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Exploring the link between neuroinflammation and psychiatric disorders.
Abstract: The current document seeks to investigate the literature on neuroinflammation and
understand its processes in relation to two major psychiatric disorders in the form of Major Depressive
Disorder and Clinical High-Risk Psychosis. This was done for the purpose of creating a comprehensive
literature response to the question of the relationship between neuroinflammation and the other two.
Various hypothesis and ideas are presented for both diseases, taking into consideration the
neuropharmacology and neuro-immunity literature which drives current research, also presented data
from a clinical perspective as these diseases are studied for the purpose of bettering the lives of patients
who suffer from them. Contradicting literature is brought together, with the majority of the scientific
data indicating a strong correlation between MDD & Neuroinflammation, and CHR-P &
Neuroinflammation.
Keywords: Psychosis, schizophrenia, neuroinflammation, psychiatric disorders, depression
Glossary of Abbreviations:
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
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

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Blood-Brain Barrier: BBB
Cerebrospinal Fluid: CSF
CHR-P: Clinical High-Risk Psychosis
Hypothalamic–pituitary–adrenal axis: HPA axis
IL-X: Interleukin-X
Interferon Gamma: IFN-γ
Lipopolysaccharide: LPS
Major Depressive Disorder: MDD
Major Histocompatibility Complex: MHC
Transforming Growth Factor Beta: TGF-β
Tryptophan: TRY
Tumour Necrosis Factor Alpha: TNF-α
1.0 - Introduction: The body of literature on neuroinflammation is vast, and the scientific
community is yet to explore all the intricacies of this complex phenomenon (Dickerson, et al., 2016).
Neuroinflammation is generally understood to be a complex biochemical response to various
encephalopathies and is mostly characterised by the activation of resident glial cells, the release of
specific cytokines and chemokines and the recruitment and infiltration of peripheral cells into the brain
parenchyma (Shabab, et al., 2017). Neuroinflammation has been associated with various
neurodegenerative and psychological comorbidities: Alzheimer’s Disease, Chronic Stress, Psychosis,
Depression and Amyotrophic Lateral Sclerosis being the most prominent examples of present literature
(Wohleb & Godbout, 2013). Recent literature has begun to investigate whether neuroinflammation
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plays a role in the aetiology of these and other disorders and to what degree the presence of one is
symptomatic of the other. The purpose of the current paper is to search the recent literature to present
an overview of the current position of the scientific community on the link between neuroinflammation
and two major psychiatric conditions: Depression and Psychosis, with special regard for schizophrenia
as its most common form, thus aiming to present a better understanding of the complex underlying
mechanisms which either confirm or negate such links.
1.1 – Psychosis & Schizophrenia: Psychosis is defined as a severe heterogeneous psychiatric
condition by which the patient loses control over his perceptual reality and lacks understanding of the
environment and reality around himself (Radua, et al., 2018). Schizophrenia is defined by the scientific
literature as an extraordinarily complex psychotic disorder that is characterised by disturbances in
cognition, emotional responsiveness, and psychosocial behavioural processes, with patients
experiencing delusions, hallucinations, disorganised speech, catatonic behaviour, and motor
retardation (Momtazmanesh, et al., 2019). Research carried out into the schizophrenic brain indicated
that architectural differences were prominent: enlarged ventricles, reduced grey matter in the prefrontal
cortex, physiological abnormalities in the temporal cortex and reduced volume in the basal ganglia and
hippocampus (Olabi, et al., 2011). These and other disturbances in the physiology and subsequent
immunochemistry of the brain are thought to play an active part in the exacerbation of
neuroinflammatory events and schizophrenia-like psychosis of various degrees (Doorduin, et al.,
2009). Post-mortem studies suggest that the predominant evidence linking neuroinflammation to CHRP lies in the increase of activated microglia cells (Wierzba-Bobrowicz, et al., 2005). In healthy
individuals, microglia display a ramified morphology and survey the microenvironment in search of
various irregularities and potential offences, and in the case of neuroinflammation, activated microglia
are responsible for controlling the spread of the infection by changing their ramified morphology into
an amoeboid form that remove irreversibly damaged brain tissues and infected cells (Dickerson, et al.,
2016). In neuropsychiatric conditions, post-mortem studies found a higher number of activated
microglia in schizophrenic patients, which is an indication of neuroinflammation, also symptomatic
within the literature of various forms of dementia (Doorduin, et al., 2009); with more recent evidence
indicating that a perturbation in microglia is linked to the early development of CHR-P, with a
particular propensity towards schizophrenia (Bloomfield, et al., 2016).
Further literature has expressed a more focused perspective, concentrating on the study of
commonalities in biomarkers between schizophrenia and general neuroinflammation. Researching
inflammatory biomarkers has the unique advantage of minimising the potential of interference by
confounding variables; this has been a great issue in patients with schizophrenia given the number of
variables which the scientific community must consider; factors such as duration of illness, diagnostic
specification, disease severity, and medications in use are all factors which modify cytokines levels
(Obuchowicz, et al., 2017; Dickerson, et al., 2016). Cytokines are known to modulate the adaptive
immune response in healthy brains and are produced by a critical component of the antigen-dependent
defence mechanism, T-lymphocytes (Momtazmanesh, et al., 2019). These mediators have various
functions and subcategorization due to the many services they provide. For the current paper, only
some of these groups will be considered: (1) pro-inflammatory cytokines such as IL-6, TNF-α, IL-1,
IL-8; (2) T-helper 1 cytokines which facilitate pro-inflammatory responses and work in autoimmune
disease against specific parasites, such as IL-2, IFN-γ, IL-12 (Warrington, et al., 2011; Debnath &
Berk, 2017). Additional studies also indicate the importance of various biomarkers in CHR-P and
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neuroinflammation: abnormal profiles of peripheral leukocytes and CSF cytokines (Khandaker, et al.,
2015), associations with MHC region genes based on genome-wide studies (Steafnsson, et al., 2009),
peripheral cytokines permeating through damaged BBB and neuroimmune cells present in the
meninges transferring into the brain’s parenchyma in a damaged or pathological state (Loveau, et al.,
2017).
Genetic-based research has also shed an important light on the link between CHR-P and
Neuroinflammation: genome-wide studies indicated novel susceptibility loci that aggravate the risk of
CHR-P (Li, et al., 2017), thus paving the way for gene identification which entices a higher chance of
CHR-P in combination with environmental factors such as exposure to pollution and psychosocial
stress which alter maternal immune activation in prenatal studies (Bergolt & Dunaevsky, 2019; Gomes,
et al., 2019). Groundbreaking research carried out in the last decade has uncovered the deep genetic
component of CHR-P in neuroinflammation. The major histocompatibility locus is found on
chromosome 6 and has been shown to have the highest correlation with the development of CHR-P,
in particular with schizophrenia, more than any other loci in the genome (Stefansson, et al., 2009).
This particular region is responsible for coding genes that modulate innate immunity such as
complement component 4A: structural variants of any degree which increase the expression of
complement component 4A dramatically increase the risk for development of CHR-P (Sekar, et al.,
2016). The cascade which this component is part of is also an integral part of the innate immune system
that recognises and eliminates foreign pathogens via phagocytosis by macrophages and microglia, thus
further demonstrating the interdependent nature of CHR-P and neuroinflammation (Veerhuis, et al.,
2011). Further research has also shown that the same cascade is also responsible for normal brain
development, normal synaptic functioning and synaptic pruning via microglia, strongly suggesting that
this protein cascade is found to be important for both pro-inflammatory processes and CHR-P (Hong,
et al., 2016).
1.2 - Depression: The present literature defines MDD as a negative state of mind which is
characterised by negative moods, low energy, loss of interest in usual activities, a pessimistic state of
mind, a tendency of catastrophizing and loss of normal biochemical needs such as appetite and sexual
arousal (Troubat, et al., 2021). The link between depression, a common psychological disorder, and
neuroinflammation, begun with the fortuitous discovery that antidepressant drugs seem to enhance
anti-inflammatory mechanisms in patients (Pereira, et al., 2018), aided by the pre-existing knowledge
that neurological defects such as neuroinflammation can produce a sickness-like behaviour which is
common in MDD (Raison, et al., 2006). Following this trend, several studies have been able to prove
the link between anti-inflammatory drugs and antidepressant properties. One review indicated that 2
different groups (one treated with adalimumab and one with etanercept) against a placebo group
showed a consistent decrease in depressive symptomatology (Kappelmann, et al., 2018)
Further studies have corroborated the idea of a link between these two conditions: IL-6 has
been strongly associated with MDD when in combination with C-reactive protein, also indicating a
prominent correlation with comorbidities such as anhedonia and motor retardation syndrome
(Haapakoski, et al., 2015). Further evidence indicated that the antidepressant effect of TNF inhibitor
drugs might be relegated only to patients who express a high level of sensitivity to C-reactive protein,
also showing that clinical symptoms such as motor retardation and suicidal thoughts were improved
in patients treated with infliximab (McIntyre, et al., 2018). The combined data from two meta-analyses,
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which covered a total of 11610 participants, indicate clearly that all nonsteroidal anti-inflammatory
drugs, cytokine-inhibitors, statins and minocycline in combination with Omega-3, except for
pioglitazone, significantly reduced depressive symptomatology and heightened chances of immediate
partial remission (Köhler-Forsberg, et al., 2019; Bai, et al., 2019). Evidence links mood swings
associated with depression with the most common biomarkers found in neuroinflammation. TNF-α
has a prominent role in chronic neuroinflammation and immune system mechanisms and has been
shown to hold a significant relevance in the disturbance of mood swings, depressive states and manic
episodes in those who suffer from MDD or a subvariant of it such as Bipolar depression, thus linking
TNF-α to CHR-P also (Munkholm, et al., 2013).
Additional research shows that astrocytes, a cell that expresses common pattern recognition
receptors, also helps in combating threats to the central nervous system when activated; this is
accomplished by experiencing morphological changes and becoming hypertrophied cells that secrete
pro-inflammatory cytokines such as IL-1β (Liddelow & Barres, 2017). Related evidence indicates that
astrocytes are activated through LPS challenge (Okada, et al., 2006), which in turn has been shown to
induce depressive behaviour, mood swings, and is a precursor for MDD and anhedonia in human and
rat models (Li, et al., 2019), while also having been linked to inflammation, mediated through the
activation of Toll-like receptors; thus suggesting that astrocytes play an essential component in the
development of inflammation via activation of the P2X7-NLRP3 inflammasome cascade, which is a
key component of MDD (Ratajczak, et al., 2019).
While the evidence presented is compelling, the hypothesis which holds more weight in
understanding the neurochemistry of MDD is the serotoninergic hypothesis, which on a basic level
indicates that individuals who suffer from MDD lack an adequate metabolism of serotonin (Hirschfeld,
2000), hence the clinical evidence showing that antidepressants focus on enhancing the bio-availability
of serotonin (Shulman, et al., 2013). Serotonin is synthesised from the amino acid TRY by the enzyme
TRY-hydroxylase, which also transforms TRY into kynurenine; this synthesis has been shown to be
strongly associated with inflammatory processes and pro-inflammatory cytokines through the
production of 2,3-di-oxygenase (O'Connor, et al., 2009). Kynurenine is metabolised into an
excitotoxic pathway and a neuroprotective pathway, the former of which has strong agonistic effects
on glutamatergic neurotransmission and creates oxidative stress (Guillemin, 2012), thus increasing
chances of dysregulated inflammatory mechanisms. Studies on TRY as a standalone compound and in
relation to TRY/Kynurenine ratio have been shown to have a profound effect on plasma in CSF in
patients who had received IFN-γ treatment, also correlating with the intensity of depressive symptoms
and suicidal tendencies (Raison, et al., 2010). Furthermore, clinical studies on suicidal behaviour and
suicide attempters indicated that a longitudinal dysregulation of the kynurenine pathway in the
excitotoxic catabolism held a strong correlation with inflammatory load and extreme depressive mood
swings, clearly indicating that understanding of kynurenine pathway activation is extremely important
in both MDD and neuroinflammatory treatment, thus further cementing the correlation between MDD
and inflammatory events (Bay-Richter, et al., 2015). This link has been corroborated also by studies
on secondary forms of MDD such as Bipolar Depression and Chronic Mood swings, all incorporating
the kynurenine pathway model, with evidence clearly indicating a strong correlation between
kynurenine dysregulation and IFN-γ playing an active role in the reduction in TRY plasma levels
(Hunt, et al., 2020).
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2.0 - Discussion: Having introduced the various neurochemical mechanisms which act as a
bridging link between neuroinflammation and MDD and CHR-P, it is paramount to understand the
detailed clinical and preclinical results from research conducted following the evidence presented, both
from a neuropharmacological perspective and from a clinical perspective.
2.1 - Psychosis & Schizophrenia: The purpose of the current paper was to determine if CHRP, especially in the form of schizophrenia, held inflammatory properties and was linked to the aetiology
of neuroinflammation with one disease being a comorbidity with the other. The evidence presented
indicates that the scientific community agrees that there is a link between the two (Comer, et al., 2020),
with some studies affirming that pro-inflammatory markers found in CHR-P patients are definitive
proof that inflammatory mechanisms provoke psychotic events and drive its cyclic nature (Fillman, et
al., 2016; Goldsmith, et al., 2020). Research indicates that roughly 40% of schizophrenia patients
experience high inflammatory mechanisms and subsequent neurodegeneration, with the inflammation
being typical of the later stages of psychosis, thus indicating that an advanced CHR-P stage is a
precursor of unbalanced pro-inflammatory cytokines (Fillman, et al., 2016). PET studies have been
paramount in this field. Data indicate that in CHR-P several translocator proteins, which are markers
of microglia, are identified as a precursor of a prognosis of grey matter loss, which is typical of certain
types of inflammation (Selvaraj, et al., 2018); however the studies are not able to identify more specific
biomarkers for in vivo models both for peripheral and focalised inflammatory mechanisms, this would
help in understanding the degree of relationship with various subtypes of psychosis.
As the above evidence indicates, the evidence linking neuroinflammation and CHR-P is mainly
found in the study and understanding of specific biomarkers. IL-6 is one of the most noted biomarkers
in the literature, as it plays a crucial role in both inflammatory mechanisms and psychotic episodes
(Momtazmanesh, et al., 2019). A considerable number of post-mortem and clinical studies showed
that elevated IL-6 levels are a trademark for psychotic episodes, especially in individuals who are using
anti-psychotics (Lesh, et al., 2018), and in patients who experienced chronic manic episodes
(Frydecka, et al., 2018). Contrasting evidence has shown a lack of increase in terms of IL-6 and TNFα in CHR-P patients (Wei, et al., 2018; Khoury & Nasrallah, 2018), but both studies lamented a lack
of adequate sample in terms of illness duration and severity of psychotic episodes, with some
indication that a longitudinal assessment might have been more adequate rather than a singular
measurement.
TNF-α is a cytokine responsible for promoting cell survival and resistance to pathogens in a
healthy brain, but in negative inflammatory events, it creates an overactivation of cytokine and
microglia which results in various degrees of damage (Zeng & Shi, 2018). Studies conducted on firstepisode psychosis patients or early development psychosis (less than 2 years) indicated elevated levels
of TNF-α (Zhu, et al., 2018), with levels spiking in chronic patients who had experienced multiple
manic episodes across the years, regardless of the antipsychotic drug of choice (Lv, et al., 2015).
Clinical studies regarding TNF-α found evidence linking an overproduction of the cytokine with an
impediment in speech and cognition (specifically visuospatial tasks) and elevated depressive
symptoms in patients with advance CHR-P who experienced more than three manic episodes, thus
indicating a progressive neurocognitive degeneration (Bossù, et al., 2015). Consistent results indicated
a reduction in neuropsychiatric symptoms such as delusions, hallucinations, and suicidal tendencies
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when TNF-α inhibitors were administered, with further studies showing a similar pool of effects with
other anti-inflammatory agents such as aspirin, estrogen and polyunsaturated fatty acids (Sommer, et
al., 2014). Studies targeting complement-dependent and microglia synaptic pruning in an in vitro
model from clinical cell cultures found that minocycline, an anti-inflammatory antibiotic, reduced all
negative microglia activation interactions as a result of TNF-α, thus indicating that targeting synaptic
pruning would be beneficial for the treatment and prevention of psychotic episodes (Sellgren, et al.,
2019). The evidence regarding microglia is however limited in its nature to some degree. Most of the
relevant studies indicate a post-mortem procedural handicap: safely collecting microglia sample for
analysis from living patients is extremely hard with the current technology, thus making it extremely
hard to discern early pro-inflammatory psychotic mechanisms at the neural level (Comer, et al., 2020),
especially considering the potential clinical implication of determining pro-inflammatory risks and
psychosis-like alterations from a developmental stage: limited literature on this particular field
indicates the importance of microglia functioning from a prenatal perspective in mice models, urging
for more in-depth research in prenatal samples (Hui, et al., 2018). Lastly, it is important to mention
related mice research which has indicated the importance of genetic manipulation from environmental
factors such as pollution in the womb: research shows that being exposed to psychosocial stress and
pollution while still in the womb has lasting effects on the ability to produce serotonin and dopamine,
both of which are essential in combating psychosis and depression; more importantly, prenatal stress
is associated with ADR axis deficits which indicate a propensity for neuroinflammation during adult
life (Ahmad, et al., 2021). These findings are extremely important in creating targeted intervention and
treatment plans in the prevention of Schizophrenia and Neuroinflammation (Comer, et al., 2020).
2.2 - Depression: Having understood and evaluated the literature on Psychosis, the present
paper also seeks to evaluate the available data on MDD and its relationship to neuroinflammation. As
the above data indicates, there is a strong correlation between MDD and neuroinflammation (Troubat,
et al., 2021). Considering a wider scope of studies on mood swings related to depression, a particular
study argues that it would be possible to attribute the cause of higher MDD cases in women, who are
twice as likely to experience it, to inflammation (Achtyes, et al., 2020); this is imputable to the fact
that women are more likely to be affected by autoimmune disease and present a higher sensitivity to
psychological stress (Troubat, et al., 2021). However, conflicting evidence indicates that MDD and
inflammation are not linked to sex hormones but rather adolescent psychosocial stress which is
correlated with adult neuroinflammation (Takizawa, et al., 2015). However, studies on Omega-3 and
aspirin did not find any particular evidence of stronger reaction in women, thus the hypothesis that
neuroinflammation is twice as likely in women due to psychological stress is rendered null (Bai, et al.,
2019). However, MDD remains strongly associated with inflammatory processes across sex and age
(Bay-Richter, et al., 2015), thus answering the question of the present paper in a positive way.
The stress perspective however is no void of value by any means. Countless studies have
identified that MDD negatively impacts the HPA axis, including glucocorticoid secretion and its
negative feedback (Vreeburg, et al., 2009). This system is paramount in response to stress and various
excitatory events through the glucocorticoids influence over metabolism, cardiovascular health and
immune responses, with further studies identifying these hormones as being responsible for HPA
abnormalities on several levels (Ulrich-Lai & Herman, 2009). Studies on depressed patients have
indicated an increase of glucocorticoids up to 65% (Howes & McCutcheon, 2017). These hormones
are known to have anti-inflammatory properties which would discredit the stress component of MDD6
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Inflammation connection studies (Busillo & Cidlowski, 2013), but the evidence suggests a more vast
perspective. These hormones are known to also exhibit pro-inflammatory properties which are
extensively detailed by Cruz-Topete & Cidlowski (2015). What is interesting and pertinent to the
current paper is the fact that glucocorticoids seem to be privileged in a stress situation, in which their
pro-inflammatory actions are intensified in animal and human models when the subject is experiencing
chronic stress, which is a prominent risk factor for MDD and subcategories of it (Dantzer, 2018).
Additionally, it is important to remember that chronic stress is also a key component of
neuroinflammation according to concording animal models (Kim & Won, 2017), thus reinforcing the
stress component in the MDD/Neuroinflammation argument. An interesting argument appears in the
HPA-MDD-Inflammatory argument. The circularity of the trifecta is somewhat unclear as to which
event comes first, with some research suggesting that HPA dysregulations are due to inflammatory
events, while others suggest that it is the other way around (Troubat, et al., 2021). What remains clear
is the dual function of glucocorticoids in combination with immune molecules for ani-inflammatory
reasons and in combination with external pro-inflammatory markers which penetrate the damaged
BBB endothelium (Busillo & Cidlowski, 2013). Studies on the BBB have indicated that under such
conditions as ischemia or inflammation-related neurodegeneration, the BBB becomes weaker and thus
allows for a higher permeability degree on behalf of LPS, which induces TNF-α and related depressive
symptomatology (Qin, et al., 2007).
The serotoninergic hypothesis is the most compelling in understanding the shared aetiology of
MDD and neuroinflammation. The excitotoxic kynurenine pathway alteration in combination with the
HPA axis dysregulations have been understood to be linked to increasing glutaminergic
neurotransmission, and this cascade of events is thought to be sustained by peripheral inflammatory
systems as research shows that inflamed circulatory markers can penetrate the BBB (Troubat, et al.,
2021). This is important when considering several pathologies which include inflammatory events in
the peripheral nervous system and are linked to circulatory biomarkers which harm the central nervous
system such as cancer, obesity and cardiovascular disease, all of which are also linked to MDD and
bipolar depression (Raison, et al., 2010). The dysregulation of kynurenine pathways has been strongly
correlated with several types of depression: chronic, MDD, post-Partum, immunotherapy related
depression and bipolar (Wurfel, et al., 2017). This is pertinent to the current paper when considering
further evidence which indicates that imbalance in kynurenine pathways, and therefore serotonin
metabolism, is activated by inflammatory events through the overproduction of TNF-α and IL-1 as
pro-inflammatory cytokines (Dostal, et al., 2017).
3.0 - Conclusion: The present paper aimed to present the current literature in response to the
question of the relationship between neuroinflammation and two major psychiatric conditions: MDD
and CHR-P. The presented literature offers a comprehensive evaluation and brief explanation of the
main points while presenting the most updated and relevant arguments. For CHR-P and MDD alike, a
common thread was discovered: pro-inflammatory cytokines are paramount in any perspective which
seeks to understand inflammation in the brain parenchyma and in the central nervous system at large.
Il-1 and TNF-α are found in the vast majority of the literature which deals with inflammatory
mechanisms. What is transparent from the literature is that inflammation covers a multitude of
comorbidities and holds relationships of some degree with most psychiatric and psychological
conditions. Microglia activation, a cornerstone of neuroinflammation, has been linked both to
hallucinatory events in CHR-P (Comer, et al., 2020) and mood swings in MDD (Kappelmann, et al.,
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2018), thus cementing the importance of research in the field. It is important to understand that the
efforts within the field are vigorous but yet unfocused as the central nervous system does not lack in
vastity or complexity, and research is encouraged in any of the areas mentioned in the presented
literature. A promising branch has been defined by the study of simultaneous assessment of
inflammatory markers both in peripheral and central inflammation as to better understand the complex
biochemistry behind it; and while the biomarker approach is widely accepted, a better and more
comprehensive understanding of the stratified complexities would greatly aid in the clinical treatment
of patients (Munkholm, et al., 2013).
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