Acute effect of a Mediterranean-style dietary pattern (MDP) on mood, anxiety and cognition in UK adults with mild to moderate anxiety and depression: the MediMood randomised controlled trial protocol

Abstract

Introduction
Psychological disorders including depression and anxiety are significant public health concerns. A Mediterranean-style dietary pattern (MDP) has been associated with improved mental well-being in observational studies. Evidence of the acute (defined as postprandial to 1 week) effects of an MDP on brain function, mood, cognition and important modulators, including sleep and the gut microbiota is limited. The current intervention aims to examine whether an MDP, compared with a Western diet (WD), improves mood, cognition and anxiety symptoms, postprandially, at 24-hour and after 5 days in adults with mild to moderate anxiety and depression.

Methods and analysis
Twenty-five UK adults (aged 18 or over) with mild to moderate anxiety and/or depression and low adherence to an MDP were recruited to a cross-over randomised controlled trial. Each participant undergoes a 5 day MDP and a 5 day WD in a randomised order with all meals provided. The co-primary outcomes are mood and anxiety, with secondary outcomes including cognitive function, brain perfusion (as assessed by MRI), sleep quality, blood pressure, plasma glucose, insulin, lipids, C-reactive protein, cortisol, brain-derived neurotrophic factor, gut microbiota speciation and microbial metabolites including short chain fatty acids. A linear mixed model and/or paired analysis will be used to compare the effects of treatments over time.

Ethics and dissemination
The study has received a favourable ethics opinion from the National Health Service London Queen Square Research Ethics Committee (22/LO/0796). The results will be disseminated through scientific journals and conferences.

Trial registration number
NCT05927376 .

Full text

1
EsgunogluL, etal. BMJ Open 2024;14:e082935. doi:10.1136/bmjopen-2023-082935
Open access
Acute effect of a Mediterranean- style
dietary pattern (MDP) on mood, anxiety
and cognition in UK adults with mild to
moderate anxiety and depression: the
MediMood randomised controlled
trial protocol
Latife Esgunoglu ,1 Marrium Liaquat,1 Rachel Gillings,1 Alpar Lazar,2
Adrian Leddy,1 Jon Brooks,3 William Penny,3 Saber Sami,1 M Hornberger,1
Emma Stevenson,4 Amy Jennings,1 Anne Marie Minihane1,5
To cite: EsgunogluL, LiaquatM,
GillingsR, etal. Acute effect of
a Mediterranean- style dietary
pattern (MDP) on mood, anxiety
and cognition in UK adults with
mild to moderate anxiety and
depression: the MediMood
randomised controlled
trial protocol. BMJ Open
2024;14:e082935. doi:10.1136/
bmjopen-2023-082935
►Prepublication history
and additional supplemental
material for this paper are
available online. To view these
les, please visit the journal
online (https://doi.org/10.1136/
bmjopen-2023-082935).
Received 07 December 2023
Accepted 18 November 2024
For numbered afliations see
end of article.
Correspondence to
Latife Esgunoglu;
l. esgunoglu@ uea. ac. uk
Protocol
© Author(s) (or their
employer(s)) 2024. Re- use
permitted under CC BY.
Published by BMJ Group.
ABSTRACT
Introduction Psychological disorders including
depression and anxiety are signicant public health
concerns. A Mediterranean- style dietary pattern (MDP)
has been associated with improved mental well- being
in observational studies. Evidence of the acute (dened
as postprandial to 1 week) effects of an MDP on brain
function, mood, cognition and important modulators,
including sleep and the gut microbiota is limited. The
current intervention aims to examine whether an MDP,
compared with a Western diet (WD), improves mood,
cognition and anxiety symptoms, postprandially, at 24- hour
and after 5 days in adults with mild to moderate anxiety
and depression.
Methods and analysis Twenty- ve UK adults (aged 18 or
over) with mild to moderate anxiety and/or depression and
low adherence to an MDP were recruited to a cross- over
randomised controlled trial. Each participant undergoes
a 5 day MDP and a 5 day WD in a randomised order with
all meals provided. The co- primary outcomes are mood
and anxiety, with secondary outcomes including cognitive
function, brain perfusion (as assessed by MRI), sleep
quality, blood pressure, plasma glucose, insulin, lipids,
C- reactive protein, cortisol, brain- derived neurotrophic
factor, gut microbiota speciation and microbial metabolites
including short chain fatty acids. A linear mixed model and/
or paired analysis will be used to compare the effects of
treatments over time.
Ethics and dissemination The study has received a
favourable ethics opinion from the National Health Service
London Queen Square Research Ethics Committee (22/
LO/0796). The results will be disseminated through
scientic journals and conferences.
Trial registration number NCT05927376.
INTRODUCTION
Mental health disorders represent a major
public health challenge.1 In 2019, depres-
sion exceeded 280 million cases globally,
and anxiety surpassed 300 million cases,
as the two most common forms of mental
health disorders.1 Mental health disorders
have constituted around 15% of ‘years lived
with disability’ worldwide since 1990,2 with
depression predicted to be the global leading
cause of disease by 2030.3 In England, nearly
20% of adults report depression, anxiety,
sleep problems, poor concentration and
forgetfulness.4
The economic impact of mental health
disorders are substantial, with an estimated
annual global cost of approximately $5 tril-
lion including loss of productivity.5 The UK
National Health Services (NHS) has allocated
STRENGTHS AND LIMITATIONS OF THIS STUDY
⇒The design of MediMood was informed by a sys-
tematic review of the literature which provided the
need for, and informed the design of, the current
randomised controlled trial (RCT).
⇒MediMood is a highly controlled efcacy RCT with
all food provided for 5 days with detailed food prepa-
ration instructions rather than dietary advice only.
⇒The study quantied key physiological determinants
of brain health including gut microbiota and brain
perfusion quantied by MRI.
⇒To minimise participant burden, the primary out-
comes (mood and anxiety) and biological samples
collection could not be conducted daily.
⇒For logistical and costs reasons, MRI scans could
not be executed at the beginning and at the end of
the 5 day interventions, to assess short- term chang-
es in brain perfusion, limiting us to assessing only
the postprandial effects of dietary intervention on
cerebral blood ow.
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a £2.3 billion budget for the years 2023–2024 for mental
health services as part of its long- term plan.6
The main treatment for mental health disorders are
antidepressant medications and psychotherapy; both
can cause negative side effects,7 stigma8 and have poor
uptake.4 Despite increased treatment in recent decades,
no decrease in the prevalence of mental disorders is
evident,9 underlining the need for alternative interven-
tion approaches.
The WHO has highlighted the critical need for ‘afford-
able, effective and feasible strategies to promote, protect
and restore mental health’, and launched several initia-
tives such as the ‘Comprehensive Mental Health Action
Plan 2013–2030’10 and the ‘World mental health report:
transforming mental health for all’11 to address these
needs.
A Mediterranean- style dietary pattern (MDP) consists
of high amounts of fruits, vegetables, legumes, nuts, olive
oil and fish. It is low in high fat dairy, red and processed
meat, carbonated beverages and free sugars, and rich
in unsaturated fatty acids, polyphenols and unrefined
complex carbohydrates,12 which aligns with healthy
eating guidelines in the UK and many other countries.13
Long- term adherence to an MDP has been consis-
tently shown to protect mental health. Longitudinal
analysis of the SUN cohort (n=10 094) reported that
higher MDP adherence was correlated with a lower
depression incidence after 4.4 years,14 supported by a
meta- analysis of observational studies showing a reduced
risk of depression associated with long- term MDP adher-
ence (OR=0.72; 95% CI, 0.60 to 0.87).15 The Prevencion
con Dieta Mediterranea (PREDIMED), the hallmark
randomised controlled trial (RCT) in the field, reported
a 41% reduction in depression among at- risk individuals
with type 2 diabetes who followed an MDP supplemented
with nuts for 3 years (HR=0.59; 95% CI, 0.36 to 0.98).16
The HELFIMED,17 SMILES18 and AMMEND19 trials, all
of which examined the effects of an MDP on depression
in adults with moderate to severe depression over the
course of 3–6 months, demonstrated significant decrease
in depressive symptoms. The cognitive benefits of an
MDP have also been consistently reported. The PRED-
IMED study showed improved cognition after MDP inter-
ventions,20 while a recent UK Biobank analysis suggested
a reduced risk of future dementia associated with MDP
consumption.21 Additionally, a meta- analysis reported
a linear dose–response relationship between an MDP
adherence and the risk of future cognitive disorders.22
On the other hand, a Western diet (WD), which
includes high amounts of saturated fat (SFA) and simple
sugars, is associated with compromised brain health, and
a higher incidence of depression, anxiety and neurolog-
ical conditions.23 24
Our systematic review investigating the short- term
effects (up to 10 days) of an MDP on brain health
revealed improved mood and cognition, in particular,
alertness, contentment and attention domains in the four
included studies.25 There were too few studies to draw
firm conclusions, and we identified several limitations
and research gaps. Three of the four studies were of 10
days duration, with no shorter term or postprandial data
available. Besides, in all reviewed studies, participants
were provided with dietary advice rather than the inter-
vention diet, and adherence to the intervention was not
monitored. Furthermore, mental health outcomes were
not comprehensively assessed to elucidate which domains
are most responsive to a short- term MDP intervention
and little attention has been given to possible underlying
mechanisms which could be mediating the acute effects of
an MDP such as changes in inflammation, glucose regula-
tion, cerebral blood flow (CBF) and the gut microbiota.25
Therefore, despite its potential benefits25 on mental
well- being and quality of life, the acute effects of an MDP
are largely unknown. The overall aim of MediMood study
is to examine the impact of an MDP versus a Western- style
diet (WD) on mood, anxiety and cognition postprandially,
at 24- hour (mood and anxiety only) and after 5 days, and
to investigate underpinning physiological mechanisms.
METHODS AND ANALYSIS
This article follows the Standard Protocol Items:
Recommendations for Interventional Trials (SPIRIT)
guidelines.26
Study setting
MediMood is a single- centre cross- over RCT conducted at
the University of East Anglia (UEA), and the NHS Clin-
ical Research Facility (CRF) intervention centre, based at
the Quadram Institute (QI), in Norwich, UK. The data
collection period spanned from June to December 2023.
Eligibility criteria
Potential participants were recruited from the general
population and from the University staff and students,
using advertising posters/leaflets, internal emails and
social media.
Twenty- five people aged 18 years or over were recruited.
Participants were eligible if they met the following
conditions:
1. Had mild to moderate level depression and/or anxi-
ety, established using the Patient Health Questionnaire
(PHQ- 9) (score 5- 14/27)27 and the Generalised
Anxiety Disorder (GAD- 7) (score 5- 14/21).28 Both
measures are commonly used in the NHS settings as
preindicators of depression and anxiety.
2. Were not already following an MDP, established using
the Mediterranean Diet Adherence Screener (ME-
DAS) (score≤7/14) (online supplemental appendix
1).29
3. Had been on the same dosage of their medication for
at least 3 months and expected to keep a stable dosage
for the next 3 months (for those who are on any anti-
depressant/antianxiety medication).
4. Were eligible to undertake an MRI scan (eg, not hav-
ing any possibility of pregnancy).
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5. Were not vegan or vegetarian.
6. Did not have food allergies or intolerances to the food
provided such as fish and nuts.
If participants reported antibiotics use in the last
month, their participation was postponed until 1 month
after treatment to allow the gut microbiota composition
to return to its habitual status. Participants are requested
to keep any probiotic supplement use and physical activity
levels stable during their participation. For MRI safety,
‘any possibility of being pregnant’ or those with specific
medical implants or devices (such as cardiac pacemakers
or artificial limbs) were precluded from participating
(online supplemental appendix 2, MRI Safety Screening
Form). Participants were advised to discuss their participa-
tion with their general practitioners (GPs) and informed
that the study researchers were going to inform their GPs
about their participation (online supplemental appendix
3, Participant Information Sheet).
Table 1 lists the full inclusion and exclusion criteria.
Recruitment
Individuals who expressed an interest in the study were
provided with the Participant Information Sheet and
directed to the study website (https://app.mantal.co.
uk/medimood), built on the Mantal platform, an online
research management portal. First, participants were
asked to provide consent (online supplemental appendix
4, Consent Form). Second, participants completed ques-
tionnaires to ascertain if they meet the study inclusion
criteria detailed above. Those meeting the criteria were
enrolled in the study and randomised to either an MDP
or a WD for arm 1 of the study, by using random number
generator in Microsoft Excel.
The study stages are displayed in figure 1.
Safeguards for maintaining psychological well-being of
participants
Enrolled participants’ GPs are notified about their
patients’ participation and provided with their PHQ- 9
and GAD- 7 scores. The GPs of participants who are inel-
igible due to severe levels of anxiety and/or depression
were also notified. All participants are signposted to
mental health and well- being support.
Interventions
The experimental arm is a 5 day MDP, with a 5 day WD
comparator arm. Both diets are designed to provide
approximately 2000 kcal/day (±10% flexibility per day,
ranging between 1800 and 2200 kcal). The MDP diet scores
14 (or 13 if no alcohol is consumed) on the MEDAS scale
(maximum score 14) on each of the 5 days. Conversely,
the WD scores zero points on the MEDAS scale on each of
the 5 days. The full meal plans are presented in the online
supplemental appendix 5.
The total macronutrient (carbohydrates, fat and
protein) composition, and free sugars, fibre, SFA and
monounsaturated fat content of the diets have been
designed to ensure that they represent typical MDP and
WD. For the MDP, the PREDIMED diet was used as the
reference standard30 and for the WD, the nutrient profile
was based on extreme nutrient intakes (lowest or highest
2.5%) of the UK population using the UK National Diet
and Nutrition Survey (NDNS) data (https://www.gov.uk/
government/collections/national-diet-and-nutrition).
Table 2 represents the nutrient compositions of the test
lunch meals, and table 3 represents the nutrient composi-
tions of the full 5 day diets.
To capture their habitual dietary intake prior to the
study, the participants are asked to complete the Euro-
pean Prospective Investigation into Cancer and Nutri-
tion study Food Frequency Questionnaire (EPIC FFQ;
https://www.epic-norfolk.org.uk/about-epic-norfolk/
nutritional-methods/ffq/) before their baseline visit. To
promote adherence, all study foods are delivered to partic-
ipants’ homes using a supermarket delivery service, with
extra food provided for the evening meals for one other
person at home. Participants are provided with booklets
(online supplemental appendix 6), with guidance as to
Table 1 The eligibility criteria
Inclusion criteria Exclusion criteria
Males and females aged 18
or over
Vegan, vegetarian
Mild to moderate level
anxiety and/or depression
(PHQ- 9 and/or GAD- 7
scores of 5–14)
Allergic to any of the study
components for example, nuts
and sh
Low MDP adherence
(MEDAS score≤7/14)
On antianxiety and/or
antidepressant medication
which has changed in the last
3 months or likely to change in
the next 3 months
Able to have an MRI scan Unwilling or unable to make
changes to their diet for 10
days (2×5 days period)
Computer literate with
internet access
Unable to attend the
intervention centre
Fluent in written and
spoken English
MEDAS score>7
Gave consent for the study
team to contact their GP
Not uent in written and
spoken English
Willing and able to comply
with all study procedures
including diet
MRI unsafety
Not agreement for the study
team to contact their GP
Not prepared to make changes
to diet for 10 days (2×5 days
period)
GAD- 7, Generalised Anxiety Disorder (includes 7- item); GP, general
practitioner; MDP, Mediterranean- style dietary pattern; MEDAS,
Mediterranean Diet Adherence Screener tool (includes 14- items);
PHQ- 9, Patient Health Questionnaire (includes 9- item).
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how to store and prepare the meals and which additional
foods and snacks can be consumed if hungry. The snacks
are chosen to ensure they do not affect the MEDAS score
of the study arm. To track dietary compliance, partici-
pants are asked to record all foods and beverages on the
daily checklists in the booklets and provide notes and
feedback. Participants are contacted daily to encourage
dietary adherence.31
Participants are asked to visit the intervention centre
on day 1 (figure 2), from 08:00 until approximately 15:30.
Before their arrival, they are required to collect a urine
and faecal sample at home using sample collection kit
provided at least 2 days prior to their day 1 visits. The kit
includes a stool sample catcher, two plastic tubes with
scoop, a biohazard bag, a sealable bag, a urine sample
collection pot with a sealable bag, a pair of disposable
gloves, an insulated cool bag, two freezer blocks with
two sterile outer bags and instructions. They are asked
to collect the faecal sample within 24 hours prior to their
clinical visit, and the urine sample as the first pass on the
Figure 1 Study ow diagram. GAD- 7, Generalised Anxiety Disorder (includes 7- item); MEDAS, Mediterranean Diet Adherence
Screener; PHQ- 9, Patient Health Questionnaire (includes 9- item); WD, Western- style diet.
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morning of their visit (day 1). Participants arrive at the
intervention centre in a fasted state (fasted from 20:00
the night before). On arrival, anthropometric (weight
and height) and blood pressure (BP) measurements
are taken. A nurse collects the baseline blood sample.
Participants are then provided with a honey and oat
cereal bar. After 15 min rest, participants undergo the
mood, anxiety, cognition and sleep testing via the study
website; 90 min after completing these tests, participants
are served either an MDP or a WD test meal (at 11:30)
depending on the arm they are randomised to. Following
the meal, participants’ BP is measured at 12:45 and start
postprandial mood and cognitive testing at 13:00. At
14:00, they undergo the brain MRI scan and provide a
postprandial blood sample at 15:15. Afterwards, partic-
ipants are provided with an afternoon snack before
leaving the unit and consume their day 1 dinner at home.
On day 2 morning, participants complete online mood
and anxiety testing at home after having a honey and oat
cereal bar. On days 2–5, participants complete a sleep
diary. An actigraphy is worn throughout the intervention
period. On completion of the 5 day intervention, partici-
pants return to the intervention centre on the morning of
day 6 (08:00–10:00) to repeat the morning assessments, as
carried out on day 1 (figure 2).
As menstruation- related hormonal fluctuations can
cause disturbance in mood,32 neurocognitive functions33
and sleep,34 a wash- out period of 23- days was chosen to
ensure female participants are on the same phase of their
menstrual cycle on each intervention arm (ie, 28 days
between arm 1 day 1 and arm 2 day 1).
Outcomes
All outcome measures are summarised in table 4.
Primary outcomes
Mood and anxiety
Mood and anxiety levels are monitored using two scales.
The primary outcome measure is the Profile of Mood
State score (POMS)35 with mood also scored using the
Bond- Lader questionnaire.36 The former has 65 items
measuring 6 elements of mood (namely anxiety, anger,
confusion, depression, fatigue and vigour); while the
latter has 16 items (alert, drowsy, calm, excited, strong,
feeble, muzzy, clear- headed, well- coordinated, clumsy,
lethargic, energetic, contented, discontented, troubled,
tranquil, mentally slow, quick witted, tense, relaxed, atten-
tive, dreamy, incompetent, proficient, happy, sad, antago-
nistic, amicable, interested, bored, withdrawn, gregarious)
under four categories (1. mental sedation or intellectual
impairment, 2. physical sedation or bodily impairment,
3. tranquillisation or calming effects and 4. other types
of feelings or attitudes) or three mood factors (alertness,
contentment and calmness). Both are commonly used in
research including three of the four studies included in
our systematic review,25 allowing a direct comparison of
our findings with the limited published literature. The
primary outcomes are the ‘contentment’ domain from
Bond- Lader and the anxiety domain from POMS.
Secondary outcomes
Cognitive performance
Changes in cognition are assessed using a cognitive
battery administered using the NeurOn online platform
(https://neuropsychology.online). The following tests
are included the following:
1. Reaction Time Test for motor function.
2. Digit Span Test for executive function.
Table 2 Nutrient composition of the lunch test meals (day
1) taken from the product labels
Mediterranean diet Western diet
Energy Kcal 1013 984
Carbohydrates g 45 123
% 18.3 50.3
Free sugars g 0 83
Fibre g 10.6 2.9
Proteins g 60 37.5
% 24.3 15.3
Total fat g 63 37.3
% 57.4 34.4
SFA g 8.8 15.2
% 7.8 14
%, contribution to the total daily energy intake as per cent; g,
grams; kcal, kilocalories; SFA, saturated fatty acids.
Table 3 Nutrient composition table of the 5 day test diets
Mediterranean
diet (mean±SD)
Western diet
(mean±SD)
Energy Kcal/
day
1878±46 2027±79
Carbohydrates g/day 154.2±16.2 230.8±24
% 32.8±3.0 45.5±4.6
Free sugars g/day 0.3±0.6 35.7±10.4
Fibre g/day 34.8±6.4 10.6±2.9
Proteins g/day 80.8±19.1 64.6±11.4
% 17.1±4 12.7±2.3
Total fat g/day 105.0±8.9 94.2±11.2
% 50.3±4.6 41.8±4.6
SFA g/day 16.1±2.0 37.1±3.9
% 7.2±1.0 16.5±1.3
MUFA g/day 43.5±6.1 5.0±2.6
PUFA g/day 16.9±7.5 2.6±3.0
Omega- 3 PUFA g/day 2.4±1.5 0.7±0.1
Omega- 6 PUFA g/day 9.3±6.6 0.6±0.7
%, contribution to the total daily energy intake as per cent; g,
grams; kcal, kilocalorie; MUFA, monounsaturated fatty acids;
PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids.
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3. Trail Making Test (Trails A and Trails B) for executive
function.
4. Sustained Attention to Response Test for executive
function and attention.
5. Word Encoding for episodic memory.
6. Word Recognition for episodic memory.
7. Go No- Go for executive function and impulse control.
8. Fragmented Letters Test for visuospatial function.
Attention is an important secondary outcome as it was
shown to improve in the short- term in our systematic
review.25 Attention is measured by the Sustained Attention
to Response Task (SART).37 In the SART test, participants
have a visual presentation of 225 digits on a computer
screen in a random order over a 4.3 min period (1150 ms
between the onsets of digits) and are expected to respond
with a key press except when they see the digit 3.37 38 It is
a commonly used measure in research and is postulated
to be sensitive to everyday attention tasks in traumatic
brain injured patients as well as normal (control) indi-
viduals.37 38
Cerebral blood ow
CBF, also known as brain perfusion, can be affected by
macronutrient composition39 40 and bioactives such as
polyphenols,41 which are abundant in an MDP. Further-
more, reduced brain energy glucose metabolism and CBF
is evident in major depressive disorders42 and cognitive
decline,43 44 which is affected by food intake. An effect
of intervention on CBF is proposed to partly underpin
the effect of intervention on mood, anxiety and cognitive
outcomes. We hypothesise a greater CBF after the MDP
meal compared with the WD meal. MRI is considered the
gold standard CBF measurement,41 with the following
sequences used:
1. Time of flight angiography to determine the labelling
plane to be used with pseudo- Continuous Arterial Spin
Labelling (p- CASL).
2. P- CASL which provides a means of quantifying region-
al CBF.45
3. Magnetisation Prepared Rapid Gradient Echo
(MPRAGE) for routine whole brain imaging using rap-
id acquisition.46
4. Fluid- Attenuated Inversion Recovery (FLAIR) to visu-
alise the white matter hyperintensities (WMH).47
MPRAGE and FLAIR sequences help to eliminate
potential confounders influencing CBF in the present
study such as atrophy and WMH.
Resting state functional MRI (rs- fMRI) is used to explore
resting neural activity and connectivity between different
brain regions including those that are concerned with self-
referential processing and salience networks.48 During
the scan, participants wear a pulse oximeter and respira-
tory belt to record the influence of cardiac and respira-
tory processes on measured signal. The scan parameters
are taken from the UK- Biobank protocol,49 allowing a
comparison to this large cohort. Analysis utilises physio-
logical noise modelling, white matter/CSF signal regres-
sion and spatial independent components analysis to
define resting state networks. Seed- based analysis utilises
regions of interest (ROIs) for example, insular cortex,
to determine whole brain connectivity. As part of a more
extensive analysis, we will employ a Functional Connec-
tivity Multivariate Pattern Analysis approach. This meth-
odology allows us to rigorously test hypotheses across
the entire functional connectome as it encompasses all
voxel- to- voxel functional connections throughout the
entire brain. This exploratory approach complements
Figure 2 The protocol for the intervention centre visits. On the day 1 visit, participants undergo the full protocol. On day 6
visit, participants undergo the morning session only. CBF, cerebral blood ow; MDP, Mediterranean- style dietary pattern; WD,
Western diet.
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the seed- based method as it does not require a predeter-
mined parcellation of the brain into ROIs.50
Blood pressure
Brachial BP is measured with the participant seated and
following a 5 min rest period. Measurements are taken
using an automatic BP monitor (Omron, 705IT) with an
appropriately sized cuff. BP is measured three times and
averaged in accordance with published guidelines.51
Biological samples
Blood, urine and faecal samples are collected at baseline
(on day 1) and on completion of the 5 day intervention (on
day 6 morning). Postprandial blood samples are collected
after the day 1 test meal; 30 mL of blood is collected in
three separate tubes (EDTA, Heparin, SST). Several
blood biomarkers of mental and cognitive health as well
as cardiometabolic health will be assessed including but
not limited to plasma glucose, lipids, cortisol and select
inflammatory markers and brain- derived neurotrophic
factor. On arrival of the day 1 and day 6 mornings, the
urine and faecal samples are frozen at −80°C for later
analysis.
Gut microbial prole
The link between the gut microbiota and anxiety, depres-
sion,52 and cognition53 is evident through the gut–brain
axis. Diet composition is an important modulator of
microbiome composition and metabolism.54 The gut
microbiome will be profiled using 16S rRNA Amplicon-
based Metagenomic Sequencing of faecal samples.55
Metabolomics prole
Metabolomics are a tool for providing mechanistic insight
into the response to dietary interventions.56 The influ-
ences of interventions on the metabolomics signature
in serum and/or faecal samples will be explored using
1H- NMR- based untargeted metabolomics approach.57
Table 4 Summary of the outcome measures
Measurement Tool used Time point
Time per
measurement point Location
Screening Mood PHQ- 9 Prebaseline 9 min Home
Anxiety GAD- 7 Prebaseline 6 min Home
Initial dietary habits MEDAS Prebaseline 10 min Home
During
interventions
Initial dietary prole EPIC FFQ Baseline 30 min Home
Mood and anxiety Bond- Lader
VAS,
POMS
Baseline, postprandial,
24 hours,
day 6
30 min Home (24 hours) and
intervention centre
(baseline, postprandial
and day 6)
Cognitive functions NeurOn battery Baseline, postprandial,
day 6
30 min Intervention centre
CBF MRI Postprandial 30 min UWWBIC
Blood pressure Baseline, postprandial,
day 6
5 min Intervention centre
Blood samples Baseline (≥10 hour
fasting), postprandial,
day 6 (≥10 hour fasting)
15 min Intervention centre
Urine and faecal
samples
Baseline,
day 6
Home collection kits
are provided
Weight and height SECA scale Baseline,
day 6
5 min Intervention centre
Initial sleep prole PSQI Baseline 10 min Intervention centre
Sleep quality Actigraphy
KSD
KSS
Over 5 days Continuously (for
actigraphy)
5 min (for KSD and
KSS)
Home
Subjective dietary
review score
Non- validated
single question
Day 6 Intervention centre
Follow- up Dietary behaviour MEDAS 3 months 10 min Home
CBF, cerebral blood ow; EPIC FFQ, European Prospective Investigation into Cancer and Nutrition study Food Frequency Questionnaire;
GAD- 7, Generalised Anxiety Disorder- 7; KSD, Karolinska Sleep Diary; KSS, Karolinska Sleepiness Scale; MEDAS, Mediterranean Diet
Adherence Screener tool (includes 14- item); PHQ- 9, Patient Health Questionaire- 9; POMS, Prole of Mood States; PSQI, Pittsburgh Sleep
Quality Index; UWWBIC, University of East Anglia Wellcome- Wolfson Brain Imaging Centre; VAS, Visual Analogue Scale.
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Targeted metabolomics by Liquid Chromatography
Tandem Mass Spectrometry will be used to measure both
straight and branched short chain fatty acids, which are
important mediators of gut–brain communication.58
Sleep timing, quality and quantity and circadian rest-activity
rhythmicity
Due to the multidirectional relationship between sleep
and circadian disturbances, anxiety and depression,59–61
cognition including alertness and attention62 and food
intake,63 we will investigate the short- term effects of
diet on sleep and circadian rhythmicity. By doing so,
we also aim to eliminate the confounding effect of low
sleep quality on mood and anxiety. The Pittsburgh Sleep
Quality Index (PSQI) will be used to establish the initial
sleep profile to detect sleep disturbances on day 0.64
Sleep quality is tracked during the two 5 day intervention
periods using the Motion Watch 8, which is a wrist- worn
actigraphy device. This will allow for the estimation of
sleep timing, duration and quality as well as the ampli-
tude and stability of circadian rest- activity rhythmicity
known to be interlinked with mental well- being. The
Karolinska Sleep Diary (KSD) is a subjective measure and
used to estimate the duration, timing and quality of all
sleep periods and will complement the actigraphy data to
increase the accuracy of the objective sleep quality estima-
tion.65 The Karolinska Sleepiness Scale (KSS) is adminis-
tered every morning during the interventions alongside
the KSD, to subjectively measure sleepiness. The KSS is a
9- point scale and asks the user to circle the number that
represents the sleepiness level during the immediately
preceding 5 min.66
Dietary behaviour
Participants will be sent the MEDAS questionnaire,
3 months after completing both arms to see if they have
made any long- term change to their diets compared with
the screening phase. They were also asked to rate how
they found following the diets on a scale of 1–10.
Statistical methods: data collection, management and
analysis
Sample size calculation
The sample size calculation was based on data from a
previous cross- over trial of the effect of MDP adherence
in a young healthy adult group.67 Assuming an error rate
of 0.05 and 90% power, we would require 15 and 20 partic-
ipants to complete each arm for the primary outcome,
which is the contentment, a mood domain from the
Bond- Lader scale (9.6 unit expected difference, SD 10.3).
To account for up to 20% dropout between random allo-
cation to treatment sequence and study completion, we
recruited 25 individuals.
Analysis
The main aim of the trial is to test if mood and anxiety
can be improved over 5 days of intervention. The primary
outcome analysis will use two- way repeated measures anal-
ysis with paired analysis taking mean change- scores.
CBF data analysis steps
1. Data preprocessing: raw data will be converted into the
Brain Imaging Data Structure format for standardised
data organisation.
2. Structural processing: individual subject- level process-
ing includes structural image processing and segmen-
tation and normalisation to enhance the quality of an-
atomical data.
3. Single- subject ASL processing: specific processing
steps tailored for ASL data will be applied at the indi-
vidual subject level, including motion correction, reg-
istration, partial volume correction and quantification
of perfusion.
Group- level analysis: group- level processing through
template creation producing a group- average image and
subsequent atlas- based ROI statistical analyses.68
Machine learning analysis
Machine learning holds considerable potential for iden-
tifying biomarkers and enhancing clinical decision-
making in varied contexts and is effective in discerning
clinical interventions. Our study will use the Random
Forest algorithm to enhance the interpretability of
the heterogeneous data. This is a supervised machine
learning approach recognised for its adeptness to handle
missing values, alleviate data noise and mitigate the risk
of overfitting making it a robust choice for our analytical
framework.69
Monitoring: incidental ndings and adverse events
Measurements that are deemed to be outside the normal
clinical range will be reported to GPs as incidental find-
ings. Potential incidental findings may be noted from
PHQ- 9 and/or GAD- 7 questionnaires, blood sample
analysis or the MRI scans. Due to the nature of the inter-
vention, that is, commercially available food products,
no adverse events are expected. If participants feel in
anyway adversely affected by any foods or the principal
investigator feels an AE necessitates cessation, the partic-
ipant will be advised not to continue, and the appro-
priate measures will be taken. All AE’s will be recorded
and handled in accordance with Good Clinical Practice
guidelines.
Patient and public involvement
None.
DISCUSSION
The MediMood study is an efficacy trial which will provide
evidence and mechanistic insights into the acute and
short- term effects of an MDP on mental health and cogni-
tive performance in UK adults.
MediMood is the first RCT examining the acute (post-
prandial up to 5 days) effects of an MDP on mood and
anxiety as the primary endpoint. Its strengths are as
follows: (1) its controlled intervention design informed by
a systematic review,25 with standardised meals supported
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EsgunogluL, etal. BMJ Open 2024;14:e082935. doi:10.1136/bmjopen-2023-082935
Open access
by full food provision and detailed preparation instruc-
tions, rather than dietary advice only, (2) its cross- over
design,70 (3) assessment of several biological mecha-
nisms which are hypothesised to mediate the effects of
diet on mental and cognitive health, (4) combination of
both objective and subjective assessment/measurement
methods, (5) its focus on at- risk individuals for future
major psychological and neurological disorders, (6)
involvement of adults with no upper age limit as people
suffer from mental disorders at every life stage and (7)
considers the effects of the menstrual cycle on the study
outcomes.
The main limitation of the study is that, to reduce the
participant burden, we do not measure mood, anxiety and
cognition every day. Second, our MRI scan is in a different
location, which causes a delay in the postprandial blood
collection. Given the nature of the diets, it is not possible
to conduct a double- blinded intervention as participants
know which diets they are following which may lead to an
‘expectation bias’.29 All clinical data, including MRI and
biological samples will be anonymously analysed. Cross-
over design requires participants to undergo two inter-
ventions which may cause attrition.70 However, as our
intervention duration is only 5 days, we think it is a low
risk for the MediMood study.
Day- to- day low mood, anxiety and poor cognitive
performance can adversely affect quality of life for not
only those with pre- existing mental and/or cognitive
health complaints but also healthy individuals. Therefore,
there is a need to identify safe and accessible approaches
impacting short- term brain health, which is the focus
of the MediMood intervention, which also has a strong
mechanistic component. The results will help inform
future management strategies and policies for individuals
with mental health complaints and in the early stages of
age- related cognitive decline.
ETHICS AND DISSEMINATION
Research ethics approval
The study has been approved by the London Queen
Square, NHS Research Ethics Committee and Health
Research Authority (22/LO/0796). Informed consent is
provided by all participants in the presence of certified
research personnel.
Dissemination policy
The findings of the study will be disseminated through
peer- reviewed publications, conference presentations,
public outreach events, local and national news and
academic blogs such as www.conversations.com for public
members.
Data deposition
Anonymised data may be made available on request for
additional analysis, by contacting AMM (senior author).
Author afliations
1Norwich Medical School, University of East Anglia, Norwich, UK
2School of Health Sciences, University of East Anglia, Norwich, UK
3School of Psychology, University of East Anglia, Norwich, UK
4Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
5Norwich Institute for Healthy Aging, Norwich, UK
X Latife Esgunoglu @LatifeEsgunoglu
Acknowledgements We would like to thank Alex Howard for his help in designing
the study website on Mantal.
Contributors LE, AJ, ES and AMM designed the study. The authors expertise and
contributions are as follows: LE, AJ, RG and AMM for the postprandial study day
design; AJ for the sample size calculation; LE, ML, AJ and AMM for the selection
of blood biomarker analysis and blood sampling protocols; LE, ML, RG and AJ for
the meal plans, booklet production and the website design; LE, ML and RG for the
delivery of the intervention; MH and ALe for the design of cognitive function and
mental health assessment; MH, JB and WP for neuroimaging. SS for MRI data
analysis. ALa for the sleep assessment. ML for the gut proling and metabolomics.
ALe for the safeguards of mental well- being of the participants. All authors drafted
and revised the manuscript with LE, AJ and AMM taking the lead role. All authors
approved the nal version of the manuscript. AMM is the guarantor.
Funding MediMood is funded by Medical Research Council NuBrain Consortium
Grant (MR/T001852/1). LE’s PhD studies are supported by The Republic of Turkiye,
and further supported by Rank Prize with a Return to Research Grant. ML’s PhD
studies are supported by the Commonwealth Scholarship Commission and the
Foreign, Commonwealth and Development Ofce in the UK. The UEA is the sponsor
of the trial and provides indemnity and insurance cover.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting or dissemination plans of this research.
Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits
others to copy, redistribute, remix, transform and build upon this work for any
purpose, provided the original work is properly cited, a link to the licence is given,
and indication of whether changes were made. See:https://creativecommons.org/
licenses/by/4.0/.
ORCID iD
LatifeEsgunoglu http://orcid.org/0000-0002-8779-870X
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