2018 Cytokines Dysregulation in Schizophrenia, A Systematic Review of Psychoneurimmune Relationship

Schizophrenia Research 197 (2018) 19–33
Contents lists available at ScienceDirect
Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres
Cytokines dysregulation in schizophrenia: A systematic review of

psychoneuroimmune relationship
Daniela Rodrigues-Amorim a, Tania Rivera-Baltanás a, Carlos Spuch b, Hector J. Caruncho c,
África González-Fernandez d, Jose M. Olivares a, Roberto C. Agís-Balboa a,⁎
a
Psychiatric Diseases Research Group, Galicia Sur Health Research Institute (IISGS), Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, CIBERSAM, Spain
b
Neurology Research Group, Galicia Sur Health Research Institute (IISGS), Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, CIBERSAM, Spain
c
Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada
d
Immunology, Biomedical Research Center (CINBIO) (Centro Singular de Investigación de Galicia), Galicia-Sur Health Research Institute (IISGS), University Campus, University of Vigo, Vigo, Spain
a r t i c l e i n f o a b s t r a c t
Article history: Introduction: Schizophrenia is a multifactorial psychiatric disease with complex interactions among the brain
Received 31 July 2017 and the immune system. A psycho-immune relationship underling schizophrenia is supported by several studies
Received in revised form 15 November 2017 and integrates a specific area of knowledge - psychoneuroimmunology.
Accepted 18 November 2017
Methods: A systematic review was performed by 2009 Preferred Reporting Items (PRISMA) recommendations.
Available online 26 November 2017
Based on the inclusion/exclusion criteria, publications with relevant information (evaluated by the Joanna Briggs
Keywords:
Institute Critical Appraisals tools to quality assessment) were included.
Schizophrenia Results: In this review, we considered the inflammatory activity promoted by cytokine alterations in schizophre-
Cytokines nia aetiology, which reflects the systemic comprehension of this disease in opposition to the traditional approach
Cytokine polymorphisms focused solely on the brain. We focus on the analysis of several specific outcomes, such as proinflammatory cy-
Cytokine mRNAs tokines, sample sort, laboratory techniques, diagnosis scales and results of each publication.
Proinflammatory cytokines Conclusion: This systematic review confirms the existence of cytokines abnormalities in schizophrenia disease.
Psychoneuroimmunology Immune imbalances such as increased levels of some cytokines (either at protein level or at mRNA expression),
cytokine mRNAs, as well as cytokine gene polymorphisms have been reported with a large support in schizo-
phrenia. These findings provide a strong evidence of a concomitant process of inflammatory activity in schizo-
phrenia illness course.
© 2017 Elsevier B.V. All rights reserved.
1. Introduction pathophysiology of schizophrenia could be associated with cytokine ab-

normalities (Hope et al., 2013; Pandey et al., 2015; Potvin et al., 2008).
Schizophrenia is a severe psychotic disorder, which pathogenesis is Specifically, proinflammatory cytokines are involved in central nervous
still partially understood (van Kesteren et al., 2017). Given the multiple system (CNS) inflammation processes, disturbing the homeostasis and
interaction between the brain and other organ systems that may have contributing to additional tissues injury (Müller et al., 2015). The in-
an incidence in the development of aberrant behavioural phenotypes, crease of proinflammatory cytokines levels and their soluble receptors
the aetiology of schizophrenia remains, in part, uncertain. One sug- in human samples such as serum, plasma or cerebrospinal fluid (CSF)
gested mechanism that may putatively underlie schizophrenia develop- was reported in several studies (Debnath and Berk, 2014; Potvin et al.,
ment, implies disturbances of the immune system and their complex 2008; Wu et al., 2016). In the other hand, anti-inflammatory cytokines
interactions with the nervous system, which may give a new insight that down-regulate the inflammatory response are also altered in
on the pathogenesis and pathophysiology of this psychotic disorder schizophrenia (Müller and Schwarz, 2010). Another important aspect
(Khandaker et al., 2017; van Kesteren et al., 2017). This relationship pointing towards the involvement of immune system abnormalities in
was hypothesized over a century ago, and is reinforced by genetic and schizophrenia vulnerability is the presence of specific cytokine gene
epidemiological studies linking infection and inflammation with brain polymorphisms that may results in inflammatory events that putatively
disorders (Khandaker et al., 2015). Evidence demonstrates that the modulate the development of the schizophrenia syndrome by
neurodevelopmental or neurodegenerative abnormalities (Fan et al.,
2007). For example, the polymorphisms in the interleukin-1 (IL-1) or
⁎ Corresponding author at: Galicia Sur Health Research Institute, IISGS, Hospital Álvaro
Cunqueiro, Bloque Técnico, Planta 2, Sala de Investigación, Estrada Clara Campoamor, 341,
IL-6 genes have been associated to schizophrenia, with increasing
36212 Vigo, Spain. blood levels of both cytokines (Debnath and Berk, 2014; Katila et al.,
E-mail address: roberto.carlos.agis.balboa@sergas.es (R.C. Agís-Balboa). 1999). In particular, evidence suggest an unequivocal role of the IL-6
https://doi.org/10.1016/j.schres.2017.11.023
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20 D. Rodrigues-Amorim et al. / Schizophrenia Research 197 (2018) 19–33
in the pathogenesis of schizophrenia, whose levels of IL-6 and sIL-6R Mental Disorders (DSM) by American Psychiatric Association, and Inter-
(receptor) are elevated in the serum of patients with schizophrenia national Classification of Diseases (ICD) by World Health Organization.
(Chase et al., 2016; Potvin et al., 2008; Upthegrove et al., 2014). Further- Additionally, other scales were applied such as Scale for the Assessment
more, analysis of mRNA expression levels of pro-inflammatory cyto- of Positive or Negative Symptoms (SAPS or SANS), Positive and Negative
kines indicates that mRNAs upregulation, bring about the changes in Syndrome Scale (PANSS), cognitive scales as Wechsler Adult Intelli-
cytokine levels observed in schizophrenia (Pandey et al., 2015). Schizo- gence Scale (WAIS), and functional scales as Global Assessment of Func-
phrenia is recognized as a systemic syndrome, involving not only the tioning (GAF) to cross specific clinical data with laboratorial findings.
nervous system, but also the immune system, as well as originating Discrepancies were resolved by deliberations among the authors.
from a combination of environmental and genetic factors. Based on
these findings, the purpose of this review is to analyse and synthetize 2.5. Data synthesis
clinical and laboratory data, allowing a functional knowledge of the
role of inflammatory activity of cytokines in schizophrenia. Therefore, After eligibility, 99 studies were included in the qualitative synthesis
the integrated data will help to understand the connection between al- (Fig. 1), and the pertinent information was recompiled in a table after
terations of the immune system (related with cytokines, their gene create a folder with the selected articles in the Mendeley organizer.
polymorphisms and mRNAs) and clinical data (e.g. stress, severity of This review analyses qualitative data, correlating the inflammatory cy-
symptomatology, cognitive and functional performance, etc.) in the tokines profile, genetic polymorphisms and mRNA levels of cytokines,
context of psychotic diseases such as schizophrenia. laboratory procedures, samples sort and evaluation scales used in
schizophrenia diagnosis.
2. Methodology
3. Results
A systematic review of literature was achieved, using the 2009 Pre-
ferred Reporting Items for Systematic Reviews and Meta-Analyses 3.1. Search results
(PRISMA) recommendations and the Joanna Briggs Institute (JBI) Criti-
cal Appraisal to quality assessment. After search, using the terms: “proinflammatory cytokines and
schizophrenia”, “proinflammatory cytokines and psychosis” or “inflam-
2.1. Study design mation and schizophrenia”, 1003 studies were identified. Implementing
the limits and eliminating the duplicate items, we selected 586 studies
This is a descriptive and qualitative systematic review, which ex- for further screening. From this collection, 420 studies were excluded
plores the role of the immune system in schizophrenia aetiology. This because after screening the title and abstract, these studies clearly did
review was realized following the guidelines of the 2009 Preferred not fulfil the criteria. Finally, we carefully examined the full text of the
Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 166 studies selected, and discarded 67 studies because they did not
statement (Liberati et al., 2009; Moher et al., 2009). meet the requirements. Thereby, 99 studies were included in the pres-
ent report (Fig. 1). The search strategy was executed without publica-
2.2. Eligibility criteria for selection tions dates limit. The purpose of this review is to identify the role of
inflammation in schizophrenia pathophysiology, applying a methodolo-
This search was performed based on all studies published until 18/ gy based on recommendations that reduce the bias risk (PRISMA rec-
05/2017, in English and focused on humans with schizophrenia disease, ommendations and JBI appraisals).
which diagnosis was based on mental, cognitive or functional scales (in-
clusion criteria). The exclusion criteria comprise studies of patients with 3.2. Study characteristics
other psychiatric/neurological diseases such as depression, bipolar dis-
order, autism, Parkinson's, Alzheimer's, autoimmune or chronic inflam- Eligible studies analysed the association between proinflammatory
matory diseases and trauma. Also, studies focused in the anti- cytokines, inflammation and schizophrenia. The characteristics of each
inflammatory response and anti-inflammatory cytokines are excluded study were examined individually. These studies were categorized
because it is not the outcome/objective of this review. Studies were in- based on the cytokines profile (involved in inflammatory processes),
cluded if they were prospective or retrospective case-control and co- gene polymorphisms and mRNA levels. The final sample of reviewed
hort, systematic reviews or other qualitative research that investigated publications involving 8234 participants (4529 male and 3601 female;
the correlation between schizophrenia and cytokines involved in in- age range: 6 to 75 years, and 111 participants whose gender was not dif-
flammatory processes (upregulation and downregulation of cytokines ferentiated in the studies). The majority of the studies used serum (n =
and their genes). 42; 42.42%) to measure the cytokine levels. However, other types of
samples were utilized such as plasma (n = 16; 16.16%), blood (n =
2.3. Data sources 11; 11.11%), CSF (n = 5; 5.05%), peripheral blood leukocytes (n = 11,
11.11%), saliva (n = 1; 1.01%), post-mortem tissue (n = 1; 1.01%),
We electronically examined publications in the PubMed, Medline, and studies including more than one sample (ex: serum and CFS;
PsycINFO and Cochrane databases, introducing the search terms “proin- serum and peripheral blood leukocytes, etc.) (n = 12; 12.12%). A con-
flammatory cytokines and schizophrenia”, “proinflammatory cytokines comitant examination was performed by some studies, which mea-
and psychosis” and “inflammation and schizophrenia”. To make the sured the cytokine levels and gene polymorphisms (Frydecka et al.,
searching process more specific and efficient, we resorted to PubMed 2015) or the cytokine and mRNAs levels (Pandey et al., 2015). We inves-
filters, detailed in the inclusion criteria. tigated 42 different cytokines, 33 gene polymorphisms, and 11 cytokine
mRNAs (Supplementary Fig. 1).
2.4. Data selection Some of these cytokines, gene polymorphisms or mRNA levels were
measured in more than two studies: IL-6, tumor necrosis factor alpha
Three researchers (DRA, TRB and RAB) independently screened the (TNF-α), IL-10, IL-2, interferon-gamma (IFN-γ), IL-4, sTNFR1, IL-1Ra,
titles and abstracts, resulting 586 reports. Full text of all relevant publi- IL-18, sIL-2R, IL-1β, IL-6R, IL-17, IL-8, IL-12, TNF-α gene -308G/A and
cations was reviewed and 99 studies were selected. All selected studies IL-6 mRNA (Table 2). Several techniques were used, being the en-
complied the schizophrenia diagnosis requirement based on mental as- zyme-linked immunosorbent assay (ELISA) the most widely used for
sessment scales. Specifically, Diagnostic and Statistical Manual of measuring the cytokine levels. Others techniques such as Luminex
D. Rodrigues-Amorim et al. / Schizophrenia Research 197 (2018) 19–33 21
Fig. 1. Schematic procedure of data recollection. PRISMA flow diagram for systematic review of proinflammatory cytokines in schizophrenia.
(Dimitrov et al., 2013; Kubistova et al., 2012), flow cytometry (Krause et TNF as TNF-α are examples of proinflammatory cytokines. Others such
al., 2012) or immunoradiometric assay (Naudin et al., 1996) were also as IL-10 and transforming growth factor beta (TGFβ) are anti-inflamma-
applied. To analyse polymorphisms, polymerase chain reaction (PCR) tory cytokines - regulatory cytokines, and alterations in their expression
was the method most applied, but others such as TaqMan® single nu- levels have also been found in schizophrenia (Altamura et al., 2014;
cleotide polymorphism (SNP) genotyping assay (Kapelski et al., 2015; Müller et al., 2015; Ratnayake et al., 2013). Increased levels of proin-
Stojanovic et al., 2014) was also an alternative. Cytokine mRNAs were flammatory cytokines such as IL-6, TNF-α, and even the mRNA levels
assessed by real-time polymerase chain reaction (RT-PCR) (Table 2). of receptors (IL-1R, TNFR1 and TNFR2) were founded in schizophrenia
To establish the correct diagnosis of schizophrenia, varied types of scales patients (Pandey et al., 2015). Decrease levels of regulatory cytokines
were achieved, being the DSM-IV, ICD-10 and PANSS the most imple- as TGF-β are also associated with schizophrenia (Kartalci et al., 2016)
mented. Statistically, diverse models were employed but the majority (Table 1).
of the studies utilized ANOVA, ANCOVA, the Mann–Whitney U test The genetic basis of schizophrenia may present cytokines polymor-
and the Chi-squared test. This review is based on the analysis and evi- phisms, correlating with the modulation of the schizophrenia vulnera-
dence of secondary data, not requiring approval by the ethical bility (Mansur et al., 2012) (Table 2). Specifically, genetic
Committee. polymorphisms and environmental toxic events are critical to neuronal
development, and the combination between cytokine gene polymor-
3.3. Quality assessment of the selected studies phisms and intrauterine events such as maternal infection, maternal
stress, trauma, etc., may lead to the inflammatory signals found in psy-
The quality and relevance assessment of the selected studies was chotic stages (Baumeister et al., 2016; Malaspina et al., 2008; Mansur et
performed using PRISMA recommendations (Moher et al., 2009), and al., 2012; Read et al., 2005).
valuated by two independent reviewers, based on JBI critical appraisal Peripheral cytokine mRNA levels are upregulated in schizophrenia
tools. JBI is an evidence-based organization that develops methodolo- patients (Fillman et al., 2016). All studies found statistically significant
gies and guidelines to correctly conduct systematic reviews (Munn et alterations of some of these cytokine mRNAs levels in schizophrenia
al., 2014). Following the literature search, critical appraisal is a crucial (Chase et al., 2016; Dean et al., 2013; Fillman et al., 2013; Ghazaryan
step in the process of systematic reviews (McGrath et al., 2004; Munn et al., 2014; Pandey et al., 2015) (Table 1). Levels of proinflammatory cy-
et al., 2014). Thus, eighty-two studies were evaluated by JBI critical ap- tokines mRNAs (e.g. TNF-α, IL-6 and IL-1β) are associated with schizo-
praisal checklist for case control studies (Supplementary Table 1). Four phrenia symptomatology (e.g. PANSS assessment), and with microglial
studies were assessed by JBI critical appraisal checklist for cohort studies density, and logically also with abnormal cytokine protein levels (Chase
(Supplementary Table 2). Three studies are represented in Supplemen- et al., 2016; Fillman et al., 2013; Fung et al., 2014; Najjar and Pearlman,
tary Table 3, and its quality was considered by JBI critical appraisal 2015; Pandey et al., 2015).
checklist for systematic reviews and research syntheses. Ten studies
are characterized in Supplementary Table 4, in which the quality is eval- 4. Discussion
uated by JBI critical appraisal checklist for qualitative research. Two re-
viewers (DRA and RAB) conducted the appraisal and their ratification. 4.1. Cytokines: what is their role in schizophrenia?
3.4. Cytokines, cytokine gene polymorphisms and cytokine mRNAs in Cytokines are the signalling molecules that synchronize the innate
schizophrenia and adaptive immunity, acting on many different cells, including neu-
rons of the CNS (Upthegrove et al., 2014). Cytokines play a role in the
Cytokines are a family of soluble polypeptides, frequently regulated neuron synaptic plasticity, tissue repair, neurogenesis and synaptogen-
in cascades (Ratnayake et al., 2013). Certain IL as IL-6, INF as INF-γ and esis (Aloisi et al., 1995; Altamura et al., 2014). For example, IFNs (type I)
Table 1
Cytokines, cytokines gene polymorphisms and cytokines mRNAs most investigated in schizophrenia.
Cytokines Characteristics No of %⁎⁎

studies⁎
Cytokines (inflammatory activity)

IL-6 Multifactorial proinflammatory cytokine involved in physiologic process such as haematopoiesis, bone metabolism and 53 74.4%
nociceptive regulator. Increased levels of IL-6 in schizophrenia seem to be involved in its pathophysiology.
TNF-α TNF-α contributes to the progress of the inflammatory response, playing an important role in schizophrenia. Moreover, the 37 70.4%
soluble receptors (sTNFR1 and sTNFR2) had increased levels in plasma or serum, and it has been considered an inflammatory
marker in severe mental disorders.
IL-10 Anti-inflammatory cytokine, whose levels were found altered in chronic patients with schizophrenia, may be due to an 26 60%
increased compensatory stimuli of the type 2 cytokine pattern. Also, IL-10 may suffer down-regulation by the use of
antipsychotic drugs.
IFN-γ Increase concentrations of IFN-γ were reported in several studies, correlating with the first episode of schizophrenia. 23 50%
Furthermore, high levels of IFN-γ were correlated with acute exacerbations and in subsequent antipsychotic treatment.
IL-1β Cytokine involved in neurodegenerative and neuroprotective processes, and in the modulation of synaptic plasticity. Reports 21 64.3%
clearly detected an increased concentration of IL-1β in schizophrenia.
IL-8 IL-8 is a chemoattractant cytokine. The role of IL-8 in schizophrenia is associated with treatment resistance and negative 19 57.9%
symptoms. Also, IL-8 levels are increased in schizophrenia.
IL-2 IL-2 and its soluble receptor (sIL-2R) levels were associated with schizophrenia and psychotic stages. These abnormal levels are 16 58.3%
also linked with antipsychotic treatments.
IL-1Ra IL-1 receptor agonist is produced in response to diverse stimuli of inflammation such as IL-1β and IL-6. This cytokines is 13 50%
expressed in many cells, including neurons. Evidence shows that IL-1Ra levels are increased in schizophrenia, as well as the
consequent immune activation and inflammatory processes.
Cytokine gene polymorphisms

IL-6 rs1800795 (IL-6 IL-6 is undoubtedly associated with the pathology of schizophrenia, which levels are increased. IL-6 gene polymorphism, 6 66.7%
-174G/C) specifically IL-6 -174G/C, was also linked to schizophrenia. Thus, IL-6 and IL-6 gene polymorphism are apparently implicated in
several CNS diseases such as acute brain injury.
TNF-α rs1800629 TNF-α is a pleiotropic cytokine (neuroprotective and neurodegenerative effects, and immune and inflammatory responses), 6 33.3%
(TNF-α -308G/A) which levels were significantly higher in schizophrenia. TNF-α gene is one of the most studied and best described
polymorphism, correlating to schizophrenia susceptibility.
Cytokine mRNAs
Il-6 mRNA Cytokine mRNAs levels are correlated with schizophrenia: cognitive deficits and anatomic abnormalities such as decrease brain 3 100%
TNFR1 mRNA volume and abnormal cortical folding. IL-6, TNFR1/TNFR2 and IL-1β mRNAs were the mostly repeatedly investigated, and their 2 100%
TNFR2 mRNA levels are associated with the pathophysiology of schizophrenia. 2 100%
IL-1β mRNA 2 100%
⁎ Number of studies, which measured the corresponding levels of cytokines, cytokine gene polymorphisms and cytokine mRNAs. The same study could have analysed more than one
cytokine.
⁎⁎ Percentage of studies, whose abnormal levels of cytokines, cytokine gene polymorphisms and cytokine mRNAs (subcategories) were detected and associated with schizophrenia or
psychosis (p b 0.05).
appear critical for neuronal homeostasis balance, IL-4 seems to play an forms, stimulating or inhibiting the cytokines activity (Altamura et al.,
essential role in social and cognitive behaviour, and IL-6 is fundamental 2014). Recent studies suggest that infection, inflammation and autoim-
in the inflammatory processes and microglial activity (Kapelski et al., munity have a relevant role in schizophrenia (Khandaker et al., 2017,
2015; Thibaut, 2017). Regarding cells, one important component in 2015; Khandaker and Dantzer, 2016). The association between proin-
the CNS corresponds to the microglia (10–15% of the total cells of the flammatory cytokines and schizophrenia is quite well-recognized, and
CNS) (Müller et al., 2015). cytokine serum levels have been correlated with exacerbation/remis-
Microglia includes glial cells derived from mesoderm that works as sion of the symptoms and with the antipsychotic treatment
macrophages, forming part of the active immune defense in the CNS. (Khandaker et al., 2017; Miller et al., 2011; Upthegrove et al., 2014). In
Its activation stimulates the production and release of proinflammatory this review, we observed that 92.9% of the analysed studies correlate
cytokines in the CNS, contributing to the neuronal changes associated to some alteration in the levels of cytokines, polymorphisms and mRNA
pathological mental conditions such as schizophrenia (Müller et al., with schizophrenia or psychotic episodes, supporting the
2015; Upthegrove et al., 2014). Moreover, the astrocytes are also re- psychoneuroimmune relationship (Fig. 2).
sponsible for cytokine secretion in the CNS (Altamura et al., 2014). Pe- The imbalance in the expression of cytokines detected in schizo-
ripheral immune cells such as T-cells are involved in phrenia is linked to different factors such as stress, severity of symptom-
neuroinflammation (Estes and McAllister, 2014), and evidence demon- atology, scoring of diagnostic, cognitive and functional scales, duration
strate an altered distribution of T-cells as well as changes in serum levels of psychotic episodes, antipsychotic therapy, treatment resistance, co-
of Th1- and Th2-related cytokines in schizophrenia (Upthegrove et al., morbidities (e.g. obesity, diabetes, etc.), childhood trauma and abnor-
2014). The inflammatory theory of schizophrenia has been based on im- mal gene expression of cytokines. Furthermore, a specific
munological abnormalities. Changes in cytokines profile imply immune immunological response varies inter-individually based on genetic
system dysfunctions, impaired neurodevelopment and neurotransmis- background thereby being essential contemplate the cytokine gene
sion dysregulation (Altamura et al., 2014). Thus, abnormal levels of cy- polymorphisms (Srinivas et al., 2016).
tokines perhaps could be used as a disease indicator, that is, it could be a Stress is a factor quite well known that strongly influences the im-
diagnostic, prognostic, or theranostic biomarker (Rodrigues-Amorim et mune system (Fagundes et al., 2014). Abnormalities in cytokines are as-
al., 2017). sociated with stress levels (Garcia-Rizo et al., 2012; Song et al., 2014).
Some cytokines have proinflammatory activity (stimulate inflam- Increase in cytokine levels such as TNF-α and IL-6 were described in
mation), whereas others help to reduce inflammation (anti-inflamma- studies that correlate stress with schizophrenia (Chiappelli et al.,
tory activity). Immune and nonimmune cells can produce cytokines, 2016; Di Nicola et al., 2013). However, the psychosocial and environ-
exercising their effects on diverse cells by specific binding to cytokine mental stressors, which are recognized as immunity disturbance factors,
receptors (Miller et al., 2011). These receptors are accessible in soluble are not measured in many of the studies, being this a limitation in the
Table 2
Inflammatory activity promoted by cytokines, their gene polymorphisms and mRNAs in schizophrenia.
References Cytokines Outcomes Samples Laboratorial Diagnosis Findings p or q Effect sizea

Techniques Scales values
Cytokines (inflammatory activity)

Mahadevan et IL-6, TNF-α, TGF-β Cytokines, acute Serum ELISA ICD-10, Baseline levels of IL-6 and TNF-α pb gIL-6 =
al. (2017) and transient BPRS, were significantly elevated during 0.001 1.68
psychosis HRSS acute psychotic episodes. gTNF-α =
0.85
Allswede et al. IL-2,, IFN-γ, IL-12, Cytokines, Serum Multiplex assay NA Results suggest that increased p= NA
(2016) IL-1β, IL-6, IL-8, psychosis risk maternal levels of 0.032
TNF-α, IL-4, IL-5, anti-inflammatory cytokines during
IL-13, IL-10 the perinatal period could protect
against the development of
psychosis.
Chiappelli et IL-6 Inflammation, Saliva ELISA DSM-IV, Abnormalities in inflammatory and pb g = 0.62
al. (2016) stress WAIS-3, stress pathways previously found in 0.05
BACS, the illness, implicating
BPRS dysregulation stress response in the
chronic inflammation state in sz.
Das et al. IFN-g, IL-10 Cytokines, Plasma ELISA ICD-10, The high prevalence of aggression in pb g = 1.07
(2016) aggression PANSS psychosis patients it is an 0.001
independent entity associated with
increased
proinflammatory/anti-inflammatory
cytokine ratio.
Kao et al. IL-2, IL-6,IL-10, IFN-γ, Cytokines, Plasma Cytometric Bead DSM-IV, Sz patients with metabolism pb NA
(2016) TNF-α metabolism, Array Kit PANSS abnormalities may involve 0.05
quetiapine disruption of expression of
effects cytokines.
Kartalci et al. IL-4, TGF-β Cytokines, drugs Plasma ELISA DSM-IV, No changes were found in the levels pb NA
(2016) resistance BPRS of IL-4. TGF-β levels were 0.0001
significantly lower in antipsychotic
treatment-resistance sz patients.
Khandaker and IL-1β, IL-6, TNF-α, Cytokines, sz Serum, CSF Multiple assays DSM-IV, Sz is linked with alteration in NA NA
Dantzer IL-10 pathophysiology ICD-10 components of immune-to-brain
(2016) communication pathways, which
include increased serum levels of
proinflammatory cytokines (IL-1β,
IL-6, TNF-α) and markers of
endothelial cell activation.
Mørch et al. sTNFR1, IL-1Ra Inflammation, Plasma EIAs DSM-IV Increased levels of the inflammatory p= g = 0.25
(2016) psychosis markers sTNFR1 and IL-1Ra in 0.002
severe mental disorders as sz.
Turhan et al. TNF-α, sTNF-αRI, Cytokines, sz Serum ELISA DSM-IV, The levels of sTNF-αRII were pb NA
(2016) sTNF-αRII symptomatology PANSS negatively correlated with the PANSS 0.05
negative symptoms in sz patients.
Wu et al. IL-18 Cytokines, Serum ELISA DSM-IV, IL-18 levels were positively p= NA
(2016) cognitive RBANS, associated with RBANS total score in 0.014
impairment PANSS sz.
Zhang et al. IL-18 Cytokines, sz Serum ELISA DSM-IV, Findings suggest that the serum pb NA
(2016) chronicity PANSS IL-18 level was significantly higher 0.01
in patients than in controls
Al-Hakeim et IL-6, IL-18, sIL-2R, Inflammation, sz Serum ELISA ICD-10 Inflammatory cytokine p= NA
al. (2015) TNFα abnormalities, but only a significant 0.02
correlation was found between the
serum levels of sIL-2R and IL-18 in
sz patients.
Borovcanin et IL-23 Cytokines, sz Serum ELISA ICD-10, Increased levels of IL-23 in psychotic p= NA
al. (2015) stages, PANSS patients independently of 0.001
antipsychotic antipsychotics therapy can be a
drugs constitutive marker.
Falcone et al. IL-1α, IL-1β, IL-2, IL-4, Cytokines, Serum Multiplex assay DSM-IV TNF-α, IL-1β, IL-6, IL-5, IL-10, and pb gmonocytes
(2015) IL-6, IL-8, IL-10, IFN-γ, pediatric IFN-γ were elevated in children 0.05 = 0.35
TNF-α, TNF-β, IL-5 psychosis with psychosis.
Fond et al. IL-1β, IL-6, IL-12, Cytokines, FEP NA Multiple assays PANSS In first-episode psychosis, there have NA NA
(2015) IFN-γ, TNF-α, sIL-2R, been a number of studies to report
IL-17, IL-15, IL-10 increased levels of cytokines such as
IL-1β, IL-6, IL-12, IFN-γ, TNF-α, sIL-2R
and more recently IL-17.
Frydecka et al. IL-6 Cytokine, Serum ELISA DMS-IV, Correlations between serum IL-6 pN NA
(2015) cognitive OPCRIT, level, illness duration and course of 0.05
impairment, PANSS, the disorder demonstrate that sz is a
clinical SAPS, progressive disorder with low-grade
manifestation SANS, inflammation.
RAVLT,
WAIS
(continued on next page)
Table 2 (continued)

Hope et al. sTNFR1, IL-1Ra, IL-6 Inflammation, Serum EIAs DSM-IV, The findings strongly support a role pb gIL-1Ra =
(2015) cognitive PANSS, for inflammation in the 0.01 0.35
impairment GAF, neurophysiology of cognitive
CDSS, impairment (sTNFR1, IL-1Ra) in sz.
WAIS,
YMRS
Mondelli et al. IL-1β, IL-2, IL-4, IL-6, Cytokines, Serum Randox Biochip, DSM-IV, Cortisol and inflammatory p≤ NA
(2015) IL-8, IL-10, IFN-γ, cortisol, Chemiluminescent OPCRIT, biomarkers at the onset of psychosis 0.04
TNF-α treatment immunoassay PANSS should be considered as possible
response predictors of treatment response.
Pandey et al. IL-6, TNF-α, IL-1R1, Cytokines, sz Plasma ELISA DSM-IV Abnormalities of proinflammatory pb gTNF-α =
(2015) TNFR1, TNFR2, IL-1β, PANSS citokines and their soluble receptors 0.01 0.84
IL-1R2, IL-1Ra, IL-6R, in the plasma of sz patients (TNF-α, gIL-6 =
GP130 IL-6, TNFR1, TNFR2 and IL-1R1). 0.56
Petrikis et al. IL-2, IL-6, IL-10, IL-17, Cytokines, drug Serum ELISA DSM-IV, The serum levels of IL-2 and IL-6 are pb gIL-6 =
(2015) TGF-β2 näive, FES PANSS increased in first episode drug-näive 0.03 0.63
patients with psychosis. gIL-2 =
0.22
Sirota et al. TNF-α, IL-1β, IL-6, Cytokines, PBMC ELISA DSM-IV, Difference between obese and pb gTNF-α =
(2015) IL-1Ra, IL-10 or IL-2, obesity PANSS, non-obese, suggesting an 0.05 0.79
IFN-γ CGI inflammatory stage in obese sz gIFN-γ =
patients (TNF-α, IFN-γ and IL-1β). 0.67
gIL-1β =
1.32
Xiu et al. IL-3 Cytokine, sz Serum ELISA DSM-IV, The results suggested that IL-3 pb NA
(2015) pathophysiology PANSS related pathway is associated with 0.05
psychopathology of sz patients.
Al-Asmari and TNF-α, IL-1β, IL-6, Cytokines, Serum ELISA DSM-IV The levels of IL-1β, IL-6, and TNF-α of pb gIL-1β =
Khan (2014) IFN-γ antioxidative sz patients were significantly higher. 0.01 3.28
defense systems Inflammation resulting from gIL-6 =
dysregulation of cytokines and altered 1.24
antioxidant systems may play a critical gTNF-α =
role in the aetiology of sz. 2.55
De Witte et al. IFN-γ, IL-1α, IL-1Ra, Cytokines, FES, Serum Multiplexed DSM-IV, Only the anti-inflammatory pb NA
(2014) IL-5, IL-10, IL-12p40, antipsychotic immunoassay PANSS cytokine IL-10 responded to 0.05
IL-15, IL-18, TNF-α treatment treatment in parallel with symptom
improvement. This finding suggests
that this could be used as a potential
treatment response biomarker in
future studies of sz
Debnath and IL-17 Cytokines, sz Plasma ELISA PANSS Plasma levels of IL-17 were NA NA
Berk (2014) pathogenesis positively correlated with the
severity of clinical symptoms based
on PANSS scores in sz patients.
Hayes et al. IL-6R, TNFR2, IL-8 Cytokines, CSF Multiplex assay DSM-IV, IL-6R and TNFR2, were decreased and q≤ gIL-8 =
(2014) infection agents ARMS IL-8 was increased in the sz group. 0.04 0.49
in psychosis
Khandaker et IL-6 Inflammation, sz Serum ELISA PLIKSi Higher levels of the systemic pb g = 0.29
al. (2014) inflammation marker IL-6 in 0.05
childhood are associated with an
increased risk of developing
depression and psychosis in young
adulthood.
Klemettillä et IL-6, IL-1Ra Cytokines, Serum ELISA, Tina-quant ICD-10 There are partly gender dependent pb gIL-6 = 0.40
al. (2014) clozapine C-reactive protein cytokine and adipocyte alterations 0.01 gIL-1Ra males
in sz patients with treatment = 1.88
resistant or under clozapine gIL-1Ra
treatment. females =
1.93
Mitchell and IL-1α, IL-1β, IL-2, IL-4,Inflammation, Serum, CSF Multiple assays NA IL-1β and IL-8 are elevated in NA NA
Goldstein IL-5, IL-6, IL-8, IL-10, children and psychosis. No significant differences in
(2014) IFN-γ, TNF-α, TNF-β adolescents with TNF-α between sz and controls. IFN-γ
sz increased and IL-10 decreased in sz.
Müller (2014) IL-1β, IL-6, IL-8, TNF-α Cytokines, sz CSF Multiple assays NA Future research is necessary to NA NA
clarify the role of the immune
system in sz.
O'Connell et al. IL-1β, IL-6, IL-8, IL-17, Cytokines, Serum Dot-immunoblotting DSM-IV, Elevated BMI is associated with pb NA
(2014) IL-23, TNFα clozapine, female BPRS, increased number of adipocytes that 0.05
gender SANS may contribute to increase serum
cytokines in females with sz.
Song et al. IL-1β, IL-6, TNF-α Cytokines, body Serum ELISA DSM-IV Risperidone treatment is associated pb gIL-1β =
(2014) weight, with changes in serum 0.001 2.13
risperidone proinflammatory cytokines levels gIl-6 = 1.64
and weight. gTNF-α =
1.28
Table 2 (continued)

Stojanovic et IL-6 Cytokines, early Serum ELISA DSM-IV, Possible active inflammatory process pb g = 0.14
al. (2014) stages of sz OPCRIT in subjects with early psychosis or 0.05
who are at risk of psychosis. IL-6 is a
possible candidate biomarker of
psychosis at early stages.
Xiu et al. IL-10 Cytokines, Serum ELISA DSM-IV, IL-10 levels may be implicated in the p= g = 0.40
(2014) severity of PANSS negative symptoms and cognitive 0.029
symptoms impairment at the acute stage of sz.
Zakharyan and IL-1β, IL-2, IL-6, IL-12, Cytokines, Serum, plasma, Multiple assays NA Increase levels of IL-8 and IL-6 in NA NA
Boyajyan IL-18, TNF-α, IFN-γ inflammation, sz immune cells, chronic treat and first episode
(2014) pathophysiology CSF, blood cells free-treat sz patients.
Altamura et al. IL-1, IL-2, IL-6, IL-8, Inflammation, sz Blood, serum, NA NA The reviewed inflammatory and NA NA
(2013) IL10, TNF-α, IFN-γ, pathophysiology CSF neurodevelopmental data represent
IFN-α, IL-1β, IL-12, the most robust evidence (besides
sIL-2R cerebral visualization
abnormalities) confuting the
conceptualization of sz as a
“functional psychosis”.
Borovcanin et TNF-α, IFN-γ, IL-4, Cytokines, Serum ELISA ICD-10, Increased serum levels of IL-4 and pb gIL-4 =
al. (2013) IL-10, IL-17, TGF-β, antipsychotics PANSS IL-10 in sz appear to be 0.01 2.44
IL-27, IL-6 down-regulated by antipsychotic
treatment.
Di Nicola et al. IL-1α, IL-1β, IL-2, IL-4, Inflammation, Serum Chemiluminescent DSM-IV, First episode psychosis is p= g = 1.60
(2013) IL-6, IL-8, IL-10, FEP, stress immunoassay OPCRIT characterized by a proinflammatory 0.01
TNF-α, IFN- γ state. Stress in childhood and closer
to psychosis onset, appear to
contribute to increase cytokine
(higher TNF-α serum levels).
Dimitrov et al. IFN-γ, IL-2, IL-12p70, Cytokines, Serum Luminex DSM-IV, Positive association between pb NA
(2013) IL-17 psychopathology PANSS cytokines and PANSS scores. These 0.05
alterations may play a role in
development of psychotic
symptoms in sz.
Dunjic-Kostic IL-6, TNF-α Cytokines, Serum ELISA DSM-IV, IL-6 was higher and TNF-α was pb gTNF-α T1 =
et al. (2013) exacerbation and PANSS lower in schizophrenic patients in 0.05 0.58
remission phase both exacerbation and remission in gTNF-α T2 =
of sz comparison with healthy controls. 0.59
gIL-6 T1 =
0.41
gIL-6 T2 =
0.54
Hope et al. sTNFR1, IL-1Ra, IL-6 Cytokines, Plasma ELISA DSM-IV, IL-1Ra and sTNFR1 are related with pb gIL-6 =
(2013) severity, PANSS, severity and psychotic features. This 0.05 0.59
psychotic GAF supports a role of immune
symptoms activation in the pathophysiology of
severe mental disorders as sz.
Kirkpatrick IL-1β, IL-6, IL-12, Inflammation, sz Serum NA NA Patients with sz have higher NA NA
and Miller IFN-γ, TNF-α concentrations of IL-1β and IL-6,
(2013) during an exacerbation of
symptoms. IL-12, IFN-γ and TNF-α
appear to be trait markers.
Noto et al., sTNFR1 Cytokines, Serum ELISA NA Sz was associated with an p= NA
2013 clinical course of inflammatory profile. This suggests 0.011
sz that sTNFR1 is a market of a
treatment-resistance and severe
clinical course in sz.
Zhang et al. IL-18 Cytokines, FES, Serum ELISA DSM-IV, IL-18 was associated with pb NA
(2013) drug naïve PANSS, visuospatial/constructional domain 0.01
RBANS in sz patients. IL-18 may play a role
in cognitive impairment in sz.
Borovcanin et TNF-α, IFN-γ, IL-4, Cytokines, FEP Serum ELISA ICD-10, The results showed decreased levels of pb NA
al. (2012) IL-10, IL-17, TGF-β, PANSS IL-17, increased levels of IL-4 and 0.05
IL-27, IL-6 levels of IL-4 in serum of sz in relapse
patients were higher than in controls.
Dennison et al. IL-1β, IL-6, IL-8, TNF-α Cytokines, Plasma ELISA DSM-IV, Patients with childhood trauma had pb gIL-6 =
(2012) childhood PANSS, higher levels of IL-6 and TNF-α than 0.05 0.34
trauma CDSS, CTQ patients without trauma and healthy gTNF-α =
controls. TNF-α levels correlated with 0.77
the extent of the trauma.
Garcia-Rizo et IL-6 Cytokines, drug Blood Serum DSM-IV, Elevate levels of IL-6 were found in pb g = 1.07
al. (2012) naïve, symptoms PANSS patients with predominantly 0.001
negative symptoms,
treatment-resistance and an
unfavourable course of sz.
Table 2 (continued)

Krause et al. TNF-α, IL-6, IL-10 Cytokines, Blood Flow cytometry DSM-IV, The results provide support for the pb g = 0.40
(2012) monocytic PANSS involvement of the immune system 0.05
system in sz in the pathophysiology of sz and
indicate that especially the
proinflammatory immune response
seems to be impaired.
Kubistova et al. IL-6, IL-8, IL-10, TNF-α Cytokines, FES Blood Luminex ICD-10, Proinflammatory state in the first pb gIL-6 P1 =
(2012) PANSS, episode of sz: decrease IL-6 plasma 0.01 1.24
M.I.N.I. levels after acute treatment. gIL-6 P2 =
2.86
Leonard et al. IL-1, IL-6, IFN-γ, Cytokines, Serum NA PANSS It is concluded that the effects of NA NA
(2012) TNF-α, IL-4, IL-10, metabolic inflammatory mediators on the
IL-13 syndrome brain causally contribute to the
pathology of sz and the ill health
that accompanies the disorder.
Palladino et al. IL-18, IL-18BP Cytokines, sz Serum ELISA DSM-IV IL-18 system is perturbed in sz. This pb NA
(2012) cytokine might be part of a pathway 0.001
of genetic and environmental
components for vulnerability to the
disease.
Pedrini et al. IL-6, IL-10, TNF-α Cytokines, Serum ELISA DSM-IV, IL-6 levels were significantly higher; pb gIL-6 ES =
(2012) oxidative stress BPRS no differences for TNF-α in patients 0.01 2.0
markers, sz with sz at early and late stages, and gIL-6 LS =
chronicity IL-10 levels were decreased at late 0.99
stage and a decrease trend in early gIL-10 ES =
stage. 0.49
gIL-10 LS =
1.30
Xiu et al. IL-18 Cytokines, Serum ELISA DSM-IV, Elevated levels of IL-18 pathway pb NA
(2012) psychopathology PANSS activity may be involved in the 0.01
psychopathology of sz.
Hope et al. TNF-R1, IL-1Ra, IL-6 Cytokines, Plasma EIA DSM-IV, There were no significant pN NA
(2011) affective GAF, associations between affective 0.05
symptoms PANSS, states or symptoms in sz.
CDSS
Igue et al. sIL-2R, IL-6, IL-1, Cytokines, Plasma ELISA DSM-IV, Quetiapine, like clozapine, elevates pb NA
(2011) IL-1Ra positive PANSS sIL-2R levels in sz. sIL-2R 0.05
symptoms, alterations can also be explained
quetiapine by interplays between
antipsychotics and the positive
symptoms.
Kunz et al. TNF-α, IL-6, IL-10 Inflammation, sz Serum ELISA DSM-IV, The findings demonstrate a chronic pb NA
(2011) BPRS, CGI immune activation in 0.001
schizophrenia.
Lin et al. IL-6, TNF-α, TGF-β Cytokines, sz Serum Serum DSM-IV Increased levels of IL-6 may play a p= gIL-6 =
(2011) role in the pathophysiology of sz. 0.02 0.59
Reale et al. IL-8, IL-18, IFN-γ Cytokines, sz PBMC ELISA DSM-IV, Significantly higher levels of IL-8 p≤ gIFN-γ =
(2011) pathophysiology PANSS, and IL-18, and lower IFN-γ levels in 0.002 0.74
SAPS, PBMC of sz patients.
SANS
Suvisaari et al. sIL-2Rα, IL-1Ra, TNF-α Cytokines, Serum ELISA DSM-IV Persons with sz had significantly pb gIL-1Ra =
(2011) metabolic and higher sIL-2Rα, IL-1Ra and persons 0.01 0.56
physical with affective psychosis almost gTNF-α =
condition, significantly higher TNF-α 0.20
antipsychotic compared to their matched controls.
medication
Ellman et al. IL-8 Cytokines, Prenatal sera MRI DSM-IV In utero, exposure to elevations in pb NA
(2010) structural brain and IL-8 may be implicated in brain 0.05
alterations neuroanatomical disturbances commonly found in sz.
regions
Hope et al. sTNFR1, IL-1Ra, IL-6 Cytokines, Plasma EIAs DSM-IV, Increased levels of sTNFR1in sz. pb NA
(2009) inflammation, sz GAF These findings may indicate an 0.0001
association between severe mental
illness and abnormal
endothelial-related inflammation.
Crespo-Facorro IL-12 Cytokines, drug Plasma ELISA DSM-IV, Patients with a first episode of pb NA
et al. (2008) naïve in FES, SAPS, psychosis have inflammatory-like 0.001
antipsychotic BPRS, immunological function during
effects SANS early phases of the illness that it is
independent of the antipsychotic
treatment used.
Potvin et al. IFN- γ, IL-4, IL-2, Cytokines, Serum, plasma Multiple assays NA Il-6 and Il-1Ra alterations in sz are NA NA
(2008) sIL-2R, IL-1β, IL-1Ra, inflammation, sz linked to the psychopathology of sz
TNF-α, IL-6, sIL-6R, or to phenotypic traits of the
IL-10, TGF-β disorder.
Table 2 (continued)

Fan et al. IL-1β,IL-2, IL-6,IL-8, Inflammation, sz CSF, serum Multiple assays PANSS Inflammation may present a NA NA
(2007) TNF-α common pathophysiological process
related to both sz psychopathology
and metabolic disturbances.
Brown et al. IL-8, IL-1β, IL-6, TNF-α Cytokines, sz risk Serum ELISA DSM-IV The second-trimester IL-8 levels in p= gIL-8 =
(2004) in adult offspring mothers of offspring with sz were 0.02 0.55
significantly higher.
Altamura et al. IL-6, IL-6R Cytokines, Plasma NA DSM-III-R, Results appear to exclude a major pN NA
(2003) season of birth BPRS role of the season of birth in 0.05
determining reported interleukins
system alterations in chronic sz.
Garver et al. IL-6 Cytokines, CSF ELISA DSM-IV, An endophenotype p= g = 0.58
(2003) endophenotypes SAPS (delayed-responders) demonstrated 0.017
elevated levels of IL-6, suggesting the
presence of an inflammatory process
during exacerbations of psychosis.
Yao et al. IL-6, IL-10 Cytokines, PUFAs CSF ELISA DSM-IV, Findings demonstrated significant pb NA
(2003) BHPR, correlation between increased CSF 0.01
BPRS, levels of IL-6 and decreased red
SANS, blood cell levels of PUFAs in sz
AIMS patients.
Cazzullo et al. IL-2, IL-4, IL-10, IFN-γ Cytokines, Blood, PBMC ELISA DSM-IV, The production of IL-2 and IFN-γ pb gIFN-γ maleS
(2002) risperidone PANSS was higher in patients than in 0.05 = 0.46
controls. With risperidone, the gIFN-γ
IFN-γ levels decreased. femaleS =
1.10
Maes et al. IL-8, IL-10 Cytokines, Serum ELISA DSM-IV, Increased serum levels of IL-8 and pb gIL-8 =
(2002) clozapine BPRS IL-10 in patients with sz. 0.05 0.81
gIL-10 =
0.54
Erbağci et al. IL-1β, sIL-2R, IL-6, IL-8, Cytokines, Plasma Chemiluminescence DSM-IV, Plasma IL-1β, sIL-2R, IL-6, IL-8 and pb gTNF-α =
(2001) TNF-α symptomatology, EIAs BPRS, TNF-α concentrations yield little. 0.01 0.24
risperidone SANS, However TNF-α may contribute to
SAPS sz symptomatology.
Kamińska et al. IL-2, IL-4, IL-6, IL-8, Cytokines, Serum, ELISA DSM-IV, Sz is characterized by activation of p≤ gIL-6 = 0.91
(2001) IL-10, IFN- α, IFN- γ, paranoid sz peripheral blood PANSS the proinflammatory response: 0.01 gIL-8 =
TNF-α leukocytes increased serum levels of IL-6, IL-8 0.89
and IFN- γ, and decreased levels of gIFN-γ =
IL-10. 0.94
gIL-10 =
0.97
Kudoh et al. IL-6,IL-8, TNF-α Cytokines, stress Plasma ELISA N.A. The plasma IL-6 concentrations pb g = 1.32
(2001) correlated with plasma cortisol 0.05
concentrations. Proinflammatory
cytokines response to abdominal
surgery is inhibited in sz.
Maes et al. IL-6, IL-6R, IL-1Ra Cytokines, Serum ELISA DSM-IV, Increased serum IL-6 and IL-1Ra pb gIL-6 =
(2000) atypical BPRS concentrations. No significances in 0.05 1.18
antipsychotics, IL-6R in treatment-resistance gIL-1Ra =
drug resistance patients. 0.64
Tanaka et al. IL-18 Cytokines, sz Serum ELISA DSM-IV Sz had significantly higher serum pb NA
(2000) IL-18 levels than control subjects. 0.002
Lin et al. IL-6, IL-6R Cytokines, Serum ELISA DSM-III, The treatment-resistance is pb gIL-6 =
(1998) treatment BPRS accompanied by increased serum 0.01 1.20
resistance IL-6 concentration. Increased
production of IL-6 and IL-6R.
Naudin et al. IL-6, TNF-α Cytokines, sz Serum Immunoradiometric DSM-III, The higher serum IL-6 levels reveal a pb gIL-6 =
(1996) assay PANSS specific inflammatory syndrome 0.02 4.36
mediated by IL-6 in sz.
Maes et al. IL-6, sIL-2R, sIL-6R Cytokines, Plasma ELISA DSM-III, An increased secretion of sIL-2R and pb gIL-6 =
(1994) clozapine BPRS IL-6 characterizes sz in younger 0.05 0.36
people. Clozapine dose-dependently
increases sIL-2R levels in sz.
Cytokine gene polymorphisms

Jemli et al. IFN-γ(+874A/T) CGP, paranoid sz Peripheral blood PCR-RFLP SAPS, The polymorphism in the IFN-γ p= NA
(2016) (rs62559044) leucocytes SANS gene is associated with paranoid sz 0.03
BPRS, GAF subtype in males.
Jemli et al. IFNGR2Q64R CGP, gender Peripheral blood PCR-RFLP SAPS, The IFNGR2Q64R polymorphism is pb NA
(2016b) leucocytes SANS correlated with male sex and 0.01
paranoid schizophrenia.
Rajasekaran et IL-10(−592C N A) CGP, sHLA-G Leukocytes PCR-RFLP DSM-IV, Findings suggest the impact of p= NA
al. (2016) (rs1800872), (−1082 levels MINI, possible correlation between IL-10 0.04
A N G) (rs1800896) SANS, and Human Leukocyte Antigen-G on
SAPS sz risk.
Table 2 (continued)

Xu et al. IL-18R1 (rs12998521, CGP pathway Blood RT-PCR, Sequenom DSM-IV Positive association of the pb NA
(2016) rs1035130), IL18RAP MassARRAY system polymorphism with sz. 0.05
(rs10490204,
rs3771150)
Zhang et al. IL-18(-607A/C) CGP, sz Blood PCR DSM-IV, Findings suggest that the association pb NA
(2016) (rs1946518) chronicity PANSS between higher IL-18 levels and 0.05
clinical symptoms in sz is dependent
on the IL-18-607A/C polymorphism.
Frydecka et al. IL6(-174G/C) CGP, cognitive Peripheral blood PCR DMS-IV, Elevated IL-6 in sz patients does not pb ghomozygotes
(2015) (rs1800795) impairment, leukocytes OPCRIT, occur due to genetic variation in its 0.027 = 1.38
clinical PANSS, gene. However, this polymorphism
manifestation SAPS, may affect the severity of positive
SANS, symptoms (SAPS) in sz.
RAVLT,
WAIS
Kapelski et al. IL-6 (rs1800795, CGP, paranoid sz Blood TaqMan SNP DSM-IV The results do not support the pN NA
(2015) rs1800797), IL-6R genotyping assays OPCRIT theory that these polymorphisms 0.05
(rs4537545, are involved in the pathogenesis of
rs4845617, sz.
rs2228145)
Stojanovic et IL-6 (rs1800795) CGP, early stages Peripheral blood TaqMan SNP DSM-IV, Possible active inflammatory pb g = 1.37
al. (2014) of sz mononuclear genotyping assay OPCRIT process in subjects with early 0.05
cells psychosis or who are at risk of
psychosis. IL-6 is a possible
candidate biomarker of psychosis at
early stages.
Debnath et al. IL-6(-174 G N C) CGP, paranoid sz Blood ABI 3730 genetic DSM-IV No significant differences in pN NA
(2013) (rs1800795), analyzer genotype as well as allele 0.06
TNF-α(-238 G N A) frequencies were observed for IL-6
(rs361525) and TNF-α variants between the
patient and control groups.
Fineberg and IL-1β(−511C/T) CGP, Plasma, CSF Neuroimaging, NA Neuroimaging studies have linked NA NA
Ellman (rs16944), IL-1RN*2 neurological and genotyping proinflammatory cytokines gene
(2013) (rs380092) neurocognitive polymorphisms with some
alterations structural and functional
abnormalities repeatedly found in
sz.
Frydecka et al. IL-2(-330T/G) CGP, sz Peripheral white PCR DSM-IV, The results indicate that the TGFB1 p= NA
(2013) (rs2069756), susceptibility blood OPCRIT +869T/C gene polymorphism is 0.018
IL-6(-174G/C) associated with schizophrenia,
(rs1800795), IFN-γ(+ especially in females.
874T/A) (rs2430561),
TGFB1(+869T/C)
(rs1800470),
TGFB1(+913G/C)
(rs1800471)
Zakharyan et IL-6(–174G/C) CGP, sz Blood PCR-SSP ICD-10, Association between IL6 rs1800795 pb g = 0.45
al. (2012) (rs1800795) DSM-IV polymorphism and the increased IL6 0.01
blood level with sz. Also, IL6
rs1800795*C alleles linked to
increased IL-6 blood levels.
Sasayama et al. IL-1β (rs2853550, CGP, sz Venus blood PCR DSM-IV, rs1143633 of IL-1β gene is pb NA
(2011) rs1143634, M.I.N.I. associated with sz susceptibility. No 0.01
rs1143633, evidence for rs16944. The results
rs1143630, rs16944) support the role of IL-1β in sz
aetiology.
Fan et al. IL-1 gene complex CGP, CSF, serum Multiple assays PANSS Inflammation may represent a NA NA
(2007) polymorphisms, TNF- psychopathology common pathophysiological process
α-G308A (rs1800629) related to sz psychopathology.
Studies examining drugs that alter
the inflammatory processes could
be of great clinical relevance in the
sz population.
Watanabe et TNF-α(-G308A) CGP, sz N.A. PCR DSM-IV Results suggest that the four pN NA
al. (2007) (rs1800629), polymorphisms in the promoter 0.05
TNF-α(-T1031C) region of the TNF-α gene appear not
(rs1799964), to confer increased susceptibility for
TNF-α(-C8575T) sz in a Japanese population.
(rs1799724),
TNF-α(-G238A)
(rs361525)
Hänninen et al. TNF-α(-G308A) CGP, sz Peripheral blood PCR DSM-IV No association with sz. However, pb g = 0.38
(2005) (rs1800629) leukocytes TNF-α−G308A (G/G 0.05
homozygosity) in male subjects had
a modest association with sz.
Table 2 (continued)

Duan et al. TNF-α(−1031T/C) CGP, sz Peripheral blood PCR DSM-IV The five polymorphisms of TNF-α pN NA
(2004) (rs1799964), TNF-α gene do not contribute to the 0.05
(−863C/A) development of sz.
(rs1800630)
TNF-α(−857C/T)
(rs1799724),
TNF-α(−308G/A)
(rs1800629),
TNF-α(−238G/A)
(rs361525)
Shih-Jen et al. TNF-α(-G308A) CGP, sz, Lymphocytes PCR DSM-IV, This polymorphism does not play a pN NA
(2003) (rs1800629) clozapine BPRS major role in susceptibility to, 0.05
clinical manifestations for, or
clozapine response in sz.
Boin et al. TNF-α(-G308A) CGP, sz Venus blood PCR DSM-IV, This gene suggests that immune pb g = 0.66
(2001) (rs1800629) BPRS dysregulation in sz could also have a 0.01
genetic component.
Katila et al. Il-1Ra (rs419598), CGP, sz Venous blood PCR DSM-IV Alleles of the IL-1 gene complex pb NA
(1999) IL-1β (−511) (homozygotism) suggest that 0.05
(rs1516944), cytokine aberrations have
IL-1α(−889) correlation with sz, and are, in part,
(rs1800587) genetically determined.
Cytokines mRNAs
Chase et al. IL-6 Cytokine mRNA, Peripheral PBMC RT-PCR DSM-IV Peripheral PBMC IL-6 mRNA levels p= g = 1.18
(2016) peripheral discriminated the diagnosis of sz. 0.014
diagnostic Also found elevated levels of IL-6
marker mRNA with earlier ages of illness
onset and worse positive symptom
presentation measured with PANSS.
Pandey et al. IL-1, TNF-α, IL-6, Cytokine mRNA, Lymphocytes RT-PCR DSM-IV Abnormal gene expression of these pb gIL-6 =
(2015) IL-1R, IL-2R, TNFR1, sz PANSS cytokines and their receptors may 0.01 1.69
TNFR2, IL-6R, IL-1β be involved in sz pathogenesis. gTNFR1 =
0.74
gTNFR2 =
0.81
Ghazaryan et IL-2RG Cytokine mRNA, Peripheral blood RT-PCR DSM-IV Over-expression of the IL-2RG gene pb NA
al. (2014) over-expression may be implicated in the altered 0.0001
of the IL2RG gene immune response in sz.
Dean et al. TNFR1, TNFR2 Cytokine mRNA, Postmortem PCR, WB DSM-IV Levels of TNFR1 mRNA are increased pb gTNFR1 BA24
(2013) sz pathways tissue in sz patients. TNFR2 mRNA was 0.05 = 0.74
decreased in the Brodmann's area in gTNFR1 BA46
people with mood disorders. = 1.59
Fillman et al. IL-6, IL-8, IL-1β Cytokine mRNA, Peripheral blood RT-PCR DSM-IV Density of major histocompatibility pb gIL-1β =
(2013) dorsolateral and brain tissue complex-II-positive cells resembling 0.05 0.53
prefrontal cortex microglia was increased and
correlated with IL-1β expression.
Changes in an inflammatory
response pathway are present in
40% of people diagnosed with sz.
IL—interleukins; TNF—tumor necrosis factor; IFN—interferon; Sz—schizophrenia; NA—not applicable; CSF—cerebrospinal fluid; PBMC—peripheral blood mononuclear cells;
ELISA—enzyme-linked immunosorbent assay; EIAs—enzyme immunoassays; MRI—magnetic resonance imaging; PCR-RFLP—polymerase chain reaction-restriction fragment length poly-
morphism; PCR—polymerase chain reaction; RT-PCR—real time-polymerase chain reaction; PCR-SSP—single specific primer-polymerase chain reaction; WB—western blot;
PUFAs—polyunsaturated fatty acids; FEP—first episode psychosis; FES—first episode schizophrenia; CGP—Cytokine gene polymorphisms; ICD—international statistical classification of dis-
eases and related health problems; BHPR-Burney-Hamburg psychosis rating; BPRS—brief psychiatric rating scale; HRSS—Holmes and Rahe stress scale; PANSS—positive and negative syn-
drome scale; DSM—diagnostic and statistical manual of mental disorders; RBANS—repeatable battery for the assessment of neuropsychological status; WAIS—Wechsler adult intelligence
scale; BACS—brief assessment of cognition in schizophrenia; OPCRIT—operational criteria for psychotic illness; SAPS—scale for assessment of positive symptoms; SANS—scale for assess-
ment of negative symptoms; RAVLT—Rey auditory verbal learning test; T1—exacerbation phase; T2—remission; P1—patients treatment subgroup; P2—patients post-treatment subgroup;
ES—early stage; LS—late stage; GAF—general assessment of functioning; CDSS—Calgary depression scale for schizophrenia; CTQ—childhood trauma questionnaire; AIMS—involuntary
movement scale; YMRS—Young mania rating scale; CGI—clinical global impression; PLIKSi: psychosis-like symptom interview; M.I.N.I.—International neuropsychiatric interview;
BA—Brodmann's area.
a
Power values are Hedge's g effect size of the most significant markers of each study. Effect size was calculated following Cohen's guidelines (Cohen, 1988) for Hedge's g effects: small:
0.20; medium: 0.50; and large: 0.80.
analysis of the connection stress – immune system alterations – schizo- al., 2015; Hope et al., 2015; Turhan et al., 2016; Xiu et al., 2014).
phrenia phenotype. Moreover, a positive association between the RBANS total score
Diagnosis, cognitive and functional assessment scales are essen- with IL-18 serum levels was also established (Wu et al., 2016). Ab-
tial instruments to more accurately measure the patient's condition. normal levels of IL-2, IL-6, IL-8 and TNF-α in schizophrenia, were
Comparison between the scales scores used to evaluate psychotic positively correlated with cognitive performance (e.g. verbal fluen-
disorders such as schizophrenia and cytokines alterations, reveals cy, visual attention, working memory, etc.) (Misiak et al., 2017). Ev-
important correlations: for example, PANSS scores were correlated idence demonstrates that cytokines play a key role in cognitive
with altered levels of sTNF-αRII, IL-17, IL-10, IFN-γ, IL-2, IL-12p70, abilities, where neurogenesis, memory consolidation and synaptic
IL-6 polymorphism (rs1800795) and IL-6 mRNA (Chase et al., plasticity are compromised by cytokines dysregulation (Misiak et
2016; Debnath and Berk, 2014; Dimitrov et al., 2013; Frydecka et al., 2017).
immune activation (proinflammatory phenotype in later life)

(Baumeister et al., 2016; Mansur et al., 2012).
Interactions between genes and environment are crucial in the
etiopathogenesis of schizophrenia (Delgado-Morales et al., 2017). Ab-
normal cytokines gene expression of cytokines and their soluble recep-
tors have been described in schizophrenia (Pandey et al., 2015).
Furthermore, polymorphic variations in some cytokine genes and the
consequent immune system disturbances have also been related with
schizophrenia (Ghazaryan et al., 2014). Our findings reveal that TNF,
IL-6 and IL-1β are the most frequently studied polymorphisms and
mRNAs. The results expose that levels of mRNA expression of TNFR1
and TNFR2 are significantly higher in schizophrenia (Pandey et al.,
2015). Moreover, peripheral blood mononuclear cells (PBMC) IL-6
mRNA levels may be a diagnostic marker due to their high levels in pa-
tients with schizophrenia (Chase et al., 2016). Regarding gene polymor-
phisms, the IL-6 rs1800795 polymorphism is the most investigated and
is associated with positive symptoms, inflammatory processes in early
psychosis stages, and increased levels of IL-6 in blood in schizophrenia
(Frydecka et al., 2015; Stojanovic et al., 2014; Zakharyan et al., 2012).
5. Limitations
There are some limitations in the present review. Firstly, this review
restricted language, and only publications written in English were in-
cluded. Secondly, many studies were excluded based on the clinical sta-
tus or when cytokine data were not available. Thirdly, some studies
have not controlled possible confounding factors such as stress, antipsy-
chotic therapy, etc., that may influence cytokine levels.
Fig. 2. Synthesis of cytokines and cytokine receptors, gene polymorphisms and mRNA
associated with schizophrenia. Cytokines, receptors, gene polymorphisms and mRNAs 6. Conclusion
assessed in this review, which immune imbalances (increased or decreased) have been
studied in schizophrenia patients.
In summary, our review based on data systematization suggests a
psychoneuroimmune relationship, strongly evidenced by the role of in-
Antipsychotic therapy is imperative in the treatment of psychotic
flammatory activity of cytokines in schizophrenia aetiology. Highlight-
episodes and schizophrenia. However, phenotypic traits relating with
ing these findings, abnormal immune responses have been implicated
pharmacological response such as responders, delayed-responders or
in the pathophysiology of schizophrenia: increasing levels of IL-6,
resistant patients are endophenotypes associated with cytokine profile
TNF-α, INF-γ, IL-2, IL-8, IL-1RA, IL-1β, IL-18, IL-10; gene polymorphisms
aberrations. Elevated levels of IL-6 were linked to the psychopathology
(TNF-α rs1800629, IL-6 rs1800795, IL-1β rs16944); and high expres-
in delayed-responders endophenotype (Garver et al., 2003). Likewise,
sion levels of IL-6, TNFR1, TNFR2 and IL-1β mRNAs. The findings suggest
treatment-resistance was linked to elevate levels of sTNFR1, IL-6 and
that they are the major responsible of the inflammatory activity in this
IL-6R (Lin et al., 1998; Noto et al., 2013). On the other hand, pharmaco-
psychotic disorder. However, the diversity of studies, which focus on
logical treatment (e.g. risperidone, clozapine, etc.) promotes changes in
the unbalanced immune activity in schizophrenia (studies based on
the proinflammatory cytokines levels such IL-1β, IL-6, TNF-α and sIL-2R
proinflammatory cytokine levels, genetic, image, therapeutic, etc.), dis-
(Igue et al., 2011; Maes et al., 1994; Song et al., 2014). Specifically, the
perses the results, being difficult to make comparisons and obtain con-
increase of sIL-2R levels in plasma/serum of patients with schizophrenia
clusive data without discrepancies.
has been associated to the treatment with clozapine, risperidone,
Furthermore, the control of confounding factors is not standardized,
olanzapine or quetiapine (Igue et al., 2011; Kluge et al., 2009). In first
whose impact may change the cytokine profiles and the immune re-
episode drug-naïve patients, levels of cytokines such as IL-1β, IL-6, IL-
sponses. Future studies should follow a well-defined rational design, a
6 polymorphism, TNF-α, IL-12, IL-23 and IFN-γ has been found elevated,
sample size adequate and homogeneous, a coherent methodology (cor-
and may be considered as state markers (Borovcanin et al., 2015;
rect access, analysis and processing of the samples; regular follow-up;
Kubistova et al., 2012; Miller et al., 2011; Petrikis et al., 2015;
and confounding factors controlled), and a consensual data
Stojanovic et al., 2014). However, evidence suggests that IL-6, IL-1β
interpretation.
and IFN-γ levels decrease when starting the treatment with antipsy-
Finally, extrapolation of results as regards brain functionality may
chotic drugs (Cazzullo et al., 2002; Miller et al., 2011; Perkovic et al.,
constitute a wrong approach of outcomes, and will always be the
2017). In addition, the levels of TNF-α, IL-12, sIL-2R and IL-23 remain al-
major limitation. These considerations demonstrate that there is a
tered after treatment, being possible to use them as trait markers
psychoimmune relationship, although, more research is required to
(Perkovic et al., 2017).
clarify exactly the role of cytokines and inflammation in schizophrenia.
Childhood traumatic experiences suggest a high risk of developing
Supplementary data to this article can be found online at https://doi.
mental disorders such as psychotic symptoms and schizophrenia in
org/10.1016/j.schres.2017.11.023.
adulthood (Baumeister et al., 2016; Dennison et al., 2012). Increased
levels of TNF-α, IL-6 and IL-8 in serum or plasma are correlated with
Conflict of interest
schizophrenia in patients with history of childhood trauma (Dennison The authors declare that they have no competing interest.
et al., 2012; Di Nicola et al., 2013). Specifically, the biological mecha-
nisms by which traumatic circumstances in early-life promote a proin- Contributors
flammatory state are relatively unknown. However, epigenetic DRA, TRB and RAB screened the titles and abstracts. DRA and RAB conducted the ap-
changes caused by childhood trauma may play a crucial role in the praisal and their ratification and literature search and analysis and interpretation of
data. CS, HJC, AGF and JMO made substantial contributions to conception and design of the Das, S., Deuri, S.K., Sarmah, A., Pathak, K., Baruah, A., Sengupta, S., Mehta, S., Avinash, P.R.,
study. All authors read and approved the final version of the manuscript. Kalita, K.N., Hazarika, J., 2016. Aggression as an independent entity even in
psychosis—the role of inflammatory cytokines. J. Neuroimmunol. 292:45–51.
https://doi.org/10.1016/j.jneuroim.2016.01.012.
De Witte, L., Tomasik, J., Schwarz, E., Guest, P.C., Rahmoune, H., Kahn, R.S., Bahn, S., 2014. Cy-
Funding
tokine alterations in first-episode schizophrenia patients before and after antipsychotic
This work was supported by a Ramón & Cajal grant (RYC-2014-15246) and by Galicia
treatment. Schizophr. Res. 154:23–29. https://doi.org/10.1016/j.schres.2014.02.005.
Innovation Agency - GAIN grant (IN607D-2016/003) to RCAB. CS was partially supported Dean, B., Gibbons, A.S., Tawadros, N., Brooks, L., Everall, I.P., Scarr, E., 2013. Different
by Fundación Tatiana Pérez de Guzman el Bueno. The work was furthermore supported by changes in cortical tumor necrosis factor-α-related pathways in schizophrenia and
ISCIII P16/00405 and cofounded by FEDER to JMO. mood disorders. Mol. Psychiatry 18:767–773. https://doi.org/10.1038/mp.2012.95.
Debnath, M., Berk, M., 2014. Th17 pathway-mediated immunopathogenesis of schizo-
phrenia: mechanisms and implications. Schizophr. Bull. 40:1412–1421. https://
Acknowledgments doi.org/10.1093/schbul/sbu049.
The authors thank Galicia Sur Health Research Institute (IISGS), Methodology and Sta- Debnath, M., Mitra, B., Bera, N.K., Chaudhuri, T.K., Zhang, Y. Ping, 2013. Lack of association
tistics Unit of IISGS and University Hospital Complex of Vigo (CHUVI) for the support. The of IL-6 (−174 G N C) and TNF-α (−238 G N A) variants with paranoid schizophrenia
authors are especially grateful to psychiatrists and nurses of Mental Health Services of the in Indian Bengalee population. Cytokine 61:455–458. https://doi.org/10.1016/
University Hospital Complex of Vigo. j.cyto.2012.10.028.
Delgado-Morales, R., Agís-Balboa, R.C., Esteller, M., Berdasco, M., 2017. Epigenetic mecha-
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Contents lists available at ScienceDirect

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Cytokines dysregulation in schizophrenia: A systematic review of

1. Introduction pathophysiology of schizophrenia could be associated with cytokine ab-

Cytokines Characteristics No of %⁎⁎

Cytokines (inﬂammatory activity)

Cytokine gene polymorphisms

References Cytokines Outcomes Samples Laboratorial Diagnosis Findings p or q Effect sizea

Cytokines (inﬂammatory activity)

(continued on next page)

References Cytokines Outcomes Samples Laboratorial Diagnosis Findings p or q Effect sizea

References Cytokines Outcomes Samples Laboratorial Diagnosis Findings p or q Effect sizea

(continued on next page)

References Cytokines Outcomes Samples Laboratorial Diagnosis Findings p or q Effect sizea

References Cytokines Outcomes Samples Laboratorial Diagnosis Findings p or q Effect sizea

Cytokine gene polymorphisms

(continued on next page)

References Cytokines Outcomes Samples Laboratorial Diagnosis Findings p or q Effect sizea

References Cytokines Outcomes Samples Laboratorial Diagnosis Findings p or q Effect sizea

immune activation (proinﬂammatory phenotype in later life)

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