Open access
Protocol
Melanie M Ashton,1,2,3 Michael Berk,1,3,4,5,6 Chee H Ng,2 Malcolm Hopwood,4,7
Bianca Kavanagh, 1 Lana J Williams,1 Jerome Sarris,2,8 Olivia M Dean1,3,4
To cite: Ashton MM, Berk M,
Ng CH, et al. Nutraceuticals
and nutritional supplements
for the treatment of bipolar
disorder: protocol for a
systematic review. BMJ Open
2019;9:e025640. doi:10.1136/
bmjopen-2018-025640
► Prepublication history and
additional material for this
paper are available online. To
view these files, please visit
the journal online (http://dx.doi.
org/10.1136/bmjopen-2018025640).
Received 25 July 2018
Revised 14 February 2019
Accepted 20 February 2019
© Author(s) (or their
employer(s)) 2019. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
BMJ.
For numbered affiliations see
end of article.
Correspondence to
Melanie M Ashton;
m.ashton@deakin.edu.au
AbstrACt
Introduction First line pharmacological treatments for
bipolar disorder (BD) can leave shortfalls in recovery
leading to patients seeking alternative and adjunctive
treatments such as nutraceuticals. This protocol for a
systematic review and proposed meta-analysis aims
to answer the research question: in patients with BD,
how does use of nutraceutical treatments compare with
placebo in reducing depressive and mania symptoms?
Methods and analysis Clinical trials will be identified
through database searches using PubMed via PubMed,
EMBASE via embase.com, Cochrane Central Register of
Controlled Clinical Trials (CENTRAL) via cochranelibrary.
com and CINAHL Complete via EBSCO. Search terms for
BD and specific nutraceuticals (75 total search terms) will
be used. Double-blind, randomised, controlled, clinical
trials of adults with BD will be included in the review. Risk
of bias will be assessed using the Cochrane Collaboration’s
tool for assessing risk of bias in randomised trials.
Ethics and dissemination This review will only look at
published data (already reviewed for ethical compliance);
therefore, ethical approval is not required. We aim to
publish the systematic review in a peer-reviewed journal
and present at conferences.
PrOsPErO registration number CRD42019100745.
IntrOduCtIOn
bipolar disorder
Bipolar disorder (BD) is a biphasic disorder
characterised by manic and depressive
episodes.1 Common pathways to pathology
include dysregulation of monoamines,
increased oxidative stress, perturbed inflammatory processes and mitochondrial disturbances.2 The depressive phase of the disorder
is more common than mania (3:1) and can be
harder to treat.3 Most first-line treatments for
BD are more effective at treating the manic
phase, including mood stabilisers (eg, lithium)
and second-generation antipsychotics (eg,
lurasidone or quetiapine).4 Antidepressants,
especially tricyclic antidepressants and selective serotonin-norepinephrine reuptake
strengths and limitations of this study
► This review will update and extend previously com-
►
►
►
►
pleted systematic reviews of the effects of nutraceuticals in bipolar disorder (BD).
This review will employ rigorous screening and assessment of studies to be included allowing for only
good quality, peer reviewed publications.
A strength of this review is the range of potential
nutraceutical agents to be assessed.
A limitation of the review will be the inherent differences in manic and depressive phases means it will
be difficult to compare agents across BD as a whole.
There is likely to be high heterogeneity for the nutraceutical agents and measures for symptomology
across the studies limiting the comparisons for a
meta-analysis.
inhibitors, can cause some people with BD
to switch to a manic phase, therefore antidepressants are not recommended as monotherapy.5–7 Other common side effects of
currently available treatments for BD can
include extrapyramidal symptoms such a
tremors, akathisia8 and weight gain.8 9 Thus,
polypharmacy is more common practice than
monotherapy.4 Due to tolerability issues and
shortfalls in recovery, additional treatment
options are often sought.
Nutraceuticals have been defined as functional foods that treat or prevent a disease
or disorder10 and in particular are nutrients
that have been standardised and of pharmaceutical grade.11 Originally described as
a combination between nutrition and pharmaceuticals,12 nutraceuticals are a growing
field of medications. The Therapeutic
Goods Association of Australia regulate
complementary medicines defined as therapeutic goods containing one or more of
the following active ingredients: amino acid,
mineral, vitamin or provitamin, choline salt,
Ashton MM, et al. BMJ Open 2019;9:e025640. doi:10.1136/bmjopen-2018-025640
1
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Nutraceuticals and nutritional
supplements for the treatment of
bipolar disorder: protocol for a
systematic review
Open access
Objectives
The objectives of this systematic review are to identify and
evaluate published clinical trials of nutraceuticals as treatments for BD. The systematic review will include both
mania and depressive phases of the disorder. However, as
the depressive phase of the disorder is the most frequent
and disabling phase and therefore been more widely
studied, it is likely to return the most results. If there is
sufficient data within two studies or more and homogeneity established, a meta-analysis will be conducted to
assess the effect of nutraceuticals compared with placebo.
If the studies demonstrate considerable heterogeneity
then subanalyses will be performed. The aim of this review
will be to answer the research question: In patients with
BD, how does use of nutraceutical treatments compare
with placebo in reducing symptoms of depression and
mania?
2
MEthOds
search methods
This systematic review protocol has been prepared in accordance with Preferred Reporting Items for Systematic Reviews
and Meta-Analysis (PRISMA) Protocols guidelines.19
Relevant literature will be identified via electronic
searches using PubMed via PubMed, EMBASE via embase.
com, Cochrane Central Register of Controlled Clinical
Trials (CENTRAL) via cochranelibrary.com and CINAHL
Complete via EBSCO. Searches will be conducted from
inception to the date of search. In addition to the database searches, reference lists of other systematic reviews
and retrieved trials will also be reviewed for studies to be
included in the screening process.
search strategy
PICO (Patient, Intervention, Comparison/Control,
Outcome) search framework was used to develop search
terms relating to BD and nutraceuticals. Key search terms will
be used as follows, by searching ‘all fields’. Relevant formatting for each database will be used. The following Medical
Subject Headings (MeSH) and Emtree terms will be used
(‘bipolar disorder’ OR ‘bipolar and related disorders’ OR
‘cyclothymic disorder’ OR ‘bipolar I disorder’ OR ‘bipolar
II disorder’) AND (prebiotics OR probiotics OR ‘nutritional
supplement’ OR ‘nutrition supplement’ OR ‘nutrition
therapy’ OR ‘nutritional support’ OR minerals OR mineral
OR ‘dietary supplement’ OR ‘complementary therapies’
OR ‘alternative medicine’ OR ‘medicine, traditional’ OR
‘traditional medicine’ OR ‘amino acids’ OR acetylcysteine
OR ‘fatty acids’ OR ‘fatty acid’ OR ‘eicosapentaenoic acid’
OR ‘fatty acid, omega-3’ OR ‘Fatty acid, omega-6’ OR ‘folic
acid’ OR antioxidants OR ‘fatty acid, essential’ OR tryptophan OR creatine OR chromium OR inositol OR choline
OR zinc OR ubiquinone OR curcumin OR ‘thioctic acid’
OR acetylcarnitine OR s-adenosylmethionine OR melatonin OR taurine) AND (‘clinical trial’ OR ‘randomized
controlled trial’ OR ‘controlled clinical trial’). In addition,
other common, non-MeSH key terms will be included in
the coinciding sections of the search: (‘bipolar affective
disorder’ OR ‘bipolar depression’ OR ‘bipolar mania’ OR
mania OR hypomania OR cyclothymia OR BPAD OR BD)
AND (Nutraceutical OR ‘functional food’ OR nutrient* OR
supplement OR ‘nutrient-based therapy’ OR complementary OR vitamin* OR ‘amino acid’ OR n-acetylcysteine OR
methylfolate OR PUFA OR cannabinoids OR omega* OR
folate OR magnesium OR tryptophan OR ‘essential fatty
acids’ OR tonic OR ‘coenzyme q10’ OR ‘alpha-lipoic acid’)
AND (RCT OR trial OR ‘randomised controlled trial’). The
full search strategy for each database can be found in online
supplementary file 1.
Inclusion/exclusion criteria
Types of studies
For this review, only peer-reviewed, published, double-blind,
randomised, controlled trials will be included. Studies may
either include adjunctive agents or monotherapy and will
be compared with either a placebo or other intervention.
Ashton MM, et al. BMJ Open 2019;9:e025640. doi:10.1136/bmjopen-2018-025640
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lipid (including an essential fatty acid or phospholipid),
a sugar, polysaccharide or carbohydrate, mucopolysaccharide, plant or herbal material, an essential oil, charcoal, micro-organism, non-human animal material, or
homeopathic preparation.13 Dietary supplements have
been defined by the Food and Drug Administration in
the Dietary Supplement and Health Education Act as an
orally administered dietary ingredient that could contain
minerals, vitamins, enzymes, amino acids or herbs.14
Approximately 30% of individuals with BD have reported
taking nutraceuticals, although the authors highlighted
that under-reporting of nutraceuticals is common due to
the perceived idea they are often considered relatively
benign. Because of this perception of nutraceuticals,
treating physicians may not be notified of the patient’s
nutraceutical use.15
The term Nutraceutical encompasses a broad range of
agents, which may have differing effects within the body on
the pathophysiology of some disorders. Some nutraceuticals have bioactive properties that can target the putative
pathophysiology of BD. For example, omega-3 is known
for its high anti-inflammatory properties, L-theanine for
its antioxidant properties and the amino acid N-acetylcysteine is known for both its anti-inflammatory, antioxidative and mitochondrial properties. We will present
an overview of nutraceuticals broadly and then explore
subgroups, based on those reported in the previous
systematic review to allow comparisons with the previous
literature (eg, fatty acids). For the purposes of this review,
lithium will not be included despite coming under the
definition of minerals. Lithium will not be included as it
has been extensively researched previously16 and will fall
outside of the scope of this review. Two previous systematic reviews have been conducted in this field (Sarris et
al17 and Sylvia et al18). However, given the expansion of
the field and progress in the understanding of the underlying biological processes, this systematic review will form
a comprehensive and much needed update of the current
literature.
Open access
Types of participants
We will review studies including adults with a diagnosis of
BD I, II, NOS based on Diagnostic and Statistical Manual
of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria. In-patient and out-patient
participants will all be included.
Subgroup analyses will be performed to determine
the effects of the study medication specifically on the
active depressive phase of BD. For the relevant studies,
current depression must be assessed using the following
standardised scales: Montgomery Åsberg Depression
Rating Scale (MADRS),20 Hamilton Depression Rating
Scale (HAM-D),21 Hospital Anxiety and Depression Scale
(HADS),22 Bipolar Depression rating scale (BDRS),23 Beck
Depression Inventory24 or Quick Inventory of Depressive Symptomatology, Patient Health Questionnaire-9.25
Mania must be assessed using the following standardised
scales: Young Mania Rating Scale (YMRS),26 The Bech-Fafaelsen Mania Rating Scale,27 the mania subscale of the
Schedule for Affective Disorders and Schizophrenia28 29
and the Altman Self-Rating Mania Scale.30 Appropriate
cut-off scores will be used for relevant severity of disorder
in each study, as determined by or established for each
scale. For example, if a study was interested in at least
moderate level of depression and utilising the MADRS,
a cut-off score of 20 or above would be appropriate given
0–6 is considered recovered, 7–19 mild depression, 20–34
moderate depression and 35–60 severe depression.31
research, consent was not required from participants and
dissemination to participants will not be required. The
authors are working towards better outcomes for participants with BD and factors that influence those outcomes
were considered when designing this review.
dAtA AnAlysIs
data management
Covidence,32 an online database tool, will be used
to manage references and search results during the
screening and reviewing process. The program allows
for handling of duplicate records and detailed tracking
of inclusion/exclusion of references allowing for easy
extraction into PRISMA flow diagrams.
Identification of eligible studies
The initial search will be conducted by one lead
reviewing author to identify relevant articles. Articles will
be screened for inclusion/exclusion based on title and
abstract; then by reviewing the full text. A second independent reviewing author will independently screen the
titles and abstracts. If there are any discrepancies, an
experienced third author will act as adjudicator to decide
on inclusion into full-text review. After screening, relevant
full-text articles will be independently reviewed for bias
and content by two independent reviewing authors. If
there are discrepancies or disagreements between the two
reviewing authors and a consensus cannot be reached, a
third independent reviewing author will adjudicate.
Patient and public involvement
Participants and the public were not involved in the design
of the review. As the review will use only previously published
Assessment of included articles
Extracted data will include study design, details of intervention(s), details of comparator arm (ie, placebo or intervention), outcome measures, characteristics of samples and risk
of bias. The extracted data will follow Consolidated Standards of Reporting Trials (CONSORT) guidelines.33 STATA
Data Analysis and Statistical Software V.15,34 will be used to
analyse data and data synthesis. Treatment effects will be
measured by standardised mean differences with 95% CI to
allow for differences in interpretation of scores across the
scales. In this model, sample sizes and standard deviations
will be used to give weightings to each study. If there are no
clear summaries of all data to fulfil the CONSORT guidelines and risk of bias then in the first instance authors will
be contacted in an attempt to fill in gaps. If contacting the
author is not possible then the studies will not be included
due to insufficient data.
The Cochrane Collaboration’s tool for assessing risk of
bias in randomised trials35 will be used to assess bias of all
included trials. The criteria for bias included scores of ‘low
risk of bias’, ‘high risk of bias’ and ‘unknown risk of bias’
in the following domains: random sequence generation,
allocation concealment, blinding, incomplete outcome
data, selective reporting and other bias. In the event of
missing data in the published study, published protocols
will also be used to assess bias, such as publication bias.
Publication bias will be assessed via funnel plots. Attempts
Ashton MM, et al. BMJ Open 2019;9:e025640. doi:10.1136/bmjopen-2018-025640
3
Types of interventions
To be included in the review, interventions must come
under the definition of nutraceuticals, complementary
medicines or dietary supplements (see the Introduction
section for definitions) and must aim to improve depressive or manic symptoms. Following the initial search, a
table of agents which are included and excluded through
the systematic review process will be provided. Comparator arms of the studies may be placebo or another intervention (eg, another medication).
Outcome measures
Primary outcome measure will be an assessment of depression or mania symptomology (eg, standardised mean differences in scores on MADRS, BDRS, YMRS and so on). In the
case of multiple outcome measures in the study, only the
primary outcome will be included in the systematic review
and potential meta-analysis. Any secondary outcomes will
not be included as they are likely to be underpowered.
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Only studies testing the effects of the medication on the
reduction of depressive or mania symptoms of BD will be
included. Therefore, prophylaxis studies and studies will be
excluded. Case reports, observational studies, open-label
trials, cross-sectional design studies, grey literature, protocol
papers and conference presentations will also be excluded.
Open access
subgroup analysis
The following subgroup analyses will be performed if
there is significant heterogeneity across the studies (if
I2 >50%). Subgroup analyses will include different phases
of BD and different groups of nutraceuticals.
1. Effect of treatment on depressive symptoms.
2. Effect of treatment on mania symptoms.
3. Depressive phase compared with euthymia.
4. Any phase of BD upon entry into study and depression or mania scores at treatment phase completion.
5. Treatment outcomes of vitamins.
6. Treatment outcomes of fatty acid supplements (eg,
omega-3).
7. Treatment outcomes of minerals (eg, zinc,
magnesium).
8. Treatment outcomes of amino acids.
9. Treatment outcomes of individual agents.
10. Combination treatments (eg, multivitamins and minerals) versus single treatments.
sensitivity analysis
Sensitivity analyses will be conducted to take into consideration the following methodological differences (1) differences in diagnostic tool (DSM vs ICD), (2) difference in
BD subgroups, (3) different measures of symptoms (eg,
MADRS vs HADs) and (4) length of study. For each sensitivity analysis data will be analysed separately and results
will be compared with the initial all-inclusive analysis to
ensure similar results. In addition, studies will be analysed
for differences in gender, age, location and dose of nutraceutical studied, if there are differing doses. If data for the
sensitivity analysis is missing in the studies, authors will be
contacted in the first instance. If more details cannot be
obtained, the study will not be included in the analysis and
this will be noted in the results.
Ethics and dissemination
This review will only use published data that has received
ethical approval, therefore specific ethical approval for
this review is not required. We aim to publish the systematic review in a peer-reviewed journal and the results may
be presented at a scientific conference.
COnClusIOn
This rigorous review will evaluate the current literature on
the use of nutraceuticals as treatments for BD. This review
may be used by clinicians to assist with treatment choices for
their patients with BD. Ultimately, this review aims to evaluate additional treatment options for BD and if positive,
with the view to reduce the burden of the disorder.
Author affiliations
1
IMPACT Strategic Resarch Centre, School of Medicine, Deakin University, Geelong,
Victoria, Australia
2
Professorial Unit, The Melbourne Clinic, Department of Psychiatry, University of
Melbourne, Richmond, Victoria, Australia
3
Florey Institute for Neuroscience and Mental Health, University of Melbourne,
Parkville, Victoria, Australia
4
Department of Psychiatry, The University of Melbourne, Royal Melbourne Hospital,
Parkville, Victoria, Australia
5
Orygen, The National Centre of Excellence in Youth Mental Health, Parkville,
Victoria, Australia
6
Centre of Youth Mental Health, The University of Melbourne, Parkville, Victoria,
Australia
7
Professorial Psychiatry Unit, The Albert Road Clinic, University of Melbourne,
Melbourne, Victoria, Australia
8
NICM Health Research Institute, Western Sydney University, Westmead, New South
Wales, Australia
Acknowledgements The authors wish to thank Blair Kelly, Deakin University, for
advice on the search strategy and library support.
Contributors MMA conceptualised and designed the research questions and
search strategy, prepared the manuscript draft, edited and approved the final
version of the manuscript. MB conceptualised the research question, revised the
search strategy and edited and approved the manuscript. CHN conceptualised
the research question, revised the search strategy and edited and approved the
manuscript. MH conceptualised the research question, revised the search strategy
and edited and approved the manuscript. BK revised the search strategy, edited and
approved the manuscript. LJW revised the search strategy, edited and approved the
manuscript. JS revised the search strategy, edited and approved the manuscript.
OMD conceptualised the research question and search strategy, edited the
manuscript and approved the final version.
Funding The authors would like to acknowledge the NHMRC Project Grant Scheme
(APP1121510) for supporting this review. MMA would further like to acknowledge
the support of Australian Rotary Health/Ian Parker Bipolar Research Fund PhD
scholarship and the ASBDD/Lundbeck PhD neuroscience scholarship. MB is
supported by a NHMRC Senior Principal Research Fellowship (APP1059660). BK
is supported by Deakin University, the Australian Government Research Training
Program Scholarship and Australian Rotary Health. LJW is supported by a NHMRC
Career Development Fellowship (APP1064272). JS is supported by an NHMRC
Clinical Research Fellowship (APP1125000). OMD is supported by a NHMRC R.D.
Wright Biomedical Research Fellowship (APP1145634). No funding bodies had any
role in developing the protocol.
Presentation and reporting of results
The review will adhere to PRISMA guidelines and data
will be reported using a PRISMA flow diagram.38 The
PRISMA flow diagram will depict numbers excluded at
each stage of screening (identification, screening, eligibility and reasons for exclusion) to show the number of
studies included and excluded in the review.
Competing interests MMA has received grant/research support from Deakin
University, Australasian Society for Bipolar Depressive Disorders, Lundbeck,
Australian Rotary Health, Ian Parker Bipolar Research Fund and Cooperative
Research Centre for Mental Health. MB has received grant support from NIH,
Simons Autism Foundation, Cancer Council of Victoria, CRC for Mental Health,
Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical
Research Foundation, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Organon,
Novartis, Mayne Pharma and Servier. MB has received Grant/Research Support
4
Ashton MM, et al. BMJ Open 2019;9:e025640. doi:10.1136/bmjopen-2018-025640
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will be made to contact corresponding authors for missing
data in the published studies. In accordance with the
Cochrane Handbook 5.136 suggestions, I2 will be used to
assess for heterogeneity of the trials. If I2 is >50% then the
studies will be considered to have a substantial heterogeneity and will be included in the summarising sections of
the systematic review, but the proposed meta-analysis will
not be conducted. Quality of evidence of the studies will be
assessed and summarised using the Grades of Recommendation, Assessment, Development Evaluation approach.37 If
a meta-analysis is possible, a random-effects model will be
used. Results will be reported as standardised mean differences with 95% CI.
Open access
Ashton MM, et al. BMJ Open 2019;9:e025640. doi:10.1136/bmjopen-2018-025640
5
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer
Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond
Blue, Rotary Health, Meat and Livestock Board, Astra Zeneca, Woolworths, Avant
and the Harry Windsor Foundation, book royalties from Oxford University Press,
Cambridge University Press, Springer Nature and Allen and Unwin, has been a
speaker for Astra Zeneca, Lundbeck, Merck and Servier and served as a consultant
to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal
Development, Grunbiotics, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan,
Otsuka and Servier. MB is a coinventor on two provisional patents regarding the use
of NAC and related compounds for psychiatric indications, assigned to the Mental
Health Research Institute. MB is a coinventor on a patent application regarding the
use of mangosteen and related compounds for psychiatric indications, assigned to
Deakin University. CHN had served in the Servier, Janssen-Cilag, Wyeth and Eli Lilly
Advisory Boards, received research grant support from Wyeth and Lundbeck, and
speaker honoraria from Servier, Lundbeck, Bristol-Myers Squibb, Organon, Eli Lilly,
GlaxoSmithKline, Janssen- Cilag, Astra-Zenaca, Wyeth, and Pfizer. MH has received
grant support from ISSCR, Servier, US DOD and Bionomics, has been a speaker for
Janssen-Cilag, Lundbeck, and Servier, and has been a consultant for AstraZeneca,
Eli Lilly, Janssen-Cilag, Lundbeck and Servier. BK has received research support
from Deakin University, the Australian Government Research Training Program
Scholarship and Australian Rotary Health. LJW has received Grant/Research support
from Eli Lilly, Pfizer, The University of Melbourne, Deakin University and the NHMRC.
JS has received either presentation honoraria, travel support, clinical trial grants,
book royalties or independent consultancy payments from: Integria Healthcare &
MediHerb, Pfizer, Scius Health, Key Pharmaceuticals, Taki Mai, FIT-BioCeuticals,
Blackmores, Soho-Flordis, Healthworld, HealthEd, HealthMasters, Kantar Consulting,
Research Reviews, Elsevier, Chaminade University, International Society for Affective
Disorders, Complementary Medicines Australia, SPRIM, Terry White Chemists, ANS,
Society for Medicinal Plant and Natural Product Research, Sanofi-Aventis, Omega-3
Centre, the National Health and Medical Research Council, CR Roper Fellowship.
OMD is a R.D. Wright Biomedical Research Fellow and has received grant support
from the Brain and Behavior Foundation, Simons Autism Foundation, Stanley
Medical Research Institute, Deakin University, Lilly, NHMRC and Australasian Society
for Bipolar and Depressive Disorders (ASBDD)/Servier.