Original Article

Journal of Child Neurology

1-7
Serum Interleukin-6 Level in Children ª The Author(s) 2018
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With Attention-Deficit Hyperactivity DOI: 10.1177/0883073818809831
journals.sagepub.com/home/jcn
Disorder (ADHD)

Amira Hamed Darwish, MD1, Tarek Mohamed Elgohary, MD2, and

Nahla A. Nosair, MD3

Abstract
Introduction: Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children, but its
specific etiology and pathophysiology are still incompletely understood. Objectives: This case-control study aimed to measure
the level of serum interleukin-6 (IL-6) as a predictor of the immunologic status in children with ADHD, and to study its correlation
with severity of symptoms. Subjects and Methods: 60 ADHD children who met the Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition, criteria for ADHD and 60 control children were subjected to complete history taking, clinical examination,
and psychometric tests. Serum interleukin-6 of ADHD patients and control children was measured by enzyme-linked immu-
nosorbent assay. Results: The mean serum level of IL-6 was 22.35 (95% confidence interval [CI], 17.68-26.99) in ADHD patients,
and it was 5.44 (95% CI, 4.81-6.06) in controls. A significantly higher level of IL-6 was reported in ADHD patients compared with
controls (P ¼ .001). No significant correlation was found between serum IL-6 level and either the Intelligence Quotient (IQ) or
the Conners’ Parent Rating Scale score. Conclusion: Serum IL-6 values were significantly higher in ADHD patients compared to
healthy control children. Increased production of IL-6 may play a role in the pathogenesis of ADHD.

Keywords
cytokines, ADHD, IL-6, Inflammation, immune

Received March 21, 2018. Received revised August 7, 2018. Accepted for publication October 5, 2018.

Attention-deficit hyperactivity disorder (ADHD) is one of the
most prevalent neurodevelopmental disorders among children
with an estimated prevalence rate of 5% to 11% among school-
age children. 1 ADHD is characterized by hyperactivity,
impulsivity, and/or inattention that are inconsistent with the
developmental age of the child. Impairments in academic and
social functioning with school underachievement and difficul-
ties in family and peer relationships are also present.2
Both genetic and environmental factors are implicated in the
etiology of ADHD, with genetic factors representing a major
role, but the exact etiology and pathogenesis of ADHD is not
completely well defined.3
Some studies have reported an association between ADHD
and autoimmune diseases, suggesting that ADHD could be an
immune-related disorder due to an altered immune response.4,5
The immune hypothesis was introduced as a pathogenic
mechanism underlying ADHD, postulating that alterations in
the immune system can lead to chronic neuroinflammation.
Elevated levels of some inflammatory markers have been
reported in children with various neuropsychiatric disorders,
including ADHD, indicating that inflammation may have a role
in the pathogenesis of these disorders.6
In addition, some genes that are detected in ADHD patients
have immune functions and genes that alter inflammatory sig-
naling in the brain have been found to be associated with
ADHD.7-9 Two previous studies have reported an association
between ADHD and the polymorphism of genes encoding
some cytokines, mainly IL-2, IL-6, and TNF-a.7,8
Cytokines regulate the immune response and inflammation.
IL-6 is a proinflammatory cytokine that has a major role in the
immune response and inflammation; deregulated continuous
release of IL-6 can cause chronic inflammation and autoimmune
disorders.10 In addition, IL-6 is essential for homeostasis of the
1
Pediatric Neurology Unit, Pediatrics, Tanta University Hospital, Faculty of
Medicine, Tanta, Egypt
2
Child Psychiatry Unit, Pediatrics, Tanta University Hospital, Faculty of
Medicine, Tanta, Egypt
3
Clinical Pathology, Kafr El-sheikh University Hospital, Faculty of Medicine,
Kafr El-sheikh, Egypt
Corresponding Author:
Amira Hamed Darwish, Pediatric Neurology Unit, Pediatrics, Tanta University
Hospital, Faculty of Medicine, 12 Farrag Street, 3111, Tanta, Egypt.
Email: amira.darwish@med.tanta.edu
2 Journal of Child Neurology XX(X)
nervous system and for normal development and function of
both glial cells and neurons. At physiological levels, IL-6 affects
brain development through its effect on neural stem cell prolif-
eration and migration and synapse formation. The increased IL-6
level can alter the neural pathways of the developing brain and
affects attention and memory through its effect on neurogenesis
and synaptic plasticity in the prefrontal cortex and hippocam-
pus.10,11 This alteration of the normal brain development and
function may participate in the pathogenesis of ADHD.
The aim of our study was measurement of IL-6 concentra-
tion in the serum of children with ADHD. We hypothesized
that children with ADHD have higher levels of serum IL-6
compared with healthy children of the same age and sex.
Although all ADHD children exhibit the same manifesta-
tions, the severity of symptoms and the degree of functional
impairment differ between the affected children. We hypothe-
sized that this variability in symptom severity could be related
to variation in serum IL-6 in ADHD children and that serum IL-
6 could be correlated with the severity of ADHD symptoms.
Subjects and Methods
The study included 60 children with ADHD aged 6-16 years, recruited
from the Child Psychiatry clinic, Tanta University Hospital, during
April 2016 to April 2017. The inclusion criteria were as follows: (1)
age 6-16 years; (2) an ADHD diagnosis based on the Diagnostic and
Statistical Manual of Mental Disorders, 5th Edition (DSM-V) cri-
teria2; and (3) drug-naive condition. The following exclusion criteria
were used: (1) chronic medical illness, for example, renal, hepatic,
epilepsy, or diabetes mellitus; (2) recent trauma, infection, or vaccina-
tion; (3) intellectual disability; (4) autism spectrum disorder; and (5)
comorbid depression and mood disorders.
The control group included 60 healthy children, recruited from the
general pediatric clinic of our pediatric department, with no history of
recent infection, trauma, or vaccination. Control children were matched
for age and sex, did not meet the criteria of ADHD, and had no history
of other psychiatric or neurologic disorders.
A case-control design was used. Both patients and controls were
assessed using the following method: (1) history and clinical interview,
which involved thorough history taking, with emphasis on obstetric,
developmental, family, and psychiatric history; (2) clinical examina-
tion, wherein patients and controls were subjected to complete physical
examination, including neurologic examination; and (3) developmental
and psychometric tests, which are explained in detail below.
Conners’ Rating Scale (Third Edition).12 The Conners’ Third Edition–
Parent Short Form (Conners 3–P(S)), which is an assessment tool for
ADHD and its common comorbid disorders in children and adoles-
cents aged 6-18 years, is based on parents’ observations of their
child’s behavior. It consists of 43 items that form the following scales:
inattention, hyperactivity/impulsivity, learning problems/executive
functioning, aggression, and peer relations.
The parents’ reports about their child’s behavior were rated on a 4-
point scale. The answer to each question is scored from 0 to 3 (0 for
never present, 1 for sometimes present, 2 if frequently present, and 3
for very frequently present).
The diagnosis of ADHD was based on combining information from
the structured clinical interview with information obtained from the
Conners 3–P(S) and clinical observations. Children and adolescents
who met DSM-V criteria were diagnosed as ADHD. According to
DSM-V criteria, the diagnosis of ADHD requires the presence of 6
or more symptoms of hyperactivity and impulsivity and/or 6 or more
symptoms of inattention, which persist for at least 6 months.2
Conners’ Abbreviated Parent-Teacher Rating Scale for
ADHD (CPRS-HI)13
The Conners’ Abbreviated Parent-Teacher Rating Scale for ADHD
(CPRS-HI), which is an abbreviated form of the Conners’ Parent-
Teacher Rating Scale that consists of 10 items, includes the hyperac-
tivity index (HI) from the long versions of the Conners scales. It
assesses both hyperactivity and inattention and is also known as the
Conners’ 10-item scale. CPRS-HI was used to assess the severity of
ADHD symptoms in the present study. An Arabic version validated in
Egyptian children was used.14
Wechsler Intelligence Scale for Children—Third
Edition (WISC-III)15
The third edition of the Wechsler Intelligence Scale for Children
(WISC-III) was used to evaluate the Intelligence Quotient (IQ) in
children aged 6 to 17 years and yields a Verbal IQ, a Performance
IQ, and a combined Full-Scale IQ. Children who had an IQ of less than
70 were excluded from the study.
V-Measurement of Serum Interleukin-6 (IL-6) by
Enzyme-Linked Immunosorbent Assay Technique
Three milliliters of venous blood was collected from each subject as a
morning sample at 9 AM, and all samples were allowed to clot for 30
minutes in a water bath at 37 C. Sera samples were separated by
centrifuge and then stored at 70 C until time of analysis.
Principle of IL-6 Assay
Estimation of IL-6 in the serum (pg/mL) by enzyme-linked immuno-
sorbent assay using the Max Human Interleukin-6 ELISA Kit supplied
by eBioscience, Inc (North America), which detects IL-6 in plasma
and serum by quantitative sandwich enzyme immunoassay tech-
nique. The standard curve for human IL-6 was used to determine the
concentration of circulating human IL-6 for each sample. Expected
values in children 6-16 years of age range from 5 to 15 pg/mL. All
samples were performed in duplicate, and the mean value was taken
as the result. The intra-assay coefficient of variation was 6%.
Ethical Considerations
Full informed consent was taken from parents. Any unexpected risks
during the course of the research were cleared to the participants and
to the Ethical Committee on time. Privacy of participants and confi-
dentiality of the data were maintained.
Statistical Analysis
Normality of data distribution was tested with Shapiro Wilk and
Kolmogorov-Smirnov tests of normality; serum IL-6 levels in ADHD
children were not normally distributed. Descriptive statistics were
calculated as mean + standard deviation (SD) for continuous vari-
ables that were normally distributed, median and IQR for continuous
Darwish et al 3

Table 1. Demographic Characteristics, Intelligence Quotient (WISC-III), and Abbreviated Conners’ Rating Scale in ADHD Patients and
Controls.

ADHD patients Controls P value

Age, y .38
Range 6-14 6-13
Mean + SD 8.4 + 1.28 8.73 + 1.89
Sex, n (%) .087
Male 50 (83.3%) 41 (68.3%)
Female 10 (16.7%) 19 (31.7%)
Residence, n (%) .56
Urban 42 (70%) 39 (65%)
Rural 18 (30%) 21 (35%)
IQ (WISC) <.001*
Range 70-97 90-107
Mean + SD 82.67 + 7.57 95.32 + 4.21
Abbreviated Conners’ Rating Scale scores <.001*
Range 17-25 2-8
Mean + SD 20 + 3.36 5.95 + 1.8
Sex distribution across ADHD subtypes
ADHD subtypes Total number Male, n (%) Female, n (%) P value
Combined 32 28 (56%) 4 (40%) .803
Inattentive 18 14 (28%) 4 (40%)
Hyperactive 10 8 (16%) 2 (20%)

Abbreviations: ADHD, attention-deficit hyperactivity disorder; IQ, intelligence quotient; WISC-III, Wechsler Intelligence Children Scale—Third Edition.
*Significant (P < .05).

data not following normal distribution, and as numbers and percen-
tages for categorical variables. Independent sample t test was used for
comparison between continuous data that had normal distribution,
whereas Mann-Whitney U test was used for comparing serum IL-6
levels in ADHD children and controls. Chi-square test was used for
comparison between the 2 or more groups as regard qualitative data.
Linear correlation coefficient [r] was used to evaluate the associations
between IL-6 and patients’ variables, for example, IQ and Conners.
All tests were 2 sided, and differences were considered significant for
a P value of <.05. Statistical package for social sciences (SPSS) for
windows (SPSS 23) was used for input and analysis of data.
Results
Demographic Characteristics of ADHD
Patients and Controls
The age of the studied ADHD group ranged from 6 to 14 years,
and the age of control group ranged from 6 to 13 years. The
male:female ratio in the ADHD patients and controls was 5:1
and 2:1, respectively. No significant difference was found
between ADHD children and controls in regard to age, sex,
and residence.
Intelligence Quotient and Conners’ Parent Rating Scale
for ADHD Symptoms (Abbreviated Form)
Among the Studied Children
ADHD patients had significantly lower IQ than controls.
Abbreviated Conners’ Parent Rating Scale for ADHD symp-
toms ranged from (17-25) in the studied ADHD patients, and
(2-8) in the controls. There was significantly higher HI score in
ADHD patients compared with controls (Table 1).
Types of ADHD in the Studied Patients and Sex
distribution Across ADHD Subtypes
The studied ADHD patients were mainly of the combined type
(53.3%), whereas 30% were of the inattentive type and 16.7%
were of the hyperactive type. No statistically significant differ-
ence was found between the 3 types regarding sex. The com-
bined type was the main type in the studied ADHD males; 56%
of the male patients were of the combined type, whereas both
the inattentive and combined types were the most common
types in females—each representing 40% (Table 1).
Serum IL-6 Levels in Patients and Controls
The box plot shows that the median serum IL-6 levels in
ADHD patients is 20.4 and the interquartile range 9.38 (14.4-
23.52), whereas the median serum IL-6 levels in controls is 5
and the interquartile range 2.4 (4-6.4) (Figures 1 and 2). Serum
IL-6 level was significantly higher in ADHD patients than
controls (Table 2).
There was no significant correlation between serum IL-6
level and either the Intelligence Quotient (IQ) or the Abbreviated
Conners Rating Scale scores for parents (Figures 3 and 4).
Discussion
ADHD is one of the most common chronic health conditions
among school children, but the definite etiology and
4 Journal of Child Neurology XX(X)

Figure 1. Serum IL-6 levels in attention-deficit hyperactivity disorder

(ADHD) patients and controls. Outlying values are shown as open Figure 3. Correlation between serum IL-6 level and Conners’ Parent
circles and extreme values are shown as asterisks. Rating Scale in attention-deficit hyperactivity disorder (ADHD)
children.

60
50
IL-6 pg/ml

40
30
20
10
0
0 10 20 30 40 50 60 70
Control group ADHD children

Figure 2. Scatter plot of serum IL-6 levels in attention-deficit

hyperactivity disorder (ADHD) children and controls.

Table 2. Serum IL-6 Levels in ADHD Patients and Controls.

ADHD Patients Controls P value

IL-6 (pg/mL)
Range 4.2 – 56.2 1.24 – 13.34
Mean + SD 22.35 + 12.47 5.44 + 2.42 .001*
Median 20.4 5
IQR 9.38 (14.4-23.52). 2.4 (4.0-6.4) Figure 4. Correlation between serum IL-6 level and IQ in attention-
Normal IL-6 level, n (%) 14 (23.33) 34 (56.67) .00** deficit hyperactivity disorder (ADHD) children.
Low IL-6 level, n (%) 2 (0.03) 26 (43.33)
Elevated IL-6 level, n (%) 44 (73.33) 0
accordance with our findings, 2 previous studies have also
Abbreviations: ADHD, attention-deficit hyperactivity disorder; IQR, the reported higher serum level of IL-6 in ADHD patients com-
interquartile range. pared with normal control children.16,17 Donfrancesco et al16
*P value was calculated using Mann-Whitney U test and is significant when <.05.
**P value was calculated using w2 test and is significant when <.05. found significantly higher levels of serum IL-6 and IL-10 in
ADHD children than control group; however, they found
insignificant difference in the levels of other cytokines
pathogenesis are still unclear. The present study investigated (IL-2, IL-4, IL-17, IFN-g, and TNF-a). Oades et al17 also
the role of cytokines and the immune system in the pathogen- reported higher serum IL-6 level in ADHD patients than in
esis of ADHD through measurement of serum interleukin-6 in controls, but the difference was statistically insignificant.
both ADHD and normal children. We found a significantly They also found nonsignificantly higher levels of other cyto-
higher serum level of IL-6 in ADHD children compared to kines (IL-2, IFN-g, IL-16, IL-10, IL-13) in ADHD patients
normal children of matched age, sex, and residence. In than normal control children.
Darwish et al
The higher serum level of IL-6 reported in ADHD patients
in our study raises multiple questions. First, what is the
underlying etiology of this high serum level of IL-6 reported
in ADHD children? Second, what are the effects of high
serum level of IL-6 and what is the role of high serum level
of IL-6 in the pathogenesis of ADHD. Third, can control of
this elevated level of serum IL-6 be of benefit in treatment
of ADHD children?
The elevated serum level of IL-6 suggests that there is acti-
vation of the immune system in ADHD patients. When the
immune system is activated, cytokines are released from
CD4-positive T-helper lymphocytes. Cytokines can cross the
blood-brain barrier, but they can also be endogenously pro-
duced in the brain. IL-6 is produced in the brain by leuko-
cytes, astrocytes, and microglia. IL-6 mediates inflammation
and affects neurogenesis, synaptic plasticity, neuromodula-
tion, myelination, and demyelination. Furthermore, it affects
neurotransmitter release, potentiating the effect of excitatory
neurotransmitters through activation of glutamate receptor
and decreasing the effect of inhibitory neurotransmitters
through inhibition of g-aminobutyric acid (GABA)
responses. In addition, IL-6 influences the reaction time and
working memory.10,11
IL-6 and other proinflammatory cytokines are strictly regu-
lated and normally present in the brain at very low levels.
Increased production of IL-6 can cause chronic inflammation
in the brain through the effect of proinflammatory cytokines
causing activation of microglial cells and glutamate-induced
toxicity, and in turn activated microglial cells release IL-6 and
other proinflammatory cytokines.10,11
Apart from its role in inflammation, IL-6 participates in
normal brain development and function through its effect on
neurogenesis, myelination, and synapse formation.10,11 Studies
have reported that excess IL-6 causes inhibition of neurogen-
esis through decrease in cell survival and neuronal differentia-
tion.18 Brain imaging studies in ADHD patients demonstrated
smaller volume of the whole brain and gray matter, and cortical
thinning, particularly in the prefrontal cortex, and the basal
ganglia.19,20 These structural brain changes in ADHD children
could be related to the inhibiting effect of IL-6 on neurogen-
esis. Thus, increased production of IL-6 can alter the normal
brain development and function through its effect on neuronal
regeneration, synaptic plasticity, and myelination, and this in
turn could be one of the possible mechanisms for the pathogen-
esis of ADHD.
Furthermore, increased levels of IL-6 causes attenuation of
the neuronal activity in the anterior cingulate and prefrontal
cortex—the main areas involved in attention, behavioral inhi-
bition, and resistance to distraction.21 Disturbances in the func-
tion of the prefrontal cortex, in the form of attenuated activity,
are evident in children and adults with ADHD.22 Thus, the
effects of increased IL-6 on brain function could cause this
functional deficit in ADHD.
In addition, increased IL-6 can disturb the balance between
norepinephrine and dopamine in the brain through its effect on
the metabolism of brain neurotransmitters. Increased
5
norepinephrine and reduced dopamine levels have been
reported on administration of IL-6.23 Similar changes in nor-
epinephrine and dopamine neurotransmitters have been found
in the prefrontal cortex in ADHD patients.24
Thus, increased IL-6 levels can contribute to the pathogen-
esis of ADHD through the following mechanisms: activation
of microglial cells, inhibition of neurogenesis, delayed cor-
tical maturation and alteration of brain development, altera-
tion of brain neurotransmitters, and impaired cortical
neuronal activity.
Increased IL-6 was reported in various psychiatric and neu-
rologic disorders, such as multiple sclerosis, depression, and
autism.11 Changes in the level of cytokines were also reported
in children with some neurologic and psychiatric disorders,
suggesting a role of inflammation in the pathogenesis of some
neuropsychiatric disorders.6,25 Some studies have also sug-
gested that inflammation is one of the pathophysiological
mechanism of ADHD.26 The normal homeostasis of the neu-
roimmune system and immune-to-brain communication are
mediated by the interaction between cytokines, chemokines,
neurotransmitters, and hormones.27
Oades et al17 reported that the elevated cytokines levels in
ADHD patients were reduced to normal level after intake of
stimulant medications; the normalizing effect of stimulant
drugs is mostly due their effect on glial function.
We found no correlation between IL-6 levels and Conners
scale scores; thus, increased IL-6 could be one of the patho-
genic mechanisms for ADHD, but other factors also contribute
to the pathogenesis of ADHD. Vogel et al28 found no associ-
ation between serum IL-6 levels and ADHD symptoms in
adults with affective disorders. On the other hand, Oades
et al29 found a positive correlation between increased IL-13
and IL-16 levels and ADHD symptoms. IL-13 levels were
correlated with symptoms of inattention, whereas increased
IL-16 levels were correlated with symptoms of hyperactivity
and oppositional behavior.
Our findings support the immune-mediated mechanisms in
ADHD and the immune hypothesis; increased IL-6 may be one
of the pathogenic mechanisms of ADHD. The increased level
of IL-6 in ADHD could be related to either genetic or environ-
mental factors. Some genes involved in cytokine regulation are
linked to ADHD. Genetic studies have reported DOCK2 genes
involved in cytokine regulation as one of the genes responsible
for the development of ADHD; thus, increased IL-6 could be
related to genetic factors.7
Although genetic factors are the main etiology of ADHD,
environmental factors also contribute to the etiology of ADHD.
The main environmental factors linked to ADHD are a low
socioeconomic level, psychosocial deprivation, and family
dysfunction. Antenatal and perinatal factors, such as maternal
tobacco smoking or alcohol intake, perinatal asphyxia, low
birth weight, and prematurity are also linked to an increased
risk of ADHD.3 Oades30 reported a significant positive associ-
ation between increased serum IL-6 in ADHD children and
smoking in their fathers, whereas the author found no associ-
ation between IL-6 and other measured cytokine levels and
6 Journal of Child Neurology XX(X)
antenatal and perinatal risk factors. Chronic alcohol exposure
can also disturb the balance in the cytokine level, causing an
increase in proinflammatory cytokines, mainly IL-6.31
Increased cytokines caused by either genetic and/or envi-
ronmental factors could play a significant role in the pathogen-
esis of ADHD.6,26 Thus, introduction of drugs that can reduce
damage caused by IL-6 and treatments that aim to reduce IL-6
levels may be of value in the treatment of ADHD. Some studies
have reported improvement of inattention and hyperactivity
symptoms and reduction of IL-6 levels in ADHD children after
intake of omega-3 fatty acid. This effect could be through the
action of omega-3 fatty acid causing inhibition of synthesis of
proinflammatory cytokines.32
The main limitation of this study is that we did not measure
the level of the other cytokines, but IL-6 has a major role in
both immune response and nervous system homeostasis, thus
representing the link between the immune system and the
central nervous system. In addition, experimental animal
studies delineated the role of IL-6 in the pathogenesis of some
neuropsychiatric disorders.11 On the other hand, previous
studies have reported normal levels of other cytokines in
ADHD children.16,17
Despite this limitation, this case-control study has several
advantages. Clinical evaluation and psychometric tests were
applied for both the patients and controls to exclude any dis-
orders, other than ADHD, which can affect IL-6 level. Both
ADHD and normal children who had infection or recent history
of trauma or vaccination were excluded from the study. In
addition, the studied ADHD children were drug-naive and
without comorbid depression, because medication may affect
the IL-6 level, and depression has been reported to be associ-
ated with increased IL-6 levels.
Conclusions
Serum IL-6 levels were significantly higher in ADHD chil-
dren compared with the healthy control children; however,
the IL-6 levels did not correlate with the severity of ADHD
symptoms. Elevated levels of IL-6 in ADHD children indi-
cate that immune activation may have a place in the patho-
genesis of ADHD. Increased IL-6 levels caused by genetic
predisposition or environmental factors may contribute to
the etiology of ADHD.
Recommendations
Our finding that children with ADHD have elevated levels of
serum IL-6 could have implications for efforts to define
pathogenesis and treatment of ADHD. Further studies are
needed to investigate the role of IL-6 and other cytokines in
the pathogenesis of ADHD. Treatment directed toward neu-
roinflammation in ADHD is a new approach that needs further
research. Improving the immune status of ADHD children
may help to control symptoms and for improving the quality
of life in these children.
Author Contribution
AHD contributed to conception and design of the study, was respon-
sible for acquisition of clinical data, analysis and interpretation of
data, and manuscript writing. TME contributed to conception and
design. NAN was responsible for measurement of serum interleu-
kin-6 level. All authors revised the manuscript and gave final
approval.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
Ethical Approval
The Institutional Review Board of Faculty of Medicine, Tanta Uni-
versity, approved the study protocol (3072-02-15).
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