Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

JOURNAL OF
NEUROINFLAMMATIONREVIEW

Open Access

Neuroinflammation and psychiatric illness
Souhel Najjar1,5*, Daniel M Pearlman2,5, Kenneth Alper4, Amanda Najjar3 and Orrin Devinsky1,4,5Abstract
Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic
autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune
encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric
symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classicalpsychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders).
Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergicand monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive.
We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental
evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders.
Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal
pathogenic clues and help target new preventive and symptomatic therapies.
Keywords: Neuroinflammation, Psychoneuroimmunology, Astrocyte, Microglia, Cytokines, Oxidative stress,
Depression, Obsessive-compulsive disorder, Bipolar disorder, Schizophrenia

Review
Introduction

As biological abnormalities are increasingly identified
among patients with psychiatric disorders, the distinction between neurological and psychiatric illness fades.
In addition to systemic autoimmune diseases associated with psychiatric manifestations (for example,
lupus) [1], more recently, patients with acute isolated
psychosis were identified with synaptic autoimmune
encephalitides (Table 1) [2-6]. These patients are often
erroneously diagnosed with refractory primary psychotic disorders, delaying initiation of effective immune
therapy (Table 1). Additionally, growing evidence supports the pathogenic role of anti-neuronal antibodies
in neuropsychiatric disorders [7].
Separation of neurological and psychiatric disorders,
supported by Descartes’s conception of the ‘mind’ as an
ontologically distinct entity and by the reproducibility ofneuropathological abnormalities, dominated medicine in* Correspondence: mna1024231@aol.com
1
Department of Neurology, New York University School of Medicine, 550
First Avenue, New York, NY 10016, USA
5
New York University Comprehensive Epilepsy Center, 550 First Avenue, New
York, NY 10016, USA
Full list of author information is available at the end of the article

the 19th and early 20th centuries [8]. Since then, an
expanding collection of reproducible biological causes,from neurosyphilis, head trauma, stroke, tumor, demyelination and many others caused symptom complexes thatoverlapped with classic psychiatric disorders [9-11]. Morerecently, neuroinflammatory and immunological abnormalities have been documented in patients with classicalpsychiatric disorders.
Peripheral immune modulators can induce psychiatric
symptoms in animal models and humans [12-19]. Healthy
animals injected with pro-inflammatory IL-1β and tumor
necrosis factor alpha (TNF-α) cytokines demonstrate ‘sickness behavior’ associated with social withdrawal [12]. In
humans, injections of low-dose endotoxin deactivate theventral striatum, a region critical for reward processing,producing anhedonia a debilitating depressive symptom[14]. Approximately 45% of non-depressed hepatitis C andcancer patients treated with IFN-α develop depressive
symptoms associated with increased serum IL-6 levels[12,15,17,18].
Medical conditions associated with chronic inflammatory and immunological abnormalities, including obesity, diabetes, malignancies, rheumatoid arthritis, andmultiple sclerosis, are risk factors for depression
and bipolar disorder [10,12,13,15,17,18]. The positive© 2013 Najjar et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

correlation between these medical conditions and psychiatric illness suggests the presence of a widespread
underlying inflammatory process affecting the brain
among other organs [10,19,20]. A 30-year populationbased study showed that having an autoimmune
disease or a prior hospitalization for serious infection
increased the risk of developing schizophrenia by 29%
and 60%, respectively [16]. Further, herpes simplex
virus, Toxoplasma gondii, cytomegalovirus, and influenza during pregnancy increase the risk of developing
schizophrenia [16].
Peripheral cellular [21,22] (Table 2), and humoral immunological abnormalities [13,21-23] are more prevalentin psychiatric patients relative to healthy controls. In bothpilot (n = 34 patients with major depressive disorder(MDD), n = 43 healthy controls) and replication studies(n = 36 MDD, n = 43 healthy controls), a serum assay
comprising nine serum biomarkers distinguished MDD
subjects from healthy controls with 91.7% sensitivity
and 81.3% specificity; significantly elevated biomarkers
for neuropsychiatric symptoms were the immunologicalmolecules alpha 1 antitrypsin, myeloperoxidase, and soluble TNF-α receptor II [23].
We first review the association between autoimmunityand neuropsychiatric disorders, including: 1) systemic
lupus erythematosus (SLE) as a prototype of systemic autoimmune disease; 2) autoimmune encephalitides associatedwith serum anti-synaptic and glutamic acid decarboxylase(GAD) autoantibodies; and 3) pediatric neuropsychiatricautoimmune disorders associated with streptococcal
infections (PANDAS) and pure obsessive-compulsive disorder (OCD) associated with anti-basal ganglia/thalamic
autoantibodies. We then discuss the role of innate inflammation/autoimmunity in classical psychiatric disorders, including MDD, bipolar disorder (BPD), schizophrenia,
and OCD.

Neuropsychiatric disorders associated with autoimmunity
Systemic lupus erythematosus

Between 25% to 75% of SLE patients have central nervous
system (CNS) involvement, with psychiatric symptoms
typically occurring within the first two years of disease onset. Psychiatric symptoms may include anxiety, mood andpsychotic disturbances [97]. Brain magnetic resonanceimaging (MRI) is normal in approximately 42% of neuropsychiatric SLE cases [97]. Microangiopathy and blood–
brain barrier (BBB) breakdown may permit entry of
autoantibodies into the brain [97]. These antibodies include anti-ribosomal P (positive in 90% of psychotic SLE
patients) [1], anti-endothelial cell, anti-ganglioside, antidsDNA, anti-2A/2B subunits of N-methyl-D-aspartate receptors (NMDAR) and anti-phospholipid antibodies [97].
Pro-inflammatory cytokines—principally IL-6 [97], S100B

Page 2 of 24[97], intra-cellular adhesion molecule 1 [97] and matrixmetalloproteinase-9 [98] are also elevated in SLE. Psychiatric manifestations of SLE, Sjögren’s disease, Susac’s
syndrome, CNS vasculitis, CNS Whipple’s disease, andBehçet’s disease were recently reviewed [1].

Neuropsychiatric autoimmune encephalitides associatedwith serum anti-synaptic and glutamic acid decarboxylase
autoantibodies

Autoimmune encephalitides are characterized by an acuteonset of temporal lobe seizures, psychiatric features, andcognitive deficits [2,3,99-108]. The pathophysiology
is typically mediated by autoantibodies targeting synaptic
or intracellular autoantigens in association with a paraneo
plastic or nonparaneoplastic origin [3]. Anti-synaptic
autoantibodies target NR1 subunits of the NMDAR[100,108,109], voltage-gated potassium channel (VGKC)
complexes (Kv1 subunit, leucine-rich glioma inactivated(LGI1) and contactin associated protein 2 (CASPR2))[101,102,106], GluR1 and GluR2 subunits of the amino-3hydroxy-5-methyl-l-4-isoxazolepropionic acid receptor(AMPAR) [6,110,111] and B1 subunits of the γ-aminobutyric acid B receptors (GABABR) [3,99,103]. Anti-intracellular autoantibodies target onconeuronal and GAD-65
autoantigens [2,3].
The inflammation associated with anti-synaptic autoantibodies, particularly NMDAR-autoantibodies, is typicallymuch milder than that associated with GAD-autoantibodies
or anti-neuronal autoantibodies related to systemic autoimmune disorders or paraneoplastic syndromes [2,107].
Although neurological symptoms eventually emerge,
psychiatric manifestations, ranging from anxiety [2,3]to psychosis mimicking schizophrenia [2-6], can initiallydominate or precede neurological features. Up to twothirds of patients with anti-NMDAR autoimmune encephalitis, initially present to psychiatric services [5].
Anti-synaptic antibodies-mediated autoimmune encephalitides must be considered in the differential of acute
psychosis [2-6]. Psychiatric presentations can include
normal brain MRI and cerebrospinal fluid (CSF) analysis, without encephalopathy or seizures [2,3,5,6,107].
We reported a case of seropositive GAD autoantibodies
associated with biopsy-proven neuroinflammation, despite normal brain MRI and CSF analyses, where the patient presented with isolated psychosis diagnosed as
schizophrenia by Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition (DSM-IV) criteria [2].
Further, seronegative autoimmune encephalitides canalso present with prominent neuropsychiatric disturbances, making diagnosis more elusive [107,112,113].
Psychiatric and neurological features associated with antisynaptic and GAD autoantibodies are summarized inTable 1 [1-6,99-108,114].

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Serum anti-synaptic and GAD autoantibodies may
occur in patients with pure psychiatric disorders[2,4,5,112,115-121]. In a prospective cohort of 29 subjects who met the DSM-IV criteria for schizophrenia,
serum anti-NMDAR autoantibodies were found in
three subjects, and anti-VGKC-complex autoantibodies
were found in one subject [5]. Using more sensitivetechniques to detect immunoglobulin G (IgG) NR1 autoantibodies in 100 patients with definite schizophrenia, noautoantibodies were identified [122]. However, this study
did not assess autoantibodies targeting the NR2 subunit of
NMDAR. Other studies reported significantly increased
odds of elevated (≥90th percentile non-psychiatric control
levels) NR2 antibody levels (odds ratio (OR) 2.78, 95%
confidence interval (CI) 1.26 to 6.14, P = 0.012) among individuals with acute mania (n = 43), but not in chronic
mania or schizophrenia [116].

PANDAS and pure obsessive-compulsive disorder associatedwith anti-basal ganglia/thalamic autoantibodies

OCD often complicates neurological disorders involving the basal ganglia including Sydenham’s chorea,
Huntington’s disease and Parkinson’s disease. Antibasal ganglia antibodies are implicated in Sydenham’schorea [123]. PANDAS is characterized by acute exacerbations of OCD symptoms and/or motor/phonic tics
following a prodromal group A β-hemolytic streptococcal infection. The pathophysiology is thought
to involve cross-reactivity between anti-streptococcal
antibodies and basal ganglia proteins [124]. The clinical overlap between the PANDAS and pure OCD suggests a common etiological mechanism [125].
Among a random cohort of 21 pure OCD patients, 91.3%
had CSF anti-basal ganglia (P <0.05) and anti-thalamic
autoantibodies (P <0.005) at 43 kDa [88], paralleling functional abnormalities in the cortico-striatal-thalamo-cortico
circuitry of OCD subjects [84]. Another study documented
that 42% (n = 21) of OCD pediatric and adolescent subjects
had serum anti-basal ganglia autoantibodies at 40, 45, and60 kDa compared to 2% to 10% of controls (P = 0.001) [7].
Anti–basal ganglia autoantibodies were detected in the seraof 64% of PANDAS subjects (n = 14), compared to only 9%(n = 2) of streptococcal-positive/OCD-negative controls(P <0.001) [126]. One study found no difference between
the prevalence of anti-basal ganglia autoantibodies in OCD(5.4%, n = 4) versus MDD controls (0%) [127]; however, alimitation was the random use of rat cortex and bovine
basal ganglia and cortex that might have limited the identification of seropositive cases.
The basal ganglia autoantigens are aldolase C (40 kDa),
neuronal-specific/non-neuronal enolase (45 kDa doublet)and pyruvate kinase M1 (60 kDa)—neuronal glycolytic
enzymes—involved in neurotransmission, neuronal metabolism

Page 3 of 24

and cell signaling [128]. These enzymes exhibit substantial structural homology to streptococcal proteins[129]. The latest study (96 OCD, 33 MDD, 17 schizophrenia subjects) tested patient serum against pyruvatekinase, aldolase C and enolase, specifically; a greater proportion of OCD subjects were sero-positive relative to controls (19.8% (n = 19) versus 4% [n = 2], P = 0.012) [130].
Yet, in the same study only one of 19 sero-positive OCD
subjects also had positive anti-streptolysin O antibody titers, suggesting that in pure OCD the anti-streptolysin O
antibody seronegativity does not exclude the presence ofanti-basal ganglia autoantibodies.
In pure OCD, sero-positivity for anti-basal ganglia/
thalamic antibodies is associated with increased levels of
CSF glycine (P = 0.03) [88], suggesting that these antibodies contribute to hyperglutamatergia observed in OCD[84,88,131]. The improvement of infection-provoked OCD
with immune therapies supports the pathogenicity of theseautoantibodies [132]. A large NIH trial assessing the efficacy of intravenous immunoglobulin (IVIG) for children
with acute onset OCD and anti-streptococcal antibodies isongoing (ClinicalTrials.gov: NCT01281969). However, thefinding of slightly higher CSF glutamate levels in OCD patients with negative CSF anti-basal ganglia/thalamic antibodies as compared to those with positive CSF antibodies
suggests that non-immunological mechanisms may playrole in OCD [84]. Other mechanisms, including cytokinemediated inflammation (Table 2), are also hypothesized.

Psychiatric disorders associated with innate inflammation

Disorders of innate inflammation/autoimmunity occur insome patients with classical psychiatric disorders. We
discuss innate inflammation-related CNS abnormalities—
including glial pathology, elevated cytokines levels, cyclooxygenase activation, glutamate dysregulation, increased
S100B levels, increased oxidative stress, and BBB dysfunction—in MDD, BPD, schizophrenia, and OCD. We also
describe how innate inflammation may be mechanisticallylinked to the traditional monoaminergic and glutamatergic
abnormalities reported in these disorders (Figures 1 and 2).
The therapeutic role of antiinflammatory agents in psychiatric disorders is also reviewed.

Astroglial and oligodendroglial histopathology

Astroglia and oligodendroglia are essential to neural metabolic homeostasis, behavior and higher cognitive functions[54-56,133-136]. Normal quiescent astroglia provide energy
and trophic support to neurons, regulate synaptic neurotransmission (Figure 2), synaptogenesis, cerebral blood
flow, and maintain BBB integrity [134,136,137]. Matureoligodendroglia provide energy and trophic support to neurons and maintain BBB integrity, and regulate axonal repair

Clinical features

NMDAR,(NR1 subunit)

VGKC-complex(Kv1 subunit, LGI1, CASPR2)AMPAR(GluR1, GluR2
subunits)

GABABR(B1 subunit)

GAD (65 kDa)

Age (years)

18 to 50

Less than 50

Less than 50

60 to 70

Less than 50

Sex (% female)

75%

66%

Greater than 50%

50%

Less than 50%

Paraneoplastic
9% to 56% have ovarian teratoma,(%, and commonly predominately females less thanoccurring cancers) 18 years of age

10% to 30%; low titers; SCLC; thymoma;
CASPR2>>LGI-1

50% to 70%; SCLC,
breast carcinoma;
thymoma

50%; SCLC
thymomaRarely associatedwith cancer

Nonparaneoplastic Approximately 50%

70%; high titers

30% to 50%

50%Frequent

TypicalTypicalTypicalEtiology

Anatomical
subtype
Limbicencephalitis

Less common

TypicalPanencephalitis

TypicalRare (involving basal ganglia)

UnclearUnclearLess common

CSF abnormal (%)

90%

40%

90%

80%

20%

PsychiatricFeatures

Common and pronounced: Anxiety, agitation,paranoid delusions, perceptual changes, erratic
behavior, speech changes, severe psychosis

Agitation, anxiety, panic-attacks, depression,
psychosis, hallucinations, delusions, delirium,
confabulation

Atypical psychosis,
which can be isolated

Paranoia, behavioral
changes

Depression, atypicalpsychosis (case reports)

Neurological
Features

Early features: seizures, cognitive/memory
impairment; Late features: catatonia, orofacial andlimb dyskinesia, dystonia, autonomic dysfunction,
reduced level of consciousness, aphasia, central
hypoventilation

LGI1: limbic encephalitis (more common):
Memory impairment,
amnesia temporal lobe seizures, tonic seizures, temporal lobe seizuresand hypernatremia. Extrapyramidal symptoms(choreoathetosis) and extra-temporal(faciobrachial dystonic) seizures (less common).
CASPR2: limbic encephalitis, Morvan's syndrome(neuromyotonia, REM disorder, insomnia, andautonomic dysfunction).

Prominent temporal lobe
seizures, memory
impairment, concomitant
glutamic acid decarboxylase
autoantibodies

Stiff-person syndrome,
cerebellar ataxia,
cognitive/memory
impairment, epilepsy(often mesial temporal)

Response totreatment

Highly responsive to immune therapy andremoval of ovarian teratoma

Highly responsive to immune therapy

Moderately responsive Moderately responsive
to immune therapy
to immune therapy

Relapse risk

20% often with psychiatric signs; may indicate
tumor reoccurrence

Rarely relapses

Tendency to relapse(based on small caseseries)Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Table 1 Clinical features of anti-synaptic and anti-glutamic acid decarboxylase autoimmune encephalitides

Often refractory to
immune therapy

Tendency to relapse (based Tendency to be chronic
on small case series)
and relapse

AMPAR, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)-propanoic acid receptor; CASPR-2, contactin associated protein 2; CNS, central nervous system; CSF, cerebrospinal fluid; GABABR, gamma aminobutyric acid B receptor;
GAD, glutamic acid decarboxylase; LGI-1, leucine-rich glioma inactivated-1; NMDAR, N-methyl-D-aspartate receptor; REM, rapid eye movements; SCLC small cell lung cancer; VGKC; voltage-gated potassium channel.

Page 4 of 24

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

and myelination of white matter tracts providing inter- andintra-hemispheric connectivity [54-56]. Both astroglia andoligodendroglia produce antiinflammatory cytokines thatcan down-regulate harmful inflammation [52,55].
In MDD, astroglial loss is a consistent post-mortem
finding in functionally relevant areas, including the anterior cingulate cortex, prefrontal cortex, amygdala, andwhite matter [35-38,42-46,55,138-147], with few exceptions [42,43]. Post-mortem studies revealed reduced glial
fibrillary acidic protein (GFAP)-positive astroglial density
primarily in the prefrontal cortex [37,38] and amygdala[36]. A large proteomic analysis of frontal cortices fromdepressed patients showed significant reductions in three
GFAP isoforms [39]. Although in one study that reported
no significant glial loss, subgroup analysis revealed a significant decrease (75%) in GFAP-positive astroglial density
among study subjects younger than 45 years of age [35]. A
morphometric study similarly showed no changes in glial
density in late-life MDD brains [148]. We hypothesize thatthe apparent absence of astroglial loss among older MDD
patients may reflect secondary astrogliosis [35] that is associated with older age [42,50] rather than a true negative.
Animal studies are consistent with human studies
showing astroglial loss in MDD. Wistar-Kyoto rats—
known to exhibit depressive-like behaviors—revealed
reduced astroglial density in the same areas as observedin humans [40]. Administration of the astroglial-toxic
agent, L-alpha-aminoadipic acid, induces depressivelike symptoms in rats, suggesting that astroglial loss ispathogenic in MDD [41].
Post-mortem studies of MDD subjects documented reduced oligodendroglial density in the prefrontal cortex
and amygdala [54-57,66], which may correlate with brain
MRI focal white matter changes occasionally noted insome MDD patients [57]. However, microvascular abnormalities may also contribute to these changes [57].
In BPD, some studies demonstrate significant glial loss
[138,143,149,150], while others do not [37,44-46]. These
inconsistent findings may result from lack of control for:1) treatment with mood stabilizers, because post-hoc analysis reported by some studies showed significant reduction in glial loss only after controlling for treatment withlithium and valproic acid [46]; 2) familial forms of BPD, as
glial loss is particularly prominent among BPD patientswith a strong family history [143]; and/or, 3) the predominant state of depression versus mania, as glial loss
is frequent in MDD [35-38,42-46,55,138-147]. Whether
astroglia or oligodendroglia account for the majority of
glial loss is unclear; while proteomic analysis revealed asignificant decrease in one astroglial GFAP isoform [39],several other post-mortem studies found either unchanged[36,37] or reduced GFAP-positive astroglial expression in
the orbitrofrontal cortex [47], or reduced oligodendroglial
density [54-56,58,59].

Page 5 of 24

In schizophrenia, astroglial loss is an inconsistent finding[48,150]. While some studies showed no significant
astroglial loss [42,50,51], several others found reduced
astroglial density [37,38,43,44,48,49,151] and significant reductions in two GFAP isoforms [39]. Inconsistent findings
may result from: 1) MDD comorbidity, which is often associated with glial loss; 2) age variation, as older patients haveincreased GFAP-positive astroglia [35,42,50]; 3) regional[150] and cortical layer variability [48]; 4) treatment with
antipsychotic drugs, as experimental studies show both reduced [152] and increased [153] astroglial-density related
to chronic antipsychotic treatment [70]; and 5) diseasestate (for example, suicidal versus non-suicidal behavior)[154]. Post-mortem studies documented oligodendroglial
loss [54,56,60-65,148,155,156], particularly in the prefrontal
cortex, anterior cingulate cortex, and hippocampus [148].
Ultrastructural examination of the prefrontal region
showed abnormally myelinated fibers in both gray andwhite matter; both age and duration of illness were positively correlated with the white matter abnormalities [157].
In contrast to neurodegenerative disorders that arecommonly associated with astroglial proliferation [136],
psychiatric disorders are instead associated with either
reduced or unchanged astroglial density [138]. The lackof increased glial density in early-onset psychiatric disorders [44,138] may reflect the slower rate of degenerative
progression in psychiatric illnesses [138].
We postulate that degenerative changes associatedwith psychiatric disorders are subtler and not severe
enough to provoke astroglial intracellular transcription
factors that positively regulate astrogliosis, including signal transducer activator of transcription 3 and nuclear
factor kappa B (NF-κB) [136].
While the majority of post-mortem studies focused on
the alteration of glial density in MDD, BPD, and schizophrenia, others described alteration of glial cell morphology, with mixed findings. In MDD and BPD, glial size
is either increased or unchanged [55]. One study foundreduced glial size in BPD and schizophrenia but not in
MDD [43]. A post-mortem study of depressed patients
who committed suicide found increased astroglial size inthe anterior cingulate white matter but not in the cortex[158]. One study in schizophrenic subjects found markedly decreased astroglial size in layer V of the dorsolateral prefrontal cortex, notwithstanding that astroglial
density is double that of controls in the same layer [48].
The mixed results may partially reflect earlier studies of
glial alterations in psychiatric illnesses that did not specify astroglia versus oligodendroglia [148].
Glial loss in psychiatric illnesses may contribute toneuroinflammation through several mechanisms, including abnormal cytokine levels (see Cytokine section),dysregulated glutamate metabolism (see Glutamate
section), elevated S100B protein (see S100B section),Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

and altered BBB function (see Blood brain barrier section), resulting in impaired cognition and behavior[44,45,54,133,159].

Microglial histopathology

Microglia are the resident immune cells of the CNS.
They provide ongoing immune surveillance and regulate
developmental synaptic pruning [160,161]. CNS injury
transforms ramified resting microglia into activatedelongated rod-shaped and macrophage-like phagocytic
amoeboid cells that proliferate and migrate towards thesite of injury along chemotactic gradients (that is, microglial activation and proliferation (MAP)) [161]. Human
microglial cells express NMDARs that may mediate
MAP leading to neuronal injury [162].
In MDD, BPD and schizophrenia, the results of postmortem studies investigating the presence of MAP are
mixed. Post-mortem studies revealed elevated MAP in only
one out of five MDD subjects [67]. In some BPD disorderpatients, increased human leukocyte antigen-DR-positive
microglia displaying thickened processes were documented
in the frontal cortex [69]. In schizophrenia, while somestudies reported elevated MAP relative to controls, others
showed no difference between groups [22,67,70]. In a
post-mortem study assessing MAP in MDD and BPD;
quinolinic acid-positive microglial cell density was increased in the subgenual anterior cingulate cortex and anterior midcingulate cortex of MDD and BPD patients who
committed suicide relative to controls [53]. Post-hoc analysis revealed this increased MAP was solely attributable to
MDD and not BPD, since the positive microglial immunostaining in MDD subjects was significantly greater than thatin the BPD subgroup in both the subgenual anterior cingulate and midcingulate cortices, and since the microglia
density was similar in both BPD and control groups [53]. A
study comparing all three disorders (nine MDD, five BPD,
fourteen schizophrenia, ten healthy controls) demonstrated
no significant difference in microglial density across thefour groups [68].
These mixed results may be attributed to variablemicroglial immunological markers used among different
studies [70] and/or the failure to control for disease severity [22,53,68]. Notably, three post-mortem studies of
MDD and schizophrenic subjects documented a strong
positive correlation between MAP and suicidality in theanterior cingulate cortex and mediodorsal thalamus, independent of psychiatric diagnosis [22,53,68]. Thus,
MAP may be a state rather than a trait marker for MDD
and schizophrenia.
In OCD, animal models suggest that dysfunction and reduction of certain microglial phenotypes, such as thoseexpressing the Hoxb8 gene, which encodes homeobox transcription factor, can cause OCD-like behavior [71,72].

Page 6 of 24

Hoxb8 knockout mice exhibit excessive grooming behavior
and anxiety in association with reduced microglial density[71,72]. This excessive grooming behavior resembles the
behavioral characteristics of human OCD. Hoxb8 injectionin adult Hoxb8 knockout mice reverses microglial loss andrestores normal behavior [71,72]. The role of these specificmicroglial phenotypes in human OCD is unclear.
Experimental data suggest that MAP comprises distinctive harmful and neuroprotective phenotypes (Figure 2).
Harmful microglia do not express major histocompatibility
complex II (MHC-II) and, therefore, cannot act as antigen
presenting cells (APC) [163,164]; they promote deleterious
effects [17,69,165] through proinflammatory cytokine
production, nitric oxide synthase signaling [17,166], promoting glial and BBB-pericyte/endothelial cyclooxygenase2 (COX-2) expression [167], inducing astroglial S100B
secretion (see S100B section), and microglial glutamate
release [17,136,168,169]. Harmful microglia also secrete
prostaglandin E-2 (PGE-2) that promotes proinflammatory
cytokines production, which in turn increases PGE-2 levels
in a feed-forward cycle [29]. Further, PGE-2 stimulates
COX-2 expression, which mediates the conversion of arachidonic acid to PGE-2, setting up another feed-forward
cycle [29].
Neuroprotective microglia by contrast can: 1) express
MHC-II in vivo and in vitro [163,166] and act as cognate
APC (Figure 2) [163,164,166]; 2) facilitate healing and limit
neuronal injury by promoting secretion of antiinflammatory
cytokines [17], brain-derived neurotrophic factor [17],and insulin-like growth factor-1 [166]; and 3) express excitatory amino acid transporter-2 (EAAT2) that eliminates
excess extracellular glutamate [163,166], and promotes
neuroprotective T lymphocytic autoimmunity (Figure 2)[163,164]. However, more studies are needed to confirm
the contributory role of neuroprotective microglia toneuropsychiatric disorders in humans.
In vitro animal studies suggest that the ratio of harmful versus neuroprotective microglia can be influenced
by the net effect of inflammatory counter-regulatory
mechanisms [15,74,164,166]. These mechanisms include
the number of neuroprotective CD4+CD25+FOXP3+ T
regulatory cells ((T regs) Figure 1) [15,74,164,166] andbrain cytokine levels; low IFN-γ levels may promote
neuroprotective microglia (Figure 2) [166], whereas highlevels can promote the harmful phenotype [166].

The role of cytokines

Proinflammatory cytokines include IL-1β, IL-2, IL-6,
TNF-α and IFN-γ. They are secreted primarily by microglia, Th1 lymphocytes and M1 phenotype monocytes/
macrophages (Figure 1) [15,170]. They promote harmful
inflammation. Antiinflammatory cytokines include IL-4,
IL-5 and IL-10. They are primarily secreted by astroglia,

Abnormalities

Major depression

Bipolar disorder

37% to 38% [24]40% to 70% [25]Schizophrenia

OCD

40% to 50% [26]80% to 87% [27]GABAAR B2 subunit, COMT, Neuregulin-1,
DISC1 [26] HLA (B, C, DRA1, and DRB1;
antigen presentation, autoimmunity) [28]

EAAT3 (SLC1A1) [27]Genetics
Concordance

2+

GWAS genes

Tryptophan hydroxylase-1,
BDNF, 5-HTTLPR, PBRM1 [24]Tryptophan hydroxylase-2, Voltage-gated Cachannel α1C, PBRM1, D22S278, ANK3 [25]Immunologic genes

Proteasome β4 subunit (antigen processing)[21], T-box 21 (T cell differentiation) [21],IL-1 [29], TNF-.alpha; [29], G-765C (COX-2)[30], BDNF [24]

BDNF gene [31]; consistent withdecreased serum BDNF levels

S100B [32,33]; consistent withincreased brain and CSF S100B levels

TNF-α [34]Density

Decreased (highly reproducible)[35-41]; few exceptions [42,43]

Reduced or no change [37,44-46]

Reduced or no change[37-39,47-49] [42,50,51]

Insufficient data

TDO, KYNA...

KYNA is increased [52,53]

Both are increased [21,52]...

Decreased [54-58]

Decreased [54,56-65]

Decreased [54-58,66]

Insufficient data

Trait and State
markers

Trait: no [53,67,68]; State (suicidal):yes [22,68]

Mixed data [53,68,69]

Trait: no [70]; State (suicidal):yes [22,68]

Insufficient data; yet, Hoxb8(−/−) mice exhibit OCD-likebehavior [71,72]

IDO, KMO

Both are increased [29]...

Both are decreased [21],[73]...

Quinolinic acid

Increased [53]

...

...

...

T cells are decreased [15,74];
T regs are decreased [15,74]

T regs are increased [75]T cells are decreased [76]; ‘CD4+:
CD8+ ratio’ is decreased [76];B cells are increased [21,76]‘CD4+: CD8+ ratio’is decreased[77] (normalized
after SRI treatment)

EAATs 1,2
(astroglial)

Both are decreased in the
DLPFC and ACC [78]

EAAT1 is increased, EAAT2
is decreased in PFC [79]Both are increased in PFC [79-81],
and thalamus [82]...

EAATs 3,4
(neuronal)

EAAT4 is decreased instriatum [83]Both are decreased instriatum [79]

EAAT3 is decreased in striatum [83];Both are increased in PFC [79-81]
and thalamus [82]

EAAT3 is decreasedin CSTC circuitry[77,84]Post-mortem
brain tissue

Glutamate and D-serine are
increased in the frontal cortex [85,86]

Glutamate and D-serine are
increased in DLPFC andhippocampus [86]. Increased
glutamine in ACC/Parietal-OCC [78]Glutamine synthetase isincreased [87]...

CSF, serum

Glutamate is increased in both;
serum levels normalized after 5-week

...

...

CSF glutamate is increased[88]; normalized after one

Astroglia

Oligodendroglia
Density

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Table 2 Summary of neuroinflammatory and immunological abnormalities observed in pure psychiatric disorders

Microglial activation

Lymphocytes
T cells, T regs,
B cells

EAAT

Glutamate, GABA

Page 7 of 24

antidepressant course [85,86];
GABA is decreased in both [85,86]
1

H MRS

dose of ketamine(NMDAR antagonist)

Glutamate is increased [85,89] Decreased
glutamine synthetase, glutamine, and
GABA (ACC, PFC, DMPFC, VMPFC, amygdala,hippocampi; normalized with ECT anddisease remission) [78]GLX is increased in medial PFC(ACC, DLPFC, parietal-OCC, OCC,
insula, hippocampus) [78,79];
independent of disease state.

Glutamate is decreased in medial
PFC (including ACC); Increased
glutamine synthetase, glutamine,and ‘glutamine:glutamate ratio’in PFC [90]GLX is increased in leftcaudate and OFC(normalized after
successful SRI treatment);
GLX is decreased in
ACC [84]

Phenotype

Proinflammatory are increased [91]Proinflammatory are increased [92];IL-1β, IL-1R, and IL-6 correlate with
post-mortem brain mRNA
expression [69]Mixed data: antiinflammatory
and/or proinflammatory, areincreased [52,94,93]

Mixed data: TNF-α
is increased or decreased;
IL-6 is increased or nochange; IL-1β isdecreased [95]Trait and State
markers

Trait markers: TNF-α, IL-6, and sIL-2R
are increased [91]State markers (suicidal):
TNF-α and IL-6 are increased, and IL-2
is decreased [96].

Depressive state: IL-6
Euthymic state: IL-4
Manic state: IL-2, IL-4,
IL-6 [92]Trait makers: IFN-γ,
TNF-α, IL-12, sIL-2R, IL-1RA,sIL-2R [93] State markers: IL-1β,
IL-6, TGF-β [93]Trait markers: mixed data
LPS-induced:
TNF-α and IL-6 aredecreased [95]

Cytokines(serum)Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Table 2 Summary of neuroinflammatory and immunological abnormalities observed in pure psychiatric disorders (Continued)

5-HTTLPR, serotonin-transporter-linked polymorphic region; ANK3, ankyrin-3; ACC, anterior cingulate cortex; BDNF, brain-derived neurotrophic factor, BPD, bipolar disorder; COMT, catechol-O-methyl transferase; COX-2,
cyclooxygenase 2; CSF, cerebrospinal fluid, CSTC, cortico-striatal-thalamic-cortico; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; EAAT, excitatory amino acid transporter: (EAATs 1 and 2 areexpressed by astroglia, EAAT3 is expressed intracellularly in the post-synaptic neurons, and EAAT4 is expressed by Purkinje cells and frontal neurons); GABA, gamma aminobutyric acid; GLX 1H MRS: (detectableglutamate, glutamine, gamma aminobutyric acid composite); GWAS, genome-wide association study (single nucleotide polymorphisms identified across the entire genome of those with a given disorder (fourth row);
includes immunologic genetic abnormalities (fifth row) whenever applicable); 1H MRS, proton magnetic resonance spectroscopy; HLA, human leukocyte antigen; IDO, indoleamine-2,3-oxygenase; IFN-γ, interferon
gamma; IL, interleukin, IL-1RA; interleukin 1 receptor antagonist; KMO, kynurenine monooxygenase; KYNA, kynurenic acid; MDD, major depressive disorder; OCC, occipital cortex; OCD, obsessive-compulsive disorder;
OFC, orbitofrontal cortex; PBRM1, protein polybromo-1; PFC, prefrontal cortex; SRI, serotonin reuptake inhibitor; T regs, CD4+CD25+FOXP3+ T regulatory cells; TDO, tryptophan-2,3-dioxygenase, TGF-β, transforming
growth factor beta; TNF-α, tumor necrosis factor alpha; VMPFC, ventromedial prefrontal cortex.

Page 8 of 24

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Th2 lymphocytes, T regs and M2 phenotype monocytes/
macrophages [15,52,74]. They can limit harmful inflammation [15,74] by converting the proinflammatory M1-phenotype into the beneficial antiinflammatory M2-phenotype[15], and potentially by promoting the neuroprotective
microglial phenotype [15,17,74,163,166]. The role of proinflammatory/antiinflammatory cytokines in psychiatric disorders is supported by several lines of evidence (Figure 1,
Table 2) [15,17,29,52,74].
In MDD, the most recent meta-analysis (29 studies,
822 MDD, 726 healthy controls) of serum proinflammatory cytokines confirmed that soluble IL-2 receptor, IL-6
and TNF-α levels are increased in MDD (trait markers)[91], while, IL-1β, IL-2, IL-4, IL-8 and IL-10, are notstatistically different from controls [91]. In a primarycytokine study comparing MDD subgroups (47 suicidalMDD, 17 non-suicidal MDD, 16 health controls),
both sera IL-6 and TNF-α were significantly higher,
while IL-2 levels were significantly lower in MDD subjects who committed suicide relative to both othergroups [96]. This finding suggests that IL-6 and TNF-α
are also state markers of MDD [96]. The decrease ofserum IL-2 levels associated with acute suicidal behavior may reflect increased binding to its upregulated receptor in the brain; parallel to the aforementioned
meta-analysis showing increased soluble IL-2 receptor
in MDD [91]. Studies investigating the clinical significance of cytokines in MDD showed that serum cytokine
levels are elevated during acute depressive episodes[171,172] and normalized following successful, but not
failed, treatment with antidepressants [17] and electroconvulsive therapy [29]; these findings suggest a possible pathogenic role for cytokines.
In BPD, serum cytokine alterations were summarized ina recent review; TNF-α, IL-6 and IL-8 are elevated during
manic and depressive phases, whereas IL-2, IL-4 and IL-6
are elevated during mania [92]. Other studies showed that
sera IL-1β and IL-1 receptor levels are not statistically different from healthy controls [92], although tissue studies
documented increased levels of IL-1β and IL-1 receptor in
the BPD frontal cortex [69].
In schizophrenia, results from studies investigating cytokine abnormalities are conflicting (Table 2). While somestudies found both decreased serum proinflammatory (IL-2,
IFN-γ) and increased serum and CSF antiinflammatory
cytokines (IL-10) [52], others found elevated serum proand antiinflammatory cytokines, with a proinflammatory
type dominance [22,173,174]. One cytokine meta-analysis(62 studies, 2,298 schizophrenia, 858 healthy controls)
showed increased levels of IL-1R antagonist, sIL-2R andIL-6 [174]. However, this study did not account for theuse of antipsychotics, which is thought to enhanceproinflammatory cytokine production [52]. A more recent
cytokine meta-analysis (40 studies, 2,572 schizophrenics,

Page 9 of 24

4,401 controls) that accounted for antipsychotics, foundthat TNF-α, IFN-γ, IL-12 and sIL-2R are consistently elevated in chronic schizophrenia independent of disease activity (trait markers), while IL-1β, IL-6 and transforming
growth factor beta positively correlate with disease activity(state markers)[173]. Cell cultures of peripheral bloodmononuclear cells (PBMC) obtained from schizophrenic
patients produced higher levels of IL-8 and IL-1β spontaneously as well as after stimulation by LPS, suggesting arole for activated monocytes/macrophages in schizophrenia pathology [175].
In OCD, results from a random survey of sera and CSF
cytokines, and LPS-stimulated PBMC studies, are inconsistent [93-95,176-179]. There is a correlation between OCD
and a functional polymorphism in the promoter region of
the TNF-α gene [34], although low-powered studies did notconfirm this association [180]. Therefore, the mixed resultsfrom studies documenting either increased or decreased
TNF-α cytokine levels [93,176-178] may reflect their variable inclusion of the subset of OCD subjects with this particular polymorphism in their cohorts.

Cytokine response polarization in major depression andschizophrenia

Cytokine response phenotypes are classified as either
proinflammatory Th1 (IL-2, IFN-γ) or antiinflammatory
Th2 (IL-4, IL-5, IL-10) according to the immune functions
they regulate. While Th1 cytokines regulate cell-mediatedimmunity directed against intra-cellular antigens, Th2 cytokines regulate humoral immunity directed against extracellular antigens [29,52]. Th1 cytokines are produced byTh1 lymphocytes and M1 monocytes whereas Th2 cytokines are produced by Th2 lymphocytes and M2 monocytes [29,52]. In the brain, microglia predominantly secrete
Th1 cytokines, whereas astroglia predominately secreteTh2 cytokines [29,52]. The reciprocal ratio of Th1:Th2 cytokines, henceforth ‘Th1-Th2 seesaw’, is influenced by the
proportion of activated microglia (excess Th1) to astroglia(excess Th2) and the interplay between activated T cells
and excessive CNS glutamate levels that we hypothesized
to favor Th1 response (Figure 2) [29,163,166].
The Th1-Th2 seesaw imbalance can influence tryptophan metabolism by altering its enzymes [21,52] thereby
shifting tryptophan catabolism towards kynurenine (KYN)
and KYN catabolism towards either of its two downstream metabolites; microglia quinolinic acid that is Th1
response-mediated or astroglial kynurenic acid (KYNA)(Figure 1) that is Th2 response-mediated [21,29,170].
Tryptophan metabolism enzymes affected by Th1-Th2
seesaw include (Figure 1): indoleamine 2,3-dioxygenase(IDO) expressed by microglia and astroglia, the ratelimiting enzymes that mediate the conversion of tryptophan to KYN and serotonin to 5-hydroxyindoleacetic acid

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Page 10 of 24

Figure 1 Influence of the ‘Th1-Th2 cytokine seesaw’ generated by glial cells and T lymphocytes on tryptophan/kynurenine
metabolism-mediated serotonergic and glutamatergic abnormalities in major depressive disorder and schizophrenia. Influence of the’Th1-Th2 seesaw’ generated by glial cells and T lymphocytes (first of three bracketed sections) on the enzymes controlling tryptophan/kynurenine
metabolism (second of three bracketed sections) leading to serotonergic and glutamatergic abnormalities in major depressive disorder andschizophrenia (third of three bracketed sections). Microglial and astroglial IDO is the rate-limiting enzyme catalyzing the conversion of tryptophan
to KYN and serotonin to 5HTT. KMO, which is solely expressed by microglia, is the rate-limiting enzyme catalyzing the conversion of KYN to
3-OH-KYN. TDO, which is solely expressed by astroglia, is the rate-limiting enzyme catalyzing the conversion of tryptophan to KYN. KAT, expressedprimarily in astroglial processes, is the rate-limiting enzyme catalyzing the conversion of KYN to KYNA. The microglial enzymes IDO and KMO are
upregulated by Th1 cytokines and downregulated by Th2 cytokines. An imbalance of the ‘Th1-Th2 seesaw’ shifts kynurenine catabolism either towards
microglial quinolinic acid (NMDA agonist) as in major depressive disorder, or towards astroglial kynurenic acid (NMDA antagonist) as in schizophrenia.
5HIAA, 5-Hydroxyindoleacetic acid; α7nAchR, alpha 7 nicotinic acetylcholine receptors; BBB, blood–brain barrier; IDO, indoleamine-2,3-dioxygenase; IL,interleukin; IFN-γ, interferon gamma; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYN, kynurenine; KYNA, kynurenic acid;
NMDAR, N-methyl-D-aspartate receptor; TNF-α, tumor necrosis factor alpha; T regs, CD4+CD25+FOXP3+ T regulatory cells; TDO, tryptophan-2,3dioxygenase; Th, T-helper.

[21,29]. Kynurenine 3-monooxygenase (KMO), solely
expressed by microglia, is the rate-limiting enzyme thatconverts KYN to 3-hydroxykynurenine (3-OH-KYN),
which is further metabolized to quinolinic acid [21,29].
Tryptophan-2,3-dioxygenase (TDO), expressed solely
by astroglia, is the rate-limiting enzyme that converts

tryptophan to KYN [21,29]. Kynurenine aminotransferase(KAT), expressed primarily in astroglial processes, is therate-limiting enzyme that mediates the conversion of KYN
to KYNA [21,29].
Th1 cytokines activate microglial IDO and KMO,
shifting microglial KYN catabolism towards quinolinicNajjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Page 11 of 24

Figure 2 Hypothesis of MDD: excess CNS glutamate may contribute to excess Th1- response promoting neuroprotective microglia.
Peripheral resting T lymphocytes constitutively express mGluR5. Activated T lymphocytes, but not resting T lymphocytes, can cross the BBB. In the
animal models, the interaction between TCR of activated T lymphocytes and their cognate antigen presenting cells downregulates mGluR5 andinduces mGluR1 expressions. Experimental data suggest that excess glutamate can bind to lymphocytic mGluR1 receptors, promoting productionof Th1 cytokines. Hypothesis: In some MDD patients, parallel to experimental data, binding of excess CNS glutamate to induced lymphocyticmGluR1 receptors may contribute to an excess Th1 response, including IFN-γ. We further hypothesize that IFN-γ in a small quantity, similar to its
in vitro effects on microglia, may induce microglial expression of MHC-II and EAAT-2, allowing microglia to serve as cognate antigen presenting
cells and to provide glutamate reuptake function, thereby transforming harmful microglia into neuroprotective phenotype that participate ineliminating excess extracellular glutamate and reducing its excitotoxicity. Therefore, we hypothesize that excess Th1 response in some MDD
patients is a double-edged sword; promoting harmful inflammation and serving as a beneficial counter-regulatory mechanism that may limit
excess glutamate-related neuroexcitotoxicity? AMPA, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)-propanoic acid; APC, antigen presenting cell; BBB,
blood–brain barrier; CNS, central nervous system, EAAT, excitatory amino acid transporter; IDO, indoleamine-2,3-dioxygenase; IFN-γ, interferon
gamma; IL, interleukin; KMO, kynurenine 3-monooxygenase; mGluR1/5, metabotropic glutamate receptors 1 and 5; MHC II, major
histocompatibility complex class 2; NMDA, N-methyl-D-aspartate; NO, nitric oxide; NR1, glycine site; QA, quinolinic acid; TCR, T-cell receptor;
Th, T-helper; TNF-α, tumor necrosis factor alpha.

acid (NMDAR agonist) synthesis, while Th2 cytokines inactivate microglial IDO and KMO, shifting astroglial KYN
catabolism towards TDO- and KAT-mediated KYNA(NMDAR antagonist) synthesis (Figure 1) [21,29].
Th1 and Th2 predominant immunophenotypes havebeen proposed for MDD and schizophrenia, respectively,
based on peripheral, rather than CNS, cytokines patterns[52,173]. We believe that peripheral cytokines patterns areunreliable surrogate markers of those in the CNS. Indeed,
peripheral cytokine levels can be influenced by many
extra-CNS variables, which are not consistently controlled
for in several of the peripheral cytokines studies, including:1) age, body mass index, psychotropic medications, smoking, stress and circadian fluctuations; 2) the influence ofdisease activity/state on the production of selected cytokines synthesis [95,173]; and 3) the effects of psychotropic
agents on cytokines production [52]. The short half-lives
and the rapid turnover of serum cytokines [181] (for example, 18 minutes for TNF-α [182] versus 60 minutes forIL-10 [183]), may further limit the reliability of interpreting
their levels measured from random sera sampling.
In MDD, there is a consensus that a proinflammatoryTh1 immunophenotype response predominates (Table 2)[17,29]. High levels of quinolinic acid in post-mortem
MDD brains [53], suggest the presence of an upregulated
Th1 response (Figure 1) [21,29]. Elevated CNS quinolinicacid can promote calcium influx mediated apoptosis of human astroglia [184], which hypothetically may blunt theNajjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

astroglia-derived Th2 response [29], tipping Th1 versus
Th2 seesaw balance in favor of the microglial Th1 response.
CNS hyposerotonergia [29] adds further support to an
excess Th1 response, which is shown to reduce CNS serotonin synthesis [185] and to increase its degradation(Figure 1) [21,29].
CNS hyperglutamatergia may also contribute to an
excess Th1 response in the brain (Figure 2). An in vitro
study suggests that the peripheral resting T lymphocytes
constitutively express metabotropic glutamate receptor
5 (mGluR5) [164], whose binding to glutamate inhibits
lymphocytic IL-6 release, thereby downregulating autoreactive T-effector cell proliferation [164]. Activated T
lymphocytes, but not resting T lymphocytes, can crossthe BBB [37].
Experimental data suggest that the interaction between
T cell receptors of activated T lymphocytes and their cognate antigen presenting cells can downregulate mGluR5
and induce mGluR1 expressions [164]. In animal models,binding of excess glutamate to lymphocytic mGluR1 receptors promotes production of Th1 cytokines, including
IFN-γ [164].
We hypothesize that in some MDD patients, parallel toexperimental data [164], the binding of excess CNS glutamate to induced lymphocytic mGluR1 receptors may contribute to an excess Th1 response, including IFN-γ (Figure 2).
We speculate that IFN-γ in a small quantity, similar to its
in vitro effects on microglia [166], may induce microglial
expression of MHC-II and EAAT2 [163,166], allowing
microglia to serve as cognate antigen presenting cells andto provide glutamate reuptake function [163,164,166],
thereby transforming harmful microglia into neuroprotective phenotype [163,166] that participate in eliminatingexcess extracellular glutamate [163,164,166]. Therefore, we
also hypothesize that excess Th1 response in subgroupsof MDD patients is a double-edged sword, promoting
harmful inflammation and serving as a beneficial counterregulatory mechanism that may limit excess glutamaterelated neuroexcitotoxicity (Figure 2).
In schizophrenia, while some peripheral cytokine
studies suggest the predominance of an antiinflammatoryTh2 immunophenotype/response [52], others refute this[173,174]. However, we agree with the authors who hypothesized that the Th2 response is the dominant phenotype in schizophrenia [52]. Elevated brain, CSF, and serum
levels of KYNA [21,52] suggest downregulation of microglial IDO and KMO, which is a function of Th2 responsethat shifts astroglial KYN catabolism towards KYNA synthesis (Figure 1) [21,52]. Reduced KMO activity and KMO
mRNA expression in post-mortem schizophrenic brains[73] is consistent with excess Th2 response (Figure 1).
Increased prevalence of Th2-mediated humoral immunity
abnormalities in subgroups of schizophrenia patients—asevidenced by increased B cell counts [21,76], increased

Page 12 of 24

production of autoantibodies including antiviral antibodies[76] and increased immunoglobulin E [52]—adds further
support to the Th2 response dominance hypothesis.

Neuroinflammation and CNS glutamate dysregulation

Glutamate mediates cognition and behavior [186]. Synaptic glutamate levels are regulated by high-affinity
sodium-dependent glial and neuronal EAATs, namely,
the XAG- system responsible for glutamate reuptake/aspartate release [137,164] and the sodium-independent
astroglial glutamate/cystine antiporter system (Xc-) responsible for glutamate release/cystine reuptake [164].
Astroglial EAAT1 and EAAT2 provide more than 90%of glutamate re-uptake [79].
Neuroinflammation can alter glutamate metabolism
and the function of its transporters [15,29,187,188], producing cognitive, behavioral, and psychiatric impairments[15,21,29,79,186,188,189]. Abnormalities of EAATs function/expression and glutamate metabolism in MDD, BPD,
schizophrenia, and OCD are summarized in Table 2.
In MDD, there is evidence for cortical hyperglutamatergia(Table 2). Cortical glutamate levels correlated positively
with the severity of depressive symptoms, and a five-weekcourse of antidepressants decreased serum glutamate concentrations [85,86]. A single dose of ketamine, a potent
NMDAR antagonist, can reverse refractory MDD for aweek [17,21,29,85]. Excess CNS glutamate levels can induce
neurotoxicity-mediated inflammation [163,164,188], including a proinflammatory Th1 response (Figure 2) [164].
Limited in vitro evidence suggests that inflammation/
proinflammatory cytokines can increase CNS glutamate
levels [188] in a feed-forward cycle through several potential mechanisms: 1) proinflammatory cytokines can inhibit[15,17,168] and reverse [45,137] astroglial EAAT-mediatedglutamate reuptake function; 2) proinflammatory cytokines can enhance microglial quinolinic acid synthesis[53], which has been experimentally shown to promote
synaptosomal glutamate release [15,17,29,190]; 3) increased
COX-2/PGE-2 and TNF-α levels can induce calcium influx[137], which, based on in vitro data, may increase astroglial
glutamate and D-serine release [191]; and 4) activatedmicroglia can express excess Xc- antiporter systems thatmediate glutamate release [164,192].
In schizophrenia, prefrontal cortical hypoglutamatergia[87,90,193,194] (Table 2) and reduced NMDAR functionality
are found [5]. Recent H1 magnetic resonance spectroscopy(MRS) meta-analysis (28 studies, 647 schizophrenia, 608
control) confirmed decreased glutamate and increased glutamine levels in the medial frontal cortex [90]. The contributory role of inflammation to hypoglutamatergia is notproven. Elevated KYNA synthesis in schizophrenia brains[21,52], typically a function of Th2 response (Figure 1), caninhibit NR1 subunit of NMDAR and alpha 7 nicotinicNajjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

acetylcholine receptor (α7nAchR) [195], leading to decreased
NMDAR function and reduced α7nAchR-mediated glutamate release [195].
In BPD and OCD, data suggest CNS cortical hyperglutamatergia in both disorders (Table 2) [78,84,88,131].
The contribution of inflammation (BPD and OCD) andautoantibodies (OCD)[7,77,84,88,130] to increased CNS
glutamate levels requires further investigation.
The role of S100B

S100B is a 10 kDa calcium-binding protein producedby astroglia, oligodendroglia, and choroid plexus ependymal cells [196]. It mediates its effects on the surrounding neurons and glia via the receptor for advanced
glycation end-product [196]. Nanomolar extracellular
S100B levels provide beneficial neurotrophic effects, limit
stress-related neuronal injury, inhibit microglial TNF-α release, and increase astroglial glutamate reuptake [196].
Micromolar S100B concentrations, predominantly produced by activated astroglia and lymphocytes [196,197],
have harmful effects transduced by receptor for advanced
glycation end product that include neuronal apoptosis,
production of COX-2/PGE-2, IL-1β and inducible nitricoxide species, and upregulation of monocytic/microglial
TNF-α secretion [21,196,198].
Serum and, particularly, CSF and brain tissue S100B
levels are indicators of glial (predominantly astroglial)activation [199]. In MDD and psychosis, serum S100B
levels positively correlate with the severity of suicidality,
independent of psychiatric diagnosis [200]. Post-mortem
analysis of S100B showed decreased levels in the dorsolateral prefrontal cortex of MDD and BPD, and increased levels in the parietal cortex of BPD [196].
Meta-analysis (193 mood disorder, 132 healthy controls) confirmed elevated serum and CSF S100B levels inmood disorders, particularly during acute depressive episodes and mania [201].
In schizophrenia, brain, CSF and serum S100B levels areelevated [199,202]. Meta-analysis (12 studies, 380 schizophrenia, 358 healthy controls) confirmed elevated serum
S100B levels in schizophrenia [203]. In post-mortem
brains of schizophrenia subjects, S100B-immunoreactive
astroglia are found in areas implicated in schizophrenia, including anterior cingulate cortex, dorsolateral prefrontal
cortex, orbitofrontal cortex and hippocampi [154]. Elevated
S100B levels correlate with paranoid [154] and negativistic
psychosis [204], impaired cognition, poor therapeutic response and duration of illness [202]. Genetic polymorphisms in S100B [32] and receptor for advanced glycation
end-product genes in schizophrenia cohorts (Table 2)[32,33,205] suggest these abnormalities are likely primary/pathogenic rather than secondary/biomarkers. Indeed, thedecrease in serum S100B levels following treatment withantidepressants [201] and antipsychotics [196] suggests

Page 13 of 24

some clinical relevance of S100B to the pathophysiology ofpsychiatric disorders.

Neuroinflammation and increased oxidative stressOxidative stress is a condition in which an excess of oxidants damages or modifies biological macromolecules
such as lipids, proteins and DNA [206-209]. This excess
results from increased oxidant production, decreasedoxidant elimination, defective antioxidant defenses, orsome combination thereof [206-209]. The brain is particularly vulnerable to oxidative stress due to: 1) elevatedamounts of peroxidizable polyunsaturated fatty acids;2) relatively high content of trace minerals that induce
lipid peroxidation and oxygen radicals (for example,
iron, copper); 3) high oxygen utilization; and 3) limited
anti-oxidation mechanisms [206,207].
Excess oxidative stress can occur in MDD [206], BPD[206,207], schizophrenia [207,209], and OCD [206,208].
Peripheral markers of oxidative disturbances include
increased lipid peroxidation products (for example,
malondialdehyde and 4-hydroxy-2-nonenal), increased
nitric oxide (NO) metabolites, decreased antioxidants(for example, glutathione) and altered antioxidant enzyme levels [206,207].
In MDD, increased superoxide radical anion production
correlates with increased oxidation-mediated neutrophil
apoptosis [206]. Serum levels of antioxidant enzymes (forexample, superoxide dismutase-1) are elevated during acutedepressive episodes and normalize after selective serotonin
reuptake inhibitors (SSRIs) treatment [206]. This suggeststhat in MDD, serum antioxidant enzyme levels are a statemarker, which may reflect a compensatory mechanism thatcounteracts acute increases in oxidative stress. [206].
In schizophrenia by contrast, CSF soluble superoxide
dismutase-1 levels are substantially decreased in early-onset
schizophrenic patients relative to chronic schizophrenic patients and healthy controls. This suggests that reduced
brain antioxidant enzyme levels may contribute to oxidative
damage in acute schizophrenia [210], though larger studies
are needed to confirm this finding.
Several additional experimental and human studies examined in more detail the mechanisms underlying thepathophysiology of increased oxidative stress in psychiatric disorders [206-262]. In animal models of depression, brain levels of glutathione are reduced while lipid
peroxidation and NO levels are increased [206,262].
Postmortem studies show reduced brain levels of total
glutathione in MDD, BPD [206] and schizophrenic subjects [206,207]. Fibroblasts cultured from MDD patientsshow increased oxidative stress independent of glutathione levels [262], arguing against a primary role of glutathione depletion as the major mechanism of oxidative
stress in depression.

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Microglial activation may increase oxidative stressthrough its production of proinflammatory cytokines andNO [206-209]. Proinflammatory cytokines and high NO
levels may promote reactive oxygen species (ROS) formation, which in turn accelerates lipid peroxidation, damaging
membrane phospholipids and their membrane-boundmonoamine neurotransmitter receptors and depleting endogenous antioxidants. Increased ROS products can enhance microglial activation and increase proinflammatory
production via stimulating NF-κB [208], which in turn
perpetuates oxidative injury [208], creating the potential
for a pathological positive feedback loop in some psychiatric disorders [206-209]. Although neuroinflammation
can increase brain glutamate levels [85,86], the role ofglutamatergic hyperactivity as a cause of oxidative stressremains unsubstantiated [207].
Mitochondrial dysfunction may contribute to increasedoxidative stress in MDD, BPD and schizophrenia [206].
Postmortem studies in these disorders reveal abnormalities in mitochondrial DNA, consistent with the highprevalence of psychiatric disturbances in primary mitochondrial disorders [206]. In vitro animal studies showthat proinflammatory cytokines, such as TNF-α, can reduce mitochondrial density and impair mitochondrial oxidative metabolism [211,212], leading to increased ROS
production [206,213]. These experimental findings may
imply mechanistic links among neuroinflammation, mitochondrial dysfunction and oxidative stress [206,213],
meriting further investigation of these intersecting pathogenic pathways in human psychiatric disorders.
The vulnerability of neural tissue to oxidative damage
varies among different psychiatric disorders based on theneuroanatomical, neurochemical and molecular pathways
involved in the specific disorder [207]. Treatment effects
may also be critical, as preliminary evidence suggests that
antipsychotics, SSRIs and mood stabilizers possess antioxidant properties [206,207,262]. The therapeutic role of adjuvant antioxidants (for example, vitamins C and E) in
psychiatric disorder remains to be substantiated by highpowered randomized clinical trials. N-acetylcysteine shows
the most promising results to-date, with several randomized placebo-controlled trials demonstrating its efficacy in
MDD, BPD and schizophrenia [207].

Blood–brain barrier dysfunction

The BBB secures the brain’s immune-privileged status by
restricting the entry of peripheral inflammatory mediators, including cytokines and antibodies that can impair
neurotransmission [214,215]. The hypothesis of BBB
breakdown and its role in some psychiatric patients[60,214,216,217] is consistent with the increased prevalence of psychiatric comorbidity in diseases associatedwith its dysfunction, including SLE [97], stroke [11],Page 14 of 24

epilepsy [218] and autoimmune encephalitides (Table 1).
An elevated ‘CSF:serum albumin ratio’ in patients with
MDD and schizophrenia suggests increased BBB permeability [214].
In one study (63 psychiatric subjects, 4,100 controls),
CSF abnormalities indicative of BBB-damage were detected in 41% of psychiatric subjects (14 MDD and BPD,
14 schizophrenia), including intrathecal synthesis of IgG,
IgM, and/or IgA, mild CSF pleocytosis (5 to 8 cells permm3) and the presence of up to four IgG oligoclonalbands [216]. One post-mortem ultrastructural study inschizophrenia revealed BBB ultrasructural abnormalities
in the prefrontal and visual cortices, which included vacuolar degeneration of endothelial cells, astroglial-end-footprocesses, and thickening and irregularity of the basal
lamina [60]. However, in this study, the authors did notcomment on the potential contribution of postmortem
changes to their findings. Another study investigatingtranscriptomics of BBB endothelial cells in schizophrenic
brains identified significant differences among genes influencing immunological function, which were not detectedin controls [217].
Oxidation-mediated endothelial dysfunction may contribute to the pathophysiology of BBB dysfunction in psychiatric disorders. Indirect evidence from clinical andexperimental studies in depression [219] and, to a lesser
extent, in schizophrenia [220] suggests that increased oxidation may contribute to endothelial dysfunction. Endothelial dysfunction may represent a shared mechanism
accounting for the known association between depression
and cardiovascular disease [219,221], which may be related
to decreased levels of vasodilator NO [221-223]. Experimental studies suggest that reduced endothelial NO levels
are mechanistically linked to the uncoupling of endothelial
nitric oxide synthase (eNOS) from its essential co-factor
tetrahydrobiopterin (BH4), shifting its substrate from Larginine to oxygen [224-226]. Uncoupled eNOS promotes
synthesis of ROS (for example, superoxide) and reactive
nitrogen species (RNS) (for example, peroxynitrite; a product of the interaction of superoxide with NO) [227] rather
than NO, leading to oxidation-mediated endothelial dysfunction [224-226].
Animal data showed that SSRIs could restore deficientendothelial NO levels [219], suggesting that anti-oxidative
mechanisms may contribute to their antidepressant effects. In humans, L-methylfolate may potentiate antidepressant effects of SSRIs [228], putatively by increasinglevels of BH4, which is an essential cofactor for eNOS recoupling-mediated anti-oxidation [229], as well as for the
rate-limiting enzymes of monoamine (that is, serotonin,
norepinephrine, dopamine) synthesis [228].
Taken together, both the recent work emphasizing therole of uncoupled eNOS-induced oxidative stress in thepathogenesis of vascular diseases [230,231] and theNajjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

epidemiological studies establishing depression as an independent risk factor for vascular pathologies, such as
stroke and heart disease [219,221], add further support
to the clinical relevance of uncoupled eNOS-mediatedendothelial oxidative damage in depression. Despite
abundant evidence for cytokine abnormalities in human
psychiatric illnesses and the experimental data showingthat proinflammatory cytokines can reduce eNOS expression [212] and increase BBB permeability [215], human evidence that directly links excess proinflammatory
cytokines to eNOS dysfunction and/or BBB impairment
is lacking.

Page 15 of 24

low signal-to-noise properties and requires an on-site
cyclotron.
Accordingly, research is being devoted to developing
improved translocator protein ligands for PET and SPECT.
Future high-powered post-mortem brain tissues studies
utilizing protein quantification aimed at elucidating
metabolic and inflammatory pathways, CNS cytokines
and their binding receptors, in psychiatric disorders areneeded to advance our understanding of the autoimmune
pathophysiology.

Role of antiinflammatory drugs in psychiatric disorders
Imaging and treating inflammation in psychiatric illness
Imaging neuroinflammation in situ

Clinically, neuroinflammation imaging may prove to be
crucial for identifying the subgroup of psychiatric patientswith neuroinflammation who would be most likely torespond favorably to immunomodulatory therapies. Additionally, such imaging may allow clinicians to monitor
neuroinflammation-related disease activity and its response
to immune therapy in psychiatric patients. Imaging inflammation in the human brain has traditionally depended
upon MRI or CT visualization of extravagated intravenous
contrast agents, indicating localized breakdown of the
BBB. Gadolinium-enhanced MRI occasionally demonstrates such breakdown in the limbic regions associatedwith emotional processing in patients with psychiatric disorders attributable to paraneoplastic or other encephalitides [107,109,113]. To our knowledge, however, abnormalenhancement has never been demonstrated in any classical psychiatric disorder [21,214,232], despite functional[214,216] and ultrastructural BBB abnormalities [60].
Whether or not subtler neuroinflammation can be visualized in vivo in classical psychiatric disorders remains
unknown. One promising technique is positron emission
tomography (PET) using radiotracers, such as C11PK11195, which bind to the translocator protein, previously known as the peripheral benzodiazepine receptor,
expressed by activated microglia [233,234].
Using this method, patients with schizophrenia wereshown to have greater microglial activation throughout
the cortex [235] and in the hippocampus during acute
psychosis [236]. One study (14 schizophrenia, 14 controls) found no significant difference between [11C]DAA1106 binding in schizophrenia versus controls, but
a direct correlation between [11C] DAA1106 binding
and the severity of positive symptoms and illness duration in schizophrenia [236].
Investigators from our institution utilized C11-PK11195
PET to demonstrate bi-hippocampal inflammation in a patient with neuropsychiatric dysfunction, including psychotic
MDD, epilepsy, and anterograde amnesia, associated with
anti-GAD antibodies [237]. However, PK11195 PET has

Several human and animal studies suggest that certain
antiinflammatory drugs may play an important adjunctiverole in the treatment of psychiatric disorders (Table 3).
Common drugs are cyclooxygenase inhibitors (Table 3)[238-245], minocycline (Table 3) [240-245], omega-3 fatty
acids [246,247], and neurosteroids [248].
Several human studies showed that COX-2 inhibitors
could ameliorate psychiatric symptoms of MDD, BPD,
schizophrenia and OCD (Table 3) [248]. By contrast, adjunctive treatment with non-selective COX-inhibitors(that is, non-steroidal antiinflammatory drugs (NSAIDs))
may reduce the efficacy of SSRIs [249,250]; two large trials reported that exposure to NSAIDs (but not to either
selective COX-2 inhibitors or salicylates) was associatedwith a significant worsening of depression among a subset of study participants [249,250].
In the first trial, involving 1,258 depressed patientstreated with citalopram for 12 weeks, the rate of remission
was significantly lower among those who had taken
NSAIDs at least once relative to those who had not (45%versus 55%, OR 0.64, P = 0.0002) [249]. The other trial, involving 1,545 MDD subjects, showed the rate of treatmentresistant depression was significantly higher among thosetaking NSAIDs (OR 1.55, 95% CI 1.21 to 2.00) [231]. The
worsening of depression in the NSAID groups may not bemechanistically linked to NSAID therapy but instead related to co-existing chronic medical conditions [10,12-18]
that necessitate long-term NSAIDs and which are known
to be independently associated with increased risk oftreatment-resistant depression [249,251]. Future studies investigating the impact of NSAIDs on depression and response to antidepressants in humans are needed.
In other experimental studies utilizing acute-stress paradigms to induce a depression-like state in mice, citalopram
increased TNF-α, IFN-γ, and p11 (molecular factor linked
to depressive behavior in animals) in the frontal cortex,
while the NSAID ibuprofen decreased these molecules;
NSAIDs also attenuated the antidepressant effects of SSRIs
but not other antidepressants [249]. These findings suggestthat proinflammatory cytokines may paradoxically exert
antidepressant effects despite overwhelming evidence from

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

Page 16 of 24

Table 3 Selected studies assessing the efficacy of antiinflammatory agents among patients with unipolar and bipolar
depression, schizophrenia, and obsessive-compulsive disorder
Study

Study Group comparison
designNumberof subjects

Functional outcome

Müller et al. 2006 [238]

RCT

Celecoxib (200 mg bid) +reboxetine versus
placebo + reboxetine

40 MDD (acute)Significantly greater decrease in depressive
symptoms in the treatment group (P = 0.035)

Akhondzadeh et al. 2009
[239]

RCT

Celecoxib (200 mg bid) +fluoxetine versus
placebo + fluoxetine

40 MDD

Significant improvement of depressive symptoms(P <0.001), and a greater percentage of responders(90% versus 50%, P = 0.01) and remission (35% versus 5%,
P = 0.04) in the treatment group

Medlewicz et al. 2006
[240]

Openlabel

Acetylsalicylic acid(160 mg qd) + SRI

24 MDD and BPD

52.4% responder rate, significant improvement
within one week (P <0.0001) following treatment;sustained at four weeks

ClinicalTrials.gov
NCT00510822 completed,pending results

RCT

Cimicoxib (50 mg bid) +sertraline versus
placebo + sertraline

169 MDD

Primary outcome measure is mean change in
Hamilton Depression Rating Scale from baseline
to six-week endpoint

Nery et al. 2008 [263]

RCT

Celecoxib versus placebo

28 BPD (depressive No significant differences in depressive
and mixed states) or manic symptoms.

Müller et al. 2002 [242]

RCT

Celecoxib (400 mg qd) +risperidone versus
placebo + risperidone

50 (acuteschizophrenia)

Significant improvement of positive and negative
symptoms (P = 0.05), as well as cognition(P <0.06) in treatment group at five weeks

Müller et al. 2010 [244]

RCTCelecoxib + amisulprideversus placebo +amisulpride

49 schizophrenia(first-episode)

Significant improvement of positive andnegative symptoms in celecoxib plus amisulpridegroup relative to amisulpride alone (P <0.001) at
six-weeks

Sayyah et al. 2011 [245]

RCT

Celecoxib (200 mg bid) +fluoxetine versus
placebo + fluoxetine

50 OCD

Significantly greater reduction in YBOCS scoresin the celecoxib treatment group at two weeks(P = 0.007) and at the eight week end-point (P = 0.037)

Levine et al. 1996 [264]CasereportMinocycline (150 mg qd)
started 20 years after
disease onset

1 BPD

Marked decrease in depressive symptoms(HAM-D score went from 25 to 8) within
one week following treatment, sustained at
two weeks.

Levkovitz et al. 2009 [265]

RCT

Minocycline (200 mg qd)
versus placebo

21 schizophrenia(early and acutephase)

Significant improvement of negative symptoms andcognitive dysfunction in treatment group (P <0.01)

COX-2 inhibitors

Minocycline

ClinicalTrials.gov
RCT
NCT01433055 recruiting,estimated completion 7/15

Minocycline (100 mg bid) + 60 schizophrenia(refractory to ≥2clozapine versus
placebo + clozapine
antipsychotics)

Primary outcome is the improvement in positive
symptoms as measured by the four-item
sub-factor of the Brief Psychiatric Rating Scale.

Miyaoka et al. 2007 [266]Caseseries

Minocycline (150 mg qd) +stable antipsychotic
regiment

2 schizophrenia

Complete resolution of positive and negative symptoms
with minocycline, sustained for one to two years.
Symptom exacerbation occurred one-week following
minocycline discontinuation (in both cases). In one
patient, the complete resolution of symptoms occurredat age 61, which was 41 years after disease onset.

Miyaoka et al. 2008 [267]Openlabel

Minocycline (150 mg tid)

22 schizophrenia

Significant improvement of positive andnegative symptoms at four to eight weeks (P = 0.0001)

Rodriguez et al. 2010 [268] Openlabel

Minocycline (100 mg bid)

9 OCD

22% had a 40% to 46% YBOCS reduction at 12 weeks; thegroup as a whole did not have a significant
change in YBOCS score.

ASA, acetylsalicylic acid; BPD, bipolar disorder; COX-2, cycloxygenase-2; HAM-D: Hamilton Depression Rating Scale; MDD, major depressive disorder; OCD, obsessivecompulsive disorder; SRI, serotonin reuptake inhibitor; RCT, randomized controlled trial; YBOCS: Yale-Brown Obsessive-Compulsive Scale.

human studies to the contrary (as reviewed above), which
can be attenuated by NSAIDs [249]. At least two considerations may account for this apparent paradox: 1) undersome experimental conditions, proinflammatory cytokines
have been associated with a neuroprotective role, [251; (forexample, IFN-γ in low levels can induce neuroprotective
microglia (Figure 2) [163,166,251]); and 2) whether these
responses observed in the context of an acute stress paradigm in an animal model are applicable to endogenous
MDD in humans remains unclear [251].

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

The therapeutic effects of COX-2 inhibitors in psychiatric disorders may involve modulation of biosynthesis of
COX-2-derived prostaglandins, including proinflammatory
PGE2 and antiinflammatory 15-deoxy-Δ12,14-PGJ2 (15dPGJ2) [252,253]. COX-2 inhibitors can reduce PGE2mediated inflammation, which may contribute to thepathophysiology of psychiatric disorders [252,253]. They
may also alter the levels 15d-PGJ2, and the activity of its
nuclear receptor peroxisome proliferator-activated nuclear
receptor gamma (PPAR-γ) [252,253].
Several studies suggest that 15d-PGJ2 and its nuclear
receptor PPAR-γ can serve as biological markers forschizophrenia [253]. In schizophrenic patients, serum
PGE2 levels are increased, whereas serum levels of 15dPGJ2 are decreased, as is the expression of its nuclear receptor PPAR-γ in PBMC [252]. While COX-2 inhibitors
may limit the potentially beneficial antiinflammatory effects of the COX-2–dependent ‘15d-PGJ2/PPAR-γ pathway’, they may advantageously reduce its harmful effects,
including 1) the increased risk for myocardial infarction
and certain infections (for example, cytomegalovirus andToxoplasma gondii) in schizophrenic patients [254] and2) its pro-apoptotic effects observed in human and animal cancer tissue [255]. Other potential mechanisms of
COX-2 inhibitors therapeutic effects may involve theirability to reduce proinflammatory cytokine levels [163],
limit quinolinic acid excitotoxicity (as in MDD) and decrease KYNA levels (as in schizophrenia) [128].
Minocycline can be effective in psychiatric disorders(Table 3) [248]. In vitro data suggest that minocycline inhibits MAP, cytokine secretion, ‘COX-2/PGE-2 expression,’and inducible nitric oxide synthase [256]. Minocycline
may also counteract dysregulated glutamatergic and dopaminergic neurotransmission [256].
Omega-3 fatty acid effectiveness in psychiatric disorders
is unclear [248]. In a 2011 meta-analysis of 15 randomizedcontrolled trials (916 MDD), omega-3 supplements
containing eicosapentaenoic acid ≥60% (dose range 200 to
2,200 mg/d in excess of the docosahexaenoic acid dose) significantly decreased depressive symptoms as an adjunctive
therapy to SRIs (P <0.001) [246]. A subsequent metaanalysis, however, concluded that there is no significant
benefit of omega-3 fatty acids in depression and that the
purported efficacy is merely a result of publication bias
[247]. A 2012 meta-analysis of 5 randomized-controlled trials including 291 BPD participants found that depressive,
but not manic, symptoms were significantly improved
among those randomized to omega-3 fatty acids relative tothose taking placebo (Hedges g 0.34, P = 0.025) [257]. In arandomized controlled trial of schizophrenic subjects
followed up to 12 months, both positive and negative
symptom scores were significantly decreased among the 66
participants randomized to long-chain omega-3 (1.2 g/day
for 12 weeks; P = 0.02 and 0.01, respectively) [258]; thePage 17 of 24

authors concluded that omega-3 augmentation during theearly course of schizophrenia can also prevent relapses anddisease progression [258].
A 2012 meta-analysis of seven randomized-controlled
trials assessing omega-3 augmentation in 168 schizophrenic patients found no benefit of treatment [259].
The authors of this meta-analysis specifically stated thatno conclusion could be drawn regarding the relapse prevention or disease progression endpoints [259]. Experimental data suggest that eicosapentaenoic acid anddocosahexaenoic acid mediate their antiinflammatory effects by promoting synthesis of resolvins and protectins,
which can inhibit leukocyte infiltration and reduce cytokine production [248].
Neurosteroids, including pregnenolone and its downstream metabolite allopregnanolone, may have a beneficial
role in some psychiatric disorders [248,260]. In MDD, several studies found decreased plasma/CSF allopregnanolone
levels correlating with symptom severity, which normalized
after successful treatment with certain antidepressants (forexample, SSRIs), and electroconvulsive therapy [261]. In
schizophrenia, brain pregnenolone levels can be altered[248] and serum allopregnanolone levels may increase aftersome antipsychotic drugs (for example, clozapine andolanzapine) [260]. In three randomized-controlled trials(100 schizophrenia (pooled); treatment duration, approximately nine weeks) positive, negative, and cognitive
symptoms, as well as extrapyramidal side effects of antipsychotics were significantly improved in one or more trials
among those randomized to pregnenolone relative to thosereceiving placebo [248]. In one trial, the improvement was
sustained with long-term pregnenolone treatment [248].
Pregnenolone can regulate cognition and behavior bypotentiating the function of NMDA and GABAA receptors[248]. Furthermore, allopregnanolone may exert neuroprotective and antiinflammatory effects [248]. More RCT studies are needed to confirm the beneficial role of neuroactive
steroids in early-onset psychiatric disorders in humans.
We are awaiting the results of several ongoing clinical trials investigating the therapeutic effects of otheranti-inflammatory agents, including salicylate, an inhibitor of NF-κB (NCT01182727); acetylsalicylic acid
(NCT01320982); pravastatin (NCT1082588); and dextromethorphan, a non-competitive NMDAR antagonist that can limit inflammation-induced dopaminergic
neuronal injury (NCT01189006).
Future treatment strategies

Although current immune therapies (for example, IVIG,
plasmapheresis, corticosteroids and immunosuppressive
agents) are often effective for treating autoimmune encephalitides wherein inflammation is acute, intense andpredominately of adaptive origin, their efficacy in classicalpsychiatric disorders wherein inflammation is chronic,Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

much milder, and predominately of innate origin, is limited [2]. Development of novel therapeutics should aim
at reversing glial loss [46,138], down-regulating harmful
MAP, while optimizing endogenous neuroprotective T
regs and beneficial MAP, rather than indiscriminately suppressing inflammation as occurs with current immunosuppressive agents. Additionally, development of potent
co-adjuvant antioxidants that would reverse oxidative injury in psychiatric disorders is needed.

Conclusions
Autoimmunity can cause a host of neuropsychiatric disorders that may initially present with isolated psychiatric
symptoms. Innate inflammation/autoimmunity may be
relevant to the pathogenesis of psychiatric symptoms ina subset of patients with classical psychiatric disorders.
Innate inflammation may be mechanistically linked tothe traditional monoaminergic and glutamatergic abnormalities and increased oxidative injury reported in psychiatric illnesses.
Abbreviations
3-OH-KYN: 3-hydroxy-kynurenine; α7nAchR: Alpha 7 nicotinic acetylcholine
receptors; AMPAR: Amino-3-hydroxy-5-methyl-l-4-isoxazolepropionic acidreceptors; APC: Antigen presenting cell; BBB: Blood–brain barrier;
BH4: Tetrahydrobiopterin; BPD: Bipolar disorder; CI: Confidence interval;
CNS: Central nervous system; COX-2: Cyclooxegenase-2; CSF: Cerebrospinal
fluid; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders 4th
Edition; EAATs: Excitatory amino acid transporters; eNOS: Endothelial nitricoxide synthase; GABAB: Gamma aminobutyric acid-beta; GAD: Glutamic aciddecarboxylase; GFAP: Glial fibrillary acidic protein; GLX: 1H MRS detectableglutamate, glutamine, gamma aminobutyric acid composite;
IDO: Indoleamine 2,3-dioxygenase; Ig: Immunoglobulin; IL: Interleukin;
IL-1RA: Interleukin 1 receptor antagonist; IFN-γ: Interferon gamma;
KAT: Kynurenine aminotransferase; KMO: Kynurenine 3-monooxygenase;
KYN: Kynurenine; KYNA: Kynurenic acid; LE: Limbic encephalitis;
LPS: Lipopolysaccharide; MAP: Microglial activation and proliferation;
MDD: Major depressive disorder; mGluR: Metabotropic glutamate receptor;
MHC: II Major histocompatibility complex class two; MRI: Magnetic resonanceimaging; MRS: Magnetic resonance spectroscopy; NF-κB: Nuclear factor
kappa B; NMDAR: N-methyl-D-aspartate receptor; NR1: Glycine site;
OCD: Obsessive-compulsive disorder; OR: Odds ratio; PANDAS: Pediatricneuropsychiatric autoimmune disorders associated with streptococcal
infections; PBMC: Peripheral blood mononuclear cells; PET: Positron emission
tomography; PFC: Prefrontal cortex; PGE-2: Prostaglandin E2; PPARγ: Peroxisome proliferator-activated nuclear receptor gamma; QA: Quinolinicacid; RNS: Reactive nitrogen species; ROS: Reactive oxygen species;sIL: Soluble interleukin; SLE: Systemic lupus erythematosus; SRI: Serotonin
reuptake inhibitor; TNF-α: Tumor necrosis factor alpha; T-regs: CD4+CD25+
FOXP3+ T regulatory cells; TDO: Tryptophan-2,3-dioxygenase; Th: T-helper;
VGKC: Voltage-gated potassium channel; XAG-: Glutamate aspartatetransporter; Xc-: Sodium-independent astroglial glutamate/cystine
antiporter system.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SN and DMP performed an extensive literature review, interpreted data,prepared the manuscript, figures, and tables. KA prepared the section
pertaining to oxidative mechanisms and contributed to the manuscript
revisions. AN and OD critically-revised and improved the design and qualityof the manuscript. All authors read and approved the final manuscript.

Page 18 of 24

Acknowledgments
We gratefully acknowledge Drs. Josep Dalmau, MD, PhD, Tracy Butler, MD, andDavid Zazag, MD, PhD, for providing their expertise in autoimmune
encephalitides, neuroinflammation imaging, and neuropathology, respectively.
Author details
1
Department of Neurology, New York University School of Medicine, 550
First Avenue, New York, NY 10016, USA. 2Geisel School of Medicine at
Dartmouth, The Dartmouth Institute for Health Policy and Clinical Practice,
30 Lafayette Street, HB 7252, Lebanon, NH 03766, USA. 3Department of
Pathology, Division of Neuropathology, New York University School of
Medicine, 550 First Avenue, New York, NY 10016, USA. 4Department of
Psychiatry, New York University School of Medicine, New York, NY, USA.
5
New York University Comprehensive Epilepsy Center, 550 First Avenue, New
York, NY 10016, USA.
Received: 21 November 2012 Accepted: 28 January 2013
Published: 1 April 2013
References
1. Kayser MS, Dalmau J: The emerging link between autoimmune disorders
and neuropsychiatric disease. J Neuropsychiatry Clin Neurosci 2011, 23:90–97.
2. Najjar S, Pearlman D, Zagzag D, Golfinos J, Devinsky O: Glutamic aciddecarboxylase autoantibody syndrome presenting as schizophrenia.
Neurologist 2012, 18:88–91.
3. Graus F, Saiz A, Dalmau J: Antibodies and neuronal autoimmune
disorders of the CNS. J Neurol 2010, 257:509–517.
4. Lennox BR, Coles AJ, Vincent A: Antibody-mediated encephalitis: atreatable cause of schizophrenia. Br J Psychiatry 2012, 200:92–94.
5. Zandi MS, Irani SR, Lang B, Waters P, Jones PB, McKenna P, Coles AJ, Vincent
A, Lennox BR: Disease-relevant autoantibodies in first episodeschizophrenia. J Neurol 2011, 258:686–688.
6. Bataller L, Kleopa KA, Wu GF, Rossi JE, Rosenfeld MR, Dalmau J:
Autoimmune limbic encephalitis in 39 patients: immunophenotypes andoutcomes. J Neurol Neurosurg Psychiatry 2007, 78:381–385.
7. Dale RC, Heyman I, Giovannoni G, Church AW: Incidence of anti-brain
antibodies in children with obsessive-compulsive disorder. Br J Psychiatry
2005, 187:314–319.
8. Kendler KS: The dappled nature of causes of psychiatric illness: replacing
the organic-functional/hardware-software dichotomy with empirically
based pluralism. Mol Psychiatry 2012, 17:377–388.
9. Keskin G, Sunter G, Midi I, Tuncer N: Neurosyphilis as a cause of cognitive
decline and psychiatric symptoms at younger age. J Neuropsychiatry Clin
Neurosci 2011, 23:E41–E42.
10. Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R, Kupfer DJ: Can
bipolar disorder be viewed as a multi-system inflammatory disease?
J Affect Disord 2012, 141:1–10.
11. Hackett ML, Yapa C, Parag V, Anderson CS: Frequency of depression after
stroke: a systematic review of observational studies. Stroke 2005, 36:1330–1340.
12. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW: From
inflammation to sickness and depression: when the immune system
subjugates the brain. Nat Rev Neurosci 2008, 9:46–56.
13. Laske C, Zank M, Klein R, Stransky E, Batra A, Buchkremer G, Schott K:
Autoantibody reactivity in serum of patients with major depression,schizophrenia and healthy controls. Psychiatry Res 2008, 158:83–86.
14. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR:
Inflammation-induced anhedonia: endotoxin reduces ventral striatum
responses to reward. Biol Psychiatry 2010, 68:748–754.
15. Haroon E, Raison CL, Miller AH: Psychoneuroimmunology meetsneuropsychopharmacology: translational implications of the impact ofinflammation on behavior. Neuropsychopharmacology 2012, 37:137–162.
16. Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB:
Autoimmune diseases and severe infections as risk factors forschizophrenia: a 30-year population-based register study. Am J Psychiatry
2011, 168:1303–1310.
17. McNally L, Bhagwagar Z, Hannestad J: Inflammation, glutamate, and glia
in depression: a literature review. CNS Spectr 2008, 13:501–510.
18. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD:
Inflammation causes mood changes through alterations in subgenual
cingulate activity and mesolimbic connectivity. Biol Psychiatry 2009,
66:407–414.

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

19. Raison CL, Miller AH: Is depression an inflammatory disorder?
Curr Psychiatry Rep 2011, 13:467–475.
20. Raison CL, Miller AH: The evolutionary significance of depression in
Pathogen Host Defense (PATHOS-D). Mol Psychiatry 2013, 18:15–37.
21. Steiner J, Bogerts B, Sarnyai Z, Walter M, Gos T, Bernstein HG, Myint AM:
Bridging the gap between the immune and glutamate hypotheses ofschizophrenia and major depression: Potential role of glial NMDA
receptor modulators and impaired blood–brain barrier integrity. World J
Biol Psychiatry 2012, 13:482–492.
22. Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein HG, Bogerts B:
Distribution of HLA-DR-positive microglia in schizophrenia reflects
impaired cerebral lateralization. Acta Neuropathol 2006, 112:305–316.
23. Papakostas GI, Shelton RC, Kinrys G, Henry ME, Bakow BR, Lipkin SH, Pi B,
Thurmond L, Bilello JA: Assessment of a multi-assay, serum-based
biological diagnostic test for major depressive disorder: a pilot andreplication study. Mol Psychiatry 2013, 18:332–339.
24. Krishnan R: Unipolar depression in adults: epidemiology, pathogenesis, andneurobiology. In UpToDate. Edited by Basow DS. Waltham, MA: UpToDate; 2013.
25. Stovall J: Bipolar disorder in adults: epidemiology and diagnosis. In
UpToDate. Edited by Basow DS. UpToDate: Waltham; 2013.
26. Fischer BA, Buchanan RW: Schizophrenia: epidemiology and pathogenesis.
In UpToDate. Edited by Basow DS. Waltham, MA: UpToDate; 2013.
27. Nestadt G, Samuels J, Riddle M, Bienvenu OJ 3rd, Liang KY, LaBuda M,
Walkup J, Grados M, Hoehn-Saric R: A family study of obsessivecompulsive disorder. Arch Gen Psychiatry 2000, 57:358–363.
28. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D,
Werge T, Pietilainen OP, Mors O, Mortensen PB, Sigurdsson E, Gustafsson O,
Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Suvisaari J,
Lonnqvist J, Paunio T, Børglum AD, Hartmann A, Fink-Jensen A, Nordentoft
M, Hougaard D, Norgaard-Pedersen B, Böttcher Y, Olesen J, Breuer R, Möller
HJ, Giegling I, et al: Common variants conferring risk of schizophrenia.
Nature 2009, 460:744–747.
29. Müller N, Schwarz MJ: The immune-mediated alteration of serotonin andglutamate: towards an integrated view of depression. Mol Psychiatry
2007, 12:988–1000.
30. Galecki P, Florkowski A, Bienkiewics M, Szemraj J: Functional polymorphismof cyclooxygenase-2 gene (G-765C) in depressive patients.
Neuropsychobiology 2010, 62:116–120.
31. Levinson DF: The genetics of depression: a review. Biol Psychiatry 2006,
60:84–92.
32. Zhai J, Cheng L, Dong J, Shen Q, Zhang Q, Chen M, Gao L, Chen X, Wang K,
Deng X, Xu Z, Ji F, Liu C, Li J, Dong Q, Chen C: S100B gene
polymorphisms predict prefrontal spatial function in both schizophrenia
patients and healthy individuals. Schizophr Res 2012, 134:89–94.
33. Zhai J, Zhang Q, Cheng L, Chen M, Wang K, Liu Y, Deng X, Chen X, Shen Q,
Xu Z, Ji F, Liu C, Dong Q, Chen C, Li J: Risk variants in the S100B gene,associated with elevated S100B levels, are also associated withvisuospatial disability of schizophrenia. Behav Brain Res 2011, 217:363–368.
34. Cappi C, Muniz RK, Sampaio AS, Cordeiro Q, Brentani H, Palacios SA,
Marques AH, Vallada H, Miguel EC, Guilherme L, Hounie AG: Association
study between functional polymorphisms in the TNF-alpha gene andobsessive-compulsive disorder. Arq Neuropsiquiatr 2012, 70:87–90.
35. Miguel-Hidalgo JJ, Baucom C, Dilley G, Overholser JC, Meltzer HY,
Stockmeier CA, Rajkowska G: Glial fibrillary acidic protein
immunoreactivity in the prefrontal cortex distinguishes younger fromolder adults in major depressive disorder. Biol Psychiatry 2000, 48:861–873.
36. Altshuler LL, Abulseoud OA, Foland Ross L, Bartzokis G, Chang S, Mintz J,
Hellemann G, Vinters HV: Amygdala astrocyte reduction in subjects withmajor depressive disorder but not bipolar disorder. Bipolar Disord 2010,
12:541–549.
37. Webster MJ, Knable MB, Johnston-Wilson N, Nagata K, Inagaki M, Yolken RH:
Immunohistochemical localization of phosphorylated glial fibrillary acidic
protein in the prefrontal cortex and hippocampus from patients withschizophrenia, bipolar disorder, and depression. Brain Behav Immun 2001,
15:388–400.
38. Doyle C, Deakin JFW: Fewer astrocytes in frontal cortex in schizophrenia,
depression and bipolar disorder. Schizophrenia Res 2002, 53:106.
39. Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey
EF, Yolken RH: Disease-specific alterations in frontal cortex brain proteinsin schizophrenia, bipolar disorder, and major depressive disorder, The
Stanley Neuropathology Consortium. Mol Psychiatry 2000, 5:142–149.

Page 19 of 24

40. Gosselin RD, Gibney S, O'Malley D, Dinan TG, Cryan JF: Region specificdecrease in glial fibrillary acidic protein immunoreactivity in the brain of
a rat model of depression. Neuroscience 2009, 159:915–925.
41. Banasr M, Duman RS: Glial loss in the prefrontal cortex is sufficient to
induce depressive-like behaviors. Biol Psychiatry 2008, 64:863–870.
42. Cotter D, Hudson L, Landau S: Evidence for orbitofrontal pathology inbipolar disorder and major depression, but not in schizophrenia.
Bipolar Disord 2005, 7:358–369.
43. Brauch RA, Adnan El-Masri M, Parker J Jr, El-Mallakh RS: Glial cell number
and neuron/glial cell ratios in postmortem brains of bipolar individuals.
J Affect Disord 2006, 91:87–90.
44. Cotter DR, Pariante CM, Everall IP: Glial cell abnormalities in major
psychiatric disorders: the evidence and implications. Brain Res Bull 2001,
55:585–595.
45. Cotter D, Mackay D, Landau S, Kerwin R, Everall I: Reduced glial cell density
and neuronal size in the anterior cingulate cortex in major depressive
disorder. Arch Gen Psychiatry 2001, 58:545–553.
46. Bowley MP, Drevets WC, Ongür D, Price JL: Low glial numbers in the
amygdala in major depressive disorder. Biol Psychiatry 2002, 52:404–412.
47. Toro CT, Hallak JE, Dunham JS, Deakin JF: Glial fibrillary acidic protein andglutamine synthetase in subregions of prefrontal cortex in schizophrenia
and mood disorder. Neurosci Lett 2006, 404:276–281.
48. Rajkowska G, Miguel-Hidalgo JJ, Makkos Z, Meltzer H, Overholser J,
Stockmeier C: Layer-specific reductions in GFAP-reactive astroglia in thedorsolateral prefrontal cortex in schizophrenia. Schizophr Res 2002, 57:127–138.
49. Steffek AE, McCullumsmith RE, Haroutunian V, Meador-Woodruff JH: Corticalexpression of glial fibrillary acidic protein and glutamine synthetase isdecreased in schizophrenia. Schizophr Res 2008, 103:71–82.
50. Damadzic R, Bigelow LB, Krimer LS, Goldenson DA, Saunders RC, Kleinman
JE, Herman MM: A quantitative immunohistochemical study of astrocytes inthe entorhinal cortex in schizophrenia, bipolar disorder and major
depression: absence of significant astrocytosis. Brain Res Bull 2001, 55:611–618.
51. Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL: Deficits insmall interneurons in prefrontal and cingulate cortices of schizophrenicand schizoaffective patients. Arch Gen Psychiatry 1991, 48:996–1001.
52. Müller N, Schwarz MJ: Immune system and schizophrenia. Curr Immunol
Rev 2010, 6:213–220.
53. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, Mawrin C,
Brisch R, Bielau H, Meyer Zu Schwabedissen L, Bogerts B, Myint AM: Severe
depression is associated with increased microglial quinolinic acid insubregions of the anterior cingulate gyrus: evidence for an immunemodulated glutamatergic neurotransmission? J Neuroinflammation 2011, 8:94.
54. Vostrikov VM, Uranova NA, Orlovskaya DD: Deficit of perineuronaloligodendrocytes in the prefrontal cortex in schizophrenia and mooddisorders. Schizophr Res 2007, 94:273–280.
55. Rajkowska G, Miguel-Hidalgo JJ: Gliogenesis and glial pathology indepression. CNS Neurol Disord Drug Targets 2007, 6:219–233.
56. Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI:
Oligodendroglial density in the prefrontal cortex in schizophrenia andmood disorders: a study from the Stanley Neuropathology Consortium.
Schizophr Res 2004, 67:269–275.
57. Uranova N: Damage and loss of oligodendrocytes are crucial in thepathogenesis of schizophrenia and mood disorders (findings form
postmortem studies). Neuropsychopharmacology 2004, 29:S33.
58. Uranova NA, Orlovskaya DD, Vostrikov VM, Rachmanova VI: Decreased
density of oligodendroglial satellites of pyramidal neurons in layer III in
the prefrontal cortex in schizophrenia and mood disorders. Schizophr Res
2002, 53:107.
59. Vostrikov VM, Uranova NA, Rakhmanova VI, Orlovskaia DD: Lowered
oligodendroglial cell density in the prefrontal cortex in schizophrenia.
Zh Nevrol Psikhiatr Im S S Korsakova 2004, 104:47–51.
60. Uranova NA, Zimina IS, Vikhreva OV, Krukov NO, Rachmanova VI, Orlovskaya
DD: Ultrastructural damage of capillaries in the neocortex inschizophrenia. World J Biol Psychiatry 2010, 11:567–578.
61. Hof PR, Haroutunian V, Friedrich VL Jr, Byne W, Buitron C, Perl DP, Davis KL:
Loss and altered spatial distribution of oligodendrocytes in the superior
frontal gyrus in schizophrenia. Biol Psychiatry 2003, 53:1075–1085.
62. Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR,
Buxbaum J, Haroutunian V: White matter changes in schizophrenia:
evidence for myelin-related dysfunction. Arch Gen Psychiatry 2003,
60:443–456.

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

63. Flynn SW, Lang DJ, Mackay AL, Goghari V, Vavasour IM, Whittall KP, Smith
GN, Arango V, Mann JJ, Dwork AJ, Falkai P, Honer WG: Abnormalities ofmyelination in schizophrenia detected in vivo with MRI, and postmortem with analysis of oligodendrocyte proteins. Mol Psychiatry 2003,
8:811–820.
64. Uranova NA, Vostrikov VM, Vikhreva OV, Zimina IS, Kolomeets NS, Orlovskaya
DD: The role of oligodendrocyte pathology in schizophrenia. Int J
Neuropsychopharmacol 2007, 10:537–545.
65. Byne W, Kidkardnee S, Tatusov A, Yiannoulos G, Buchsbaum MS,
Haroutunian V: Schizophrenia-associated reduction of neuronal andoligodendrocyte numbers in the anterior principal thalamic nucleus.
Schizophr Res 2006, 85:245–253.
66. Hamidi M, Drevets WC, Price JL: Glial reduction in amygdala in major
depressive disorder is due to oligodendrocytes. Biol Psychiatry 2004,
55:563–569.
67. Bayer TA, Buslei R, Havas L, Falkai P: Evidence for activation of microglia inpatients with psychiatric illnesses. Neurosci Lett 1999, 271:126–128.
68. Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, Bernstein HG,
Bogerts B: Immunological aspects in the neurobiology of suicide:elevated microglial density in schizophrenia and depression isassociated with suicide. J Psychiatr Res 2008, 42:151–157.
69. Rao JS, Harry GJ, Rapoport SI, Kim HW: Increased excitotoxicity andneuroinflammatory markers in postmortem frontal cortex from bipolar
disorder patients. Mol Psychiatry 2010, 15:384–392.
70. Bernstein HG, Steiner J, Bogerts B: Glial cells in schizophrenia:
pathophysiological significance and possible consequences for therapy.
Expert Rev Neurother 2009, 9:1059–1071.
71. Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR:
Hematopoietic origin of pathological grooming in Hoxb8 mutant mice.
Cell 2010, 141:775–785.
72. Antony JM: Grooming and growing with microglia. Sci Signal 2010, 3:jc8.
73. Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE,
Kajii Y, Thaker GK, Schwarcz R: Downregulated kynurenine 3monooxygenase gene expression and enzyme activity in schizophrenia
and genetic association with schizophrenia endophenotypes. Arch Gen
Psychiatry 2011, 68:665–674.
74. Raison CL, Lowry CA, Rook GA: Inflammation, sanitation, andconsternation: loss of contact with coevolved, tolerogenic
microorganisms and the pathophysiology and treatment of major
depression. Arch Gen Psychiatry 2010, 67:1211–1224.
75. Drexhage RC, Hoogenboezem TH, Versnel MA, Berghout A, Nolen WA,
Drexhage HA: The activation of monocyte and T cell networks in patientswith bipolar disorder. Brain Behav Immun 2011, 25:1206–1213.
76. Steiner J, Jacobs R, Panteli B, Brauner M, Schiltz K, Bahn S, Herberth M,
Westphal S, Gos T, Walter M, Bernstein HG, Myint AM, Bogerts B: Acuteschizophrenia is accompanied by reduced T cell and increased B cell
immunity. Eur Arch Psychiatry Clin Neurosci 2010, 260:509–518.
77. Rotge JY, Aouizerate B, Tignol J, Bioulac B, Burbaud P, Guehl D: The
glutamate-based genetic immune hypothesis in obsessive-compulsive
disorder, An integrative approach from genes to symptoms.
Neuroscience 2010, 165:408–417.
78. Yüksel C, Ongür D: Magnetic resonance spectroscopy studies ofglutamate-related abnormalities in mood disorders. Biol Psychiatry 2010,
68:785–794.
79. Rao JS, Kellom M, Reese EA, Rapoport SI, Kim HW: Dysregulated glutamate
and dopamine transporters in postmortem frontal cortex from bipolarand schizophrenic patients. J Affect Disord 2012, 136:63–71.
80. Bauer D, Gupta D, Harotunian V, Meador-Woodruff JH, McCullumsmith RE:
Abnormal expression of glutamate transporter and transporter
interacting molecules in prefrontal cortex in elderly patients withschizophrenia. Schizophr Res 2008, 104:108–120.
81. Matute C, Melone M, Vallejo-Illarramendi A, Conti F: Increased expressionof the astrocytic glutamate transporter GLT-1 in the prefrontal cortex ofschizophrenics. 2005, 49:451–455.
82. Smith RE, Haroutunian V, Davis KL, Meador-Woodruff JH: Expression of
excitatory amino acid transporter transcripts in the thalamus of subjects
with schizophrenia. Am J Psychiatry 2001, 158:1393–1399.
83. McCullumsmith RE, Meador-Woodruff JH: Striatal excitatory amino acidtransporter transcript expression in schizophrenia, bipolar disorder,and major depressive disorder. Neuropsychopharmacology 2002,
26:368–375.

Page 20 of 24

84. Pittenger C, Bloch MH, Williams K: Glutamate abnormalities in obsessive
compulsive disorder: neurobiology, pathophysiology, and treatment.
Pharmacol Ther 2011, 132:314–332.
85. Hashimoto K: Emerging role of glutamate in the pathophysiology ofmajor depressive disorder. Brain Res Rev 2009, 61:105–123.
86. Hashimoto K, Sawa A, Iyo M: Increased levels of glutamate in brains frompatients with mood disorders. Biol Psychiatry 2007, 62:1310–1316.
87. Burbaeva G, Boksha IS, Turishcheva MS, Vorobyeva EA, Savushkina OK,
Tereshkina EB: Glutamine synthetase and glutamate dehydrogenase in
the prefrontal cortex of patients with schizophrenia. Prog
Neuropsychopharmacol Biol Psychiatry 2003, 27:675–680.
88. Bhattacharyya S, Khanna S, Chakrabarty K, Mahadevan A, Christopher R,
Shankar SK: Anti-brain autoantibodies and altered excitatoryneurotransmitters in obsessive-compulsive disorder.
Neuropsychopharmacology 2009, 34:2489–2496.
89. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL,
Krystal JH, Mason GF: Subtype-specific alterations of gammaaminobutyric acid and glutamate in patients with major depression.
Arch Gen Psychiatry 2004, 61:705–713.
90. Marsman A, van den Heuvel MP, Klomp DW, Kahn RS, Luijten PR, Hulshoff
Pol HE: Glutamate in schizophrenia: a focused review and meta-analysis
of 1H-MRS studies. Schizophr Bull 2013, 39:120–129.
91. Liu Y, Ho RC, Mak A: Interleukin (IL)-6, tumour necrosis factor alpha(TNF-alpha) and soluble interleukin-2 receptors (sIL-2R) are elevated inpatients with major depressive disorder: a meta-analysis and metaregression. J Affect Disord 2012, 139:230–239.
92. Brietzke E, Stabellini R, Grassis-Oliveira R, Lafer B: Cytokines in bipolar
disorder: recent findings, deleterious effects but promise for future
therapeutics. CNS Spectr 2011. http://www.cnsspectrums.com/aspx/
articledetail.aspx?articleid=3596.
93. Denys D, Fluitman S, Kavelaars A, Heijnen C, Westenberg H: Decreased
TNF-alpha and NK activity in obsessive-compulsive disorder.
Psychoneuroendocrinology 2004, 29:945–952.
94. Brambilla F, Perna G, Bellodi L, Arancio C, Bertani A, Perini G, Carraro C, Gava
F: Plasma interleukin-1 beta and tumor necrosis factor concentrations inobsessive-compulsive disorders. Biol Psychiatry 1997, 42:976–981.
95. Fluitman S, Denys D, Vulink N, Schutters S, Heijnen C, Westenberg H:
Lipopolysaccharide-induced cytokine production in obsessivecompulsive disorder and generalized social anxiety disorder. Psychiatry
Res 2010, 178:313–316.
96. Janelidze S, Mattei D, Westrin A, Traskman-Bendz L, Brundin L: Cytokine
levels in the blood may distinguish suicide attempters from depressed
patients. Brain Behav Immun 2011, 25:335–339.
97. Postal M, Costallat LT, Appenzeller S: Neuropsychiatric manifestations insystemic lupus erythematosus: epidemiology, pathophysiology andmanagement. CNS Drugs 2011, 25:721–736.
98. Kozora E, Hanly JG, Lapteva L, Filley CM: Cognitive dysfunction insystemic lupus erythematosus: past, present, and future.
Arthritis Rheum 2008, 58:3286–3298.
99. Lancaster E, Martinez-Hernandez E, Dalmau J: Encephalitis and antibodies tosynaptic and neuronal cell surface proteins. Neurology 2011, 77:179–189.
100. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon
R: Clinical experience and laboratory investigations in patients with antiNMDAR encephalitis. Lancet Neurol 2011, 10:63–74.
101. Lai M, Huijbers MG, Lancaster E, Graus F, Bataller L, Balice-Gordon R, Cowell
JK, Dalmau J: Investigation of LGI1 as the antigen in limbic encephalitis
previously attributed to potassium channels: a case series. Lancet Neurol
2010, 9:776–785.
102. Lancaster E, Huijbers MG, Bar V, Boronat A, Wong A, Martinez-Hernandez E,
Wilson C, Jacobs D, Lai M, Walker RW, Graus F, Bataller L, Illa I, Markx S, Strauss
KA, Peles E, Scherer SS, Dalmau J: Investigations of caspr2, an autoantigen of
encephalitis and neuromyotonia. Ann Neurol 2011, 69:303–311.
103. Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J, Friedman
D, Skeen MB, Grisold W, Kimura A, Ohta K, Iizuka T, Guzman M, Graus F,
Moss SJ, Balice-Gordon R, Dalmau J: Antibodies to the GABA(B) receptor in
limbic encephalitis with seizures: case series and characterisation of theantigen. Lancet Neurol 2010, 9:67–76.
104. Lancaster E, Martinez-Hernandez E, Titulaer MJ, Boulos M, Weaver S, Antoine
JC, Liebers E, Kornblum C, Bien CG, Honnorat J, Wong S, Xu J, Contractor A,
Balice-Gordon R, Dalmau J: Antibodies to metabotropic glutamate
receptor 5 in the Ophelia syndrome. Neurology 2011, 77:1698–1701.

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

105. Ances BM, Vitaliani R, Taylor RA, Liebeskind DS, Voloschin A, Houghton DJ,
Galetta SL, Dichter M, Alavi A, Rosenfeld MR, Dalmau J: Treatmentresponsive limbic encephalitis identified by neuropil antibodies: MRI andPET correlates. Brain 2005, 128:1764–1777.
106. Tofaris GK, Irani SR, Cheeran BJ, Baker IW, Cader ZM, Vincent A:
Immunotherapy-responsive chorea as the presenting feature of LGI1antibody encephalitis. Neurology 2012, 79:195–196.
107. Najjar S, Pearlman D, Najjar A, Ghiasian V, Zagzag D, Devinsky O:
Extralimbic autoimmune encephalitis associated with glutamic aciddecarboxylase antibodies: an underdiagnosed entity? Epilepsy Behav
2011, 21:306–313.
108. Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, Honig
LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N,
Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F,
Dalmau J: Treatment and prognostic factors for long-term outcome inpatients with anti-NMDA receptor encephalitis: an observational cohort
study. Lancet Neurol 2013, 12:157–165.
109. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK,
Rosenfeld MR, Balice-Gordon R, Lynch DR: Anti-NMDA-receptor
encephalitis: case series and analysis of the effects of antibodies.
Lancet Neurol 2008, 7:1091–1098.
110. Graus F, Boronat A, Xifro X, Boix M, Svigelj V, Garcia A, Palomino A, Sabater
L, Alberch J, Saiz A: The expanding clinical profile of anti-AMPA receptor
encephalitis. Neurology 2010, 74:857–859.
111. Lai M, Hughes EG, Peng X, Zhou L, Gleichman AJ, Shu H, Mata S, Kremens
D, Vitaliani R, Geschwind MD, Bataller L, Kalb RG, Davis R, Graus F, Lynch DR,
Balice-Gordon R, Dalmau J: AMPA receptor antibodies in limbic
encephalitis alter synaptic receptor location. Ann Neurol 2009, 65:424–434.
112. Najjar S, Pearlman D, Devinsky O, Najjar A, Nadkarni S, Butler T, Zagzag D:
Neuropsychiatric autoimmune encephalitis with negative VGKC-complex,
NMDAR, and GAD autoantibodies: a case report and literature review,
forthcoming. Cogn Behav Neurol. in press.
113. Najjar S, Pearlman D, Zagzag D, Devinsky O: Spontaneously resolving
seronegative autoimmune limbic encephalitis. Cogn Behav Neurol 2011,24:99–105.
114. Gabilondo I, Saiz A, Galan L, Gonzalez V, Jadraque R, Sabater L, Sans A,
Sempere A, Vela A, Villalobos F, Viñals M, Villoslada P, Graus F: Analysis ofrelapses in anti-NMDAR encephalitis. Neurology 2011, 77:996–999.
115. Barry H, Hardiman O, Healy DG, Keogan M, Moroney J, Molnar PP, Cotter
DR, Murphy KC: Anti-NMDA receptor encephalitis: an importantdifferential diagnosis in psychosis. Br J Psychiatry 2011, 199:508–509.
116. Dickerson F, Stallings C, Vaughan C, Origoni A, Khushalani S, Yolken R:
Antibodies to the glutamate receptor in mania. Bipolar Disord 2012,
14:547–553.
117. O'Loughlin K, Ruge P, McCauley M: Encephalitis and schizophrenia: amatter of words. Br J Psychiatry 2012, 201:74.
118. Parratt KL, Allan M, Lewis SJ, Dalmau J, Halmagyi GM, Spies JM: Acutepsychiatric illness in a young woman: an unusual form of encephalitis.
Med J Aust 2009, 191:284–286.
119. Suzuki Y, Kurita T, Sakurai K, Takeda Y, Koyama T: Case report of anti-NMDA
receptor encephalitis suspected of schizophrenia. Seishin Shinkeigaku
Zasshi 2009, 111:1479–1484.
120. Tsutsui K, Kanbayashi T, Tanaka K, Boku S, Ito W, Tokunaga J, Mori A,
Hishikawa Y, Shimizu T, Nishino S: Anti-NMDA-receptor antibody detectedin encephalitis, schizophrenia, and narcolepsy with psychotic features.
BMC Psychiatry 2012, 12:37.
121. Van Putten WK, Hachimi-Idrissi S, Jansen A, Van Gorp V, Huyghens L:
Uncommon cause of psychotic behavior in a 9-year-old girl: a casereport. Case Report Med 2012, 2012:358520.
122. Masdeu JC, Gonzalez-Pinto A, Matute C, Ruiz De Azua S, Palomino A, De
Leon J, Berman KF, Dalmau J: Serum IgG antibodies against the NR1
subunit of the NMDA receptor not detected in schizophrenia. Am J
Psychiatry 2012, 169:1120–1121.
123. Kirvan CA, Swedo SE, Kurahara D, Cunningham MW: Streptococcal mimicry
and antibody-mediated cell signaling in the pathogenesis ofSydenham's chorea. Autoimmunity 2006, 39:21–29.
124. Swedo SE: Streptoccocal infection, Tourette syndrome, and OCD: is there
a connection? Pandas: Horse or zebra? Neurology 2010, 74:1397–1398.
125. Morer A, Lazaro L, Sabater L, Massana J, Castro J, Graus F: Antineuronalantibodies in a group of children with obsessive-compulsive disorderand Tourette syndrome. J Psychiatr Res 2008, 42:64–68.

Page 21 of 24

126. Pavone P, Bianchini R, Parano E, Incorpora G, Rizzo R, Mazzone L, Trifiletti RR:
Anti-brain antibodies in PANDAS versus uncomplicated streptococcal
infection. Pediatr Neurol 2004, 30:107–110.
127. Maina G, Albert U, Bogetto F, Borghese C, Berro AC, Mutani R, Rossi F,
Vigliani MC: Anti-brain antibodies in adult patients with obsessivecompulsive disorder. J Affect Disord 2009, 116:192–200.
128. Brimberg L, Benhar I, Mascaro-Blanco A, Alvarez K, Lotan D, Winter C, Klein J,
Moses AE, Somnier FE, Leckman JF, Swedo SE, Cunningham MW, Joel D:
Behavioral, pharmacological, and immunological abnormalities after
streptococcal exposure: a novel rat model of Sydenham chorea andrelated neuropsychiatric disorders. Neuropsychopharmacology 2012,
37:2076–2087.
129. Dale RC, Candler PM, Church AJ, Wait R, Pocock JM, Giovannoni G:
Neuronal surface glycolytic enzymes are autoantigen targets inpost-streptococcal autoimmune CNS disease. J Neuroimmunol 2006,
172:187–197.
130. Nicholson TR, Ferdinando S, Krishnaiah RB, Anhoury S, Lennox BR, MataixCols D, Cleare A, Veale DM, Drummond LM, Fineberg NA, Church AJ,
Giovannoni G, Heyman I: Prevalence of anti-basal ganglia antibodies inadult obsessive-compulsive disorder: cross-sectional study. Br J Psychiatry
2012, 200:381–386.
131. Wu K, Hanna GL, Rosenberg DR, Arnold PD: The role of glutamate
signaling in the pathogenesis and treatment of obsessive-compulsive
disorder. Pharmacol Biochem Behav 2012, 100:726–735.
132. Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard
HL, Swedo SE: Therapeutic plasma exchange and intravenous
immunoglobulin for obsessive-compulsive disorder and tic disorders inchildhood. Lancet 1999, 354:1153–1158.
133. Pereira A Jr, Furlan FA: Astrocytes and human cognition: modelinginformation integration and modulation of neuronal activity.
Prog Neurobiol 2010, 92:405–420.
134. Barres BA: The mystery and magic of glia: a perspective on their roles inhealth and disease. Neuron 2008, 60:430–440.
135. Verkhratsky A, Parpura V, Rodriguez JJ: Where the thoughts dwell: thephysiology of neuronal-glial "diffuse neural net". Brain Res Rev 2011,66:133–151.
136. Sofroniew MV: Molecular dissection of reactive astrogliosis and glial scarformation. Trends Neurosci 2009, 32:638–647.
137. Hamilton NB, Attwell D: Do astrocytes really exocytose neurotransmitters?
Nat Rev Neurosci 2010, 11:227–238.
138. Rajkowska G: Postmortem studies in mood disorders indicate alterednumbers of neurons and glial cells. Biol Psychiatry 2000, 48:766–777.
139. Coupland NJ, Ogilvie CJ, Hegadoren KM, Seres P, Hanstock CC, Allen PS:
Decreased prefrontal Myo-inositol in major depressive disorder.
Biol Psychiatry 2005, 57:1526–1534.
140. Miguel-Hidalgo JJ, Overholser JC, Jurjus GJ, Meltzer HY, Dieter L, Konick L,
Stockmeier CA, Rajkowska G: Vascular and extravascular immunoreactivity
for intercellular adhesion molecule 1 in the orbitofrontal cortex ofsubjects with major depression: age-dependent changes. J Affect Disord
2011, 132:422–431.
141. Miguel-Hidalgo JJ, Wei JR, Andrew M, Overholser JC, Jurjus G, Stockmeier
CA, Rajkowska G: Glia pathology in the prefrontal cortex in alcohol
dependence with and without depressive symptoms. Biol Psychiatry 2002,
52:1121–1133.
142. Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY,
Uylings HB, Friedman L, Rajkowska G: Cellular changes in the postmortem
hippocampus in major depression. Biol Psychiatry 2004, 56:640–650.
143. Ongür D, Drevets WC, Price JL: Glial reduction in the subgenual prefrontal
cortex in mood disorders. Proc Natl Acad Sci USA 1998, 95:13290–13295.
144. Gittins RA, Harrison PJ: A morphometric study of glia and neurons in theanterior cingulate cortex in mood disorder. J Affect Disord 2011,
133:328–332.
145. Cotter D, Mackay D, Beasley C, Kerwin R, Everall I: Reduced glial density
and neuronal volume in major depressive disorder and schizophrenia in
the anterior cingulate cortex [abstract]. Schizophrenia Res 2000, 41:106.
146. Si X, Miguel-Hidalgo JJ, Rajkowska G: GFAP expression is reduced in thedorsolateral prefrontal cortex in depression. In Society for Neuroscience; 2003.
Neuroscience Meeting Planne: New Orleans; 2003.
147. Legutko B, Mahajan G, Stockmeier CA, Rajkowska G: White matter astrocytes
are reduced in depression. In Society for Neuroscience. Neuroscience Meeting
Planner: Washington, DC; 2011.

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

148. Edgar N, Sibille E: A putative functional role for oligodendrocytes inmood regulation. Transl Psychiatry 2012, 2:e109.
149. Rajkowska G, Halaris A, Selemon LD: Reductions in neuronal and glial
density characterize the dorsolateral prefrontal cortex in bipolar
disorder. Biol Psychiatry 2001, 49:741–752.
150. Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP: Reduced
neuronal size and glial cell density in area 9 of the dorsolateralprefrontal cortex in subjects with major depressive disorder. Cereb Cortex
2002, 12:386–394.
151. Stark AK, Uylings HB, Sanz-Arigita E, Pakkenberg B: Glial cell loss in theanterior cingulate cortex, a subregion of the prefrontal cortex, in
subjects with schizophrenia. Am J Psychiatry 2004, 161:882–888.
152. Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson
AR, Lewis DA: Effect of chronic antipsychotic exposure on astrocyte andoligodendrocyte numbers in macaque monkeys. Biol Psychiatry 2008,
63:759–765.
153. Selemon LD, Lidow MS, Goldman-Rakic PS: Increased volume and glial
density in primate prefrontal cortex associated with chronic
antipsychotic drug exposure. Biol Psychiatry 1999, 46:161–172.
154. Steiner J, Bernstein HG, Bielau H, Farkas N, Winter J, Dobrowolny H, Brisch R,
Gos T, Mawrin C, Myint AM, Bogerts B: S100B-immunopositive glia iselevated in paranoid as compared to residual schizophrenia: amorphometric study. J Psychiatr Res 2008, 42:868–876.
155. Carter CJ: eIF2B and oligodendrocyte survival: where nature and nurture
meet in bipolar disorder and schizophrenia? Schizophr Bull 2007,
33:1343–1353.
156. Hayashi Y, Nihonmatsu-Kikuchi N, Hisanaga S, Yu XJ, Tatebayashi Y:
Neuropathological similarities and differences between schizophrenia
and bipolar disorder: a flow cytometric postmortem brain study.
PLoS One 2012, 7:e33019.
157. Uranova NA, Vikhreva OV, Rachmanova VI, Orlovskaya DD: Ultrastructural
alterations of myelinated fibers and oligodendrocytes in the prefrontal
cortex in schizophrenia: a postmortem morphometric study.
Schizophr Res Treatment 2011, 2011:325789.
158. Torres-Platas SG, Hercher C, Davoli MA, Maussion G, Labonte B, Turecki
G, Mechawar N: Astrocytic hypertrophy in anterior cingulate whitematter of depressed suicides. Neuropsychopharmacology 2011,36:2650–2658.
159. Pereira A Jr, Furlan FA: On the role of synchrony for neuron-astrocyte
interactions and perceptual conscious processing. J Biol Phys 2009,35:465–480.
160. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A: Physiology of
microglia. Physiol Rev 2011, 91:461–553.
161. Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A: The roleof microglia in the healthy brain. J Neurosci 2011, 31:16064–16069.
162. Kaindl AM, Degos V, Peineau S, Gouadon E, Chhor V, Loron G, Le
Charpentier T, Josserand J, Ali C, Vivien D, Collingridge GL, Lombet A, Issa L,
Rene F, Loeffler JP, Kavelaars A, Verney C, Mantz J, Gressens P: Activation of
microglial N-methyl-D-aspartate receptors triggers inflammation andneuronal cell death in the developing and mature brain. Ann Neurol
2012, 72:536–549.
163. Schwartz M, Shaked I, Fisher J, Mizrahi T, Schori H: Protective
autoimmunity against the enemy within: fighting glutamate toxicity.
Trends Neurosci 2003, 26:297–302.
164. Pacheco R, Gallart T, Lluis C, Franco R: Role of glutamate on T-cellmediated immunity. J Neuroimmunol 2007, 185:9–19.
165. Najjar S, Pearlman D, Miller DC, Devinsky O: Refractory epilepsy associatedwith microglial activation. Neurologist 2011, 17:249–254.
166. Schwartz M, Butovsky O, Bruck W, Hanisch UK: Microglial phenotype: is thecommitment reversible? Trends Neurosci 2006, 29:68–74.
167. Wang F, Wu H, Xu S, Guo X, Yang J, Shen X: Macrophage migration
inhibitory factor activates cyclooxygenase 2-prostaglandin E2 in cultured
spinal microglia. Neurosci Res 2011, 71:210–218.
168. Zhang XY, Xiu MH, Song C, Chenda C, Wu GY, Haile CN, Kosten TA, Kosten
TR: Increased serum S100B in never-medicated and medicatedschizophrenic patients. J Psychiatr Res 2010, 44:1236–1240.
169. Kawasaki Y, Zhang L, Cheng JK, Ji RR: Cytokine mechanisms of central
sensitization: distinct and overlapping role of interleukin-1beta,
interleukin-6, and tumor necrosis factor-alpha in regulating synaptic andneuronal activity in the superficial spinal cord. J Neurosci 2008,
28:5189–5194.

Page 22 of 24

170. Müller N, Schwarz MJ: The immunological basis of glutamatergic
disturbance in schizophrenia: towards an integrated view. J Neural
Transm Suppl 2007, 72:269–280.
171. Hestad KA, Tonseth S, Stoen CD, Ueland T, Aukrust P: Raised plasma levelsof tumor necrosis factor alpha in patients with depression: normalization
during electroconvulsive therapy. J ECT 2003, 19:183–188.
172. Kubera M, Kenis G, Bosmans E, Zieba A, Dudek D, Nowak G, Maes M:
Plasma levels of interleukin-6, interleukin-10, and interleukin-1 receptor
antagonist in depression: comparison between the acute state and after
remission. Pol J Pharmacol 2000, 52:237–241.
173. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B: Meta-analysis ofcytokine alterations in schizophrenia: clinical status and antipsychotic
effects. Biol Psychiatry 2011, 70:663–671.
174. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E: Inflammatory
cytokine alterations in schizophrenia: a systematic quantitative review.
Biol Psychiatry 2008, 63:801–808.
175. Reale M, Patruno A, De Lutiis MA, Pesce M, Felaco M, Di Giannantonio M, Di
Nicola M, Grilli A: Dysregulation of chemo-cytokine production inschizophrenic patients versus healthy controls. BMC Neurosci 2011, 12:13.
176. Fluitman SB, Denys DA, Heijnen CJ, Westenberg HG: Disgust affects TNFalpha, IL-6 and noradrenalin levels in patients with obsessive-compulsive
disorder. Psychoneuroendocrinology 2010, 35:906–911.
177. Konuk N, Tekin IO, Ozturk U, Atik L, Atasoy N, Bektas S, Erdogan A: Plasma
levels of tumor necrosis factor-alpha and interleukin-6 in obsessive
compulsive disorder. Mediators Inflamm 2007, 2007:65704.
178. Monteleone P, Catapano F, Fabrazzo M, Tortorella A, Maj M: Decreased
blood levels of tumor necrosis factor-alpha in patients with obsessivecompulsive disorder. Neuropsychobiology 1998, 37:182–185.
179. Marazziti D, Presta S, Pfanner C, Gemignani A, Rossi A, Sbrana S, Rocchi V,
Ambrogi F, Cassano GB: Immunological alterations in adult obsessivecompulsive disorder. Biol Psychiatry 1999, 46:810–814.
180. Zai G, Arnold PD, Burroughs E, Richter MA, Kennedy JL: Tumor necrosis
factor-alpha gene is not associated with obsessive-compulsive disorder.
Psychiatr Genet 2006, 16:43.
181. Rodríguez AD, González PA, García MJ, de la Rosa A, Vargas M, Marrero F:
Circadian variations in proinflammatory cytokine concentrations in acute
myocardial infarction. Rev Esp Cardiol 2003, 56:555–560.
182. Oliver JC, Bland LA, Oettinger CW, Arduino MJ, McAllister SK, Aguero SM,
Favero MS: Cytokine kinetics in an in vitro whole blood model following
an endotoxin challenge. Lymphokine Cytokine Res 1993, 12:115–120.
183. Le T, Leung L, Carroll WL, Schibler KR: Regulation of interleukin-10 gene
expression: possible mechanisms accounting for its upregulation and formaturational differences in its expression by blood mononuclear cells.
Blood 1997, 89:4112–4119.
184. Lee MC, Ting KK, Adams S, Brew BJ, Chung R, Guillemin GJ:
Characterisation of the expression of NMDA receptors in humanastrocytes. PLoS One 2010, 5:e14123.
185. Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B:
Kynurenine pathway in major depression: evidence of impaired
neuroprotection. J Affect Disord 2007, 98:143–151.
186. Sanacora G, Treccani G, Popoli M: Towards a glutamate hypothesis ofdepression: an emerging frontier of neuropsychopharmacology formood disorders. Neuropharmacology 2012, 62:63–77.
187. Saleh A, Schroeter M, Jonkmanns C, Hartung HP, Modder U, Jander S: In
vivo MRI of brain inflammation in human ischaemic stroke. Brain 2004,
127:1670–1677.
188. Tilleux S, Hermans E: Neuroinflammation and regulation of glial glutamate
uptake in neurological disorders. J Neurosci Res 2007, 85:2059–2070.
189. Helms HC, Madelung R, Waagepetersen HS, Nielsen CU, Brodin B: In vitro
evidence for the brain glutamate efflux hypothesis: brain endothelial
cells cocultured with astrocytes display a polarized brain-to-bloodtransport of glutamate. 2012, 60:882–893.
190. Leonard BE: The concept of depression as a dysfunction of the immune
system. Curr Immunol Rev 2010, 6:205–212.
191. Labrie V, Wong AH, Roder JC: Contributions of the D-serine pathway to
schizophrenia. Neuropharmacology 2012, 62:1484–1503.
192. Gras G, Samah B, Hubert A, Leone C, Porcheray F, Rimaniol AC: EAAT
expression by macrophages and microglia: still more questions thananswers. Amino Acids 2012, 42:221–229.
193. Livingstone PD, Dickinson JA, Srinivasan J, Kew JN, Wonnacott S:
Glutamate-dopamine crosstalk in the rat prefrontal cortex is modulatedNajjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

by Alpha7 nicotinic receptors and potentiated by PNU-120596. J Mol
Neurosci 2010, 40:172–176.
194. Kondziella D, Brenner E, Eyjolfsson EM, Sonnewald U: How do glialneuronal interactions fit into current neurotransmitter hypotheses ofschizophrenia? Neurochem Int 2007, 50:291–301.
195. Wu HQ, Pereira EF, Bruno JP, Pellicciari R, Albuquerque EX, Schwarcz R: The
astrocyte-derived alpha7 nicotinic receptor antagonist kynurenic acidcontrols extracellular glutamate levels in the prefrontal cortex. J Mol
Neurosci 2010, 40:204–210.
196. Steiner J, Bogerts B, Schroeter ML, Bernstein HG: S100B protein inneurodegenerative disorders. Clin Chem Lab Med 2011, 49:409–424.
197. Steiner J, Marquardt N, Pauls I, Schiltz K, Rahmoune H, Bahn S, Bogerts B,
Schmidt RE, Jacobs R: Human CD8(+) T cells and NK cells express andsecrete S100B upon stimulation. Brain Behav Immun 2011, 25:1233–1241.
198. Shanmugam N, Kim YS, Lanting L, Natarajan R: Regulation of
cyclooxygenase-2 expression in monocytes by ligation of the receptor
for advanced glycation end products. J Biol Chem 2003, 278:34834–34844.
199. Rothermundt M, Ohrmann P, Abel S, Siegmund A, Pedersen A, Ponath G,
Suslow T, Peters M, Kaestner F, Heindel W, Arolt V, Pfleiderer B: Glial cell
activation in a subgroup of patients with schizophrenia indicated byincreased S100B serum concentrations and elevated myo-inositol.
Prog Neuropsychopharmacol Biol Psychiatry 2007, 31:361–364.
200. Falcone T, Fazio V, Lee C, Simon B, Franco K, Marchi N, Janigro D: Serum
S100B: a potential biomarker for suicidality in adolescents? PLoS One
2010, 5:e11089.
201. Schroeter ML, Abdul-Khaliq H, Krebs M, Diefenbacher A, Blasig IE: Serum
markers support disease-specific glial pathology in major depression.
J Affect Disord 2008, 111:271–280.
202. Rothermundt M, Ahn JN, Jorgens S: S100B in schizophrenia: an update.
Gen Physiol Biophys 2009, 28 Spec No Focus:F76–F81.
203. Schroeter ML, Abdul-Khaliq H, Krebs M, Diefenbacher A, Blasig IE: Neuronspecific enolase is unaltered whereas S100B is elevated in serum ofpatients with schizophrenia–original research and meta-analysis.
Psychiatry Res 2009, 167:66–72.
204. Rothermundt M, Missler U, Arolt V, Peters M, Leadbeater J, Wiesmann M,
Rudolf S, Wandinger KP, Kirchner H: Increased S100B blood levels in
unmedicated and treated schizophrenic patients are correlated withnegative symptomatology. Mol Psychiatry 2001, 6:445–449.
205. Suchankova P, Klang J, Cavanna C, Holm G, Nilsson S, Jonsson EG, Ekman A:
Is the Gly82Ser polymorphism in the RAGE gene relevant toschizophrenia and the personality trait psychoticism? J Psychiatry Neurosci
2012, 37:122–128.
206. Scapagnini G, Davinelli S, Drago F, De Lorenzo A, Oriani G: Antioxidants as
antidepressants: fact or fiction? CNS Drugs 2012, 26:477–490.
207. Ng F, Berk M, Dean O, Bush AI: Oxidative stress in psychiatric disorders:evidence base and therapeutic implications. Int J Neuropsychopharmacol
2008, 11:851–876.
208. Salim S, Chugh G, Asghar M: Inflammation in anxiety. Adv Protein Chem
Struct Biol 2012, 88:1–25.
209. Anderson G, Berk M, Dodd S, Bechter K, Altamura AC, Dell'osso B, Kanba S,
Monji A, Fatemi SH, Buckley P, Debnath M, Das UN, Meyer U, Müller N,
Kanchanatawan B, Maes M: Immuno-inflammatory, oxidative and nitrosative
stress, and neuroprogressive pathways in the etiology, course and treatment
of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013, 42:1–42.
210. Coughlin JM, Ishizuka K, Kano SI, Edwards JA, Seifuddin FT, Shimano MA,
Daley EL, et al: Marked reduction of soluble superoxide dismutase-1(SOD1) in cerebrospinal fluid of patients with recent-onset
schizophrenia. Mol Psychiatry 2012, 18:10–11.
211. Bombaci M, Grifantini R, Mora M, Reguzzi V, Petracca R, Meoni E, Balloni S,
Zingaretti C, Falugi F, Manetti AG, Margarit I, Musser JM, Cardona F, Orefici
G, Grandi G, Bensi G: Protein array profiling of tic patient sera reveals abroad range and enhanced immune response against Group A
Streptococcus antigens. PLoS One 2009, 4:e6332.
212. Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L,
Cantoni O, Clementi E, Moncada S, Carruba MO, Nisoli E: TNF-alphadownregulates eNOS expression and mitochondrial biogenesis in fat
and muscle of obese rodents. J Clin Invest 2006, 116:2791–2798.
213. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B: Mitochondria, oxidative
stress and cell death. Apoptosis 2007, 12:913–922.
214. Shalev H, Serlin Y, Friedman A: Breaching the blood–brain barrier as a gate
to psychiatric disorder. Cardiovasc Psychiatry Neurol 2009, 2009:278531.

Page 23 of 24

215. Abbott NJ, Ronnback L, Hansson E: Astrocyte-endothelial interactions at the
blood–brain barrier. Nat Rev Neurosci 2006, 7:41–53.
216. Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG:
Cerebrospinal fluid analysis in affective and schizophrenic spectrum
disorders: identification of subgroups with immune responses andblood-CSF barrier dysfunction. J Psychiatr Res 2010, 44:321–330.
217. Harris LW, Wayland M, Lan M, Ryan M, Giger T, Lockstone H, Wuethrich I,
Mimmack M, Wang L, Kotter M, Craddock R, Bahn S: The cerebral
microvasculature in schizophrenia: a laser capture microdissection study.
PLoS One 2008, 3:e3964.
218. Lin JJ, Mula M, Hermann BP: Uncovering the neurobehaviouralcomorbidities of epilepsy over the lifespan. Lancet 2012, 380:1180–1192.
219. Isingrini E, Belzung C, Freslon JL, Machet MC, Camus V: Fluoxetine effect onaortic nitric oxide-dependent vasorelaxation in the unpredictablechronic mild stress model of depression in mice. Psychosom Med 2012,
74:63–72.
220. Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC: The effect ofrisperidone treatment on superoxide dismutase in schizophrenia. J Clin
Psychopharmacol 2003, 23:128–131.
221. Lavoie KL, Pelletier R, Arsenault A, Dupuis J, Bacon SL: Association between
clinical depression and endothelial function measured by forearm
hyperemic reactivity. Psychosom Med 2010, 72:20–26.
222. Chrapko W, Jurasz P, Radomski MW, Archer SL, Newman SC, Baker G, Lara N,
Le Melledo JM: Alteration of decreased plasma NO metabolites andplatelet NO synthase activity by paroxetine in depressed patients.
Neuropsychopharmacology 2006, 31:1286–1293.
223. Chrapko WE, Jurasz P, Radomski MW, Lara N, Archer SL, Le Melledo JM:
Decreased platelet nitric oxide synthase activity and plasma nitric oxide
metabolites in major depressive disorder. Biol Psychiatry 2004, 56:129–134.
224. Stuehr DJ, Santolini J, Wang ZQ, Wei CC, Adak S: Update on mechanism
and catalytic regulation in the NO synthases. J Biol Chem 2004,
279:36167–36170.
225. Chen W, Druhan LJ, Chen CA, Hemann C, Chen YR, Berka V, Tsai AL, Zweier
JL: Peroxynitrite induces destruction of the tetrahydrobiopterin andheme in endothelial nitric oxide synthase: transition from reversible toirreversible enzyme inhibition. Biochemistry 2010, 49:3129–3137.
226. Chen CA, Wang TY, Varadharaj S, Reyes LA, Hemann C, Talukder MA, Chen
YR, Druhan LJ, Zweier JL: S-glutathionylation uncouples eNOS andregulates its cellular and vascular function. Nature 2010, 468:1115–1118.
227. Szabo C, Ischiropoulos H, Radi R: Peroxynitrite: biochemistry,pathophysiology and development of therapeutics. Nat Rev Drug Discov
2007, 6:662–680.
228. Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L,
Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T,
Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M: Lmethylfolate as adjunctive therapy for SSRI-resistant major depression:
results of two randomized, double-blind, parallel-sequential trials. Am J
Psychiatry 2012, 169:1267–1274.
229. Antoniades C, Shirodaria C, Warrick N, Cai S, de Bono J, Lee J, Leeson P,
Neubauer S, Ratnatunga C, Pillai R, Refsum H, Channon KM: 5methyltetrahydrofolate rapidly improves endothelial function anddecreases superoxide production in human vessels: effects on vasculartetrahydrobiopterin availability and endothelial nitric oxide synthase
coupling. Circulation 2006, 114:1193–1201.
230. Masano T, Kawashima S, Toh R, Satomi-Kobayashi S, Shinohara M, Takaya T,
Sasaki N, Takeda M, Tawa H, Yamashita T, Yokoyama M, Hirata K: Beneficial
effects of exogenous tetrahydrobiopterin on left ventricular remodelingafter myocardial infarction in rats: the possible role of oxidative stresscaused by uncoupled endothelial nitric oxide synthase. Circ J 2008,
72:1512–1519.
231. Alp NJ, Channon KM: Regulation of endothelial nitric oxide synthase by
tetrahydrobiopterin in vascular disease. Arterioscler Thromb Vasc Biol 2004,
24:413–420.
232. Szymanski S, Ashtari M, Zito J, Degreef G, Bogerts B, Lieberman J:
Gadolinium-DTPA enhanced gradient echo magnetic resonance scans infirst episode of psychosis and chronic schizophrenic patients.
Psychiatry Res 1991, 40:203–207.
233. Butler T, Weisholtz D, Isenberg N, Harding E, Epstein J, Stern E, Silbersweig
D: Neuroimaging of frontal-limbic dysfunction in schizophrenia andepilepsy-related psychosis: toward a convergent neurobiology.
Epilepsy Behav 2012, 23:113–122.

Najjar et al. Journal of Neuroinflammation 2013, 10:43
http://www.jneuroinflammation.com/content/10/1/43

234. Butler T, Maoz A, Vallabhajosula S, Moeller J, Ichise M, Paresh K, Pervez F,
Friedman D, Goldsmith S, Najjar S, Osborne J, Solnes L, Wang X, French J,
Thesen T, Devinsky O, Kuzniecky R, Stern E, Silbersweig D: Imaging
inflammation in a patient with epilepsy associated with antibodies toglutamic acid decarboxylase [abstract]. In Am Epilepsy Society Abstracts,
Volume 2. Baltimore: American Epilepsy Society; 2011:191.
235. van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers
E, Luurtsema G, Windhorst AD, Cahn W, Lammertsma AA, Kahn RS:
Microglia activation in recent-onset schizophrenia: a quantitative (R)[11C]PK11195 positron emission tomography study. Biol Psychiatry 2008,
64:820–822.
236. Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC:
Neuroinflammation in schizophrenia-related psychosis: a PET study.
J Nucl Med 2009, 50:1801–1807.
237. Takano A, Arakawa R, Ito H, Tateno A, Takahashi H, Matsumoto R, Okubo Y,
Suhara T: Peripheral benzodiazepine receptors in patients with chronic
schizophrenia: a PET study with [11C]DAA1106. Int J
Neuropsychopharmacol 2010, 13:943–950.
238. Müller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B,
Spellmann I, Hetzel G, Maino K, Kleindienst N, Möller HJ, Arolt V, Riedel M:
The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects inmajor depression: results of a double-blind, randomized, placebo
controlled, add-on pilot study to reboxetine. Mol Psychiatry 2006,
11:680–684.
239. Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, MohebbiRasa S, Raznahan M, Kamalipour A: Clinical trial of adjunctive celecoxib
treatment in patients with major depression: a double blind andplacebo controlled trial. Depress Anxiety 2009, 26:607–611.
240. Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N:
Shortened onset of action of antidepressants in major depression using
acetylsalicylic acid augmentation: a pilot open-label study. Int Clin
Psychopharmacol 2006, 21:227–231.
241. Uher R, Carver S, Power RA, Mors O, Maier W, Rietschel M, Hauser J,
Dernovsek MZ, Henigsberg N, Souery D, Placentino A, Farmer A, McGuffin P:
Non-steroidal anti-inflammatory drugs and efficacy of antidepressants inmajor depressive disorder. Psychol Med 2012, 42:2027–2035.
242. Müller N, Riedel M, Scheppach C, Brandstatter B, Sokullu S, Krampe K,
Ulmschneider M, Engel RR, Moller HJ, Schwarz MJ: Beneficial antipsychotic
effects of celecoxib add-on therapy compared to risperidone alone inschizophrenia. Am J Psychiatry 2002, 159:1029–1034.
243. Müller N, Riedel M, Schwarz MJ, Engel RR: Clinical effects of COX-2
inhibitors on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci
2005, 255:149–151.
244. Müller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M,
Moller HJ, Klauss V, Schwarz MJ, Riedel M: Celecoxib treatment in an earlystage of schizophrenia: results of a randomized, double-blind, placebocontrolled trial of celecoxib augmentation of amisulpride treatment.
Schizophr Res 2010, 121:118–124.
245. Sayyah M, Boostani H, Pakseresht S, Malayeri A: A preliminary randomized
double-blind clinical trial on the efficacy of celecoxib as an adjunct inthe treatment of obsessive-compulsive disorder. Psychiatry Res 2011,
189:403–406.
246. Sublette ME, Ellis SP, Geant AL, Mann JJ: Meta-analysis of the effects ofeicosapentaenoic acid (EPA) in clinical trials in depression. J Clin
Psychiatry 2011, 72:1577–1584.
247. Bloch MH, Hannestad J: Omega-3 fatty acids for the treatment ofdepression: systematic review and meta-analysis. Mol Psychiatry 2012,
17:1272–1282.
248. Keller WR, Kum LM, Wehring HJ, Koola MM, Buchanan RW, Kelly DL: A
review of anti-inflammatory agents for symptoms of schizophrenia.
J Psychopharmacol.
249. Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P:
Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs)
are attenuated by antiinflammatory drugs in mice and humans. Proc Natl
Acad Sci USA 2011, 108:9262–9267.
250. Gallagher PJ, Castro V, Fava M, Weilburg JB, Murphy SN, Gainer VS, Churchill
SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH: Antidepressant response
in patients with major depression exposed to NSAIDs: apharmacovigilance study. Am J Psychiatry 2012, 169:1065–1072.
251. Shelton RC: Does concomitant use of NSAIDs reduce the effectiveness ofantidepressants? Am J Psychiatry 2012, 169:1012–1015.

Page 24 of 24

252. Martinez-Gras I, Perez-Nievas BG, Garcia-Bueno B, Madrigal JL, AndresEsteban E, Rodriguez-Jimenez R, Hoenicka J, Palomo T, Rubio G, Leza JC:
The anti-inflammatory prostaglandin 15d-PGJ2 and its nuclear receptor
PPARgamma are decreased in schizophrenia. Schizophr Res 2011,
128:15–22.
253. Garcia-Bueno B, Perez-Nievas BG, Leza JC: Is there a role for the nuclear
receptor PPARgamma in neuropsychiatric diseases? Int J
Neuropsychopharmacol 2010, 13:1411–1429.
254. Meyer U: Anti-inflammatory signaling in schizophrenia. Brain Behav
Immun 2011, 25:1507–1518.
255. Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M,
Hinz B: COX-2 and PPAR-gamma confer cannabidiol-induced apoptosisof human lung cancer cells. Mol Cancer Ther 2013, 12:69–82.
256. Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF,
Godbout JP: Minocycline attenuates lipopolysaccharide (LPS)-induced
neuroinflammation, sickness behavior, and anhedonia.
J Neuroinflammation 2008, 5:15.
257. Sarris J, Mischoulon D, Schweitzer I: Omega-3 for bipolar disorder: metaanalyses of use in mania and bipolar depression. J Clin Psychiatry 2012,
73:81–86.
258. Amminger GP, Schafer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan
SM, Mackinnon A, McGorry PD, Berger GE: Long-chain omega-3 fatty acids
for indicated prevention of psychotic disorders: a randomized, placebocontrolled trial. Arch Gen Psychiatry 2010, 67:146–154.
259. Fusar-Poli P, Berger G: Eicosapentaenoic acid interventions in
schizophrenia: meta-analysis of randomized, placebo-controlled studies.
J Clin Psychopharmacol 2012, 32:179–185.
260. Zorumski CF, Paul SM, Izumi Y, Covey DF, Mennerick S: Neurosteroids,
stress and depression: Potential therapeutic opportunities.
Neurosci Biobehav Rev 2013, 37:109–122.
261. Uhde TW, Singareddy R: Biological Research in Anxiety Disorders. In
Psychiatry as a Neuroscience. Edited by Juan Jose L-I, Wolfgang G, Mario M,
Norman S. Chichester: John Wiley & Sons, Ltd; 2002:237–286.
262. Gibson SA, Korado Z, Shelton RC: Oxidative stress and glutathione
response in tissue cultures from persons with major depression.
J Psychiatr Res 2012, 46:1326–1332.
263. Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN,
Bowden CL, Soares JC: Celecoxib as an adjunct in the treatment ofdepressive or mixed episodes of bipolar disorder: a double-blind,randomized, placebo-controlled study. 2008, 23:87–94.
264. Levine J, Cholestoy A, Zimmerman J: Possible antidepressant effect of
minocycline. 1996, 153:582.
265. Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G,
Fennig S, Treves I, Kron S: A double-blind, randomized study of
minocycline for the treatment of negative and cognitive symptoms inearly-phase schizohprenia. J Clin Psychiatry 2010, 71:138–149.
266. Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J:
Possible antipsychotic effect of minocycline in patients withschizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31:304–307.
267. Miyaoka J, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J:
Minocycline as adjunctive therapy for schizophrenia: an open-label
study. 2008, 31:287–292.
268. Rodriguez CI, Bender J Jr, Marcus SM, Snape M, Rynn M, Simpson HB:
Minocycline augmentation of pharmacotherapy in obsessive-compulsive
disorder: an open-label trial. 2010, 71:1247–1249.
doi:10.1186/1742-2094-10-43
Cite this article as: Najjar et al.: Neuroinflammation and psychiatricillness. Journal of Neuroinflammation 2013 10:43.