REVIEW

published: 18 March 2020

doi: 10.3389/fpsyt.2020.00160

The Role of Inflammation in the

Treatment of Schizophrenia
Guillaume Fond*, Christophe Lançon, Theo Korchia, Pascal Auquier and Laurent Boyer
Hôpitaux Universitaires de Marseille (HUM), Aix-Marseille University, School of Medicine - La Timone Medical Campus, EA
3279: CEReSS - Health Service Research and Quality of Life Center, Marseille, France

Background: Inflammation plays a major role in the onset and maintenance of

schizophrenia. The objective of the present work was to synthetize in a narrative review
the recent findings in the field of inflammation in schizophrenia and their application in
daily practice.
Method: This review was based on the most recent meta-analyses and randomized
controlled trials.
Results: The disturbed cytokines depend on the phase of the illness. A meta-analysis of
cytokines in schizophrenia found higher levels of pro-inflammatory and anti-inflammatory
cytokines in the peripheral blood in both patients with first-episode schizophrenia
and relapsed patients than in healthy controls. Exploring detailed data on
immune-inflammatory disturbances in SZ reveals that IL-6 is one of the most
consistently disturbed cytokines. Other cytokines, including IL1, TNF, and IFN, are
Edited by:
also disturbed in schizophrenia. Choosing a broad spectrum anti-inflammatory agent
Ole Köhler-Forsberg,
Aarhus University, Denmark that may inhibit subsequent pathways might be particularly useful for the treatment of
Reviewed by: inflammatory schizophrenia. Highly sensitive C-Reactive Protein is a useful screening
Romain Rey, marker for detecting inflammation in SZ subjects. Anti-inflammatory agents have
Centre Hospitalier Le Vinatier, France
Jasmina Mallet, shown effectiveness in recently published meta-analyses. Only one study found a
Assistance Publique Hopitaux De significant difference between celecoxib and placebo, but two found a trend toward
Paris, France
significance on illness severity and one on positive symptoms. In addition, other
*Correspondence:
published and unpublished data were included in another meta-analysis that concluded
Guillaume Fond
[email protected] the significant effect of add-on celecoxib in positive symptoms in first episode patients.
There is a lack of data to determine if aspirin is truly effective in schizophrenia to date.
Specialty section:
Other anti-inflammatory agents have been explored, including hormonal therapies,
This article was submitted to
Schizophrenia, antioxidants, omega 3 fatty acids, and minocycline, showing significant effects for
a section of the journal reducing total, positive, and negative score symptoms and general functioning.
Frontiers in Psychiatry
However, each of these agents has multiple properties beyond inflammation and it
Received: 07 December 2019
Accepted: 20 February 2020
remains unclear how these drugs improve schizophrenia.
Published: 18 March 2020 Conclusion: The next step is to tailor anti-inflammatory therapy in schizophrenia,
Citation: with two main challenges: 1. To provide a more efficient anti-inflammatory therapeutic
Fond G, Lançon C, Korchia T,
Auquier P and Boyer L (2020) The approach that targets specific pathways associated with the pathology of schizophrenia.
Role of Inflammation in the Treatment 2. To develop a more personalized approach in targeting patients who have the best
of Schizophrenia.
chance of successful treatment.
Front. Psychiatry 11:160.
doi: 10.3389/fpsyt.2020.00160 Keywords: inflammation, schizophrenia, treatment, anti-inflammatory, cytokines

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Fond et al. Inflammation and Schizophrenia

INTRODUCTION The Role of Inflammation in the

Pathogenesis and Maintenance of
Though conventional treatments have improved schizophrenia
prognosis, they and the response rate of antipsychotics in Schizophrenia
schizophrenia remain unsatisfactory. The antipsychotics The pathophysiological underpinnings of inflammation and its
introduced in the 1950s have shown moderate global potential role in schizophrenia onset and maintenance have been
effectiveness with a mean effect size of 0.38 (1). The response previously synthetized (3). Schizophrenia is characterized by risk
rate of clozapine—the most effective antipsychotic—is genes that promote inflammation, and by environmental stress
only 33% after 3 months of treatment (1). Antipsychotics factors and alterations of the immune system. Neuromediator
are effective on positive symptoms but unsatisfactory on alterations classically described in schizophrenia (dopamine,
negative/depressive symptoms, social functioning, and quality of serotonine, glutamate) have also been identified in low-level
life (1). neuro inflammation and may be key triggers of schizophrenia
An explanation for this high rate of non-response and symptoms onset and maintenance (4). The contribution of
relapses relies on the observation that current pharmacological chronic inflammation to major mental disorders has received
treatments are primarily based on the monoaminergic increased attention, revealing a host of pharmacologic targets.
hypothesis, without involving the personalized medicine Indeed, multiple recent reviews clearly demonstrate that
approach. According to this hypothesis, schizophrenia schizophrenia is associated with a dysregulation of immune
is principally due to a dopamine dysfunction in the responses, as reflected by the observed abnormal profiles of
brain (with an excess in the striatum ventral tegmental circulating pro- and anti-inflammatory cytokines in affected
area and a deficit in the prefrontal cortex). All current patients (5). Impaired central nervous system volume and
antipsychotics target dopamine deficits in the brain. microglial activations in schizophrenia have been confirmed in
Yet clozapine, the antipsychotic that has shown the best neuroimaging studies (4).
effectiveness, has also one of the lowest potentials to reduce Among potential sources of chronic low-grade inflammation,
dopamine in the brain (2). This paradox remains unsolved infectious agents and environmental toxins (including tobacco
to date. smoke and cannabis) have been identified (6–11). It may also
The high rate of therapeutic failure in psychiatry can be a secondary reaction to trauma-related neuronal lesions or a
most likely be accounted for by the limitations pertaining to genetic effect (4).
brain-orientated treatments. Current treatments do improve Microglia constitute between 10 and 20% of all cells in the
neurotransmitter deficits, but without addressing the source of CNS and are the most important component of the local CNS
these deficits. This may explain the high relapsing rates and immune system (12). Microglia is activated in case of injury
chronic illness causes. or disease such as systemic infection, and is involved in the
The objective of the present review was to synthetize the activation of cytokines, the key mediators of inflammation.
state of knowledge of the role of inflammation in the treatment A variety of low-level stimuli including aging,
of schizophrenia. neurodegeneration and stress can also cause microglia to
be “sensitized” or “primed,” a process that elicits an exaggerated
immune response (4). Once microglia are primed, an additional
low-level stimulus, e.g., minor systemic inflammation, may
MATERIALS AND METHODS exacerbate or re-exacerbate an immune response in the CNS
with behavioral consequences (13).
This review was based on the most recent meta-analyses
and randomized controlled trials, and if these were not
available, on preliminary data. The Medline R database Inflammatory Markers in Schizophrenia
was explored from its inception to September 10th 2019, Fibrin is a protein that is increased in inflammatory processes.
without language restriction. The research paradigm was: Degradation products of fibrin have been found in postmortem
(schizophrenia) AND (inflammation OR anti-inflammatory brains of schizophrenia patients and in the cerebrospinal fluid
agents OR cytokines OR C reactive-protein). The references (CSF) of about 50% of them (14). The density of microglia
of each article were also checked. Given the broad spectrum is significantly increased in schizophrenia [mostly in the
of the subject, the systematic review design was not adapted temporal cortex (14)] yet with substantial heterogeneity between
to the present work and a narrative review form has been studies. Astrocytes and oligodendrocytes’ densities did not differ
preferred. Thus, no flow-chart or study quality assessment has significantly between schizophrenia and healthy controls. The
been provided. results of postmortem histology are paralleled with an overall
increase in expression of proinflammatory genes in SZ patients,
while anti-inflammatory gene expression levels were not different
RESULTS between SZ patients and controls. These results strengthen the
hypothesis that immune system disturbances are involved in the
Two thousand two hundred seventy-eight articles were identified pathogenesis of schizophrenia.
in the Medline search. Of them, 41 were included in the A meta-analysis of cytokines in schizophrenia found higher
present review. levels of proinflammatory cytokines in the peripheral blood

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Fond et al. Inflammation and Schizophrenia

in both patients with first-episode schizophrenia and relapsed included in another meta-analysis that concluded the significant
patients than in healthy controls, but it also found higher levels effect of add-on celecoxib in SZ in PANSS total and PANSS
of some anti-inflammatory cytokines in these patients than in positive scores in first episode SZ patients (25).
controls (15). The disturbed cytokines depend on the phase of COX-1 inhibitor (low-dose aspirin) has been studied in two
the illness. RCTs, with positive results on all PANSS scores in one study
In first-episode psychosis, interferon-γ (IFN-γ), IL-1RA, IL- (26), and a positive but small effect on PANSS total- and positive
1β, IL-6, IL-8, IL-10, IL-12, sIL-2R, TGF-β, and TNF were score in the other (27). Aspirin is to date the anti-inflammatory
all significantly increased, and levels of IL-4 were significantly agent that has shown the greatest potential for effectiveness in
decreased. Age, sex, illness duration, smoking, and BMI were all schizophrenia (20). This effect was driven by a high-baseline
unrelated to IL-6 and TNF-α increase in first-episode psychosis. PANSS score subgroup. Yet the methodology of these trials has
In acute exacerbation of chronic SZ, an increase of IFN-γ, IL- been questioned, especially due to the differences in antipsychotic
1RA, IL-1β, IL-6, IL-8, IL-12, sIL-2R, TGF-β, and TNF alongside treatments in each groups and the statistically significant but
a decrease of IL-4 and IL-10 levels were found in SZ compared clinically non-significant effect reported in these trials (28). In
to controls. summary, there is a lack of data to determine if aspirin is truly
In chronically ill SZ, IL-6, TNF, sIL-2R, IL-1β were increased effective in SZ to date. Moreover, aspirin is at increased risk of
and IFN-γ was decreased in SZ patients compared to controls, ulcer and hemorrhagic side effects, limiting its prescription.
with no significant difference in the levels of IL-2, IL-4, or IL-10. Other anti-inflammatory agents have been explored, yet with
Age, sex, illness duration, smoking, and BMI were all unrelated a broad spectrum of other properties. These agents included
to the association between IL-6 and SZ. Of note, a meta-analysis hormonal therapies, antioxidants, omega 3 fatty acids, and
of cytokines in the CSF of SZ showed increased levels of IL-6 and minocycline, an antibiotic that penetrates the brain. Overall, anti-
IL-8 (16). inflammatory agents (mostly celecoxib, aspirin, minocycline)
Inflammation has been bilaterally associated with cortisol have shown significant effects for reducing total, (effect size
disturbances (17). Cortisol disturbances have shown associations = 0.41, 95% confidence interval (CI) = [0.26, 0.56]), positive
with treatment non-response in schizophrenia and major (effect size = 0.31, 95% CI = [0.14, 0.48]), and negative
depression, which is frequent in SZ patients (18). (effect size = 0.38, 95% CI = [0.23, 0.52]) scores in the
In summary, IL-6 is the most consistent increased cytokine PANSS. General functioning was also significantly enhanced
in all phases of schizophrenia, but a large bundle of other by overall anti-inflammatory agents. However, each of these
cytokines is found to be disturbed. These findings suggest that agents has multiple properties beyond inflammation (e.g.,
choosing a broad-spectrum anti-inflammatory agent that may hormonal for estrogens/pregnelonone, antibiotic/glutamatergic
inhibit subsequent pathways may be particularly useful for the for minocycline, antioxidant for N-acetyl-cysteine) and it
treatment of inflammatory schizophrenia. remains unclear how these drugs improve schizophrenia.

Anti-inflammatory Therapies Tested So Far DISCUSSION/PERSPECTIVES

in Schizophrenia Schizophrenia Patients With Chronic
A detailed overview of the efficacy of anti-inflammatory
treatment in schizophrenia was published in 2014 and provides
Low-Grade Peripheral Inflammation: The
one of the most convincing pieces of evidence that inflammation Best Candidates for Anti-inflammatory
is involved in schizophrenia (19). This work has been recently Treatment
updated (20). Sixty-two double-blind randomized clinical trials To improve anti-inflammatory drug effectiveness, it is necessary
including 2,914 SZ patients were included in the latter. to identify best candidate SZ patients using inflammatory
The cyclooxygenase (COX) inhibitors were the first anti- markers. This is contrary to previous studies, which only included
inflammatory agents to be tested in schizophrenia in the early SZ patients using clinical criteria [for review see (21)]. This
2000’s. The prostaglandin inflammatory cascade is activated by has led to high heterogeneity in previous meta-analyses (25).
two COX enzymes named COX-1 and COX-2. The COX 1 is a We have seen that defining an inflammation signature in
permanent/state COX responsible for the baseline inflammatory schizophrenia was difficult due to the multiple cytokines that
response (e.g., reacting to a wound). The COX-2 is activated may be disturbed according to the state of the illness. We
only in case of acute inflammation (in case of infection for have recently published a review on the interest of hs-CRP
example) (21). to identify peripheral inflammation in schizophrenia (29). Hs-
That’s why celecoxib, a specific COX-2 inhibitor, has been the CRP is the most common peripheral marker of inflammation
first and most studied COX-targeted anti-inflammatory agent in and is synthesized by the liver in response to IL-1 and IL-6
schizophrenia. Four RCTs investigated the effects of celecoxib in according to the following pathway. It has been reliably used
195 patients (22–24) with inconsistent findings. Only one study in multiple randomized controlled trials for exploring the role
found a significant difference between celecoxib and placebo (24), of inflammation in treatment response (30–34). Recent data
but two found a trend toward significance on PANSS total score indicate that blood CRP concentrations have been associated
(p = 0.06 for both) and one on PANSS positive score (p = 0.05) with high central glutamate, which correlated with symptoms of
(22). In addition, other published and unpublished data were anhedonia, one of the symptoms of schizophrenia (35).

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Fond et al. Inflammation and Schizophrenia

In stabilized SZ patients, around one third exhibit high LIMITS

CRP levels (>3 mg/L) (36). These patients were found to have
more resistance to conventional treatments and more cognitive This review has shown one major limit in the field of
impairment, which confirms the clinical interest of targeting this inflammation in schizophrenia, i.e., the definition of a consensual
specific subgroup of patients (36, 37). inflammatory signature to determine which patients may benefit
The blood–brain barrier protects the brain from from anti-inflammatory strategies. While TSPO-PET imaging
peripheral inflammation, and the cytokines state in the appears as the gold standard to explore neuro-inflammation
blood does not reflect the situation in the brain. Yet to date (42), its costs and its dissemination (limited by MRI
different pathways exist between the peripheral and the availability and genotyping) prevents it from being widely
CNS immune systems. Hs-CRP appears to be a good reflector distributed. Hs-CRP appears as a potentially good biomarker, but
of central inflammation in non-SZ populations (35). It seems further studies should confirm if peripheral CRP is a good marker
also well-suited for guiding immunotherapies targeting of central neuro-inflammation in schizophrenia, as suggested in
IL-6 (35). one study in depression (35).
In summary, hs-CRP is a useful screening marker for detecting
inflammation in SZ subjects. CONCLUSION
Janus-Kinase Inhibitors (JAKinibs): A The next step is to tailor anti-inflammatory therapy with the
Promising Treatment for Inflammatory best response and highest safety in schizophrenia. There are two
Schizophrenia main challenges:
We have seen that schizophrenia was associated with a - to provide a more efficient anti-inflammatory therapeutic
broad range of disturbed cytokines. These cytokines bind to approach that targets specific pathways associated with the
receptors that activate downstream the so-called JAK/STAT pathology of schizophrenia. Exploring detailed data on
signaling pathway (38) involved in gliogenesis, synaptic plasticity, immune-inflammatory disturbances in schizophrenia reveals
microglia activation and neurogenesis, all implicated in the that IL-6 is one of the most consistently disturbed cytokines
pathophysiology of schizophrenia (39). Moreover, depressive in SZ. Other cytokines including IL1, TNF, and IFN are also
symptoms are frequent in schizophrenia and the antidepressant disturbed in schizophrenia.
actions of current treatments have been confirmed to be - to develop a more personalized approach in targeting patients
mediated by JAK/STAT-dependent mechanisms (40). Small- who have the best chance of successful treatment. We
molecule inhibitors of JAKs (jakinibs) have been shown as hypothesize that SZ patients with chronic low-grade peripheral
safe and efficacious options for the treatment of rheumatoid inflammation (SZ-CPI) defined by hs-CRP blood level ≥3
arthritis, psoriasis, and inflammatory bowel disease (41), and mg/L (a reliable marker used in previous works) make the best
may be promising treatments for schizophrenia that should candidates for anti-inflammatory treatments.
be evaluated.
AUTHOR CONTRIBUTIONS
To Destroy the Root Cause of the Evil:
Addressing the Sources of Inflammation GF and LB wrote the first draft of this work. All authors reviewed
Adding an anti-inflammatory agent may be not sufficient and validated the final version of the manuscript.
if the potential sources of inflammation are not addressed.
Among them, tobacco smoking, Toxoplasma latent infection, FUNDING
microbiota disturbances, lack of physical activity, and poor
diet have been identified as major modifiable sources of This work was funded by Assistance Publique- Hôpitaux
inflammation in SZ patients that should be addressed in de Marseille.
schizophrenia daily care (7–10). Tobacco smoking cessation,
Mediterranean or anti-inflammatory diets, and physical activity ACKNOWLEDGMENTS
appear as promising interventions to be tested in inflammatory
SZ patients, yet further studies are needed to determine We express all our thanks to the patients who have participated
their effectiveness. in the studies presented in this article.

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signaling pathway in N-acetylcysteine-mediated antidepressant-like effects. Conflict of Interest: The authors declare that the research was conducted in the
Exp Biol Med Maywood NJ. (2016) 241:509–18. doi: 10.1177/1535370215 absence of any commercial or financial relationships that could be construed as a
619707 potential conflict of interest.
41. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ.
JAK inhibition as a therapeutic strategy for immune and inflammatory Copyright © 2020 Fond, Lançon, Korchia, Auquier and Boyer. This is an open-access
diseases. Nat Rev Drug Discov. (2017) 16:843–62. doi: 10.1038/nrd. article distributed under the terms of the Creative Commons Attribution License (CC
2017.201 BY). The use, distribution or reproduction in other forums is permitted, provided
42. Yoder KK, Nho K, Risacher SL, Kim S, Shen L, Saykin AJ. Influence the original author(s) and the copyright owner(s) are credited and that the original
of TSPO genotype on 11C-PBR28 standardized uptake values. J Nucl publication in this journal is cited, in accordance with accepted academic practice.
Med Off Publ Soc Nucl Med. (2013) 54:1320–2. doi: 10.2967/jnumed.112. No use, distribution or reproduction is permitted which does not comply with these
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Frontiers in Psychiatry | www.frontiersin.org 6 March 2020 | Volume 11 | Article 160