REVIEW

Inammation in Children and Adolescents

With Neuropsychiatric Disorders:
A Systematic Review
Rachel H.B. Mitchell, MD, MSc, AND Benjamin I. Goldstein, MD, PhD, FRCPC

Objective: There has been rapid growth in research regarding inammation in neuropsychi-
atric disorders as it relates to youth. We therefore set out to systematically review the literature
on inammation and neuropsychiatric disorders in children and adolescents. Method: A
systematic review of the literature was performed according to the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were included if
proinammatory markers (PIMs) in children and/or adolescents with neuropsychiatric disor-
ders were measured. Results: Sixty-seven studies were included, involving 3,952 youth.
Evidence for a proinammatory state is strongest for autism spectrum disorders (ASD). PIMs
are elevated in children and adolescents with major depressive disorder (MDD), bipolar
disorder (BD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD),
Tourettes disorder (TD), attention-decit/hyperactivity disorder (ADHD), and schizophrenia
(SZ). However, the data are inconsistent. Evidence for specic PIMs is equivocal at this
stage, although the ndings in youth with MDD, BD, and PTSD converge with the
extant adult literature in these areas. Denitive conclusions are limited by methodologic
factors including cross-sectional and retrospective study design, between-study differences in
specic markers and methods of analysis, small sample size, and other sources of hetero-
geneity. Conclusion: The literature regarding inammation among children and adolescents
with neuropsychiatric disorders represents nearly 4,000 youth. There is preliminary evidence
for elevated markers of inammation in this population. Larger, prospective studies are
needed to realize the goal of inammatory markers informing clinical practice. In the interim,
present ndings suggest that further examination of this topic is warranted. J. Am. Acad. Child
Adolesc. Psychiatry, 2014;53(3):274296. Key Words: cytokines, inammation, psychiatric
disorders

O
ver the past 2 decades, evidence has
accumulated to support a pathophysio-
logical relationship between inamma-
tion and psychiatric disorders. Inammation is a
well-established factor in the pathogenesis of
chronic diseases that are highly comorbid with
psychiatric disorders such as coronary artery
disease and rheumatoid arthritis,1 as well as
in diseases with a pediatric onset, such as juve-
nile rheumatoid arthritis (JRA) and inamma-
tory bowel disease (IBD).1,2 Furthermore, among
children and adolescents with psychiatric disor-
ders, there is a high prevalence of conditions
associated with inammation, such as asthma
and obesity.3,4
Inammation comprises a complex reaction to
a broad spectrum of noxious stimuli, including
vascular responses, migration and activation of
leukocytes, and systemic reactions.1 Cytokines
are molecules that function as key modulators
of inammation and essential mediators between
the immune system and the central nervous
system.1 Cytokines are pleotropic and can
be proinammatory, anti-inammatory, or both.
However, for parsimony, and to encompass the
important inammatory marker C-reactive pro-
tein (CRP), this article will use the term proin-
ammatory markers (PIMs).
PIMs have the potential to serve as biomar-
kers for psychiatric diagnosis, disease course,
and therapeutic intervention, and therefore have
been a major focus of recent investigation.5-8
Indeed, recent studies have examined the poten-
tial psychiatric applications of anti-inammatory

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 INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH
medications including aspirin,9,10 nonsteroidal
anti-inammatory drugs (NSAIDs),11-12,13 tumor
necrosis factor (TNF)a antagonists,14 and omega-
3 fatty acids.15
Evidence supporting the pathogenic link
among inammation, PIMs, and psychiatric dis-
orders is strongest in adults with major depres-
sive disorder (MDD). Prospective studies have
consistently found that interferon (IFN)a ther-
apy induces depression in a substantial pro-
portion of patients being treated for hepatitis
C, particularly in a subset of patients with the
serotonin transporter promoter region suscepti-
bility polymorphism.16-18 Furthermore, a meta-
analysis evaluating cytokines in MDD revealed
a signicantly higher concentration of interleu-
kin (IL)6 and TNF-a in depressed subjects as
compared with nondepressed subjects, although
studies included were largely cross-sectional and
cannot infer causality.19 Adult bipolar disorder
(BD)20 and schizophrenia21 have also been asso-
ciated with inammation. Putative mechanisms
include glucocorticoid resistance,22 bloodbrain
barrier disruption,23,24 altered neurotransmitter
metabolism,24,25 impaired functional connecti-
vity,26 increased oxidative stress,27 astrocyte
and micgrolia activation,20,28 neuronal damage
and degeneration,29,30 and reduced neurotrophic
support.31,32
Cytokine production, however, differs in chil-
dren as compared with adults, and ndings in
adults cannot necessarily be extrapolated to chil-
dren.33 Furthermore, the study of PIMs in chil-
dren and adolescents with psychiatric disorders
may optimize signal detection because of shorter
illness duration and less allostatic load as com-
pared to those in adults.34,35 It also presents
a unique opportunity to better elucidate mecha-
nisms of the association between inammation
and psychiatric disorders without the confound-
ing burden of medical comorbidities in the adult
population. Indeed, ndings from adults suggest
that examining PIMs as putative biomarkers
and using anti-inammatory medications as pu-
tative treatments may be more fruitful among
adults who are younger and/or earlier in their
course of illness. These considerations also sug-
gest the possibility that children and adolescents
with psychiatric disorders may be particularly
amenable to treatment with anti-inammatory
medications, although at present this literature
is sparse.
The literature evaluating the role of inam-
mation in the pathogenesis of a number of
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VOLUME 53 NUMBER 3 MARCH 2014
psychiatric disorders in children and adolescents
has grown signicantly in recent years. None-
theless, to our knowledge, there is no published
review synthesizing the salient ndings in this
area. Therefore, the purpose of this article is to
systematically review, for the rst time, the cur-
rent evidence regarding inammation and psy-
chiatric disorders in children and adolescents.
METHOD
A systematic review of the literature on inammation
and neuropsychiatric disorders in children and ado-
lescents was performed according to The Preferred
Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) statement.36 MEDLINE searches
were conducted of all studies published from 1946
to August 2013 using the following medical subject
headings (MeSH) terms and keywords (listed alpha-
betically): anxiety disorders (AD) or generalized anxiety
disorder (GAD); Asperger syndrome (AS) or Asperger
disorder (AD); attention decit disorder (ADD) with
hyperactivity or attention decit and hyperactivity disorder
(ADHD), bipolar disorder (BD), child development disor-
ders, pervasive or autism spectrum disorder (ASD) or
pervasive developmental disorder (PDD), depressive disor-
der, major or major depressive disorder (MDD), dysthymic
disorder (DD) or dysthymia, obsessive-compulsive disorder
(OCD), phobic disorders and social anxiety disorders (SAD),
stress disorders, post-traumatic or post-traumatic stress
disorder (PTSD), schizophrenia (SZ), and Tourette syn-
drome or Tourettes disorder (TD) each cross-referenced
with C-reactive protein (CRP), cytokines, interleukin (IL),
inammation, inammatory, tumor necrosis factor (TNF),
or anti-inammatory and adolescent, child, paediatric, pe-
diatric, or youth.
Two independent unblinded reviewers (R.H.B.M.,
B.I.G.) assessed study eligibility by screening the titles
and abstracts in a standardized manner. Full texts were
reviewed in more detail by the rst author. Given the
preliminary stage of research in this area, only minimal
exclusion criteria were used. Studies were included if
they were published in English and measured PIMs in
either children or adolescents with any of the afore-
mentioned psychiatric disorders, regardless of sample
size, study design, or laboratory procedure. Studies
measured PIMs in various mediums and using an
array of techniques, for example, circulating in vivo
in peripheral blood (serum and plasma) or cerebro-
spinal uid (CSF), in vitro exposure of peripheral blood
mononuclear cells (PBMC) to stimulation by mitogen,
lipopolysaccharide, or phytohemagglutinin, cytokine
expression of stimulated post-mortem brain tissue or
lymphocyte staining of spontaneous intracellular cy-
tokines in intestinal biopsy samples. Provided that they
met the aforementioned inclusion criteria, studies were
also included if they evaluated cytokine gene expres-
sion, protein production, or genetic polymorphisms.
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MITCHELL AND GOLDSTEIN
Studies were excluded if the majority of the sample
was older than 18 years, if age and/or data for youth
were not reported separately, if no data on inamma-
tory markers were reported, or if no original data or
analyses were reported.
Vascular cell adhesion molecules (VCAM), other
acute phase reactants, immunomodulators, and chem-
ical mediators of inammation are to varying degrees
related to the subject of this review; however, for
parsimony, we elected to focus exclusively on proin-
ammatory and anti-inammatory cytokines and CRP.
RESULTS
A total of 67 studies were identied for nal in-
clusion. The MEDLINE search yielded 667 cita-
tions. An additional 7 studies were identied and
included after checking references from included
papers. After adjusting for duplicates (n 80),
593 citations remained. Of these, 526 were ex-
cluded (not primary psychiatric disorder 188,
not cytokines 163, adults 97, not primary
research 61, not English 14, not human 3).
A ow diagram is provided in Figure 1.
Table 137-63 summarizes the signicant nd-
ings from the 28 studies involving children and
adolescents with MDD or other mood disorder
(n 178), completed suicide (n 24), BD (n
30), PTSD (n 32), TD (n 453), TD  OCD (n
110), acute psychosis/SZ (n 86), and ADHD/
ADD (n 1,488). Because of the comparatively
large amount of research on this topic, signicant
ndings from the 39 studies involving children
and adolescents with ASD (n 1,551) are sum-
marized separately in Table 2.65-103 The ndings
are discussed below.
Inammation in Children and Adolescents With
Major Depressive Disorder, Dysthymia, and/or
Suicidality
Studies investigating inammation in children
and adolescents with MDD point toward in-
creased levels of PIMs. Gabbay et al. reported a
trend toward increased IL-642 and signicantly
elevated levels of IFN-g in adolescents with
MDD41,42 and in adolescents with MDD and
active suicidal ideation (SI).41 Henje et al.37 re-
ported signicantly elevated IL-1b, IL-2, and
IL-10 in female children and adolescents with
MDD and/or anxiety disorders (AD) and signif-
icantly elevated IL-6 in the unmedicated group
as compared to controls. Brambilla et al.43 re-
ported elevated IL-1b in youth with dysthymia.
By contrast, there was no difference in TNF-a
observed between adolescents with MDD or
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controls,37,43 and TNF-a was decreased in ado-
lescents with dysthymia43 and in adolescents
with MDD and suicidal intent.41
Pandey et al. examined post-mortem samples
of adolescents who completed suicide and found
signicantly increased mRNA and protein ex-
pression levels of IL-1b, and TNF-a in Brodmans
area in the prefrontal cortex, as compared to
controls, with a trend toward increased expres-
sion of IL-6.38
Miller et al. examined 187 healthy female ad-
olescents at high risk for depression (dened
as having a rst-degree relative with history of
depression and/or elevated scores on cognitive
vulnerability to depression) and found signi-
cantly increased IL-6 and CRP during a major
depressive episode (MDE) compared to euthymic
periods in subjects with a history of high child-
hood adversity.39 Elevated CRP persisted over
6 months, and elevated IL-6 predicted future
MDEs after controlling for confounding vari-
ables.39 These ndings did not apply to subjects
without exposure to childhood adversity.
Inammation in Children and Adolescents With
Bipolar Disorder
One recent study examining 30 participants in
the Course and Outcome of Bipolar Youth
(COBY) study104 found that high-sensitivity CRP
(hsCRP) but not IL-6 was associated with manic
symptom severity, although this association was
reduced to a trend when obesity was included in
multivariate analysis.44 Notably, 40% of partici-
pants had hsCRP levels 2 mg/mL,44 which is an
independent predictor of rst cardiovascular
events among healthy adults.105-107 One study
examined offspring of parents with BD (n 16
with a mood disorder) and identied a proin-
ammatory gene expression signature of 19 genes
aberrantly expressed in inammation.45 This
proinammatory signature was present in 52%
of adults with BD, 85% of offspring with a mood
disorder, 100% of offspring who developed a
mood disorder, as well as 19% of euthymic
offspring.45
Inammation in Children and Adolescents With
Posttraumatic Stress Disorder
Pervanidou et al. examined PIMs in children the
morning after a motor vehicle accident (MVA),
and found that elevated serum IL-6 predicted
development of PTSD at 6-month follow-up and
that the elevated IL-6 values normalized over
time.46
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 INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH
Inammation in Children and Adolescents With
Obsessive Compulsive Disorder and/or Tourettes
Disorder or Tic Disorder
The studies investigating inammation in chil-
dren and adolescents with OCD and/or TD or
tic disorders reported increased PIMs overall;
however, there were differences in the ndings.
Both Gabbay et al.53 and Leckman et al.54 found
increased plasma and serum IL-12, respectively,
in co-morbid TD and OCD. However, only
Leckman et al.54 reported increased IL-12 in iso-
lated TD. Cheng et al. reported increased plasma
IL-1, IL-6, and IL-17 in isolated TD as compared
to controls, but did not examine IL-12,47 whereas
Gabbay et al. reported no signicant difference in
IL-6 but did not examine IL-1 or IL-17.53
Findings regarding TNF-a were also inconsis-
tent. Leckman et al. found increased serum TNF-a
in co-morbid TD and OCD at baseline and during
symptom exacerbation,54 whereas Matz et al. re-
ported increased TNF-a in controls,48 and other
studies reported no difference.51,53 Mittelman
et al.56 evaluated PIMs in the cerebrospinal uid
(CSF) of children with OCD or schizophrenia
(compared to the CSF of children with ADHD)
and found a relative imbalance of PIMs in OCD
(high IL-2; undetectable anti-inammatory cyto-
kines IL-4 and IL-10). A prospective, longitudinal
study of patients with OCD and/or TD found no
signicant difference in hsCRP as compared to
controls at baseline, during symptom exacerba-
tion, or in follow-up.55
Several studies investigated genetic associa-
tions between polymorphisms in cytokine genes
and susceptibility to TD, and found an associa-
tion with IL1RN (odds ratio 7.65)52 but none
with IL10-592A/T,50 IL8-251A/T, IL12B-1188A/
C, or TNF-a-238A/G.49
Inammation in Children and Adolescents With
Attention-Decit/Hyperactivity Disorder
Three studies investigated inammation in a
sample of children and adolescents with ADHD.
One study showed modest increase approaching
signicance in some cytokines (e.g., IFN-g) with
normal levels in the medicated group.59 A second
study found a correlation between increa-
sed cytokines and certain symptoms of ADHD,
specically, increased IL-13 (anti-inammatory)
and inattention and increased IL-16 (proin-
ammatory) and hyperactivity.58 A third study
explored associations between elevated serum
cytokines in children and adolescents with
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ADHD and pregnancy/perinatal features of the
index pregnancy. Signicant correlations were
observed between increased IFN-g and shorter
pregnancy and lower birth weight, decreased
TNF-a and obstetrical problems, and between
increased IL-6 and paternal smoking.57
In a sample of children with ADHD, OCD, or
schizophrenia, the CSF of children with ADHD
contained intermediate levels of cytokines rela-
tive to the OCD and schizophrenia groups, that
were not skewed toward either pro- or anti-
inammatory cytokines.56
Molecular genetics studies have also examined
the link between ADHD and polymorphisms in
inammation-related genes. One study showed
an association between a greater likelihood of
ADHD and the transmission of the IL-1 receptor
antagonist (IL-1Ra) 4-repeat allele63; however,
this nding was not replicated in a larger study.61
Drtiklova et al. found increased allelic and
genotypic frequency of the -174 polymorphism
(C allele) of the IL-6 gene in boys with ADHD
versus controls.108 A recent genome-wide scan of
958 ADHD childparent trios reported that 2
single nucleotide polymorphisms (SNPs) in the
IL-16 gene were associated with the inattentive
phenotype, whereas another analysis reported a
nominal association for IL-3 (NFIL3: C allele)
with earlier-onset ADHD.61,62
Inammation in Children and Adolescents With
Schizophrenia and/or Acute Psychosis
One study of children with childhood-onset
schizophrenia found that TNF-a was not ele-
vated as compared to controls before or after
treatment with clozapine; however, TNF-a was
positively correlated with body mass index
(BMI).64 Mittelman et al.56 found a relative im-
balance of anti-inammatory cytokines in the
CSF of children with schizophrenia (as compared
to those with ADHD) with IL-4 detectable only in
schizophrenia. A study of 64 suicidal adolescents
with acute psychosis (n 40) and/or a mood
disorder (n 24) had elevated serum IL-1b and
IL-8 as compared to controls.40
Inammation in Children and Adolescents With
Autism Spectrum Disorders
Thirty-nine studies investigating PIMs in ASD
were identied. IFN-g was elevated in the
plasma,67,70,101 the supernatant of whole-blood
cultures,95 the CSF,91 and the frozen brain tis-
sue81 of children and adolescents with ASD as
compared to controls. Another study found a
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MITCHELL AND GOLDSTEIN
trend toward increased stimulated IFN-g with
a signicantly higher IFN-g/IL-10 ratio as com-
pared to controls.88 Other studies evaluating
IFN-g in the plasma,72,109 in vitro via PBMC
stimulation,98 or intracellularly74,99 did not nd
elevated levels. Findings for IL-1271,72,76,79,92,101
and IFN-a71,101,102 were also contradictory.
Eight70-72,74,88,91,92,99 of 9 studies70-72,74,88,91,92,99,103
measuring IL-2, and both studies measuring
IL-2R,100,103 did not reveal elevated levels in sub-
jects with ASD as compared to controls. Similarly,
771,74,82,84,91,92,109 of 9 studies71,72,74,82,84,91,92,98,109
did not report elevated levels of IL-1b in ASD.
One study evaluating stimulated PBMC cytokine
production in vitro reported differential sensitivity
of IL-1b (with similar results for IL-6 and TNF-a)
to toll-like-receptor (TLR) ligands.80
The evidence for TNF-a is also inconsis-
tent.70-74,82,86,91,92,95,98,101,109 As compared to controls,
TNF-a levels were increased in the lympho-
blasts74 and the post-mortem brain tissue of
children and adolescents with ASD78,82,91 but
were decreased in the serum,73 with no differ-
ence in the CSF.91,92 Stimulated PBMC TNF-a
production was also increased in individuals
with ASD versus controls.71
Another study found the mean concentration
of TNF-a to be signicantly higher in the CSF of
patients with ASD than in the serum, and the
CSF-to-serum ratio to be higher in ASD than in
other diseases or controls in the medical litera-
ture, and higher still in individuals previously
treated with immunosuppressant medications.86
Yet, there was no correlation between serum
and CSF levels of TNF-a.86 With regards to TNF
receptors, levels of TNFRI and TNFRII were
elevated in the plasma and serum,92,98 but not in
the CSF,92, and there was no correlation between
serum and CSF levels of TNFRI or TNFRII.86
Many studies have examined levels of IL-
6, with contradictory ndings.68,71-74,78,91,92,98,99
IL-6 was both increased72 and decreased,68
in the plasma, and increased in the CSF,91
lymphoblasts,74 and post mortem brain tis-
sue78,82,91specically, the anterior cingulate
gyrus (ACG)78,82,91of children and adolescents
with ASD, as compared to controls. IL-6 was
also reported as decreased in the serum,73 after
in vitro PBMC stimulation71 and exposure to the
environmental contaminant BDE-47.81
Findings for the anti-inammatory cytokine
IL-10 were consistently lower or similar in sub-
jects with ASD as compared to controls across
all but 1 study91 among 10 pertinent studies,
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regardless of methodology and despite elevated
PIMs.70,71,74,78,82,84,88,92,95,98 Findings for other
anti-inammatory cytokines, such as IL-4 and IL-
5, were less consistent, with levels increased
peripherally in the plasma,70 intracellularly,61 and
after in vitro PBMC stimulation in some
studies59,62 but not in others,71 and not centrally
in frozen brain tissue82,92 or in lymphoblasts.74
IL-17, in 2 studies,65,76 and IL-23, in 1 study,84
showed increased levels peripherally in subjects
with ASD. By contrast, Enstrom et al. reported
decreased levels of IL-23 in the plasma85 and in
vitro after PBMC stimulation,83 with no differ-
ence in IL-17. Recent studies reported increased
plasma76 and stimulated PBMC production71 of
IL-13 in subjects with ASD as compared to con-
trols, although another study reported decreased
serum IL-13.77 IL-8 was elevated in vitro,71 as
well as in the plasma,72,76 CSF,91 and post mor-
tem brain tissue of patients with ASD,82 but not
in lymphoblasts.74
Jyonouchi et al. evaluated a small subset
of children with ASD characterized by uctu-
ating behavioral symptoms after immune insults
with specic polysaccharide antibody deciency
(SPAD),69,84 chronic gastrointestinal symptoms,75
or both, and found decreased in vitro production
of multiple proinammatory cytokines as com-
pared to controls, which was not solely attribut-
able to SPAD. By contrast, they also found
increased IL-12 and TNF-a production upon
stimulation with cows milk protein in the same
subset of patients.89,90,97
One of 2 studies examining proinammatory
cytokines produced by intestinal biopsies in
children with ASD found increased produc-
tion,93 whereas the other study did not.96 One
of 2 studies evaluating the effectiveness of hy-
perbaric oxygen treatment (HBOT) revealed a
post-treatment lowering of CRP if pretreatment
levels were elevated66; however, the other study
revealed no change in PIMs,87 and neither study
included a control group.
DISCUSSION
This systematic review includes 67 studies eval-
uating PIMs in 3,952 children and adolescents
with neuropsychiatric disorders. The study me-
thods were largely heterogeneous, however, the
majority of studies (50/67) were cross-sectional
in design and sampled in vivo circulating PIMs
from serum or plasma or in vitro stimulated
PBMC cytokine production. Although the ndings
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 INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH
vary according to disorder, are somewhat incon-
sistent, and do not inform the mechanism or the
nature of the relationship, the literature provides
preliminary evidence that psychiatric disorders
among children and adolescents tend toward an
association with a proinammatory state. The
adult literature on the inammation and psy-
chiatric disorders, albeit far from conclusive, is
more substantive. Therefore, to facilitate inter-
pretation of the ndings of this review and to
offer a neurodevelopmental perspective on the
role of inammation in neuropsychiatric disor-
ders, where possible, these ndings are inter-
preted in the context of the extant adult literature.
Major Depressive Disorder, Dysthymia, and/or
Suicidality
The studies evaluating PIMs in children and ad-
olescents with MDD are fewer in number relative
to the adult literature, yet show that the same
PIMsIL-6, CRP, IL-1b, IFN-gare signicantly
elevated as compared to controls.19,37,42,43 This may
suggest an exaggerated proinammatory state in
MDD across the lifespan.
Two studies focusing on suicidality in adoles-
cents reported increased PIMs (with the exception
of decreased TNF-a) in the plasma of patients
with active suicidal ideation,41 as well as increased
gene and protein expression of PIMs in the post-
mortem prefrontal cortex of suicide completers.38
The signicance of decreased TNF-a is uncertain;
however, these ndings from the adolescent pop-
ulation are generally consistent with the ndings
from the adult population of increased PIMs in
the plasma110 and CSF111 of suicide attempters
and post mortem tissue of suicide completers.112
Bipolar Disorder
Only 1 study has examined PIMs in children
and adolescents with BD; therefore, conclusions
are limited. Preliminary ndings, however, ten-
tatively reinforce the adult literature. Hypoma-
nia/mania is positively correlated with CRP in
both adolescents44 and adults.113 The plausibility
of a pathophysiological relationship between BD
and inammation is further reinforced by evi-
dence that a proinammatory gene expression
signature preceded the rst mood episode in
previously healthy offspring45 of adults with BD.
Posttraumatic Stress Disorder
Similar to BD, only 1 study has examined PIMs
in children and adolescents with PTSD; there-
fore, conclusions are also limited. Tentatively,
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however, the ndings echo the evidence in adults
in that IL-6 is elevated in both the pediatric,114
and the adult115,116 populations with PTSD.
The pathophysiological link between height-
ened inammatory activity and PTSD, however,
may differ in children and adults. In a longitu-
dinal study evaluating children who developed
PTSD, the higher levels of IL-6 measured just af-
ter the trauma normalized over time,46 whereas
in some studies involving adults with PTSD, IL-6
remained chronically elevated.117,118 IL-6 is stim-
ulated by catecholamines and is a potent stimu-
lator of the hypothalamic pituitary axis (HPA),
which is negatively controlled by glucocorti-
coids.119 Therefore, the normalization of IL-6 in
children over time may be explained, in part, by
the absence of prior trauma and other risk factors
such as substance abuse and psychiatric comor-
bidities that may be chronically activating the
HPAcytokine interaction in adults. Indeed,
recent evidence suggests that comorbid PTSD
and MDD can be distinguished from PTSD alone
by sustained higher levels of overnight IL-6 and
decreased sensitivity to hydrocortisone.118
There is substantial evidence highlighting the
longitudinal burden of early childhood maltreat-
ment as an established predictor of a proin-
ammatory state in adulthood1,118,120,121 among
adults with and without MDD. For example,
recent ndings suggest that adults with PTSD
and a history of childhood maltreatment have
increased nuclear factorkB (NF-kB) DNA bind-
ing activitya proxy for a proinammatory
state.122 Mounting evidence also suggests that
the relationship between inammation and MDD
is more pronounced in a sub-group of patients
exposed to childhood adversity. For example,
the association between inammation and MDD
among adults may be partially explained by
childhood maltreatment,123,124 and adolescents
exposed to childhood adversity are more likely to
have clustering of inammation and MDD.39
Obsessive-Compulsive Disorder, Tourettes
Disorder, and Tic Disorder
The increase in IL-12 and TNF-a in children and
adolescents with co-morbid TD and OCD53,54
has not been observed in the adult population
as adult studies have not consistently examined
these cytokines.125 The reported predominance of
PIMs in the CSF of children and adolescents with
isolated OCD56 has also not been corroborated in
the adult literature, and studies examining other
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MITCHELL AND GOLDSTEIN
FIGURE 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
PIMs in adult OCD are inconclusive, with pre-
dominantly negative ndings.125,126
There is other preliminary evidence impli-
cating inammation in the pathophysiology of
early-onset OCD and/or TD, including signi-
cantly elevated cell adhesion molecules in chil-
dren and adults with TD127 and associations
between OCD and 2 polymorphisms in the pro-
moter region of the TNF-a gene128 and TD and a
polymorphism in IL1RN.52 However, no associ-
ation was found between TD and a poly-
morphism in the IL-10 gene50 or in the IL-8, IL-12,
or TNF-a genes.49
The evidence for pediatric autoimmune
neuropsychiatric disorders associated with strep-
tococcus (PANDAS) remains inconclusive.129 To
better elucidate and substantiate the role of
inammation in the pathophysiology of OCD
and/or TD, however, more research is needed in
exclusively non-PANDAS pediatric OCD and/or
TD populations.
Attention-Decit/Hyperactivity Disorder
Russell et al. have proposed that the endopheno-
type of ADHD is secondary to astrocyte (type of
JOURNAL
280 www.jaacap.org
glial cell) dysfunction, as evidenced by the inad-
equate production of ATP to maintain rapid
neuronal ring in cortical and limbic circuitry.130
Oades et al. indirectly tested this hypothesis by
focusing on indicators of glial cell function, among
other PIMs and metabolites of the kynurenine
pathway.57,58,59 The results of these studies,
however, were equivocal, showing only a modest
increase in PIMs in ADHD, with normal levels
in the medicated group and weak associations
with specic ADHD symptoms and ante-, peri-,
and post-partum risk factors for ADHD.
Taken in context of genetic studies reporting
associations between ADHD and polymorphisms
in proinammatory genes,60-63,108 ndings by
Oades et al. emphasize the importance of future
investigations to clarify the role of PIMS, kynur-
enine metabolites, and other markers of glial
function in the pathogenesis of ADHD.
Schizophrenia
Given the paucity of studies examining PIMs
among youth with schizophrenia, little can be
said about the link between inammation and
schizophrenia in this age group, and it is difcult
OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY
VOLUME 53 NUMBER 3 MARCH 2014
 TABLE 1 Characteristics and Findings Regarding Proinflammatory Markers in Children and Adolescents With Psychiatric Disorders
VOLUME 53 NUMBER 3 MARCH 2014
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

Study by Psychiatric Disorder Country Participants Measures Findings

Major Depressive Disorder (MDD), Dysthymia, and Completed Suicide
Henje et al.,37 2012 Sweden 60 MDD or AD Plasma IL-1b, IL-2, IL-6, IL-10, Increased IL-2, IL-1b, IL-10 vs. controls; subgroup not
60 female IFN-g, TNF-a treated with SSRIs increased IL-6, IL-1, IL-1b vs.
14.5e18.4 y controls; IL-6 and IFN-g positively correlated with
44 controls self-report symptoms of anxiety and/or depression
Pandey et al.,38 2012 US 24 completed suicide Postmortem PFC, mRNA and Increased mRNA and protein expression levels of
14 male protein expression of IL-1b, IL-1b and TNF- a in Brodmanns area of PFC;
12e20 y IL-6, TNF-a trend towards increased expression of IL-6
24 controls
Miller et al.,39 2012 US 147 at risk for MDD Serum IL-6, CRP Increased IL-6 and CRP in female adolescents
(40 developed MDE) who developed MDD with a history of
147 female childhood adversity
5e19 y
No controls
Falcone et al.,40 2010 See Schizophrenia
Gabbay et al.,41 2009 USA 12 MDD SI Plasma IL-1b, IL-4, IL-6, IFN-g, TNF-a Decreased TNF-a in MDDSI vs. MDD-SI;
5 male increased IFN-g in MDDSI vs. controls; increased

INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH

4e19 y IFN-g in MDD-SI vs. controls; increased IFN-
18 MDD e SI g/IL-4 in MDD-SI vs. controls; no difference
6 male between medicated and non-medicated groups;
12e19 y no correlation with PIM concentrations and
15 controls MDD symptoms
Gabbay et al.,42 2009 USA 30 MDD Plasma IL-1b, IL-4, IL-6 IFN-g, TNF-a Increased IFN- g in MDD vs. controls; trend for
19 male increased IL-6 in MDD vs. controls; no signicant
12e19 y differences in TNF-a, IL-1b, or IL-4; no association
15 controls between MDD symptoms and PIM concentration
Brambilla et al.,43 2004 Italy 11 MDD Plasma IL-1b, TNF-a Increased IL-1b in dysthymia vs. controls, no signicant
9 male, difference between MDD and controls or MDD and
8e14 y dysthymia; decreased TNF-a in dysthymia vs.
www.jaacap.org

11dysthymia controls, no signicant difference between MDD

8 male and controls or MDD and dysthymia; positive
6e14 y correlation between TNF-a and depression
11 controls symptom severity
Bipolar Disorder (BD)
Goldstein et al.,44 2011 USA 30 BD-I, II, NOS Serum IL-6, hsCRP Manic symptom severity positively correlated
24 male with hsCRP (trend when controlled for obesity);
12e19 y no correlation with IL-6; depressive symptom
281

severity not correlated with hsCRP or IL-6;

40% sample hsCRP  2mg/mL
 TABLE 1 Continued
282

MITCHELL AND GOLDSTEIN

Study by Psychiatric Disorder Country Participants Measures Findings

Padmos et al.,45 2008 Netherlands 42 adult BD Inammatory gene expression 19 aberrantly expressed genes involved in
www.jaacap.org

16 male in monocytes inammation and inammation processes in

26e57 y monoctyes of BD forming gene expression
54 offspring, 16 with signature; gene signature found in 85% of offspring
mood disorder with mood disorder, 100% of offspring who
26 male developed mood disorder, 19% euthymic offspring;
12e26 y lithium and antipsychotic medication downregulated
70 child controls gene expression of inammatory genes
33 male
11e29 y
25 controls
Posttraumatic Stress Disorder (PTSD)
Pervanidou et al.,46 2007 Greece 56 post- MVA Serum IL-6 Increased IL-6 in morning post-MVA in children who
40 male developed PTSD at 6 months vs. no PTSD; increased
7e18 y IL-6 normalized in PTSD group at 6 months
40 controls
Obsessive-Compulsive Disorder (OCD) and/or Tourette Disorder (TD) or Tic Disorder
Cheng et al.,47 2012 China 40 TD Plasma IL-1, IL-6, sIL-6R, IL-17 Increased IL-1, IL-6, IL-17 in TD vs. controls;
JOURNAL

28 male decreased sIL-17R in TD vs. controls

7e19 y
OF THE

40 Controls
Matz et al.,48 2012 Germany 15 TD Serum IL-1Ra TNF-a Increased TNF-a and IL-1Ra in controls vs. TD
<18 y
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

10 controls
age and gender data
not available
VOLUME 53 NUMBER 3 MARCH 2014

Liu et al.,49 2011 China 108 TD and parents IL8-251A/T, IL12B-1188A/C, No association between studied
83 male TNF-a-238A/G polymorphisms polymorphisms and TD
5e18 y
Liu et al.,50 2011 China 108 TD and parents IL-10-592A/C functional No association between IL-10-592A/C
83 male polymorphism polymorphism and TD
5e18 y
Bos-Veneman Netherlands 66 TD Serum IL-2, IL-4, IL-5, IL-10, No signicant difference in serum
et al.,51 2010 57 male IL-12, IFN-g, TNF-a concentrations of PIMs in TD vs. controls
6e18 y
71 controls
Chou et al.,52 2010 Taiwan 159 TD SNP in IL-1RA and IL-1b Polymorphism in IL1RN gene associated with TD;
175 controls odds ratio 7.65
age and gender data
not available
 TABLE 1 Continued
VOLUME 53 NUMBER 3 MARCH 2014
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

Study by Psychiatric Disorder Country Participants Measures Findings

Gabbay et al.,53 2009 USA 32 TD Plasma IL-1b, IL-2, IL-6, IL-12, TNF-a Increased IL-12 in TDOCD vs. controls but not vs.
27 male TD only; increased IL-2 in TDOCD vs. TD only;
7e18 y no signicant differences in TNF-a, IL-1b or IL-6;
17 TDOCD TNF-a inversely correlated with OCD symptom
14 male severity; trend toward IL-2 association with
7e18 y OCD symptom severity
16 controls
Leckman et al.,54 2005 USA 46 TD  OCD Serum IL-2, IL-4, IL-5, IL-10, IL-12, Increased IL-12 and TNF-a in TD/OCD vs. controls;
34 male IFN-g, TNF-a at baseline, during increased TNF-a in non-PANDAS TD/OCD vs.
7.1e16.9 y and after symptom exacerbation controls; increased IL-12 and TNF-a during
31 controls TD/OCD symptom exacerbation
Luo et al.,55 2004 USA 47 TD/OCD or TDOCD Serum hsCRP No signicant difference in hsCRP between groups;
35 male no signicant difference in hsCRP during symptom
7e17 y exacerbation
19 controls
Mittleman et al.,56 1997 USA See schizophrenia
Attention-Decit/Hyperactivity Disorder (ADHD)

INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH

Oades et al.,57 2011
Oades et al.,58 2010
Oades et al.,59 2011
www.jaacap.org
Germany 35 ADHD (14 medicated); Serum IL-1b, IL-2, IL-3, IL-6, Increased IFN-g associated with lower birth
26 male IL-10, IL-13, IL-16, IFN-g, TNF-a weight and shorter pregnancy; increased IL-6
10.4  2.5 y associated with paternal smoking; decreased
21 controls TNF-a associated with obstetric problems
Germany 35 ADHD Serum IL-2, IL-6, IL-10, IL-13, ADHD symptoms of hyperactivity, motor measures
26 male IL-16, IFN-g, TNF-a and errors of commission associated with increased
medicated IL-16; symptoms of inattention and errors of
8.9  1.4 y omission associated with increased IL-13
non-medicated
12  2.1 y
21 controls
Germany 21 ADHD (non-medicated); Serum IL-1b, IL-2, IL-3, IL-6, IL-10, Trend towards increased IFN-g in ADHD

14 male IL-13, IL-16, IFN-g, TNF-a (non-medicated) vs. controls with no difference
6.6e11.7 y in medicated group vs. controls; no signicant
20 controls difference in other PIMs
14 ADHD (medicated)
4 male
9.0e14.4 y
7 controls
21 controls
283
 TABLE 1 Continued
284

MITCHELL AND GOLDSTEIN

Study by Psychiatric Disorder Country Participants Measures Findings

Lasky-Su et al.,60 2008 USA 958 ADHD probande Genotyping via SNP analysis 2 SNPs in IL-16 gene associated with inattentive
www.jaacap.org

parent trios ADHD phenotype

816 male probands
10.88  2.1 y
Misener et al.,61 2004 Canada 178 ADHD families IL-1Ra gene VNTR No evidence for association of IL-1Ra gene
220 probands polymorphism with ADHD
7e16 y
Lasky-Su et al.,62 2008 USA 930 ADHD Time to onset analysis on IL-3 (NFIL3: C allele) associated with
parenteoffspring trios genome wide association earlier-onset ADHD
7e16 y data for ADHD
Segman et al.,63 2002 Israel 86 ADHD and parents IL-1Ra gene VNTR polymorphisms IL-1Ra 4-repeat allele transmission increased in ADHD;
6e17 y IL-1Ra 2-repeat allele transmission decreased in
no gender data available ADHD; IL-1Ra 4-repeat allele associated with
increased risk ADHD; IL-1Ra 2repeat allele
associated with decreased risk ADHD
Mittleman et al.,56 1997 USA See schizophrenia
Schizophrenia (SZ)
Falcone et al.,40 2010 USA 40 acute psychosis Serum IL-1 a, IL-1b, IL-2, IL-4, Increased IL-1b and IL-8 in suicidal adolescents
JOURNAL

24 mood disorders IL-6, IL-8, IL-10, IFN-g, TNF-a with psychosis and/or mood disorders vs. controls
37 male
OF THE

12e18 y
20 controls
Sporn et al.,64 2005 USA 24 child onset SZ Serum TNF-a pre and post No signicant differences in TNF-a between groups
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

15 male 6-week treatment with clozapine or pre and post treatment

8e18 y
21 controls
VOLUME 53 NUMBER 3 MARCH 2014

Mittleman et al.,56 1997 USA 22 SZ Frequency of detection and mean IL-2 similar concentration in SZ and ADHD, increased
12 male absolute values of CSF IL-2, IL-4, in OCD; IFN-g rare but increased in SZ; TNF-b/LT
10e18.8 y IL-5, IL-10, IFN-g, TNF-a, TNF-b, decreased in OCD; IL-10 decreased in ADHD and
24 OCD TNF-bLT SZ, not detected in OCD; no difference between
13 male groups in IL-5; IL-4 only detected in SZ
9.8e22.7 y
42 ADHD
42 male
6e12.3 y
Note: Sex and age (range) of participants is listed if available; if range is unavailable, mean age  SD is listed. Unless otherwise stated, controls are matched for age and gender. AD anxiety disorders; CRP C-reactive
protein; IFN interferon; IL interleukin; MDE major depressive episode; mRNA messenger ribonucleic acid; MVA motor vehicle accident; PFC prefrontal cortex; PIM proinflammatory markers; SI suicide
ideation; SNP single nucleotide polymorphism; SSRI selective serotonin reuptake inhibitor; TNF tumor necrosis factor; VNTR variable number tandem repeat.
 TABLE 2 Characteristics and Findings Regarding Proinflammatory Markers in Children and Adolescents With Autism Spectrum Disorders
VOLUME 53 NUMBER 3 MARCH 2014
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

Study Country Participants Measures Findings

65
Al-Ayadhi, 2012 Saudi Arabia 45 ASD Serum IL-17A Signicantly increased IL-17A in ASD vs. controls
36 male
8.44  1.73 y
40 controls
Manzardo et al.,68 2012 USA 99 ASD Plasma IL-1a, IL-1b, IL-1Ra, IL-2, IL-2Ra, Signicantly decreased IL-1a, IL-6 in ASD vs. controls
74 male IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10,
7.82  1.47 y IL-12 (p40), IL-12 (p70), IL-13, IL-15,
40 controls IL-17, IFN-g, IFN-a, TNF-a, TNF-b, TGF-a
Bent et al.,66 2012 USA 10 ASD Plasma IL-1a, IL-1b, IL-2, IL-3, IL-4, IL-5, IL-6, No change in PIM concentrations after HBOT
5.3  1.8 y IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70),
No controls IL-13, IL-15, IL-17, IFN-g, IFN-a, TNF-a,
No gender data available TNF-b before and after HBOT
El-Ansary,67 2012 Saudi Arabia 20 male ASD Plasma IFN-g Signicantly increased IFN-g in ASD vs. controls
3e16 y
19 controls
Jyonouchi et al.,69 2012 USA 8 ASD/SPAD Stimulated PBMC production of IL-1, IL-6, Decreased production of IL-1, IL-6, IL-12p40, IL-17,
6 male IL-12p40, IL-17, IL-23, IFN-g, TNF-a IL-23, IFN-g, TNF-a in ASD/SPAD vs. controls;

INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH

8e18 y no difference in ASD non-SPAD vs. controls;
39 ASD/non-SPAD decreased production of IL-6, IL-10, IL-23 in
35 male non-ASD/SPAD vs. controls; decreased IL-10
5e17 y in both ASD/SPAD and non-ASD/SPAD
12 non-ASD/ SPAD
6 male
6e17 y
37 controls
Tostes et al.,70 2012 Brazil 24 ASD Plasma IL-1, IL-2, IL-4, IL-6, IL-10, IFN-g, TNF-a Increased plasma IFN-g in ASD vs. controls; no
24 controls signicant difference in other PIMs
6 males
7.4  2.7 y
Ashwood et al.,71 2011 Stimulated PBMC production of IL-1b, IL-2, Increased IFN-g, TNF-a in ASD vs. controls;
www.jaacap.org

USA 66 ASD
59 male IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-13, decreased IL-12p40; no difference in other PIMs
2e5 y IFN-g, TNF-a
77 controls
Ashwood et al.,72 2011 USA 97 ASD Plasma multiplex luminex analysis IL-1b, Increased IL-1b, IL-6, IL-8, IL-12p40 in ASD vs.
84 male IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, healthy controls
median age 3.4 y TNF-a IFN-g
87 controls
285

39 developmental
delay controls
286

MITCHELL AND GOLDSTEIN

TABLE 2 Continued
Study Country Participants Measures Findings
www.jaacap.org

El-Ansary et al.,73 2011 Saudi Arabia 25 ASD Serum IL-6, TNF-a Decreased serum IL-6, TNF-a in ASD vs. controls
25 male
4e12 y
16 controls
Malik et al.,74 2011 USA 6 ASD Lymphoblast IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, Increased TNF-a and IL-6 in ASD vs. controls; no
mean 8.4 y IL-10, IFN-g, TNF-a difference in other PIMs
6 controls
Jyonouchi et al.,75 2011 USA 30 ASD/ INF; 19ASD/ Stimulated PBMC production of IL-1b, IL-2, Decreased production of IL-6, IL-b, IL-12, Il-23,
INF GI symptoms IL-3, IL-5, IL-6, IL-10, IL-12 (p40), IL-17, IL-10, sTNFRII, TGF-b in ASD/INFGI vs.
27 male IFN-g, TNF-a, TGF-b, sTNFRII ASD/no-INF and controls; IL-17 production
3e16 y was not decreased
28 ASD/no-INF
23 male
3e18 y
26 controls
Suzuki et al.,76 2011 Japan 28 ASD 48 plasma PIMs including: IL-1 b, IL-1RA, All listed PIMs increased in ASD vs. controls
JOURNAL

28 male IL-5, IL-8, IL-12(p70), IL-13, IL-17

7e15 y
28 controls
OF THE

Tobiasova et al.,77 2011 USA Pilot study: 21 ASD Serum IFN-g, IL -13, IL-17, IL-1, IL-1RA Serum IL-13 decreased in ASD vs. controls; no
28 male effect of risperidone on PIMs over 8 weeks
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

5.2e15.2 y vs. placebo

15 controls
Treatment study: 77 ASD
VOLUME 53 NUMBER 3 MARCH 2014

Wei et al.,78 2011
Ashwood et al.,79 2010
32 male
5.2e16.9 y
19 controls
USA 6 ASD Frozen cerebellum IL-6 expression Increased IL-6 expression in cerebellum in ASD
4 male vs. controls; overexpressed IL-6 altered neural cell
4e14 y adhesion, migration and formation of granule
6 controls cell excitatory but not inhibitory synapses
USA 40 ASD/Fragile X; 40 male Plasma multiplex luminex analysis: IL-1a, Increased IL-1a and IL-12p40 in ASD/Fragile X
64 Fragile X/no ASD IL-1b, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, vs. controls. IL-1a increased in Fragile X with
64 male IL-10, IL-12p40, IL-12p70, IL-13, IL-15, and without ASD; other PIMs not above
19 controls TNF-a, IFN-g detectable limit
Age data not available
 TABLE 2 Continued
Study Country Participants Measures Findings
VOLUME 53 NUMBER 3 MARCH 2014
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

Enstrom et al.,80 2010 USA 17 ASD Stimulated PBMCs production of (multiplex Differential PIM response to toll-like-receptor
14 male luminex analysis): IL-1b, IL-6, IL-8, TNF-a ligands in ASD vs. controls: increased IL-1b,
2.2e5 y IL-6, TNF-a; decreased IL-1b, IL-6, TNF-a
16 controls
Ashwood et al.,81 2009 USA 19 ASD PBMC treated with BDE-47 and stimulated Decreased IL-6, IL-12p40, and TNF-a in controls
16 male for production of PIMs vs. decreased IL-6 in ASD; increased IL-8 in
2.42e5 y ASD vs. controls
18 controls
Li et al.,82 2009 USA 8 ASD frozen brain tissue Frozen frontal cortex IL-1b, IL-2, IL-4, IL-5, Increased IL-6, TNF-a, IFN-g in ASD vs. controls;
5 male; 4e37 y IL-6, IL-8, IL-10, IFN-g, TNF-a no signicant difference in IL-1b, IL-4, IL-5,
(6/8 subjects <18 y) IL-10; increased IFN- g /IL-4 in ASD vs. controls;
8 controls increased IL-8 in ASD vs. controls
Onore et al.,83 2009 USA 34 ASD Stimulated PBMC production Decreased IL-23 vs. controls; no difference in IL-17
29 male of IL-17, IL-23
3.17e4.25 y
18 controls
Jyonouchi et al.,84 2008 USA 26 ASD with frequent Stimulated PBMC production of TNF-a, Decreased IL-1b L-10 in ASD vs. controls;
infections; 25 male IL-1b, IL-6, IL-12p40, IL-23, IL-10, sTNFRI increased IL-23 in ASD vs. controls; decreased
2.3e13.4 y sTFNRII in ASD vs. controls

INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH

107 ASD controls;
92 male
1.5e17.3 y
24 non-ASD controls with
food allergies; 24 male
1.0e13.7 y
38 non-ASD controls with
frequent infections
27 male
1.0e17.8 y
43 controls
Enstrom et al.,85 2008 USA 40 ASD (20 regressive, Plasma IL-17, IL-23 Decreased IL-23 in early onset ASD; no
www.jaacap.org

20 early onset) difference in IL-17

36 male
2e5 y
20 controls
Chez et al.,86 2007 USA 10 ASD CSF TNF-a, serum TNF-a Increased CSF TNF-a in ASD vs. other diseases in
1 Lennox-Gastaut literature and vs. sera of ASD; no correlation
10 male between serum and CSF
2.5e9 y
287

No controls
288

TABLE 2 Continued

MITCHELL AND GOLDSTEIN

Study Country Participants Measures Findings
www.jaacap.org

Rossignol et al.,87 2007 USA 18 ASD Plasma CRP before and after HBOT High CRP in 3 ASD; signicant improvement
14 male in CRP after HBOT in high-CRP group only
3e6 y
No controls
Molloy et al.,88 2006 USA 20 ASD Stimulated and unstimulated PBMC Increased in stimulated IL-4, IL-5, IL-13 in
17 male production of IL-2, IL-4, IL-5, IL-10, ASD vs. controls; increased unstimulated
3.5e10.7 y IL-13, IFN-g IFN-g/IL-10 and IL-13/IL-10 increased in
20 controls ASD vs. controls; no difference in IL-10 or
other PIMs
Jynouchi et al.,89 2005 USA 75 ASD GI symptoms PBMC production of IL-2, IL-4, IL-5, IL-10, Increased TNF-a and IL-12 in ASD vs. control,
61 male IL-12p40, TNF-a, IFN-g stimulated by irrespective of GI symptoms; no difference
1.8e10.6 y dietary proteins (e.g., cows milk protein) in IL-5 or IL-10; IL-2 and IL-4 undetectable
34 ASD - GI symptoms
32 male
2.1e10.2 y
15 NFH; 10 male
JOURNAL

1.3e7.8 y
19 controls
Jyonouchi et al.,90 2005 USA USA Stimulated PBMC production of IL-1b, Increased TNF-a, in ASD with NFH, regardless
OF THE

177 ASD IL-1Ra, IL-6, IL-10, IL-12, TNF-a, sTNFRII of dietary intervention
Unrestricted diet: 71 ASD
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

59 male
1.8e10.6 y
29 GI-ASD
VOLUME 53 NUMBER 3 MARCH 2014

27 male
2.1e10.2 y
14 NFH
13 controls
Restricted diet: 68 GIASD
62 male
2.2e10.9 y
9 GI-ASD
7 male
2.3e7.4 y
16 NFH
VOLUME 53 NUMBER 3 MARCH 2014
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

TABLE 2 Continued
Study Country Participants Measures Findings

Vargas et al.,91 2005 USA Frozen brain tissue: 15 ASD Brain tissue and CSF: IL-1a, IL-1b, IL-2, Increased IL-6 and IL-10 in anterior cingulate
12 male IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-15, gyrus; increased IL-6, IFN-g, IL-8 in CSF of
5e44 y IL-16, IFN-g, TNF-a, TNF-b ASD vs. controls
9/15 <18 y
(7 samples available
for analysis)
12 controls
CSF: 6 ASD
4 male
3e10 y
9 controls
Zimmerman et al.,922005 USA CSF and serum: 12 ASD CSF IL-1RA, IL-1b, IL-2, IL-4, IL-5, IL-6, CSF IL-1b, IL-2, IFN-g undetectable in CSF or
10 male IFN-g, TNF-a, IL-12, IL-1ra, IL-10, serum of ASD vs. controls; decreased IL-1ra
33 moe10 y sTNFRI, sTNFRII and IL-6 in CSF of ASD vs. controls; no
27 controls with signicant difference in CSF sTNFRI or
neurologic disorders; sTNFRII; increased sTNFRII ASD vs. controls

INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH

Serum: 35 ASD
32 male
2.8e43 y
35 controls
Ashwood et al.,93 2004 USA 21 ASD Intestinal biopsy samples stained for Increased CD3TNF, CD3IL-2, CD3IFN-g,
15 male intracellular IL-2, IL-4, IL-10, TNF-a, IFN-g CD3IL-4 in ASD vs. controls; decreased
2e16 y CD3IL-10 in ASD vs. controls
65 controls
Sweeten et al.,94 2004 USA 29 ASD Plasma IL-1, IFN-g, TNF-a No signicant difference in PIMs in
25 male ASD vs. controls
2e12 y
27 controls
Croonenberghs et al.,95 Netherlands 13 ASD Whole-blood IL-1RA, IL-6, IL-10, IFN-g, Increased whole-blood IFN-g, and IL-1RA
www.jaacap.org

2002 13 male, TNF-a; serum IL-6, IL-2R, IL-1RA in ASD vs. controls; trend toward increased
12e18 y whole-blood IL-6 and TNF-a in ASD vs. controls;
13 controls no signicant difference in whole-blood IL-10
or serum IL-6, IL-1RA, or IL-2R
DeFelice et al.,96 2003 USA 6 ASD Intestinal biopsy samples stimulated for No difference in PIM production in ASD vs. controls
6 male IL-1b, IL-6, IL-8
2.1e14 y
289

9 controls
290

MITCHELL AND GOLDSTEIN

TABLE 2 Continued
Study Country Participants Measures Findings
www.jaacap.org

Jyonouchi et al.,97 2002 USA 72 ASD PBMC production of IL-5, TNF-a and IFN-g Increased stimulated TNF-a and IFN-g; no
59 male stimulated by dietary proteins compared increase in IL-5
1e17 y to endotoxin stimulation
24 non-ASD with dietary
protein intolerance
17 male
0.5e13 y
26 ASD siblings
18 male
0.5e20 y
15 controls
Jyonouchi et al.,98 2001 USA 71 ASD with developmental Stimulated and unstimulated PBMC Increased stimulated IL-1b, IL-5, IL-6, TNF-a in
regression production of IL-1RA, IL-1b, IL-4, IL-5, ASD vs. controls; increased unstimulated
56 male IL-6, IL-10, TNF-a, sTNFRI, sTNFRII sTNFRI and sTNFRII in ASD vs. controls;
2e14 y decreased stimulated IL-10 in ASD vs. controls
JOURNAL

23 siblings
16 male
10 mo to 20 y
OF THE

17 controls
Gupta et al.,99 1998 USA 20 ASD Intracellular IL-2, IL-4, IL-6, IL-10, IFN-g Decreased IFN-gCD4 and IL-2CD4 T cells
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY

16 male (in CD4 and CD8 T cells) in ASD vs. controls; decreased IFN-gCD8
3e7 y and IL-2CD8 in ASD vs. controls; increased
20 controls IL-4CD4 and IL-4CD8 in ASD vs. controls
VOLUME 53 NUMBER 3 MARCH 2014

17 male
4e8 y
Denney et al.,100 1996 USA 10 ASD Stimulated and unstimulated serum Decreased stimulated bIL-2R in ASD vs. controls
10 male sIL-2R and bound IL-2R (bIL-2R) and inversely associated with symptom severity;
7e15 y no signicant difference for stimulated sIL-2R
10 controls or unstimulated bIL-2R or sIL-2R
10 male
7e15 y
Singh et al.,101 1996 USA 20 ASD Plasma IL-6, IL-12, IFN-a, IFN-g, TNF-a Increased IL-12, IFN-g in ASD vs. controls;
16 male no signicant different in IL-6, IFN-a, or TNF-a
mean 10.7 y
20 controls
 INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH

to compare ndings to those in the adult literature.

BDE pentabromodiphenyl ether; CSF cerebral spinal fluid; CRP C-reactive protein; GI gastrointestinal; HBOT hyperbaric oxygen treatment; IFN interferon; INF infection; IL interleukin; MR mental
retardation; NFH non-allergenic food hypersensitivity; PBMC peripheral blood mononuclear cell; PIM proinflammatory markers; SPAD specific polysaccharide antibody deficiency; TFR tumor necrosis factor
Note: Sex and age (range) of participants is listed if available; if range is unavailable, mean age  SD is listed. Unless otherwise stated, controls are matched for age and gender. ASD autism spectrum disorder;
Future research should focus on the rst-episode
psychosis population, and on the specic PIMs
that are among the candidate genes for schizo-

Increased sIL-2 in ASD vs. controls and MR;

no signicant difference in sIL-2R or sIL-1
phrenia (such as TNF-a and IL-1b)131,132 and that
Increased IFN-a in ASD vs. controls predominate in the adult literature (such as IL-1Ra,
IL-2, and IL-6).21 This considered, similar to BD,45
the recent nding of an inammatory monocyte
Findings

gene signature specic to schizophrenia133 is

perhaps suggestive of an overactive inammatory
state at baseline in this population.

Autism Spectrum Disorders

Although dating back to the 1980s, the area of
ASD and inammation has grown rapidly over
the last 5 years.134 The number of studies exam-
ining PIMs in children and adolescents with
ASD that met inclusion criteria exceeded the
number of studies in all of the other populations
combined (39 versus 28). Furthermore, in contrast
to other diagnoses, the literature on PIMs in
children and adolescents with ASD informs the
adult literature in this area, not vice versa.
Measures

The 39 studies strongly suggest a proin-

Serum sIL-1, sIL-2, sIL-2R

ammatory state in ASD as compared to controls,

although the evidence for specic PIMs remains
equivocal and the direction of the relationship is
Serum IFN-a

unclear. This evidence is more broadly based

and includes elevated PIMs in the plasma,109
whole blood,95 CSF,86 and frozen brain tissue82
of patients with ASD. Furthermore, the consis-
tently decreased level of the anti-inammatory
No gender data available

cytokine IL-10 across studies despite the active

No age or gender data

proinammatory state82,84,88,92,95,98 suggests that

children and adolescents with ASD lack the
appropriate compensatory response, which may
Participants

exacerbate the impact of the inammatory state.

33 controls
available
4 controls

A hypothesis on the etiology of autism135

<10 y

<10 y
10 ASD

23 ASD

15 MR

integrates the ndings of a proinammatory

state in individuals with ASD with the literature
showing an association between a maternal
proinammatory state136 and/or maternal infec-
Country

USA

USA

tion and offspring with ASD.137 Briey, it postu-

lates that PIMs cross the placenta in a maternal
receptor; TNF tumor necrosis factor.

hyperinammatory state, enter into fetal circula-

tion, cross the bloodbrain barrier, activate mic-
grolia, and produce a cytokine storm that leads
Stubbs et al.,102 1995

Singh et al.,103 1991

to excessive neuronal growth, aberrant neural

Continued

plasticity, and, ultimately, autistic symptoms.138

This neuroimmune hypothesis has recently been
reinforced by epidemiological evidence from a
Danish populationbased cohort study that re-
TABLE 2
Study

ports associations between hospitalization for

maternal viral infection in the rst trimester

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VOLUME 53 NUMBER 3 MARCH 2014 www.jaacap.org 291
MITCHELL AND GOLDSTEIN
and maternal bacterial infection in the second
trimester and the diagnosis of ASD in offspring
(adjusted hazard ratio 2.98, condence in-
terval 1.297.15, and adjusted hazard ratio
1.42, condence interval 1.081.87, respecti-
vely),139 and with molecular evidence from re-
ports of elevated PIMs in amniotic uid
samples140,141 and neonatal dried blood spots142
of individuals diagnosed with ASD later in life
compared to matched controls. Recent integrated
genomic evidence, however, suggests that mu-
tations in ASD genes themselves may result in
aberrant signaling regulation of immune and
inammatory cells during neurodevelopment,
and argues for a direct link between ASD-
implicated genes and central cytokine signaling
pathways.143
The literature on inammation in neuropsy-
chiatric disorders in children and adolescents
is constrained by several important limitations,
including between-study heterogeneity in terms
of the cytokines examined, sample sources (CSF
versus plasma), sampling and measuring tech-
niques, and diagnostic phenotypes. For example,
although in vitro cytokine stimulation constitutes
a signicant proportion of the literature and
in general is a reliable measure of cytokine-
producing potential,144 there may be differences
between in vitro and in vivo techniques, such
as cytokine level norms,145 that may affect study
ndings. Furthermore, most studies did not
control for general confounds important in
child and adolescent populations, such as
medication exposure, sleep, obesity, or family
history. Finally, most studies were limited by
modest sample sizes and were not adequately
powered to examine the associations between the
aforementioned sources of variability.
The interpretation of the ndings of this re-
view is also constrained by several factors. First,
there are inherent differences in the inammatory
process across the various biological substrates
examined. For example, the relationship between
peripheral and central cytokines is complex, and
although they are integrated, they are differ-
entially regulated146; therefore, increased PIMs
centrally may not be indicative of increased PIMs
peripherally and vice versa. Second, genetic
polymorphisms and/or increased gene expres-
sion are considered markers of cell potential for
cytokine production rather than direct in-
dicators,147 and therefore are also not necessarily
indicative of a pathological inammatory state,
JOURNAL
292 www.jaacap.org
either peripherally or centrally. Third, cytokines
at the peripheral level may be especially inu-
enced by unaccounted for environmental and
biological phenomena, such as stress or illness,
via an intricate interplay with the autonomic
nervous system.6 Fourth, although cytokines
share important properties, they can have differ-
ent functions in the body; for example, IL-6
and TNF-a tend to be involved in innate immu-
nity, whereas IFN-g tends to activate other
inammatory cells.1 Therefore, elevated levels
of PIMs may have different implications, and
the differential impact of individual cytokines on
psychiatric disorders is not yet understood.
Finally, the vast majority of studies were cross-
sectional and retrospective, and can only infer
an association between inammation and
neuropsychiatric disorders in children and ado-
lescents and not a causal pathogenic link; as
such, the potential value of prospectively exam-
ining the association between inammation
and psychopathology among youth is not yet
known.
In summary, the objective of this systematic
review was to synthesize the current state of the
literature on inammation and neuropsychia-
tric disorders among children and adolescents.
Despite the limitations, the ndings provide
preliminary evidence for the role of inammation
in neuropsychiatric disorders among children
and adolescents. Although larger, prospective,
and disorder-specic studies are needed to better
delineate the relationship and integrate the nd-
ings, this body of evidence has important im-
plications for the clinical utility of PIMs as
biomarkers in the treatment of children and ad-
olescents with neuropsychiatric disorders. Given
the overlap among neuropsychiatric disorders,
PIMs are unlikely to serve as diagnostic bio-
markers. PIMs, however, may serve as essential
markers of illness activity and treatment response
in addition to providing a feasible and cost-
effective means to monitor at-risk populations.
Furthermore, although the nature of the rela-
tionship is unknown, ndings from the current
review may suggest that inammation is salient
to common biological processes across several
neuropsychiatric disorders in children and ado-
lescents. This cross-diagnostic approach is in
keeping with the reconceptualization of mental
illness according to shared biological un-
derpinnings rather than the categorical clustering
of symptoms.148
OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY
VOLUME 53 NUMBER 3 MARCH 2014
 INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH
Little is known about the association between
PIMs and neuroimaging or neurocognitive pa-
rameters. Progress in this area would serve to
validate peripheral measures of PIMs. PIMs may
also serve as a bridge between medical and psy-
chiatric illness, a link that may offer novel ave-
nues of monitoring and treatment. To date, the
eld of child and adolescent psychiatry lacks
clinically applicable biomarkers with potential
applications in monitoring and treatment. Future
research efforts that overcome the limitations of
previous studies may lead to clinically applicable
biomarkers, which are greatly needed in psychi-
atry in general, but in child and adolescent psy-
chiatry in particular. &
REFERENCES
1. Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS. Robbins
and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia:
Elsevier Saunders; 2005.
2. Szigethy E, McLafferty L, Goyal A. Inammatory bowel disease.
Pediatr Clin North Am. 2011;58:903-920. x-xi.
3. Ortega AN, Huertas SE, Canino G, Ramirez R, Rubio-Stipec M.
Childhood asthma, chronic illness, and psychiatric disorders.
J Nerv Ment Dis. 2002;190:275-281.
4. Goldstein BI, Liu SM, Zivkovic N, Schaffer A, Chien LC,
Blanco C. The burden of obesity among adults with bipolar
disorder in the United States. Bipolar Disord. 2011;13:387-395.
5. Miller AH, Maletic V, Raison CL. Inammation and its discon-
tents: the role of cytokines in the pathophysiology of major
depression. Biol Psychiatry. 2009;65:732-741.
6. Raison CL, Capuron L, Miller AH. Cytokines sing the blues:
inammation and the pathogenesis of depression. Trends
Immunol. 2006;27:24-31.
7. Miller AH, Manji HK. On redening the role of the immune
system in psychiatric disease. Biol Psychiatry. 2006;60:796-798.
8. Smith RS. The immune system is a key factor in the etiology of
psychosocial disease. Med Hypotheses. 1991;34:49-57.
9. 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.
10. Savitz J, Preskorn S, Teague TK, Drevets D, Yates W, Drevets W.
Minocycline and aspirin in the treatment of bipolar depression: a
protocol for a proof-of-concept, randomised, double-blind, pla-
cebo-controlled, 2x2 clinical trial. BMJ Open. 2012;2:e000643.
11. Akhondzadeh S, Jafari S, Raisi F, et al. Clinical trial of adjunctive
celecoxib treatment in patients with major depression: a double
blind and placebo controlled trial. Depress Anxiety. 2009;26:
607-611.
12. Muller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2
inhibitor celecoxib has therapeutic effects in major depression:
results of a double-blind, randomized, placebo controlled, add-
on pilot study to reboxetine. Mol Psychiatry. 2006;11:680-684.
13. Nery FG, Monkul ES, Hatch JP, et al. Celecoxib as an adjunct in
the treatment of depressive or mixed episodes of bipolar disor-
der: a double-blind, randomized, placebo-controlled study. Hum
Psychopharmacol. 2008;23:87-94.
14. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized
controlled trial of the tumor necrosis factor antagonist Iniximab
for treatment-resistant depression: the role of baseline inam-
matory biomarkers. JAMA Psychiatry. 2013;70:31-41.
15. Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 fatty acids:
evidence basis for treatment and future research in psychiatry.
J Clin Psychiatry. 2006;67:1954-1967.
16. Lotrich FE, Rabinovitz M, Gironda P, Pollock BG. Depression
following pegylated interferon-alpha: characteristics and
vulnerability. J Psychosom Res. 2007;63:131-135.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY
VOLUME 53 NUMBER 3 MARCH 2014
Accepted December 13, 2013.
Dr. Mitchell is with the University of Toronto. Dr. Goldstein is with
Sunnybrook Health Sciences Centre, University of Toronto.
Disclosure: Dr. Goldstein has received grant or research support from
the Canadian Institute of Health Research, the Depressive and Bipolar
Disorder Alternative Treatment Foundation, the Heart and Stroke
Foundation of Ontario, the National Institute of Mental Health, and the
Ontario Mental Health Foundation; has served as a consultant to
Bristol-Myers Squibb; and has received honoraria from Purdue Pharma.
Dr. Mitchell reports no biomedical nancial interests or potential con-
icts of interest.
Correspondence to Rachel H.B. Mitchell, MD, MSc, Sunnybrook
Health Sciences Centre, F-53, 2075 Bayview Avenue, Toronto, ON
M4N 3M5, Canada; e-mail: rach.mitchell@mail.utoronto.ca
0890-8567/$36.00/2014 American Academy of Child and
Adolescent Psychiatry
http://dx.doi.org/10.1016/j.jaac.2013.11.013
17. Lotrich FE. Major depression during interferon-alpha treatment:
vulnerability and prevention. Dialogues Clin Neurosci. 2009;11:
417-425.
18. Lotrich FE, Ferrell RE, Rabinovitz M, Pollock BG. Risk for
depression during interferon-alpha treatment is affected by the
serotonin transporter polymorphism. Biol Psychiatry. 2009;65:
344-348.
19. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of
cytokines in major depression. Biol Psychiatry. 2010;67:446-457.
20. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inamma-
tion and the phenomenology, pathophysiology, comorbidity, and
treatment of bipolar disorder: a systematic review of the litera-
ture. J Clin Psychiatry. 2009;70:1078-1090.
21. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E.
Inammatory cytokine alterations in schizophrenia: a systematic
quantitative review. Biol Psychiatry. 2008;63:801-808.
22. Pace TW, Miller AH. Cytokines and glucocorticoid receptor
signaling. Relevance to major depression. Ann N Y Acad Sci.
2009;1179:86-105.
23. M uller N, Ackenheil M. Psychoneuroimmunology and the cyto-
kine action in the CNS: implications for psychiatric disorders.
Prog Neuropsychopharmacol Biol Psychiatry. 1998;22:1-33.
24. Kronfol Z, Remick DG. Cytokines and the brain: implications for
clinical psychiatry. Am J Psychiatry. 2000;157:683-694.
25. Christmas DM, Potokar J, Davies SJ. A biological pathway link-
ing inammation and depression: activation of indoleamine 2,3-
dioxygenase. Neuropsychiatr Dis Treat. 2011;7:431-439.
26. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A,
Critchley HD. Inammation causes mood changes through al-
terations in subgenual cingulate activity and mesolimbic con-
nectivity. Biol Psychiatry. 2009;66:407-414.
27. Wolkowitz OM, Mellon SH, Epel ES, et al. Leukocyte telomere
length in major depression: correlations with chronicity, inam-
mation and oxidative stresspreliminary ndings. PLoS One.
2011;6:e17837.
28. Hannestad J, Gallezot JD, Schafbauer T, et al. Endotoxin-induced
systemic inammation activates microglia: [(11)C]PBR28 posi-
tron emission tomography in nonhuman primates. Neuroimage.
2012;63:232-239.
29. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration.
Nat Rev Neurosci. 2001;2:734-744.
30. Raison C, Miller A. Brain-immune system interaction: Relevance
to the pathophysiology and treatment of neuropsychiatric dis-
orders. In: Schatzberg A, Nemeroff C, eds. American Psychiatric
Publishing Textbook of Psychopharmacology. 3rd ed. Washing-
ton DC: American Psychiatric Press; 2004:147-162.
31. Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic
factor, depression, and antidepressant medications: meta-
analyses and implications. Biol Psychiatry. 2008;64:527-532.
32. Post RM. Role of BDNF in bipolar and unipolar disorder: clinical
and theoretical implications. J Psychiatr Res. 2007;41:979-990.
www.jaacap.org 293
MITCHELL AND GOLDSTEIN
33. Lilic D, Cant AJ, Abinun M, Calvert JE, Spickett GP. Cytokine
production differs in children and adults. Pediatr Res. 1997;42:
237-240.
34. Kapczinski F, Vieta E, Andreazza AC, et al. Allostatic load in
bipolar disorder: implications for pathophysiology and treat-
ment. Neurosci Biobehav Rev. 2008;32:675-692.
35. McEwen BS. Protective and damaging effects of stress mediators.
N Engl J Med. 1998;338:171-179.
36. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred
Reporting Items for Systematic Reviews and Meta-Analyses: the
PRISMA statement. PLoS Med. 2009;6:e1000097.
37. Henje Blom E, Lekander M, Ingvar M, Asberg  M, Mobarrez F,
Serlachius E. Proinammatory cytokines are elevated in adoles-
cent females with emotional disorders not treated with SSRIs.
J Affect Disord. 2012;136:716-723.
38. Pandey GN, Rizavi HS, Ren X, et al. Proinammatory cytokines
in the prefrontal cortex of teenage suicide victims. J Psychiatr Res.
2012;46:57-63.
39. Miller GE, Cole SW. Clustering of depression and inammation
in adolescents previously exposed to childhood adversity. Biol
Psychiatry. 2012;72:34-40.
40. Falcone T, Fazio V, Lee C, et al. Serum S100B: a potential
biomarker for suicidality in adolescents? PLoS One. 2010;5:
e11089.
41. Gabbay V, Klein RG, Guttman LE, et al. A preliminary study of
cytokines in suicidal and nonsuicidal adolescents with major
depression. J Child Adolesc Psychopharmacol. 2009;19:423-430.
42. Gabbay V, Klein RG, Alonso CM, et al. Immune system dysre-
gulation in adolescent major depressive disorder. J Affect Disord.
2009;115:177-182.
43. Brambilla F, Monteleone P, Maj M. Interleukin-1beta and tumor
necrosis factor-alpha in children with major depressive disorder
or dysthymia. J Affect Disord. 2004;78:273-277.
44. Goldstein BI, Collinger KA, Lotrich F, et al. Preliminary ndings
regarding proinammatory markers and brain-derived neuro-
trophic factor among adolescents with bipolar spectrum disor-
ders. J Child Adolesc Psychopharmacol. 2011;21:479-484.
45. Padmos RC, Hillegers MH, Knijff EM, et al. A discriminating
messenger RNA signature for bipolar disorder formed by an
aberrant expression of inammatory genes in monocytes. Arch
Gen Psychiatry. 2008;65:395-407.
46. Pervanidou P, Kolaitis G, Charitaki S, et al. Elevated morning
serum interleukin (IL)-6 or evening salivary cortisol concentra-
tions predict posttraumatic stress disorder in children and ado-
lescents six months after a motor vehicle accident.
Psychoneuroendocrinology. 2007;32:991-999.
47. Cheng YH, Zheng Y, He F, et al. Detection of autoantibodies
and increased concentrations of interleukins in plasma from
patients with Tourettes syndrome. J Mol Neurosci. 2012;48:
219-224.
48. Matz J, Krause DL, Dehning S, et al. Altered monocyte activation
markers in Tourettes syndrome: a case-control study. BMC
Psychiatry. 2012;12:29.
49. Liu S, Yi M, Wang M, Sun Y, Che F, Ma X. Association of IL8
-251A/T, IL12B -1188A/C and TNF-a -238A/G polymorphisms
with Tourette syndrome in a family-based association study in a
Chinese Han population. Neurosci Lett. 2011;495:155-158.
50. Liu S, Yi M, Qi F, Che F, Ma X. Lack of association between
polymorphism -592A/C in the promoter region of the IL10 gene
and Tourettes syndrome in a family-based association study in
the Chinese Han population. Genet Test Mol Biomarkers. 2011;
15:733-735.
51. Bos-Veneman NG, Bijzet J, Limburg PC, Minderaa RB,
Kallenberg CG, Hoekstra PJ. Cytokines and soluble adhesion
molecules in children and adolescents with a tic disorder. Prog
Neuropsychopharmacol Biol Psychiatry. 2010;34:1390-1395.
52. Chou IC, Lin HC, Wang CH, et al. Polymorphisms of interleukin
1 gene IL1RN are associated with Tourette syndrome. Pediatr
Neurol. 2010;42:320-324.
53. Gabbay V, Coffey BJ, Guttman LE, et al. A cytokine study in
children and adolescents with Tourettes disorder. Prog Neuro-
psychopharmacol Biol Psychiatry. 2009;33:967-971.
54. Leckman JF, Katsovich L, Kawikova I, et al. Increased serum
levels of interleukin-12 and tumor necrosis factor-alpha in
Tourettes syndrome. Biol Psychiatry. 2005;57:667-673.
JOURNAL
294 www.jaacap.org
55. Luo F, Leckman JF, Katsovich L, et al. Prospective longitudinal
study of children with tic disorders and/or obsessive-compulsive
disorder: relationship of symptom exacerbations to newly ac-
quired streptococcal infections. Pediatrics. 2004;113:e578-e585.
56. Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL,
Swedo SE, Shearer GM. Cerebrospinal uid cytokines in pedi-
atric neuropsychiatric disease. J Immunol. 1997;159:2994-2999.
57. Oades RD. An exploration of the associations of pregnancy and
perinatal features with cytokines and tryptophan/kynurenine
metabolism in children with attention-decit hyperactivity dis-
order (ADHD). Atten Dec Hyperact Disord. 2011;3:301-318.
58. Oades RD, Myint AM, Dauvermann MR, Schimmelmann BG,
Schwarz MJ. Attention-decit hyperactivity disorder (ADHD)
and glial integrity: an exploration of associations of cytokines and
kynurenine metabolites with symptoms and attention. Behav
Brain Funct. 2010;6:32.
59. Oades RD, Dauvermann MR, Schimmelmann BG, Schwarz MJ,
Myint AM. Attention-decit hyperactivity disorder (ADHD) and
glial integrity: S100B, cytokines and kynurenine metabolism
effects of medication. Behav Brain Funct. 2010;6:29.
60. Lasky-Su J, Neale BM, Franke B, et al. Genome-wide association
scan of quantitative traits for attention decit hyperactivity dis-
order identies novel associations and conrms candidate gene
associations. Am J Med Genet B Neuropsychiatr Genet. 2008;
147B:1345-1354.
61. Misener VL, Schachar R, Ickowicz A, et al. Replication test for
association of the IL-1 receptor antagonist gene, IL1RN, with
attention-decit/hyperactivity disorder. Neuropsychobiology.
2004;50:231-234.
62. Lasky-Su J, Anney RJ, Neale BM, et al. Genome-wide association
scan of the time to onset of attention decit hyperactivity disor-
der. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:
1355-1358.
63. Segman RH, Meltzer A, Gross-Tsur V, et al. Preferential trans-
mission of interleukin-1 receptor antagonist alleles in attention
decit hyperactivity disorder. Mol Psychiatry. 2002;7:72-74.
64. Sporn AL, Bobb AJ, Gogtay N, et al. Hormonal correlates of
clozapine-induced weight gain in psychotic children: an explor-
atory study. J Am Acad Child Adolesc Psychiatry. 2005;44:
925-933.
65. Al-Ayadhi LY, Mostafa GA. Elevated serum levels of interleukin-
17A in children with autism. J Neuroinammation. 2012;9:158.
66. Bent S, Bertoglio K, Ashwood P, Nemeth E, Hendren RL. Brief
report: Hyperbaric oxygen therapy (HBOT) in children with
autism spectrum disorder: a clinical trial. J Autism Dev Disord.
2012;42:1127-1132.
67. El-Ansary A, Al-Ayadhi L. Neuroinammation in autism spec-
trum disorders. J Neuroinammation. 2012;9:265.
68. Manzardo AM, Henkhaus R, Dhillon S, Butler MG. Plasma
cytokine levels in children with autistic disorder and unrelated
siblings. Int J Dev Neurosci. 2012;30:121-127.
69. Jyonouchi H, Geng L, Streck DL, Toruner GA. Immunological
characterization and transcription proling of peripheral blood
(PB) monocytes in children with autism spectrum disorders
(ASD) and specic polysaccharide antibody deciency (SPAD):
case study. J Neuroinammation. 2012;9:4.
70. Tostes MH, Teixeira HC, Gattaz WF, Brand~ao MA, Raposo NR.
Altered neurotrophin, neuropeptide, cytokines and nitric oxide
levels in autism. Pharmacopsychiatry. 2012;45:241-243.
71. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R,
Pessah IN, Van de Water J. Altered T cell responses in children
with autism. Brain Behav Immun. 2011;25:840-849.
72. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I,
Van de Water J. Elevated plasma cytokines in autism spectrum
disorders provide evidence of immune dysfunction and are
associated with impaired behavioral outcome. Brain Behav
Immun. 2011;25:40-45.
73. El-Ansary AK, Ben Bacha AG, Al-Ayadhi LY. Proinammatory and
proapoptotic markers in relation to mono and di-cations in plasma
of autistic patients from Saudi Arabia. J Neuroinammation. 2011;
8:142.
74. Malik M, Sheikh AM, Wen G, Spivack W, Brown WT, Li X.
Expression of inammatory cytokines, Bcl2 and cathepsin D are
altered in lymphoblasts of autistic subjects. Immunobiology.
2011;216:80-85.
OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY
VOLUME 53 NUMBER 3 MARCH 2014
 INFLAMMATION IN NEUROPSYCHIATRIC DISORDERS OF YOUTH
75. Jyonouchi H, Geng L, Streck DL, Toruner GA. Children with
autism spectrum disorders (ASD) who exhibit chronic gastroin-
testinal (GI) symptoms and marked uctuation of behavioral
symptoms exhibit distinct innate immune abnormalities and
transcriptional proles of peripheral blood (PB) monocytes.
J Neuroimmunol. 2011;238:73-80.
76. Suzuki K, Matsuzaki H, Iwata K, et al. Plasma cytokine proles in
subjects with high-functioning autism spectrum disorders. PLoS
One. 2011;6:e20470.
77. Tobiasova Z, van der Lingen KH, Scahill L, et al. Risperidone-
related improvement of irritability in children with autism is not
associated with changes in serum of epidermal growth factor and
interleukin-13. J Child Adolesc Psychopharmacol. 2011;21:
555-564.
78. Wei H, Zou H, Sheikh AM, et al. IL-6 is increased in the cere-
bellum of autistic brain and alters neural cell adhesion, migration
and synaptic formation. J Neuroinammation. 2011;8:52.
79. Ashwood P, Nguyen DV, Hessl D, Hagerman RJ, Tassone F.
Plasma cytokine proles in Fragile X subjects: is there a role for
cytokines in the pathogenesis? Brain Behav Immun. 2010;24:
898-902.
80. Enstrom AM, Onore CE, Van de Water JA, Ashwood P. Differ-
ential monocyte responses to TLR ligands in children with autism
spectrum disorders. Brain Behav Immun. 2010;24:64-71.
81. Ashwood P, Schauer J, Pessah IN, Van de Water J. Preliminary ev-
idence of the in vitro effects of BDE-47 on innate immune responses
in children with autism spectrum disorders. J Neuroimmunol. 2009;
208:130-135.
82. Li X, Chauhan A, Sheikh AM, et al. Elevated immune response in
the brain of autistic patients. J Neuroimmunol. 2009;207:111-116.
83. Onore C, Enstrom A, Krakowiak P, et al. Decreased cellular IL-23
but not IL-17 production in children with autism spectrum dis-
orders. J Neuroimmunol. 2009;216:126-129.
84. Jyonouchi H, Geng L, Cushing-Ruby A, Quraishi H. Impact of
innate immunity in a subset of children with autism spectrum
disorders: a case control study. J Neuroinammation. 2008;5:52.
85. Enstrom A, Onore C, Picciotto IH, Croen L, Van De Water J,
Ashwood P. Detection of IL-17 and IL-23 in plasma samples of
children with autism. Am J Biochem Biotechnol. 2008;4:114-120.
86. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M.
Elevation of tumor necrosis factor-alpha in cerebrospinal uid of
autistic children. Pediatr Neurol. 2007;36:361-365.
87. Rossignol DA, Rossignol LW, James SJ, Melnyk S, Mumper E.
The effects of hyperbaric oxygen therapy on oxidative stress,
inammation, and symptoms in children with autism: an open-
label pilot study. BMC Pediatr. 2007;7:36.
88. Molloy CA, Morrow AL, Meinzen-Derr J, et al. Elevated cytokine
levels in children with autism spectrum disorder. J Neuroimmunol.
2006;172:198-205.
89. Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B.
Evaluation of an association between gastrointestinal symptoms
and cytokine production against common dietary proteins in
children with autism spectrum disorders. J Pediatr. 2005;146:
605-610.
90. Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Dysregulated
innate immune responses in young children with autism spec-
trum disorders: their relationship to gastrointestinal symptoms
and dietary intervention. Neuropsychobiology. 2005;51:77-85.
91. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW,
Pardo CA. Neuroglial activation and neuroinammation in the
brain of patients with autism. Ann Neurol. 2005;57:67-81.
92. Zimmerman AW, Jyonouchi H, Comi AM, et al. Cerebrospinal
uid and serum markers of inammation in autism. Pediatr
Neurol. 2005;33:195-201.
93. Ashwood P, Anthony A, Torrente F, Wakeeld AJ. Spontaneous
mucosal lymphocyte cytokine proles in children with autism
and gastrointestinal symptoms: mucosal immune activation and
reduced counter regulatory interleukin-10. J Clin Immunol. 2004;
24:664-673.
94. Sweeten TL, Fujinami RS. A potential link between measles virus
and autism: age-matched control groups are essential. Pediatr
Neurol. 2004;30:78; author reply 78.
95. Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M.
Activation of the inammatory response system in autism.
Neuropsychobiology. 2002;45:1-6.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY
VOLUME 53 NUMBER 3 MARCH 2014
96. DeFelice ML, Ruchelli ED, Markowitz JE, et al. Intestinal cyto-
kines in children with pervasive developmental disorders. Am J
Gastroenterol. 2003;98:1777-1782.
97. Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with
inammatory responses and cytokine production against com-
mon dietary proteins in patients with autism spectrum disorder.
Neuropsychobiology. 2002;46:76-84.
98. Jyonouchi H, Sun S, Le H. Proinammatory and regulatory
cytokine production associated with innate and adaptive
immune responses in children with autism spectrum disorders
and developmental regression. J Neuroimmunol. 2001;120:
170-179.
99. Gupta S, Aggarwal S, Rashanravan B, Lee T. Th1- and Th2-like
cytokines in CD4 and CD8 T cells in autism.
J Neuroimmunol. 1998;85:106-109.
100. Denney DR, Frei BW, Gaffney GR. Lymphocyte subsets and
interleukin-2 receptors in autistic children. J Autism Dev Disord.
1996;26:87-97.
101. Singh VK. Plasma increase of interleukin-12 and interferon-
gamma. Pathological signicance in autism. J Neuroimmunol.
1996;66:143-145.
102. Stubbs G. Interferonemia and autism. J Autism Dev Disord. 1995;
25:71-73.
103. Singh VK, Warren RP, Odell JD, Cole P. Changes of soluble
interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-
1 in the serum of autistic children. Clin Immunol Immunopathol.
1991;61:448-455.
104. Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal
course of children and adolescents with bipolar spectrum disor-
ders: the Course and Outcome of Bipolar Youth (COBY) study.
Am J Psychiatry. 2009;166:795-804.
105. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive
protein and other markers of inammation in the prediction
of cardiovascular disease in women. N Engl J Med. 2000;342:
836-843.
106. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of
C-reactive protein and low-density lipoprotein cholesterol levels
in the prediction of rst cardiovascular events. N Engl J Med.
2002;347:1557-1565.
107. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to pre-
vent vascular events in men and women with elevated C-reactive
protein. N Engl J Med. 2008;359:2195-2207.
108. Drtilkova I, Sery O, Theiner P, et al. Clinical and molecular-
genetic markers of ADHD in children. Neuro Endocrinol Lett.
2008;29:320-327.
109. Sweeten TL, Posey DJ, Shankar S, McDougle CJ. High nitric oxide
production in autistic disorder: a possible role for interferon-
gamma. Biol Psychiatry. 2004;55:434-437.
110. 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.
111. Lindqvist D, Janelidze S, Erhardt S, Traskman-Bendz L,
Engstr om G, Brundin L. CSF biomarkers in suicide attemptersa
principal component analysis. Acta Psychiatr Scand. 2011;
124:52-61.
112. Tonelli LH, Stiller J, Rujescu D, et al. Elevated cytokine expression
in the orbitofrontal cortex of victims of suicide. Acta Psychiatr
Scand. 2008;117:198-206.
113. Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R.
Elevated serum levels of C-reactive protein are associated with
mania symptoms in outpatients with bipolar disorder. Prog
Neuropsychopharmacol Biol Psychiatry. 2007;31:952-955.
114. Pervanidou P. Biology of post-traumatic stress disorder in
childhood and adolescence. J Neuroendocrinol. 2008;20:632-638.
115. Maes M, Lin AH, Delmeire L, et al. Elevated serum interleukin-6
(IL-6) and IL-6 receptor concentrations in posttraumatic stress
disorder following accidental man-made traumatic events. Biol
Psychiatry. 1999;45:833-839.
116. Baker DG, Ekhator NN, Kasckow JW, et al. Plasma and cere-
brospinal uid interleukin-6 concentrations in posttraumatic
stress disorder. Neuroimmunomodulation. 2001;9:209-217.
117. Gill J, Vythilingam M, Page GG. Low cortisol, high DHEA, and
high levels of stimulated TNF-alpha, and IL-6 in women with
PTSD. J Trauma Stress. 2008;21:530-539.
www.jaacap.org 295
 MITCHELL AND GOLDSTEIN
118. Gill J, Luckenbaugh D, Charney D, Vythilingam M. Sustained
elevation of serum interleukin-6 and relative insensitivity to hy-
drocortisone differentiates posttraumatic stress disorder with and
without depression. Biol Psychiatry. 2010;68:999-1006.
119. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The
pathophysiologic roles of interleukin-6 in human disease. Ann
Intern Med. 1998;128:127-137.
120. Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood
maltreatment predicts adult inammation in a life-course study.
Proc Natl Acad Sci U S A. 2007;104:1319-1324.
121. Lehto SM, Elomaa AP, Niskanen L, et al. Serum adipokine levels
in adults with a history of childhood maltreatment. Prog Neu-
ropsychopharmacol Biol Psychiatry. 2012;37:217-221.
122. Pace TW, Wingenfeld K, Schmidt I, Meinlschmidt G,
Hellhammer DH, Heim CM. Increased peripheral NF-kB
pathway activity in women with childhood abuse-related post-
traumatic stress disorder. Brain Behav Immun. 2012;26:13-17.
123. Pace TW, Mletzko TC, Alagbe O, et al. Increased stress-induced
inammatory responses in male patients with major depression
and increased early life stress. Am J Psychiatry. 2006;163:1630-1633.
124. Danese A, Moftt TE, Pariante CM, Ambler A, Poulton R,
Caspi A. Elevated inammation levels in depressed adults with a
history of childhood maltreatment. Arch Gen Psychiatry. 2008;65:
409-415.
125. da Rocha FF, Correa H, Teixeira AL. Obsessive-compulsive dis-
order and immunology: a review. Prog Neuropsychopharmacol
Biol Psychiatry. 2008;32:1139-1146.
126. Krause DL, Wagner JK, Wildenauer A, et al. Intracellular mono-
cytic cytokine levels in schizophrenia show an alteration of IL-6.
Eur Arch Psychiatry Clin Neurosci. 2012;262:393-401.
127. Martino D, Church AJ, Defazio G, et al. Soluble adhesion mole-
cules in Gilles de la Tourettes syndrome. J Neurol Sci. 2005;
234:79-85.
128. Hounie AG, Cappi C, Cordeiro Q, et al. TNF-alpha poly-
morphisms are associated with obsessive-compulsive disorder.
Neurosci Lett. 2008;442:86-90.
129. Murphy TK, Kurlan R, Leckman J. The immunobiology of
Tourettes disorder, pediatric autoimmune neuropsychiatric dis-
orders associated with Streptococcus, and related disorders: a
way forward. J Child Adolesc Psychopharmacol. 2010;20:317-331.
130. Russell VA, Oades RD, Tannock R, et al. Response variability in
attention-decit/hyperactivity disorder: a neuronal and glial
energetics hypothesis. Behav Brain Funct. 2006;2:30.
131. Boin F, Zanardini R, Pioli R, Altamura CA, Maes M,
Gennarelli M. Association between -G308A tumor necrosis factor
alpha gene polymorphism and schizophrenia. Mol Psychiatry.
2001;6:79-82.
132. Hanninen K, Katila H, Saarela M, et al. Interleukin-1 beta gene
polymorphism and its interactions with neuregulin-1 gene
polymorphism are associated with schizophrenia. Eur Arch
Psychiatry Clin Neurosci. 2008;258:10-15.
133. Drexhage RC, van der Heul-Nieuwenhuijsen L, Padmos RC, et al.
Inammatory gene expression in monocytes of patients with
schizophrenia: overlap and difference with bipolar disorder. A
study in naturalistically treated patients. Int J Neuropsycho-
pharmacol. 2010;13:1369-1381.
JOURNAL
296 www.jaacap.org
134. Rossignol DA, Frye RE. A review of research trends in physio-
logical abnormalities in autism spectrum disorders: immune
dysregulation, inammation, oxidative stress, mitochondrial
dysfunction and environmental toxicant exposures. Mol Psychi-
atry. 2012;17:389-401.
135. Buehler MR. A proposed mechanism for autism: an aberrant
neuroimmune response manifested as a psychiatric disorder.
Med Hypotheses. 2011;76:863-870.
136. Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Wagner RL,
Yolken RH. Maternal cytokine levels during pregnancy and adult
psychosis. Brain Behav Immun. 2001;15:411-420.
137. Brown AS. Epidemiologic studies of exposure to prenatal infec-
tion and risk of schizophrenia and autism. Dev Neurobiol. 2012;
72:1272-1276.
138. Dammann O, Leviton A. Maternal intrauterine infection, cyto-
kines, and brain damage in the preterm newborn. Pediatr Res.
1997;42:1-8.
139. Atladottir HO, Thorsen P, stergaard L, et al. Maternal infection
requiring hospitalization during pregnancy and autism spectrum
disorders. J Autism Dev Disord. 2010;40:1423-1430.
140. Abdallah MW, Larsen N, Grove J, et al. Amniotic uid chemo-
kines and autism spectrum disorders: an exploratory study uti-
lizing a Danish Historic Birth Cohort. Brain Behav Immun. 2012;
26:170-176.
141. Abdallah MW, Larsen N, Grove J, et al. Amniotic uid inam-
matory cytokines: Potential markers of immunologic dysfunction
in autism spectrum disorders. World J Biol Psychiatry. 2013;14:
528-538.
142. Abdallah MW, Larsen N, Mortensen EL, et al. Neonatal levels
of cytokines and risk of autism spectrum disorders: An
exploratory register-based historic birth cohort study utilizing
the Danish Newborn Screening Biobank. J Neuroimmunol.
2012;252:75-82.
143. Ziats MN, Rennert OM. Expression proling of autism candidate
genes during human brain development implicates central im-
mune signaling pathways. PLoS One. 2011;6:e24691.
144. Friberg D, Bryant J, Shannon W, Whiteside TL. In vitro cytokine
production by normal human peripheral blood mononuclear
cells as a measure of immunocompetence or the state of activa-
tion. Clin Diagn Lab Immunol. 1994;1:261-268.
145. Katial RK, Sachanandani D, Pinney C, Lieberman MM. Cytokine
production in cell culture by peripheral blood mononuclear cells
from immunocompetent hosts. Clin Diagn Lab Immunol. 1998;
5:78-81.
146. Licinio J, Wong ML. The role of inammatory mediators in
the biology of major depression: central nervous system
cytokines modulate the biological substrate of depressive
symptoms, regulate stress-responsive systems, and contribute
to neurotoxicity and neuroprotection. Mol Psychiatry. 1999;4:
317-327.
147. Breen EC, McDonald M, Fan J, Boscardin J, Fahey JL. Cytokine
gene expression occurs more rapidly in stimulated peripheral
blood mononuclear cells from human immunodeciency virus-
infected persons. Clin Diagn Lab Immunol. 2000;7:769-773.
148. Insel TR, Wang PS. Rethinking mental illness. JAMA. 2010;303:
1970-1971.
OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY
VOLUME 53 NUMBER 3 MARCH 2014