolute RBC levels of DHA in the active treatment group.34 Reasons for this null result could include the use of too small a dose, too short an intervention period, the “wrong” omega-3 fatty acid, broken blinding, low power, or failure to modify the on-study background intake of omega-6 fatty acids.

Notwithstanding the noncomparability of interventions, comparators and populations (i.e., with32, 42, 43 or without a formal diagnosis of AD/HD;41 with32 or without significant comorbidity41, 43), the complex definitions of the intervention where it was impossible to tease out the possible specific benefit of omega-3 fatty acids,41 evidence for selection bias,43 or the failure to specify study enrollees' specific diagnostic subtype of AD/HD (e.g., Inattentive),44 the results of the three RCTs32, 41, 42 and the comparative before-after study43 addressing the question about the primary treatment of AD/HD were inconsistent. Thus, no definitive conclusions can be drawn about the value of omega-3 fatty acids as primary treatment for AD/HD.

One RCT examined E-EPA as primary treatment for borderline personality disorder and observed significant clinical effects, as the E-EPA group had, at study end, significantly lower mean scores on both clinical outcomes compared with the placebo group.31 Despite its strong applicability to the North American population, this is a small study requiring replication.

While the results of Peet, et al.'s trial37 indicate placebo-controlled benefits accruing to omega-3 fatty acids as primary treatment for schizophrenia, this was a small albeit methodologically adequate pilot trial with little applicability to a North American population. More work is required before we can determine omega-3 fatty acids' promise in this context.

Supplemental Treatment

Peet, et al.'s dose-ranging RCT of ethyl eicosapentaenoate (E-EPA) as supplemental treatment for depression found that only 1 g/d for 12 weeks had a significant impact on various clinical outcomes.2 Two RCTs of shorter duration also showed significant benefits associated with 2 g/d E-EPA and 6.6 g/d of EPA+DHA, respectively;27, 33 the significant clinical effect reported by Su, et al. was associated with a significant increase in RBC EPA exclusively in the active treatment group.33 However, we decided to forego meta-analysis due to study differences on the basis of the intervention (i.e., type, dose, followup length) and comparator (i.e., placebo source). Also, unlike the other two trials, Peet, et al.'s did not formally identify patients with a depressive disorder.2 This may account for their finding that 1 g/d E-EPA had a beneficial effect on depressive symptomatology.2 A low dose might not have helped the treatment-resistant depressive disorders investigated in the other RCTs. Yet, this likely cannot explain why Peet, et al.'s higher doses (2 g/d, 4 g/d) did not likewise ameliorate depressive symptoms, or why more responders (i.e., 50% improvement) were found in the placebo group than in the 2 g/d E-EPA group. Su, et al.'s trial may have been confounded by uncontrolled combinations of medication.33 The question of omega-3 fatty acids as supplemental treatment for depression requires additional investigation.

Two studies, one RCT 38 and one defined merely as “controlled,” 45 evaluated the supplemental treatment of bipolar disorder. Only the RCT report gave us an opportunity to assess its study parameters and results.38 While it had to be stopped prematurely, their very high dose of 9.6 g/d EPA+DHA produced a significantly longer period of remission in the active treatment group compared with controls. This study's limitations (i.e., loss of power due to its stoppage; broken blind) require its replication. Therefore, the evidence base is too limited to allow us to conclude anything about the value of omega-3 fatty acids as supplemental therapy for bipolar disorder. Likewise, one underpowered and flawed crossover RCT, which failed to show that E-EPA is effective as supplemental treatment for obsessive-compulsive disorder, is insufficient to permit drawing a definitive conclusion.25

Inconsistencies in the results produced by three RCTs, the occasional use of a complex intervention making it impossible to tease out the possible specific benefit of omega-3 fatty acids,46 the confirmation by parents—but not by professionals—of an AD/HD diagnosis,46 interventions that did not last long enough,30, 42, 46 and failures to weight-adjust doses of omega-3 fatty acids prevent us from identifying clear conclusions about their value as supplemental treatment for AD/HD.30, 42, 46

Three of four good quality placebo-controlled RCTs investigating the supplemental treatment of schizophrenia26, 3537 reported significant clinical effects in favor of EPA using total PANSS scores,26, 36, 37 although Peet, et al.'s study observed this effect only for those receiving clozapine as primary treatment.36 Emsley, et al.'s RCT also found that the reduction in PANSS total scores associated with E-EPA supplementation was greater in patients taking clozapine. However, the latter's placebo-controlled difference only approached being statistically significant.26 Results of our meta-analysis of two studies' PANSS total data revealed that dose influenced outcome. A significant placebo-controlled effect was identified for 2g/d EPA yet not for doses of at least 3g/d EPA.36, 37 However, these results might have been different had we been able to analyze data by type of psychotropic medication, had both studies used either the purified or unpurified form of EPA as well as the same placebo oils, had their intervention periods lasted longer, or had both trials employed capsules to deliver the omega-3 fatty acids. While the findings are suggestive, they remain inconclusive given that the data subjected to meta-analysis were derived from two small trials exhibiting certain limitations.

Primary Prevention (i.e., Onset) Via Omega-3 Fatty Acid Intake

Inconsistent results, in addition to too few studies exhibiting sound methodologies or research designs that are ideally suited to investigate this question (e.g., prospective, controlled, with subject-level data), suggest that it is too early to conclude whether or not the intake of omega-3 fatty acids protects against the onset of depressive disorders or symptomatology.1, 24, 28, 4755 The same issues prevent us from concluding whether or not the intake of omega-3 fatty acids protects against the onset of suicidal ideation or behavior.51, 55 Given the inability of any cross-national ecological analysis to provide meaningful subject-level data, and the failure to control for key confounders (i.e., socioeconomic status, urban/rural ratio, educational level, marital status, alcohol consumption, smoker status or family history), we cannot conclude anything about the value of seafood consumption as protection against the onset of bipolar disorder.56

Two RCTs failed to clarify the protective value of omega-3 fatty acid intake with respect to the onset of symptoms, not disorders, of anxiety.28, 47 However, these small studies do not constitute optimal tests of this potential. Based on one cross-sectional study, which controlled for age, income, smoking, alcohol consumption and eating patterns, mental health difficulties were more prevalent in those consuming no fish.57 However, this design precludes inferring a causal link between fish consumption and the onset of mental health difficulties.

Four RCTs,28, 39, 40, 58 three of which enrolled healthy volunteers, one single population cross-sectional survey59 and one cross-national ecological analysis60 studied the possible association between omega-3 fatty acid intake and the onset of tendencies or behavior with the potential to harm others. Overall, their findings are too inconsistent and involve too few research designs permitting the drawing of causal inferences or too many different definitions of the exposure, population or outcome to permit us to draw a consistent, individual/patient-level conclusion regarding the value of omega-3 fatty acid intake to protect against tendencies or behavior with the potential to harm others.

Research designs were not identified which—due to their prospective and controlled nature—are most appropriate for addressing the question of the possible relationship between intake of omega-3 fatty acids (e.g., via breastfeeding) and the onset of schizophrenia. Five case-control designs,22, 6164 one single prospective cohort65 and three cross-national ecological analyses50, 56, 66 were found. The only prospective study was not controlled, and its followup was very short.65 Moreover, failures to control for confounders were common (e.g., maternal feeding patterns, sex of children, maternal age, socioeconomic status, early mother-infant contact). Thus, nothing definitive can be asserted about a reliable association between omega-3 fatty acid intake and the onset of schizophrenia.

Secondary Prevention (i.e., Continuation, Recurrence) Via Omega-3 Fatty Acid Intake

One small, multiple-group cross-sectional study revealing that, relative to healthy controls, AD/HD children consumed significantly lesser amounts of LA and ALA is insufficient to permit us to conclude anything definitive regarding the potential of these PUFAs to alter the course, or continuation, of AD/HD.23 Likewise, a single RCT demonstrating that a complex intervention including omega-3 fatty acids—whose independent effect could not be ascertained—provided young adult prisoners with some protection against committing new offences29 is insufficient to determine its capacity to prevent the recurrence of tendencies or behavior with the potential to harm others (i.e., antisocial behavior).29

Primary Prevention (i.e., Onset) Via Lipid Biomarker Content

Inconsistent results as well as too few studies exhibiting sound methodologies (e.g., protection against selection bias; control for smoking, alcohol use, and psychotropic medication) or research designs (e.g., prospective, controlled) that are ideally suited to investigate this question suggest that it is too early to conclude whether or not omega-3 fatty or omega-6/omega-3 acid content in biomarkers protects against the onset of depressive disorders or symptomatology. One RCT24 and seven multiple-group cross-sectional studies1, 6772 were included.

The inconsistency in findings across two multiple-group cross-sectional studies,73, 74 which is potentially attributable to the fact that the studies obtained their PUFA samples from different biomarker sources, in addition to the recognition that this type of research design is less than an ideal test of the research question, and the observation that the studies failed to control for different key confounders together indicate that nothing definitive can be concluded about the ability of specific lipid biomarker content to protect against the onset of bipolar disorder. Irrespective of the limited agreement in observing that both ALA and total omega-6 fatty acid levels in plasma phospholipids were significantly lower in anorexic patients compared with controls, the use of cross-sectional designs in two small studies prevent the drawing of causal inferences regarding the role of lipid biomarker content in the onset of anorexia nervosa.75, 76 Inconsistent findings from three multiple-group cross-sectional studies whose designs are of limited use in investigating the research question,7779 the failures to control for dietary intake,77 to formally rule out the presence of psychopathology in the control subjects, or to employ formal diagnostic criteria (i.e., DSM-III) to identify their hyperactive subjects78 made it impossible to draw causal inferences about the role of omega-3 or omega-6/omega-3 fatty acid content in biomarkers to prevent the onset of AD/HD.

Three multiple-group cross-sectional studies examined the possible association of the onset of tendencies or behavior with the potential to harm others with the omega-3 or omega-6/omega-3 fatty acid content of biomarkers.8082 Inconsistent results, small sample sizes, and the exclusive use of cross-sectional designs preclude deriving clear inferences regarding etiology. Two multiple-group cross-sectional studies investigated the possible association of the onset of alcoholism with the omega-3 or omega-6/omega-3 fatty acid content of biomarkers.83, 84 However, conflicting results and the use of cross-sectional designs do not allow us to draw conclusions regarding this possible etiology of alcoholism.

While medication status may have had somewhat of an influence on between-group differences in RBC or plasma phospholipid fatty acid content when the comparison group was healthy controls, because these data were obtained exclusively from twelve, multiple-group cross-sectional studies74, 8595 or two single prospective cohort studies with methodologic flaws,96, 97 no meaningful possibility exists to permit drawing causal inferences regarding patterns of lipid biomarker content and the onset of schizophrenia. The same criticism relating to cross-sectional designs applies to the single study examining biomarkers data with respect to the onset of autism.98

Secondary Prevention (i.e., Continuation, Recurrence) Via Lipid Biomarker Content

This question could not be evaluated since studies meeting eligibility criteria were not identified.

Discussion

A notable safety profile (i.e., beyond occasional and mild discomfort) for any type or dose of omega-3 fatty acid supplementation was not observed. Overall, other than for the topics of schizophrenia and depression, few studies were identified.

Only with respect to the supplemental treatment of schizophrenia is the evidence even somewhat suggestive of omega-3 fatty acids' potential as short-term intervention. However, these meta-analytic results exclusively pertaining to 2 g/d EPA require replication using design and methods refinements. Additional research might reveal the short-term or long-term therapeutic value of omega-3 fatty acids.

One study demonstrating a significant placebo-controlled clinical effect related to 1 g/d E-EPA given, over 12 weeks, to 17 patients with depressive symptoms—rather than depressive disorders—cannot be taken to support the view of the utility of this exposure as a supplemental treatment for depressive symptomatology or disorders. Nothing can yet be concluded concerning the clinical utility of omega-3 fatty acids as supplemental treatment for any other psychiatric disorder or condition, or as a primary treatment for all psychiatric disorders or conditions examined in our review. Primary treatment studies were rare.

Much more research, implementing design and methods improvements, is needed before we can begin to ascertain the possible utility of (foods or supplements containing) omega-3 fatty acids as primary prevention for psychiatric disorders or conditions. Studies of omega-3 fatty acids' primary protective potential in mental health could be “piggybacked” onto longitudinal studies of their impact on general health and development.

Overall, almost nothing is known about the therapeutic or preventive potential of each source, type, dose or combination of omega-3 fatty acids. Likewise, limitations within the evidence base prevented us from identifying the influence of key covariables (e.g., smoking, alcohol use, psychotropic medication) on the relationship between omega-3 fatty acid content and clinical outcomes.

Because of limited study designs, little is known about the relationship between PUFA biomarker profiles and the onset of any psychiatric disorder or condition. Studies examining the possible association between the intake of omega-3 fatty acids, or the PUFA content of biomarkers, and the continuation or recurrence of psychiatric disorders or conditions were virtually nonexistent.

If future research is going to produce data that are unequivocally applicable to North Americans, it will likely need to enroll either North American populations or populations exhibiting a high omega-6/omega-3 fatty acid intake ratio similar to what has been observed in the diet of North Americans.

Furthermore, if a reasonable view is that omega-3 fatty acids may play a role in mental health, then given the observed or proposed inter-relationships among omega-3 and omega-6 fatty acid contents both in the human diet and metabolism, it may behoove researchers to investigate the possible therapeutic or preventive value of the dietary omega-6/omega-3 fatty acid intake ratio.

Availability of Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the University of Ottawa Evidence-based Practice Center under Contract No. 290-02-0021. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 116, Effects of Omega-3 Fatty Acids on Mental Health.

The Evidence Report is can also be downloaded as a PDF file (3.6 MB). PDF Help.

AHRQ Publication Number 05-E022-1 Current as of July 2005

Internet Citation:

Schachter HM, Kourad K, Merali Z, et al. Effects of Omega-3 Fatty Acids on Mental Health. Summary, Evidence Report/Technology Assessment: Number 116. AHRQ Publication No. 05-E022-1, July 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/o3mentsum.htm

References

1.
Edwards R, Peet M, Shay J. et al. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord. 1998;48(23):149–55. [PubMed: 9543204]
2.
Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59(10):913–9. [PubMed: 12365878]
3.
Horrobin DF, Bennett CN. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes. Prostaglandins Leukot Essent Fatty Acids. 1999;60(4):217–34. [PubMed: 10397403]
4.
Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res. 1998;30(3):193–208. [PubMed: 9589514]
5.
Mahadik SP, Mukherjee S, Correnti EE. et al. Plasma membrane phospholipid and cholesterol distribution of skin fibroblasts from drug-naive patients at the onset of psychosis. Schizophr Res. 1994;13(3):239–47. [PubMed: 7841137]
6.
Fukuzako H, Fukuzako T, Hashiguchi T. et al. Changes in levels of phosphorus metabolites in temporal lobes of drug-naive schizophrenic patients. Am J Psychiatry. 1999;156(8):1205–08. [PubMed: 10450261]
7.
Jadad AR. Randomised controlled trials. London: BMJ Publishing Group, 1998.
8.
Moher D, Cook DJ, Eastwood S. et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999;354(9193):1896–900. [PubMed: 10584742]
9.
Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12. [PubMed: 8721797]
10.
Schulz KF, Chalmers I, Hayes RJ. et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408–12. [PubMed: 7823387]
11.
Wells GA Shea B O'Connell D Peterson J Welch V Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 3rd Symposium on Systematic Reviews: Beyond the Basics; July 2000; Oxford. 2000.
12.
Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–84. [PMC free article: PMC1756728] [PubMed: 9764259]
13.
Fehily AMA. Long chain polyunsaturated fatty acids and depressive illness. British Reports, Translations and Theses 1981; (3):191.
14.
Tur JA, Cortes C, Puig MS. et al. Food consumption patterns among drug abusers involved in a methadone treatment program in the Balearic Islands. Rev Esp Nutr Comunitaria. 2003;9(1):20–9.
15.
Rapisarda V, Petralia A, De Pasquale C. et al. Assessment of immune system function in schizophrenic and depressed patients treated with omega-3 fatty acids. Ital J Psychiatry Behav Sci. 2000;10(1):22–5.
16.
Anonymous. Lipids. Fortschr Med 1993; 111(14):1–4.
17.
Peet M, Horrobin DF. The role of phospholipids in schizophrenia (Abstract). Society of Biological Psychiatry annual meeting, 7th world congress, July 1–6, 2001. Berlin, Germany.
18.
Hirayama T. Life-style and Mortality: A large Census-based Cohort Study in Japan. Basel, Switzerland: Karger, 1990.
19.
Peet M. Nutrition and schizophrenia: an epidemiological and clinical perspective. Nutr Health. 2003;17(3):211–9. [PubMed: 14703154]
20.
Norman RJ, Flight IHK, Ress MCP. Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women. Cochrane Database Syst Rev 2003;(Suppl 1). [PubMed: 10796730]
21.
Smith C, Collins C, Cyna A, et al. Complementary and alternative therapies for pain management in labour. Cochrane Database Syst Rev 2003;(Suppl 1). [PubMed: 12804474]
22.
Peet M, Poole J, Laugharne J. Infant feeding and the development of schizophrenia. Schizophr Res. 1997;24:255–6.
23.
Yang S-C, Chiu W-C, Chen J-R. et al. Dietary intakes of 4–8 years old children with attention-deficit hyperactivity disorder. Nutr Sci J. 1999;24(2):153–65.
24.
Llorente AM, Jensen CL, Voigt RG. et al. Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing. Am J Obstet Gynecol. 2003;188(5):1348–53. [PubMed: 12748510]
25.
Fux M, Benjamin J, Nemets B. A placebo-controlled cross-over trial of adjunctive EPA in OCD. J Psychiatr Res. 2004;38(3):323–5. [PubMed: 15003438]
26.
Emsley R, Myburgh C, Oosthuizen P. et al. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry. 2002;159(9):1596–8. [PubMed: 12202284]
27.
Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159(3):477–9. [PubMed: 11870016]
28.
Wardle J, Rogers P, Judd P. et al. Randomized trial of the effects of cholesterol-lowering dietary treatment on psychological function. Am J Med. 2000;108(7):547–53. [PubMed: 10806283]
29.
Hyldstrup L, Beck AM, Bjornsbo KS. et al. Nutrition and aging. Ugeskr Laeger. 2002;164(49):5757–9. [PubMed: 12523213]
30.
Voigt RG, Llorente AM, Jensen CL. et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder [comment] J Pediatr. 2001;139(2):189–96. [PubMed: 11487742]
31.
Zanarini MC, Frankenburg FR. omega-3 Fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003;160(1):167–9. [PubMed: 12505817]
32.
Hirayama S, Hamazaki T, Terasawa K. Effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder—A placebo-controlled double-blind study. Eur J Clin Nutr. 2004;58(3):467–73. [PubMed: 14985685]
33.
Su KP, Huang SY, Chiu CC. et al. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13(4):267–71. [PubMed: 12888186]
34.
Marangell LB, Martinez JM, Zboyan HA. et al. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry. 2003;160(5):996–8. [PubMed: 12727707]
35.
Fenton WS, Dickerson F, Boronow J. et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia [comment] Am J Psychiatry. 2001;158(12):2071–4. [PubMed: 11729030]
36.
Peet M, Horrobin DF. Study Group E-EM. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res. 2002;36(1):7–18. [PubMed: 11755456]
37.
Peet M, Brind J, Ramchand CN. et al. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res. 2001;49(3):243–51. [PubMed: 11356585]
38.
Stoll AL, Severus WE, Freeman MP. et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.[comment] Arch Gen Psychiatry. 1999;56(5):407–12. [PubMed: 10232294]
39.
Hamazaki T, Sawazaki S, Nagao Y. et al. Docosahexaenoic acid does not affect aggression of normal volunteers under nonstressful conditions. A randomized, placebo-controlled, double-blind study. Lipids. 1998;33(7):663–7. [PubMed: 9688168]
40.
Hamazaki T, Sawazaki S, Itomura M. et al. The effect of docosahexaenoic acid on aggression in young adults. A placebo-controlled double-blind study. J Clin Invest. 1996;97(4):1129–33. [PMC free article: PMC507162] [PubMed: 8613538]
41.
Richardson AJ, Puri BK. A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(2):233–9. [PubMed: 11817499]
42.
Brue AW, Oakland TD, Evans RA. The use of a dietary supplement combination and an essential fatty acid as an alternative and complementary treatment for children with attention-deficit/hyperactivity disorder. Sci Rev Altern Med. 2001;5(4):187–94.
43.
Harding KL, Judah RD, Gant CE. Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD. Altern Med Rev. 2003;8(3):319–30. [PubMed: 12946241]
44.
Schachter HM, Pham B, King J. et al. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis. CMAJ. 2001;165(11):1475–88. [PMC free article: PMC81663] [PubMed: 11762571]
45.
Akkerhuis GW, Nolen WA. Lithium-associated psoriasis and omega-3 fatty acids. Am J Psychiatry. 2003;160(7):1355. [PubMed: 12832259]
46.
Stevens L, Zhang W, Peck L. et al. EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors. Lipids. 2003;38(10):1007–21. [PubMed: 14669965]
47.
Ness AR, Gallacher JEJ, Bennett PD. et al. Advice to eat fish and mood: A randomised controlled trial in men with angina. Nutr Neurosci. 2003;6(1):63–5. [PubMed: 12608739]
48.
Hibbeln JR. Seafood consumption, the DHA content of mothers' milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord. 2002;69(13):15–29. [PubMed: 12103448]
49.
Hibbeln JR. Fish consumption and major depression [comment] Lancet. 1998;351(9110):1213. [PubMed: 9643729]
50.
Peet M. International variations in the outcome of schizophrenia and the prevalence of depression in relation to national dietary practices: an ecological analysis. Br J Psychiatry. 2004;184:404–8. [PubMed: 15123503]
51.
Tanskanen A, Hibbeln JR, Hintikka J. et al. Fish consumption, depression, and suicidality in a general population [comment] Arch Gen Psychiatry. 2001;58(5):512–3. [PubMed: 11343534]
52.
Tanskanen A, Hibbeln JR, Tuomilehto J. et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv. 2001;52(4):529–31. [PubMed: 11274502]
53.
Suzuki S, Akechi T, Kobayashi M. et al. Daily omega-3 fatty acid intake and depression in Japanese patients with newly diagnosed lung cancer. Br J Cancer. 2004;90(4):787–93. [PMC free article: PMC2410186] [PubMed: 14970854]
54.
Woo J, Ho SC, Yu ALM. Lifestyle factors and health outcomes in elderly Hong Kong Chinese aged 70 years and over. Gerontology. 2002;48(4):234–40. [PubMed: 12053113]
55.
Hakkarainen R, Partonen T, Haukka J. et al. Is low dietary intake of omega-3 fatty acids associated with depression? Am J Psychiatry. 2004;161(3):567–9. [PubMed: 14992986]
56.
Noaghiul S, Hibbeln JR. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am J Psychiatry. 2003;160(12):2222–7. [PubMed: 14638594]
57.
Silvers KM, Scott KM. Fish consumption and self-reported physical and mental health status. Public Health Nutr. 2002;5(3):427–31. [PubMed: 12003654]
58.
Hamazak T, Thienprasert A, Kheovichai K. et al. The effect of docosahexaenoic acid on aggression in elderly Thai subjects—a placebo-controlled double-blind study. Nutr Neurosci. 2002;5(1):37–41. [PubMed: 11929196]
59.
Iribarren C, Markovitz JH, Jacobs DR Jr. et al. Dietary intake of n-3, n-6 fatty acids and fish: Relationship with hostility in young adults—The CARDIA study. Eur J Clin Nutr. 2004;58(1):24–31. [PubMed: 14679363]
60.
Hibbeln JR. Seafood consumption and homicide mortality: A cross-national ecological analysis. 4th Congress of the International Society for the Study of Fatty Acids and Lipids (ISSFAL 2000). World Rev Nutr Diet. 2000;88:41–6. [PubMed: 11935968]
61.
Amore M, Balista C, McCreadie RG. et al. Can breast-feeding protect against schizophrenia? Case-control Study. Biol Neonate. 2003;83(2):97–101. [PubMed: 12576752]
62.
Leask SJ, Done DJ, Crow TJ. et al. No association between breast-feeding and adult psychosis in two national birth cohorts. Br J Psychiatry. 2000;177:218–21. [PubMed: 11040881]
63.
McCreadie RG. The Nithsdale Schizophrenia Surveys. 16. Breast-feeding and schizophrenia: preliminary results and hypotheses. Br J Psychiatry. 1997;170:334–7. [PubMed: 9246251]
64.
Sasaki T, Okazaki Y, Akaho R. et al. Type of feeding during infancy and later development of schizophrenia. Schizophr Res. 2000;42(1):79–82. [PubMed: 10706988]
65.
Mellor JE, Laugharne JDE, Peet M. Omega-3 fatty acid supplementation in schizophrenic patients. HUM. 1996;11(1):39–46.
66.
Christensen O, Christensen E. Fat consumption and schizophrenia. Acta Psychiatr Scand. 1988;78(5):587–91. [PubMed: 3232536]
67.
Maes M, Christophe A, Delanghe J. et al. Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res. 1999;85(3):275–91. [PubMed: 10333380]
68.
Peet M, Murphy B, Shay J. et al. Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry. 1998;43(5):315–19. [PubMed: 9513745]
69.
Maes M, Smith R, Christophe A. et al. Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids. J Affect Disord. 1996;38(1):35–46. [PubMed: 8735157]
70.
Tiemeier H, van Tuijl HR, Hofman A. et al. Plasma fatty acid composition and depression are associated in the elderly: the Rotterdam Study. Am J Clin Nutr. 2003;78(1):40–6. [PubMed: 12816769]
71.
Ellis FR, Sanders TAB. Long chain polyunsaturated fatty acids in endogenous depression. J Neurol Neurosurg Psychiatry. 1977;40(2):168–9. [PMC free article: PMC492633] [PubMed: 864481]
72.
Fehily AMA, Bowey OAM, Ellis FR. et al. Plasma and erythrocyte membrane long chain polyunsaturated fatty acids in endogenous depression. Neurochem Int. 1981;3(1):37–42. [PubMed: 20487806]
73.
Chiu CC, Huang SY, Su KP. et al. Polyunsaturated fatty acid deficit in patients with bipolar mania. Eur Neuropsychopharmacol. 2003;13(2):99–103. [PubMed: 12650953]
74.
Mahadik SP, Mukherjee S, Horrobin DF. et al. Plasma membrane phospholipid fatty acid composition of cultured skin fibroblasts from schizophrenic patients: comparison with bipolar patients and normal subjects. Psychiatry Res. 1996;63(23):133–42. [PubMed: 8878309]
75.
Langan SM, Farrell PM. Vitamin E, vitamin A and essential fatty acid status of patients hospitalized for anorexia nervosa. Am J Clin Nutr. 1985;41(5):1054–60. [PubMed: 3993608]
76.
Holman RT, Adams CE, Nelson RA. et al. Patients with anorexia nervosa demonstrate deficiencies of selected essential fatty acids, compensatory changes in nonessential fatty acids and decreased fluidity of plasma lipids. J Nutr. 1995;125(4):901–7. [PubMed: 7722693]
77.
Stevens LJ, Zentall SS, Deck JL. et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr. 1995;62(4):761–768. [PubMed: 7572706]
78.
Mitchell EA, Aman MG, Turbott SH. et al. Clinical characteristics and serum essential fatty acid levels in hyperactive children. Clin Pediatr (Phila). 1987;26(8):406–11. [PubMed: 2439249]
79.
Mitchell EA, Lewis S, Cutler DR. Essential fatty acids and maladjusted behaviour in children. Prostaglandins Leukot Med. 1983;12(3):281–7. [PubMed: 6581484]
80.
Hibbeln JR, Umhau JC, Linnoila M. et al. A replication study of violent and nonviolent subjects: cerebrospinal fluid metabolites of serotonin and dopamine are predicted by plasma essential fatty acids. Biol Psychiatry. 1998;44(4):243–9. [PubMed: 9715355]
81.
Virkkunen ME, Horrobin DF, Jenkins DK. et al. Plasma phospholipid essential fatty acids and prostaglandins in alcoholic, habitually violent, and impulsive offenders. Biol Psychiatry. 1987;22(9):1087–96. [PubMed: 2958095]
82.
Buydens-Branchley L, Branchey M, McMakin DL. et al. Polyunsaturated fatty acid status and aggression in cocaine addicts. Drug Alcohol Depend. 2003;71(3):319–23. [PubMed: 12957349]
83.
Hibbeln JR, Linnoila M, Umhau JC. et al. Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics. Biol Psychiatry. 1998;44(4):235–42. [PubMed: 9715354]
84.
Alling C, Gustavsson L, Kristensson-Aas A. et al. Changes in fatty acid composition of major glycerophospholipids in erythrocyte membranes from chronic alcoholics during withdrawal. Scand J Clin Lab Invest. 1984;44(4):283–289. [PubMed: 6463560]
85.
Arvindakshan M, Sitasawad S, Debsikdar V. et al. Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients. Biol Psychiatry. 2003;53(1):56–64. [PubMed: 12513945]
86.
Khan MM, Evans DR, Gunna V. et al. Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res. 2002;58(1):1–10. [PubMed: 12363384]
87.
Assies J, Lieverse R, Vreken P. et al. Significantly reduced docosahexaenoic and docosapentaenoic acid concentrations in erythrocyte membranes from schizophrenic patients compared with a carefully matched control group. Biol Psychiatry. 2001;49(6):510–22. [PubMed: 11257236]
88.
Peet M, Laugharne J, Rangarajan N. et al. Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients. J Psychiatr Res. 1995;29(3):227–32. [PubMed: 7473298]
89.
Fischer S, Kissling W, Kuss HJ. Schizophrenic patients treated with high dose phenothiazine or thioxanthene become deficient in polyunsaturated fatty acids in their thrombocytes. Biochem Pharmacol. 1992;44(2):317–23. [PubMed: 1642646]
90.
Kaiya H, Horrobin DF, Manku MS. et al. Essential and other fatty acids in plasma in schizophrenics and normal individuals from Japan. Biol Psychiatry. 1991;30(4):357–62. [PubMed: 1912126]
91.
Horrobin DF, Manku MS, Morse-Fisher N. et al. Essential fatty acids in plasma phospholipids in schizophrenics. Biol Psychiatry. 1989;25(5):562–8. [PubMed: 2920191]
92.
Obi FO, Nwanze EA. Fatty acid profiles in mental disease. Part 1. Linolenate variations in schizophrenia. J Neurol Sci. 1979;43(3):447–54. [PubMed: 521838]
93.
Yao J, Stanley JA, Reddy RD. et al. Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites. Biol Psychiatry. 2002;52(8):823–30. [PubMed: 12372654]
94.
Arvindakshan M, Ghate M, Ranjekar PK. et al. Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr Res. 2003;62(3):195–204. [PubMed: 12837515]
95.
Ranjekar PK, Hinge A, Hegde MV. et al. Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. Psychiatry Res. 2003;121(2):109–22. [PubMed: 14656446]
96.
Vaddadi KS, Gilleard CJ, Soosai E. et al. Schizophrenia, tardive dyskinesia and essential fatty acids. Schizophr Res. 1996;20(3):287–94. [PubMed: 8827855]
97.
Evans DR, Parikh VV, Khan MM. et al. Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent Fatty Acids. 2003;69(6):393–9. [PubMed: 14623492]
98.
Vancassel S, Durand G, Barthelemy C. et al. Plasma fatty acid levels in autistic children. Prostaglandins Leukot Essent Fatty Acids. 2001;65(1):1–7. [PubMed: 11487301]

Views

  • PubReader
  • Print View
  • Cite this Page

Related publications

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...