Effects of Omega-3 Fatty Acids on Mental Health

418 Pages·2005·3.71 MB·English

Evidence Report/Technology Assessment
Number 116

Effects of Omega-3 Fatty Acids on Mental Health

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov

Contract No. 290-02-0021

Prepared by:
University of Ottawa Evidence-based Practice Center at
The University of Ottawa, Ottawa, Canada

Investigators
Howard M Schachter, PhD
Kader Kourad, MD, PhD
Zul Merali, PhD
Andrew Lumb, BA
Khai Tran, PhD
Maia Miguelez, PhD
Gabriela Lewin, MD
Margaret Sampson, MLIS
Nick Barrowman, PhD
Hope Senechal, BSc
Candice McGahern, HRA
Li Zhang, BSc
Andra Morrison, BSc
Jakov Shlik MD, PhD
Yi Pan, MSc
Elizabeth C Lowcock, BScH
Isabelle Gaboury, MSc
Jacques Bradwejn, MD
Anne Duffy, MD

AHRQ Publication No. 05-E022-2
July 2005
This report is based on research conducted by the University of Ottawa Evidence-based
Practice Center (EPC), under contract to the Agency for Healthcare Research and Quality
(AHRQ), Rockville, MD (Contract No. 290-02-0021). The findings and conclusions in this
document are those of the authors, who are responsible for its contents; the findings and
conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this
report should be construed as an official position of AHRQ or of the U.S. Department of
Health and Human Services.
The information in this report is intended to help health care decisionmakers, patients and
clinicians, health system leaders, and policymakers make well-informed decisions and thereby
improve the quality of health care services. This report is not intended to be a substitute for
the application of clinical judgment. Anyone who makes decisions concerning the provision
of clinical care should consider this report as they would any medical reference and in
conjunction with all other pertinent information, i.e., in the context of available resources and
circumstances presented by individual patients.
This report may be used, in whole or in part, as the basis for development of clinical practice
guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage
policies. Neither AHRQ’s nor the U.S. Department of Health and Human Services’
endorsement of such derivative products may be stated or implied.
This document is in the public domain and may be used and reprinted without permission except
those copyrighted materials noted for which further reproduction is prohibited without the
specific permission of copyright holders.

Suggested Citation:
Schachter H, Kourad K, Merali Z, Lumb A, Tran K, Miguelez M, et al. Effects of Omega-3
Fatty Acids on Mental Health. Evidence Report/Technology Assessment No. 116. (Prepared by
the University of Ottawa Evidence-based Practice Center, Under Contract No. 290-02-0021.)
AHRQ Publication No. 05-E022-2. Rockville, MD: Agency for Healthcare Research and
Quality. July 2005.

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Preface

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based
Practice Centers (EPCs), sponsors the development of evidence reports and technology
assessments to assist public- and private-sector organizations in their efforts to improve the
quality of health care in the United States. This report was requested and funded by the Office of
Dietary Supplements, National Institutes of Health. The reports and assessments provide
organizations with comprehensive, science-based information on common, costly medical
conditions and new health care technologies. The EPCs systematically review the relevant
scientific literature on topics assigned to them by AHRQ and conduct additional analyses when
appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health
technology assessments, AHRQ encourages the EPCs to form partnerships and enter into
collaborations with other medical and research organizations. The EPCs work with these partner
organizations to ensure that the evidence reports and technology assessments they produce will
become building blocks for health care quality improvement projects throughout the Nation. The
reports undergo peer review prior to their release.
AHRQ expects that the EPC evidence reports and technology assessments will inform
individual health plans, providers, and purchasers as well as the health care system as a whole by
providing important information to help improve health care quality.
We welcome comments on this evidence report. They may be sent by mail to the Task Order
Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road,
Rockville, MD 20850, or by email to [email protected].

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H.
Director Director
Agency for Healthcare Research and Quality Center for Outcomes and Evidence
Agency for Healthcare Research and Quality
Paul M. Coates, Ph.D.
Director Kenneth S. Fink, M.D., M.G.A., M.P.H.
Office of Dietary Supplements Director, EPC Program
National Institutes of Health Agency for Healthcare Research and Quality

Beth A. Collins Sharp, R.N., Ph.D.
EPC Program Task Order Officer
Agency for Healthcare Research and Quality

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Acknowledgments

The authors would like to thank numerous individuals for their support of the present project:
Isabella Steffensen and Christine Murray for their ability to clarify the meaning of our words,
figures and tables; Pieter Oosthuizen and Robin Emsley for responding affirmatively to our
request for data; Malcolm Peet for trying to facilitate the sharing of data he collected yet which
are now held by one of his studies’ funding sources; Bill Hodge for arranging timely help with
assessors of study quality; Samantha Fulton for helping check some of our work; Vladimir Fox
for arranging the expert and timely translation of non-English language articles; Herb Woolf for
responding with substance to our request of industry for evidence; Peter O’Blenis for assuring
that the Internet-based software we used for all aspects of the review process was adapted to our
needs; our collaborators at SC-RAND and Tufts-NEMC EPCs; Beth Collins-Sharp, Rosaly
Correa-de-Araujo and Jacqueline Besteman who, as our Task Order Officers, provided steady
support and guidance on behalf of AHRQ; and, Anne Thurn of the Office of Dietary
Supplements for her thoughtful direction on behalf of the Federal Partners. Sections of Chapter
1 were developed in collaboration with Tufts-NEMC EPC, and with contributions from SC-
RAND EPC.

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Structured Abstract

Context: One popular view holds that psychiatric problems reflect disorders of brain
functioning. Fifty percent to 60% of the adult brain is composed of lipids (dry weight), of which
35% are phospholipids comprised of unsaturated fatty acids. Of these, the polyunsaturated fatty
acids docosahexaenoic acid (an omega-3 fatty acid) and arachidonic acid (an omega-6 fatty acid)
are found in the highest concentrations. Thus, it has been proposed that omega-3 fatty acids
could play an important role in mental health.

Objectives: The purpose of this study was to conduct a systematic review of the scientific-
medical literature to identify, appraise and synthesize the evidence for the effects of omega-3
fatty acids in mental health. Evidence was sought to permit the investigation of three basic
questions: the efficacy and safety of omega-3 fatty acids as (primary or supplemental) treatment
of psychiatric disorders or conditions (e.g., symptoms alone); the association between intake of
omega-3 fatty acids and the onset, continuation or recurrence of psychiatric disorders or
conditions; and, the association between the fatty acid content of biomarkers and the onset,
continuation or recurrence of psychiatric disorders or conditions. The latter two questions
examined the protective value of omega-3 fatty acid content in the diet and/or blood lipid
biomarkers. The impact of effect modifiers was examined as well. The results will be used
largely to inform a research agenda.

Data Sources: A comprehensive search for citations was conducted using five databases
(Medline, Embase, 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]; fish oil);
and, relevant population terms (e.g., mental disorders). Additional published or unpublished
literature was sought through manual searches of references lists of included studies and key
review articles, and from the files of content experts.

Study Selection: Studies were considered relevant if they described live human populations
of any age, investigated the use of any foods or supplements known to contain omega-3 fatty
acids, and utilized mental health outcomes. Studies examining the questions concerning
treatment efficacy or the fatty acid content of biomarkers had to employ a controlled research
design, whereas any type of design other than a case series or case study was permitted to
address the possible association of the intake of omega-3 fatty acids and clinical outcomes.
Three levels of screening for relevance, and two reviewers per level, were employed.
Disagreements were resolved by forced consensus and, if necessary, third party intervention.

Data Extraction: All data were abstracted by one reviewer, then verified by another. Data
included characteristics of the report, study, population, intervention/exposure, comparator(s),
cointerventions, discontinuations (and reasons), and outcomes (i.e., clinical, biomarkers, safety).
Study quality (internal validity) and applicability (external validity) were appraised.

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Data Synthesis: Question-specific qualitative syntheses of the evidence were derived. Meta-
analysis was conducted with data concerning the supplemental treatment of schizophrenia.
Limited numbers of studies addressing the other research questions precluded further meta-
analysis. Eighty-six reports, describing 79 studies, were deemed relevant for the systematic
review, with each of 6 studies described by more than one report.

Conclusions: A notable safety profile 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 longterm 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. Overall, almost nothing is known about the therapeutic or preventive potential of
each source, type, dose or combination of omega-3 fatty acids. Studies of their primary
protective potential in mental health could be “piggybacked” onto longitudinal studies of their
impact on general health and development. 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 between omega-3 and omega-6 fatty acid contents both in the
regular diet and in the human biosystem, it may behoove researchers to investigate the possible
therapeutic or preventive value of the dietary omega-6/omega-3 fatty acid intake ratio.

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Contents

Evidence Report

Chapter 1. Introduction..........................................................................................................3
Metabolism and Biological Effects of Essential Fatty Acids...........................................3
Metabolic Pathways of Omega-3 and Omega-6 Fatty Acids............................................4
U.S. Population Intake of Omega-3 Fatty Acids..............................................................8
Dietary Sources of Omega-3 Fatty Acids.........................................................................9
Disorders of Mental Health: an Overview........................................................................11
Affective Disorders...........................................................................................................11
Treatment Options.......................................................................................................12
Anxiety Disorders.............................................................................................................13
Treatment Options.......................................................................................................13
Anorexia Nervosa.............................................................................................................13
Treatment Options.......................................................................................................14
Attention Deficit/Hyperactivity Disorder.........................................................................14
Treatment Options.......................................................................................................14
Tendencies or Behaviors With the Potential to Harm Others: the Spectrum of
Anger/Hostility, Aggression and Violence.......................................................................14
Treatment Options.......................................................................................................15
Alcoholism........................................................................................................................15
Treatment Options.......................................................................................................15
Borderline Personality Disorder.......................................................................................15
Treatment Options.......................................................................................................16
Schizophrenia....................................................................................................................16
Treatment Options.......................................................................................................16
Autism...............................................................................................................................16
Treatment Options.......................................................................................................17
Omega-3 Fatty Acids and Mental Health.........................................................................17

Chapter 2. Methods...............................................................................................................19
Overview...........................................................................................................................19
Key Questions Addressed In This Report.........................................................................19
Analytic Framework.........................................................................................................21
Study Identification...........................................................................................................24
Search Strategy............................................................................................................24
Eligibility Criteria........................................................................................................25
Study Selection Process...............................................................................................27
Data Abstraction...............................................................................................................28
Summarizing the Evidence...............................................................................................29
Overview......................................................................................................................29
Study Quality...............................................................................................................29
Study Applicability......................................................................................................31
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Summary Matrix..........................................................................................................33
Qualitative Data Synthesis...........................................................................................33
Quantitative Data Synthesis.........................................................................................34

Chapter 3. Results..................................................................................................................37
Results of Literature Search..............................................................................................37
Report and Study Design Characteristics of Included Studies.........................................38
Are Omega-3 Fatty Acids Efficacious as Primary Treatment for Depression?................40
Overview of Relevant Study’s Characteristics and Results.........................................40
Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for Depression?.......42
Overview of Relevant Studies.....................................................................................42
Qualitative Synthesis of Relevant Studies’ Key Characteristics.................................44
Qualitative Synthesis of Individual Study Results.......................................................47
Quantitative Synthesis.................................................................................................49
Impact of Covariates and Confounders........................................................................51
Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated
With the Onset, Continuation or Recurrence of Depression?...........................................51
Overview of Relevant Studies.....................................................................................52
Qualitative Synthesis of Relevant Studies’ Key Characteristics.................................58
Qualitative Synthesis of Individual Study Results.......................................................64
Quantitative Synthesis.................................................................................................66
Impact of Covariates and Confounders........................................................................66
Is the Onset, Continuation or Recurrence of Depression Associated With Omega-3
or Omega-6/Omega-3 Fatty Acid Content of Biomarkers?..............................................67
Overview of Relevant Studies.....................................................................................67
Qualitative Synthesis of Relevant Studies’ Key Characteristics.................................72
Qualitative Synthesis of Individual Study Results.......................................................76
Quantitative Synthesis.................................................................................................78
Impact of Covariates and Confounders........................................................................78
Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated
With the Onset, Continuation or Recurrence of Suicidal Ideation or Behavior?..............78
Overview of Relevant Studies’ Characteristics and Results........................................79
Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for Bipolar
Disorder?...........................................................................................................................80
Overview of Relevant Studies’ Characteristics and Results........................................80
Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated
With the Onset, Continuation or Recurrence of Bipolar Disorder?..................................83
Overview of Relevant Study’s Characteristics and Results.........................................83
Is the Onset, Continuation or Recurrence of Bipolar Disorder Associated With
Omega-3 or Omega-6/Omega-3 Fatty Acid Content of Biomarkers?..............................84
Overview of Relevant Studies’ Characteristics and Results........................................85
Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated
With the Onset, Continuation or Recurrence of Anxiety?................................................87
Overview of Relevant Studies’ Characteristics and Results........................................87
Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for
Obsessive-Compulsive Disorder?.....................................................................................89
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Overview of Relevant Study’s Characteristics and Results.........................................89
Is the Onset, Continuation or Recurrence of Anorexia Nervosa Associated With
Omega-3 or Omega-6/Omega-3 Fatty Acid Content of Biomarkers?..............................90
Overview of Relevant Studies’ Characteristics and Results........................................90
Are Omega-3 Fatty Acids Efficacious as Primary Treatment for Attention
Deficit/Hyperactivity Disorder?........................................................................................92
Overview of Relevant Studies.....................................................................................92
Qualitative Synthesis of Relevant Studies’ Key Characteristics.................................94
Qualitative Synthesis of Individual Study Results.......................................................97
Quantitative Synthesis.................................................................................................97
Impact of Covariates and Confounders........................................................................97
Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for Attention
Deficit/Hyperactivity Disorder?........................................................................................98
Overview of Relevant Studies.....................................................................................98
Qualitative Synthesis of Relevant Studies’ Key Characteristics.................................100
Qualitative Synthesis of Individual Study Results.......................................................102
Quantitative Synthesis.................................................................................................102
Impact of Covariates and Confounders........................................................................103
Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated
With the Onset, Continuation or Recurrence of Attention Deficit/Hyperactivity
Disorder?...........................................................................................................................103
Overview of Relevant Study’s Characteristics and Results.........................................103
Is the Onset, Continuation or Recurrence of Attention Deficit/Hyperactivity Disorder
Associated With Omega-3 or Omega-6/Omega-3 Fatty Acid Content of Biomarkers?...104
Overview of Relevant Studies’ Characteristics and Results........................................105
Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated
With the Onset, Continuation or Recurrence of Mental Health Status Difficulties?........107
Overview of Relevant Study’s Characteristics and Results.........................................107
Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated
With the Onset, Continuation or Recurrence of Tendencies or Behaviors With the
Potential to Harm Others?.................................................................................................108
Overview of Relevant Studies.....................................................................................109
Qualitative Synthesis of Relevant Studies’ Key Characteristics.................................114
Qualitative Synthesis of Individual Study Results.......................................................117
Quantitative Synthesis.................................................................................................119
Impact of Covariates and Confounders........................................................................119
Is the Onset, Continuation or Recurrence of Tendencies or Behaviors With the
Potential to Harm Others Associated With Omega-3 or Omega-6/Omega-3 Fatty
Acid Content of Biomarkers?............................................................................................120
Overview of Relevant Studies’ Characteristics and Results........................................120
Quantitative Synthesis.................................................................................................122
Impact of Covariates and Confounders........................................................................123
Is the Onset, Continuation or Recurrence of Alcoholism Associated With Omega-3
or Omega-6/Omega-3 Fatty Acid Content of Biomarkers?..............................................123
Overview of Relevant Studies’ Characteristics and Results........................................123
Quantitative Synthesis.................................................................................................125
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