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Depression is a major public health
concern (Murray,
& Lopez., 1997; Mathers, & Loncar., 2006; WHO., 2012). With a
lifetime prevalence rate between 4.4% -20% (Bakish, 2001), it has been
repeatedly examined. As a result important attention has been invested in the
effects of cytokines of the innate immune system on the brain and behaviour. Their
influence on the neuro-circuity and neurotransmitter systems results in
behavioural alterations (Haroon, Raison, & Miller., 2012). This is apparent in chronic
medical conditions (heart disease, diabetes, and multiple sclerosis) as increased
levels of pro-inflammatory cytokines occur, thus causing the development of neuropsychiatric
dysfunction including major depression (Trivedi et al., 2006; Dantzer, O’Connor, Freund,
Johnson, & Kelley., 2008; Shelton & Miller., 2010; Slavich and Irwin.,
2014). This
has been evident with the administration of cytokines, in humans and animals, producing
neuropsychiatric symptoms and behavioural alterations that mirror depression
that is distinguishable to the non-medically ill population (Miller, Maletic,
& Raison., 2009; Shelton & Miller., 2010). Three different
meta-analysis found that depressed patients have an increased level of
pro-inflammatory cytokines (Dowlati et al., 2010; Duivis, de Jonge, Penninx,
Na, Cohen, & Whooley., 2011; Liu, Ho, Mak., 2012). The most consistently
replicated findings include higher levels of interleukin-6 (IL-6), C-reactive
protein (CRP), and tumour necrosis factor-alpha (TNF-?) (Raison, Capuron, & Miller., 2006; Miller., 2009;
Howren, Lamkin, & Suls., 2009).

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In a meta-analysis, excluding
medical co-morbidity, higher levels of IL-6 and TNF-? were predictors of
developing depressive symptoms (Dowlati et al., 2010). Likewise, many
prospective studies have found that depression also predicted increase levels
of IL-6 and TNF-? (Deverts et al., 2010; Mattews et al., 2010; Duivis et al.,
2011; Copeland,
Shanahan, Worthman, Angold, & Costello., 2012). Research has shown a
dose-response relationship between depression and inflammation, whereby more
severe depressive symptoms were associated with higher levels of CRP and IL-6
(Miller et al., 2002). Thus, depression facilitates inflammatory responses and
inflammation promotes depression. Interestingly, an ample body of research has
found that diet-related factors can moderate inflammation.

Two recent systematic reviews and meta-analyses have found
that a Mediterranean diet (MD) including, olive oil, fruit, vegetables, fish,
and moderate consumptions of dairy products and wine, has beneficial effects in
reducing the level of inflammatory markers due to its anti-inflammatory actions
(Schwingshackl ., 2014;
Schwingshackl Christoph, & Hoffmann., 2015). This benefit has been
apparent in those with metabolic syndrome. For instance, Richard et al., (2012)
found that adhering to a MD showed lower levels of IL-6 in patients with
metabolic syndrome. However, in a similar study, when adjusting for BMI of
levels of CRP and IL-6 were attenuated, suggesting that elevated levels of
pro-inflammatory markers are possibly due to adiposity (Miller et al., 2002).
However, studies have found this to be inconsistent as lower levels of
pro-inflammatory markers were still apparent, when adhering to a MD,
independent of weight loss (Aksungar, Topkaya, & Akyildiz., 2007; Richard
et al., 2012). This suggests that diet quality influences inflammation,
which previous systematic reviews have not explored. Omega-3 fatty acids found in oily fish inhibit
inflammation such as endotoxin-induced TNF (Calder., 2004). Studies have found
that feeding mice with fish oil decreases TNF and IL-6 concentrations when
injected with endotoxin (Yaqoob & Calder., 1995; Sadeghi, Wallace, &
Calder., 1999). This is consistent in healthy humans (Trebble et al., 2003), as
it has found to have anti-inflammatory effects (Talukdar et al., 2010). Similarly,
the high prevalence
of omega-3 in combination with unsaturated fatty-acids and antioxidants typically
found in a MD has been found to lower the risk of depression. A follow-up
prospective study found individuals following a MD were less likely to develop
depression in comparison to those who did not, as a result 480 new cases of
depression were reported (Sánchez-Villegas et al., 2009). This may be a result of a higher consumption
of trans-fat increasing the risk of depression (Sánchez-Villegas et al., 2011).
Therefore, the accumulating literature suggests that diet may play a role in inflammatory
markers and depression, due to its bi-directional nature.

In a prospective study, depressed
patients who did not follow a MD showed larger increased IL-6 levels at a
6-year follow-up. However, IL-6 levels did not appear to change for depressed
patients who followed a MD (Milaneschi et al., 2011), suggesting that a
healthier diet can buffer the impact of depression on inflammation.
Additionally, levels of inflammatory markers, due to dietary patterns, can
predict depression in later life. For instance, food frequency questionnaire
results (based on an inflammatory dietary pattern score related to CRP, IL-6
and TNF) in the large Nurse’s Health study were collect six times over 18 years
and found that higher inflammatory scores at baseline, in women who were not
depressed, had an elevated risk of developing depression later (Lucas et al.,
2014). Relatedly, in
a double-blind randomised cross-over study, participants with higher levels of
saturated fat (activating
pro-inflammatory signalling pathways) in their meals had increased CRP levels. Whereas, participants that had
higher levels of oleic sunflower oil (monounsaturated palmioleate) meals had
lower levels of CRP, independent of stress (Kielcolt-Glaser, Fagundes,
Andridge, Peng, Malarkey, Habash, & Belurt., 2017), consistent with
previous studies (Kiecolt-Glaser et al., 2007; Kiecolt-Glaser et al., 2015). Therefore, a sufficient body of
research suggests that reasons behind diet-related factors offering protections
against depressive symptoms/disorders may be due to its anti-inflammatory
action. To our knowledge this will be the first systematic review and
meta-analysis on the effect diet has on the depression, and inflammation. The
aim of the present systematic review is to synthesize data of relevant literature
investigating the effects diet-related factors have on markers of inflammation,
as well as depression and depressive symptoms. We hypothesise that, due to its
anti-inflammatory action (Calder et al., 2004; Talukdar et al., 2010), a Mediterranean-style diet;
high in omega-3 and monounsaturated fats will have a positive effect on
inflammation, and depression, as they are bi-directional in nature (Dowlati et
al., 2010; Copeland et al., 2012). In turn, this would hopefully direct future
research specifically investigating the relationship between diet, inflammation
and depression, a promising factor for nonpharmacological treatments. This is
extremely clinically relevant as depression is continuing to increase along
with the aging Western world (Mathers et al., 2006; WHO., 2012).


Search strategy

Systematic review of articles
published until September 2017 in MEDLINE, and PsycINFO, electronic databases
were performed. A
combination of the following search items; ‘Mediterranean diet’, ‘Mediterranean’,
‘Omega-3’, ‘fish-oils’, ‘inflammation’, pro-inflammatory cytokines’, ‘inflammatory
markers, ‘depression’, ‘Major depressive disorder’, ‘depressive symptoms’. These
search terms were chosen in order to gain the substantial and relevant evidence.
This systematic review conducted in adherence to standards of quality for
reporting meta-analysis (,

Inclusion and exclusion criteria

Studies were included if they met the following criteria: human
participants, full-text articles written in English, randomised controlled, cross-over design, or prospective
studies; no exclusion criteria for sample size (sensitivity analysis will be
performed according to study population), depression or depressive symptoms,
markers of inflammation (CRP, IL-6, and TNF-?, as they have been consistently
replicated), dietary intervention or provision of dietary factors relevant to
the MD with components including; high monounsaturated/saturated fats, high
consumptions of fruits and vegetables, low consumption of meat and increased
consumption of fish, moderate consumption of mild and diary product. In order
to obtain the most relevant factors that were thought, from previous
literature, to influence inflammation and/or depression.

Data extraction and analysis

The following data were extracted
from each study: the first author’s last name, year of publication, study
length, gender distribution and age, BMI, study design, and description of the

Studies providing effect estimates
of relative risk (RR) for the association between diet and the outcomes
mentioned. Statistical
analysis including pooling of studies. Random-effects models will be
appropriately used to calculate pooled effect estimates. Between-study heterogeneity
will be assessed with a standard ?2 test. In order to determine whether the
effects across studies are due to chance or not.  


This research project is a
meta-analysis of published studies which does not include data on identifiable
individuals, therefore no ethical consideration was needed. 

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