Psychiatria Danubina, 2020; Vol. 32, Suppl.

1, pp 114-120 Conference paper

© Medicinska naklada - Zagreb, Croatia

THE EFFECT OF NUTRITION ON MENTAL HEALTH:

A FOCUS ON INFLAMMATORY MECHANISMS
Shantal D. Edirappuli1, Ashwin Venkatesh1 & Rashid Zaman2,3
1
School of Clinical Medicine, University of Cambridge, UK
2
Department of Psychiatry, University of Cambridge, UK
3
Hertfordshire Partnership University NHS Foundation Trust, UK

SUMMARY
Neuropsychiatric disorders are closely associated with a persistent low-grade inflammatory state. This suggests that the
development of psychopathology is not only limited to the brain, but rather involves an additional systemic aspect, accounting for the
large body of evidence demonstrating co-presentation of mental illness with chronic inflammatory conditions and metabolic
syndromes. Studies have shown that inflammatory processes underlie the development of neuropsychiatric symptoms, with recent
studies revealing not only correlative, but causative relationships between the immune system and psychopathology.
Lifestyle factors such as diet and exercise may influence psychopathology, and this may occur via a bidirectional relationship.
Mental illness may prevent health-seeking behaviours such as failing to maintain a balanced diet, whilst adopting a ‘healthy’ diet
rich in fruits, vegetables and fish alongside nutritional supplementation correlates with a reduction in psychiatric symptoms in
patients. Obesity and the gut microbiome have proven to be further factors which play an important role in inflammatory signalling
and the development of psychiatric symptoms. In a related paper we focus on the role of exercise (another significant lifestyle factor)
on mental health (Venkatesh et al. 2020).
Lifestyle modifications which target diet and nutrition may prove therapeutically beneficial for many patients, especially in
treatment-resistant subgroups. The current evidence base provides equivocal evidence, however future studies will prove significant,
as this is a highly attractive therapeutic avenue, due to its cost efficacy, low side effect profile and preventative potential. By
promoting lifestyle changes and addressing the limitations and barriers to adoption, these therapies may prove revolutionary for
mental health conditions.

Key words: diet – nutrition – inflammation - mental health - neuropsychiatric disorders

* * * * *

INTRODUCTION The modulation of lifestyle factors such as diet and

exercise can influence psychopathology, and this may
Neuropsychiatric disorders are closely associated with occur via a bidirectional relationship. Mental illness may
a persistent systemic low-grade inflammatory state, sug- prevent health-seeking behaviours such as failing to
gesting that the development of psychopathology is not maintain a balanced diet, whilst adopting a ‘healthy’ diet
only limited to the brain, but also comprises a systemic rich in fruits, vegetables and fish alongside nutritional
aspect, accounting for the large body of evidence de- supplementation correlates with a reduction in psychiatric
monstrating the concomitant presentation of mental symptoms in patients. It is recognised that obesity is
illness with chronic inflammatory conditions and meta- another significant factor correlated with the develop-
bolic syndromes. This co-presentation may provide an ment of neuropsychiatric symptoms and in part due to
evolutionary advantage as depressive symptoms may the effect of dysregulated insulin signalling and down-
co-exist with social withdrawal and low energy, creating stream inflammation. Studies in rodent models have
the conditions to recover and rehabilitate. However, further found the gut-microbiota-brain to play an impor-
with prolonged mental illness and chronic inflammatory tant role in inflammatory signalling between the enteric
states, this can instead prove to be crippling for many and central nervous system, further elucidating a potential
patients (Rosenblat et al. 2014). association between nutrition and psychopathology.
Studies in both animal and human models have Lifestyle modifications which target diet and nutri-
shown that inflammatory processes underlie the deve- tion may prove therapeutically beneficial for many pa-
lopment of neuropsychiatric symptoms. Inflammation tients, especially in treatment-resistant subgroups. The
and oxidative stress can act in synchrony to further current evidence base provides equivocal evidence,
perpetuate the inflammatory processes. In situations of however future studies will prove highly significant, as
chronic disease, this process may continue in the brain, this is a highly desirable therapeutic avenue, due to its
an organ particularly vulnerable to tissue injury, fur- cost efficacy, low side effect profile and preventative
ther causing symptoms of neuropsychiatric disease potential. By promoting healthy dietary lifestyle
(Ng et al. 2008). Recent studies have revealed not only changes and addressing the limitations and barriers to
correlative, but causative relationships between the adoption, these therapies may prove revolutionary for
immune system and psychopathology. mental health conditions.

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INFLAMMATION IS A CENTRAL NUTRITION PLAYS A KEY ROLE

UNDERLYING DRIVER PROCESS IN PSYCHOPATHOLOGY VIA
FOR PSYCHOPATHOLOGY INFLAMMATORY MECHANISMS
Inflammatory processes have been shown to underly The bidirectional relationship of nutrition
psychopathology. This has been shown through experi- with mental health conditions
mental induction of inflammation in healthy volunteers Individuals with a poor diet are at a greater risk of
preceding development of psychiatric disturbances, and developing psychopathology. A large body of evidence
also the co-occurrence of systemic chronic inflam- supports this association particularly with regards to one
matory conditions with cognitive impairment that can of the most common mental health conditions, depres-
greatly detriments patients’ quality of life (Borsini et al. sion. A meta-analysis showed that adherence to a ‘healthy’
2017; Drevets et al. 2008). Genetic studies have added diet was significantly associated with a lower risk of
further weight to this association between the immune developing depressive symptoms (Molendijk et al. 2018).
system and mental health (Sekar et al. 2016). Longi- A similar study determined a significant relationship bet-
tudinal research has demonstrated that elevated Inter- ween increased saturated fatty acid (SFA) intake and the
leukin 6 (IL-6) in childhood may predispose to depres- risk of developing depression later in life (Sánchez-Ville-
sion and psychosis later in a dose-dependent fashion gas et al. 2011). One group employed a pseudo-panel ap-
(Khandaker et al. 2014). However, whether the inflam- proach to assessing whether obesity causes depression and
mation is a cause or consequence of psychopathology is found that an increased BMI was significantly associated
yet to be determined. The Insight study aims to evaluate with increased frequency of depressive symptoms (Ha et
the therapeutic benefits of targeting IL-6 in patients with al. 2017). A meta-analysis assessing the longitudinal rela-
depression and evidence of inflammation and this tionships between depression and obesity found that not
randomised controlled trial is likely to provide further only did obesity predispose to depression by 55% but
evidence for the field (Khandaker et al. 2018). also that the opposite was true and depressed individuals
Inflammatory pathways such as the kynurenine were at a 55% greater risk of developing obesity (Luppino
pathway have been implicated in contributing to chronic et al. 2010). This suggests the converse relationship, that
background inflammation by reducing the availability of mental health illnesses can affect the dietary intake and
tryptophan and by encouraging the production of free patterns of an individual. Further evidence corroborates
radical and potent neurotoxins (O’Connor et al. 2009, this as one prospective cohort study showed that the
Vancassel et al. 2018). Studies have shown that targe- atypical form of depression is a significant predictor of
ting these inflammatory pathways may prove especially obesity (Lasserre et al. 2014). This evidence strongly
useful in therapeutically intractable subgroups that have points towards a bidirectional relationship with mental
a background level of inflammation (Mondelli et al. health conditions.
2015). In a related paper, we discuss these concepts in There is now evidence to suggest that these pathways
further detail (Venkatesh et al. 2020) (Figure 1). may be due to the direct effect nutrition has on down-
stream inflammatory pathways which lead to the deve-
lopment of psychopathology. A comprehensive review of
the literature reveals three main aspects of nutrition that
contribute to pro- or anti-inflammatory states. The first
is the variation in dietary patterns and the concept that
diets may be rich in pro- or anti-inflammatory foods.
These differing nutritional constituents may have a direct
effect on the level of chronic systemic inflammation in
the body. Secondly, it may be that the dietary pattern
itself is not significant, but rather the overall surplus of
food intake combined with lack of exercise creates a
positive energy balance leading to obesity which itself is
inflammatory. Lastly, emerging research into the gut-
microbiota-brain axis suggests that the early gut micro-
biome may affect mental health, primarily through its
effects on brain function and development at an early age.
Figure 1. Inflammation shifts the metabolism of tryp-
tophan to the kynurenine pathway. This increases the The evidence for anti-inflammatory mechanisms
production of 3-hydroxykynurenine (3-HK) and quino- of nutritional variation in mental health
linic acid (an NMDA receptor antagonist) which may
contribute to neuropsychiatric disorders (Figure adap- Dietary patterns
ted from O’Connor et al. (2009) and Vancassel et al. Mediterranean-style diets have been shown to be pro-
(2018)) tective in the development of mental disorders whereas

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Western diets which are typically much richer in (SFAs) improvement in the positive symptoms (psychosis), sup-
and refined sugars may have the opposite effect. A plementation was associated with enhanced cognitive
meta-analysis conducted by Lai et al. showed that a diet ability. Despite this positive response, the evidence base
which is high in fruit, vegetables, fish and whole grains for Vitamin D3 supplementation in mental health con-
reduced the odds of developing depression (Lai et al. ditions is poor and requires further investigation.
2014). Furthermore, there is a large body of evidence
which confirms that this pattern of dietary intake is Obesity
associated with reduced all-cause mortality. The anti- Obesity is a highly prevalent condition affecting our
inflammatory nature of these foods may be the linking population today and is defined as a BMI of greater than
factor by which there is reduced prevalence of mental 30. It is a multifactorial disease which draws on both
health conditions. Conversely, the high SFAs have a genetic and environmental factors and is strongly asso-
largely pro-inflammatory effect which may influence ciated with increased morbidity and mortality. A bidirec-
the underlying pathology through various mechanisms. tional relationship between obesity and psychiatric dis-
Diets rich in pro-inflammatory foods such as SFAs orders is evident, particularly with disorders of mood
may lead to the development of psychiatric symptoms. and cognition. A meta-analysis conducted by Luppino et
Animal models suggest that these effects are mediated al. found conclusive evidence that there is a strong
through elevated levels of cytokines which result in reciprocal relationship between obesity and depression
downstream low-grade inflammation. Rats fed a high and that having one condition significantly predisposes
fat diet (60%) for 16 weeks exhibited anxiety and an- to developing the other (Luppino et al. 2010).
hedonic behaviour (Dutheil et al. 2016). Researchers The development of dementia is well known to be
found that this was accompanied by increased levels of linked to inflammatory risk factors such as obesity and
cytokines, primarily IL-1ȕ, IL-6 and TNF-Į in the hippo- other metabolic syndromes such as type 2 diabetes
campus – a structure which is intimately involved in mellitus, insulin resistance and hypertension (de la
learning, memory and the target of many antidepres- Torre 2013). Moreover, a 27-year longitudinal popula-
sants. Similarly, abnormalities and alterations in the tion-based study illustrated that obesity in middle-age
levels of inflammatory cytokines has been well establi- correlated with a 74% significantly increased risk of
shed in patients with schizophrenia and these changes developing dementia in later life (Whitmer et al. 2005).
are more distinct in treatment-resistant patients. More- This study not only suggests that obesity is correlated
over, a higher ratio of omega-6 to omega-3 intake, which with dementia, but that this relationship may, in fact, be
is a key feature of Western diets, has been associated with highly preventable. Alzheimer’s dementia is a subtype
systemic inflammatory conditions such as cardiovascular of dementia which is characterised by the production
disease and cancer, whereas a low ratio has suppressive of Aȕ amyloid plaques in the brain and research into
effects on inflammation (Simopoulos 2002). the role of inflammation in Alzheimer’s dementia
Neuroinflammation may also be affected by foods found that obese patients with dementia had increased
with anti-inflammatory properties such as polyun- systemic amyloid levels in blood plasma which was
saturated fatty acids (PUFAs). PUFAs are an integral reduced with active weight loss (Jahangiri et al. 2013).
part of the neuronal cell membrane, with both anti-in- Another study revealed enhanced permeability of the
flammatory and anti-apoptotic properties. The litera- blood-brain barrier in individuals who were over-
ture suggests two main omega-3 PUFAs of note, doco- weight or obese in middle-age (Gustafson et al. 2007).
sahexaenoic acid (DHA) and eicosapentaenoic acid There is growing evidence that dysregulated insulin
(EPA), that have long been associated with cardio- signalling is an important pathway by which metabolic
vascular health and recent evidence suggests they may conditions such as obesity exert their inflammatory
hold some significance in mental health too. Indeed, effects on the brain. It is understood that obesity may
McNamara et al. conducted post-mortem analyses of lead to systemic insulin resistance which will in turn
patients with depression and found that there was a result in reduced insulin signalling in the brain. The
deficit of DHA in the orbitofrontal cortex of these pa- physiological effects of this will include alterations in
tients (McNamara et al. 2007). A further study asses- cerebral glucose metabolism but this has also been
sed whether these effects could be reversed by supple- associated with increased levels of monoamine oxi-
mentation of the EPA (Mocking et al. 2016), which dases (MAO) and enhanced dopamine clearance. As
found a beneficial effect comparable to that of anti- illustrated by the monoamine hypothesis of depression
depressant administration. and the dopamine hypothesis of schizophrenia, this
Vitamin D has also been identified as an anti-inflam- activity is negatively correlated with psychiatric symp-
matory nutrient. Low levels of Vitamin D3 have been toms. In mice, this was investigated using a brain-spe-
associated with depression and attention deficit hyper- cific knockout of the insulin receptor and it was shown
activity disorder (ADHD). A randomised control trial to lead to anxiety and depressive behaviours (Klein-
assessed the outcomes of supplementing Vitamin D3 in ridders et al. 2015). Further investigation showed that
clozapine-treated schizophrenic patients (Krivoy et al. this behaviour was in fact allayed by administration of
2017). Findings showed that although there was no MAO inhibitors.

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Figure 2. The gut-microbiota-brain axis is the communication pathway by which the enteric nervous system can
communicate with the central nervous system by means of the vagus nerve (CN X). The gut microbiota may be able to
influence neuroinflammation by two hypotheses: (i) neuroactive endocrine secretions, (ii) dysbiosis, or the ‘leaky gut
hypothesis; and thereby contribute to neuropsychiatric disease

It is worth mentioning that obesity will have a di- Gut microbiota

rect effect on mental health due to social and cultural The gut microbiota refers to the community of bac-
factors. In the western world, low BMI is seen as teria that inhabit the gut environment and the genetic
desirable attribute and thus individuals who are obese makeup is referred to as the gut microbiome. It has
are more likely to suffer from low self-esteem and been determined that this will vary with age, gender
body dysmorphic disorders, which is conducive to the and other environmental factors and in human popula-
development of psychiatric disorders, particularly mood tions, differing diets lead to differences in the gut
disorders. microbiome. It is theorised that the composition of the
Psychiatric disorders can also predispose to the de- early gut microbiome may affect adult behaviour, in
velopment of obesity and in fact one study showed that terms of the development of neuropsychiatric symp-
depressed patients have a 58% increased chance of toms, primarily through the effects on early-life brain
becoming obese (Luppino et al. 2010). This risk rela- function and development. This is thought to stem
tionship was also significantly greater than the chance from enteric nervous system signalling to the central
of becoming overweight, thus suggesting a dose-de- nervous system (CNS) through the vagus nerve: a
pendent relationship between depression and BMI. The communication pathway known as the gut-microbiota-
inherent pathology of mental health conditions such as brain axis (Figure 2).
depression involves changes in appetite. It has been Our understanding of the workings of this axis co-
shown that atypical depression in particular is asso- mes chiefly from rodent models. Feeding high-fat diets
ciated with increased appetite and subsequent increase to mice for 8 weeks induced a depressed phenotype in
in bodyweight. Other symptoms such as low mood and these animals which was accompanied by decreased
energy in depression, or avolition in schizophrenia, population of Bacteroidetes in the gut (Hassan et al.
often lead to individuals adopting an unhealthy life- 2019). A similar study showed that simply transplanting
style which may involve overeating or lack of regular the faecal microbiota from depressed human patients
exercise. There is also evidence that psychiatric con- into mice induced anhedonic and anxiety-like behaviours
ditions may have a causal link with obesity through (Zheng et al. 2016). These studies strongly suggest that
neuroendocrine pathways and long-term activation of there is an association between the gut microbiome and
the HPA axis. This can involve enhanced levels of cor- psychiatric symptoms. Another group assessed whether
tisol and insulin which can lead to insulin resistance ingestion of the probiotic bacteria Lactobacillus by
and subsequent dysregulated insulin signalling. Further- mice would affect their behaviour (Bravo et al. 2011).
more, it is important to note that weight gain is often a The study showed anxiolytic and antidepressive effects
side effect of many commonly prescribed psychiatric of this particular probiotic, but also that these effects
drugs. It is thought that this is primarily due to the did not occur in vagotomised mice.
effects of medications interacting with the central ap- The gut is known to secrete neuroactive compounds
petite and feeding centres in the brain. such as serotonin, dopamine and GABA. ‘Chemical im-

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balances’ in these substances have been implicated in low-inflammatory index may be of particular signifi-
the pathogenesis of mood disorders and schizophrenia cance as it may provide a reduction in the low-grade
and thus it is thought that secretion allows for increa- chronic inflammation. Ketogenic diets are high-fat, low-
sed bioavailability in the CNS which may contribute to carbohydrate diets which have an anti-inflammatory
alterations in levels of these compounds. Similarly, effect. This diet has been used in the treatment of neuro-
secretions of potentially harmful substances such as psychiatric conditions such as epilepsy and Alzheimer’s
amyloid peptides and lipopolysaccharides (LPS) are disease and has shown to result in improved cognition
thought to increase the permeability of the blood brain (Brietzke et al. 2018). Further approaches in nutritional
barrier (BBB) and contribute to some degree of neuro- psychiatry include nutraceutical interventions which in-
inflammation. volves targeting specific nutritional alterations known to
Another theory as to how the gut induces an inflam- be involved in inflammation and psychopathology. As
matory state is illustrated by the ‘leaky gut’ hypothesis mentioned earlier PUFAs have been shown to have a
which states that alterations to the composition of gut beneficial effect in depression as well as other con-
microbiota, ‘dysbiosis’, may result in the development ditions such as ADHD and Alzheimer’s disease. Recent
of psychiatric disorders by inducing an immune res- evidence suggests that simply supplementing either
ponse which leads to low-grade inflammation. It has DHA or EPA is insufficient for therapeutic benefit and
emerged this dysbiotic state and the production of rather the ratio of these substances is important. As
potential pathogens leads to an increased permeability illustrated by many clinical trials, it seems as though a
of the intestinal wall which allows for leakage of sub- dose with high EPA:DHA ratio is more effective in
stances such as LPS into the bloodstream. LPS acts treating symptoms of depression, whereas doses of high
upon toll-like receptor (TLR) 4 to induce a systemic DHA:EPA are more effective in improving cognition
inflammatory response. TLR-4 activation has been im- (Song et al. 2016).
plicated in many other metabolic inflammatory condi- Targeting the gut-microbiota-brain axis has been sug-
tions such as increased dietary fat intake, obesity and gested by prebiotics (non-digestible food components
dysregulated insulin signalling. such as complex carbs which are thought to nurture and
cultivate enteric flora as well as by the ingestion of
Therapeutic implications, limitations probiotic microorganisms in foods such as natural bio-
and barriers to adoption yoghurt. The latter may be of particular importance in
older patients as it is known that the population of gut
Current management of psychiatric disorders prima- microbiota decreases with age.
rily consists of pharmacological and psychological the- The evidence for the effectiveness of using nutrition
rapies (i.e. cognitive behavioural therapy). However, in treating disorders is promising but inconclusive and
these interventions are only effective in treating around there are many more questions to be answered. Of the
half of the disease burden with large number of patients studies conducted, many are relatively short-term, often
being treatment-resistant. From the evidence as presen- under 6 months, and thus the impact of a long-term die-
ted above, diet and nutrition play a highly significant tary change remains unknown. Despite psychiatric dis-
role in the development of mental health conditions. orders and variations in the gut microbiome having a
Further investigation to enhance our understanding may significant genetic and environmental component, most
allow for careful manipulation of these biochemical and of the research has been conducted in Western countries
physiological systems to provide therapeutic benefit to or with populations composed mainly of Caucasian
patients. individuals. Similarly, even though nutritional interven-
The novel field of nutritional psychiatry harnesses tions are likely to have been used in treatment-resistant
our current understanding of diet and its role in mental subgroups of patients, our understanding of the benefit
health with a view to managing and treating some of of nutritional interventions in varying severity of mental
these conditions. A comprehensive literature search to illness is lacking. Another noteworthy point is that a
ascertain effectiveness of using diet as treatment reveals modified diet may only be of benefit in specific psychia-
equivocal data. One randomised control trial analysed tric conditions. For example, a systematic review asses-
the benefits of implementing a modified Mediterranean sing the effectiveness of nutritional supplementation in
diet in patients with depression (Jacka et al. 2017). Over children with autism spectrum disorder revealed in-
the course of twelve weeks, individuals underwent conclusive evidence for beneficial use (Sathe et al.
weekly diet and nutritional counselling. Their results 2017). However, it was noted that not surprisingly there
show a significant improvement in depression scores of is often a very low side-effect profile associated with
the Mediterranean diet cohort (using the Montgomery- nutritional therapies.
A‫ޡ‬sberg Depression Rating Scale) compared to the control In the future, with greater understanding of nutri-
group and indeed a significant number of individuals tional psychiatry and its effectiveness in treating neuro-
achieved remission. Moreover, a further meta-analysis psychiatric disorders, it is hoped that ‘healthy’ dietary
revealed that adherence to a Mediterranean diet resulted strategies will be adopted by patients. A scoping review
in low depression scores in a dose-response manner analysing the barriers to ‘healthy eating’ in young adults
(Molendijk et al. 2018). Similarly adopting a diet with a found the key barriers to include, relative indifference of

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A FOCUS ON INFLAMMATORY MECHANISMS Psychiatria Danubina, 2020; Vol. 32, Suppl. 1, pp 114-120

men to health-conscious behaviours, unhealthy diets 3. Brietzke E, Mansur RB, Subramaniapillai M, Balanzá-
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Correspondence:
Rashid Zaman, BSc (Hons) MB BChir (Cantab) DGM MRCGP FRCPsych
HPFT & Department of Psychiatry, University of Cambridge
Cambridge, UK
E-mail: [email protected] http://www.cmhr-cu.org/

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