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Biomarkers in the Diagnosis of ADHD

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Curr Psychiatry Rep (2014) 16:497
DOI 10.1007/s11920-014-0497-1
ATTENTION-DEFICIT DISORDER (A ROSTAIN, SECTION EDITOR)
Biomarkers in the Diagnosis of ADHD Promising Directions
Stephen V. Faraone & Cristian Bonvicini &
Catia Scassellati
Published online: 10 October 2014
# Springer Science+Business Media New York 2014
Abstract The etiology and pathogenesis of attention-deficit/
hyperactivity disorder (ADHD) are unclear and a more valid
diagnosis would certainly be welcomed. Starting from the
literature, we built an hypothetical pyramid representing a
putative set of biomarkers where, at the top, variants in
DAT1 and DRD4 genes are the best candidates for their
associations to neuropsychological tasks, activation in specific
brain areas, methylphenidate response and gene expression
levels. Interesting data come from the noradrenergic system
(norepinephrine transporter, norepinephrine, 3-methoxy-4-
hydroxyphenylglycol, monoamine oxidase, neuropeptide Y)
for their altered peripheral levels, their association with neu-
ropsychological tasks, symptomatology, drugs effect and
brain function. Other minor putative genetic biomarkers could
be dopamine beta hydroxylase and catechol-O-methyltrans-
ferase. In the bottom, we placed endophenotype biomarkers.
A more deep integration of omics sciences along with more
accurate clinical profiles and new high-throughput computa-
tional methods will allow us to identify a better list of bio-
markers useful for diagnosis and therapies.
Keywords Biomarkers . Attention-deficit/hyperactivity
disorder . Dopaminergic pathway . Noradrenergic pathway .
Metabolism enzymes . CNS developmental network .
Environmental risk factors . Endophenotypes . SLC6A3 .
DRD4 . DBH . COMT . Reaction time variability .
This article is part of the Topical Collection on Attention-Deficit Disorder
S. V. Faraone
Department of Psychiatry, SUNY Upstate Medical University,
Syracuse, NY, USA
S. V. Faraone
Department of Neuroscience and Physiology, SUNY Upstate
Medical University, Syracuse, NY, USA
C. Bonvicini : C. Scassellati (*)
Genetic Unit - IRCCS Centro S. Giovanni di Dio Fatebenefratelli,
Via Pilastroni 4, 25123 Brescia, Italy
e-mail: cscassellati@fatebenefratelli.it
Vigilance/sustained attention . Executive functions .
Working memory . EEG Theta/Beta ratio
Introduction
The aetiology and pathogenesis of attention-deficit/hyperac-
tivity disorder (ADHD) is not yet fully understood [1, 2].
ADHD is also a highly heritable disease, with estimated
heritability rates of up to 80 % [3]. A recent review on genetics
of ADHD summarized that all variants associated with the
pathology explain only a small fraction of heritability: pheno-
type complexity and variants of small effect contribute to the
missing heritability issue [4]. To gain more insight into the
mechanisms leading from a genetic/biological basis of the
disease to the full clinical phenotype, endophenotypes are a
promising strategy [5].
The DSM and ICD diagnoses of ADHD are based on a
consensus about clusters of clinical symptoms. However, this
diagnostic procedure has been criticized for not allowing
sufficiently reliable and valid diagnoses [6]. NIMH recently
has approved the Research Domain Criteria (RDoC) project
where a set of assumptions permit to found a new classifica-
tion system, by integrating genetics, imaging and cognitive
information [6]. The RDoC approach suggests that a biomarker
approach to diagnosis may be a more valid way to classify
complex mental disorders such as ADHD. Biomarkers offer the
opportunity to standardize and improve diagnostic assessment
while providing insights into etiological mechanisms.
What is a Biomarker?
The United States food and drug administration (FDA) de-
fines a biomarker as an objective measure of normal process-
es, pathological processes or pharmacological response [7].
For psychiatry, biomarkers could be used to screen for, diag-
noses, or predict the development of, not only psychiatric
disorders but also of personality or behavioral traits and
497, Page 2 of 20
RDoC domains. Biomarkers could potentially be used to
inform treatment decisions.
Because no single biomarker candidate may be sufficient
for accurate and reliable diagnosis, the current trend in psy-
chiatry has shifted towards identifying sets of biomarkers [8,
9, 10, 11]. For example, Pies et al. defined a set of bio- higher commission errors, more impulsive responses and greater
markers for schizophrenia comprising:-neuregulin-1 muta-
tions; -abnormal smooth-pursuit eye movements; -reduced
anterior cingulate volumes, enlarged lateral and third ventric-
ular volumes and white matters abnormalities [12].
Despite their promise, the search for biomarkers of psychiatric
disorders has largely proven elusive. In a comprehensive review
[10], the authors concluded that according to their stringent
criteria, no biomarker is available for diagnosing ADHD.
The main goal of this review is to present evidence for a
putative signature set of biomarkers for ADHD using geno-
mic, neurophysiological/neuropsychological, neuroimaging,
pharmacogenomic and proteomic knowledge to diagnose
ADHD. In Table 1 we report data from genomics and meta-
bolomics classified according to neurophysiological/neuro-
psychological, neuroimaging, pharmacogenomic, biochemi-
cal and gene expression findings. Table 2 presents data from
endophenotypes studies to define a further potential signature
set of biomarkers useful for ADHD diagnosis.
Potential Dopaminergic Biomarkers for ADHD
Genomics
Deficiencies of dopaminergic and noradrenergic neurotrans-
mitter systems have been associated with ADHD and the main
symptoms of ADHD, but the dopamine system has been the
main focus of genomic research [69].
Dopamine Transporter Gene (DAT1, SLC6A3)
There are at least four main reasons for a central role of DAT1 in
ADHD genetics: 1) dopaminergic neurotransmission is con-
trolled by the DAT1 protein; 2) the DAT1 protein is the main
target for two ADHD medications: methylphenidate (MPH) and
amphetamine (AMP); 3) knockout mice for DAT1 show hyper-
activity and deficits in inhibitory behavior [69]; 4) DAT1 has
been mapped near to a susceptibility locus for ADHD, 5p13 [70].
The most studied DAT1 variant is a variable number of tandem
repeats (VNTR) of 40 base pairs located at the 3-untranslated
region (3-UTR) of the gene. The ten repeat (10R) and nine
repeat (9R) alleles are the most common. It has been demon-
strated that the DAT density measured in vivo using neuroimag-
ing was significantly higher in ADHD children with homozy-
gosity for the 10R in basal ganglia, a brain area participating in
inhibitory behaviors. This suggests a functional effect of the 10R
allele [71]. A recent meta-analysis demonstrated an association
Curr Psychiatry Rep (2014) 16:497
between the 10R allele and ADHD [13], although a reverse
association has been seen for ADHD adults [72].
Kebir and Joober and Barnes et al. summarized DAT1 studies
of neuropsychological tasks [21, 22]. As regards the association
between attention tasks and the 10R allele, some studies showed
reaction time variability (RTV) using the continuous performance
test (CPT) and sustained attention to response test (SART). Other
studies reported no association or opposite results [21]. Moreover
boys scoring high on a teacher-rated report of ADHD symptoms
and who were homozygous for the 10R allele displayed poorer
response inhibition on the opposite word task. Concerning execu-
tive functions, the 10/10 genotype predicted better performance on
the Tower of London (TOL), the self-order pointing task, and the
Wechsler Intelligence Scale for Children-III (WISC-III) arithmetic
and digit span subtests. Associations between a neurocognitive
phenotype-spatial attentional bias and 10R allele was reported in
children with ADHD [73, 74]. The attentional phenotype (left-
sided inattention) was related to higher symptom severity [74].
Several studies have been conducted on neuroimaging and 3
UTR VNTR variant in ADHD. Genotype 10/10 individuals
were found to generate more activations corresponding to inhi-
bition tasks, showing also its interaction with diagnostic status
(ADHD vs. controls) [15]. Moreover on non-ADHD siblings of
ADHD probands and controls, an influence was observed be-
tween the variant and the activation in striatum and cerebellum
vermis, with its interaction with familial risk for ADHD [18].
Similarly in another study, 10/10 individuals were more activat-
ed in left striatum, right dorsal premotor cortex, and bilateral
temporoparietal junction [20]. In contrast, Congdon et al. ob-
served greater neural activation associated with carriers of the 9R
[23]. Finally caudate volumes were overall smaller in 10/10 than
9/10 children, particularly in the left than right hemisphere [14].
Positron emission tomography (PET) and single photon
emission tomography (SPECT) have been used to determine
if ADHD patients show abnormal activity of the DAT in
striatum. In a meta-analysis of these studies, Fusar-Poli et al.
concluded that DAT activity was 14 % higher in ADHD
patients compared with controls [24]. A meta-analysis of neu-
roimaging studies of humans found that the 9R allele was
associated with increased DAT activity in striatum [75]. This
study was conducted considering different neuropsychiatric
illnesses and this strengths the issue that VNTR polymorphism
regulates dopamine activity in the striatal brain regions not only
in presence of ADHD but also of other disorders
A recent review on neuroimaging and pharmacogenetics
reported some studies on DAT1 [25]. In particular an asso-
ciation with 10R was found with higher regional cerebral
blood flow in medial frontal and left basal ganglia regions,
and with poorer treatment response, in children with ADHD
receiving MPH for 4 days before SPECT imaging session.
Moreover this allele was associated with greater DAT avail-
ability in basal ganglia following treatment and poorer
Table 1 Data from genomic and metabolomic studies classified according to neurophysiological/neuropsychological, neuroimaging, pharmacogenomic, biochemical and gene expression findings
Systems Potential biomarker Gene function/rationale
Genomics Dopaminergic system Dopamine transporter
(DAT1, SLC6A3)
Encodes a transmembrane
transport protein mediating
the active reuptake of DA
from the synapse and serves
as a critical regulator of
dopaminergic
neurotransmission in the
brain.
1) dopaminergic neurotransmission
is controlled by the DAT1;
2) it is the main target for MPH;
3) DAT1 knockout mice lead to
suggestive behavior of
ADHD;
4) maps near a susceptibility
locus .
Dopamine D4 receptor A member of the dopamine D2-
(DRD4) like receptor family inhibiting
adenylyl cyclase. Expressed
in frontal lobe regions
(orbitofrontal cortex and
anterior cingulated regions).
It was the first associated with
novelty-seeking personality
trait
Dopamine D2 receptor A member of the dopamine D2-
(DRD2) like receptor family.
Expressed in neostriatum,
olfactory tubercle, substantia
Location, polymorphism,
risk allele, functionality
3-UTR, VNTR, 10R, 1.12, 3.66, 0.028 [13]
higher expression levels
of the transporter
Intron VIII, VNTR, 3R
Intron, rs403636, Intron,
rs463379, Intron,
rs393795, Intron,
rs37020
Exon, rs6350
Exon III, VNTR, 7R, less
responsive to DA.
3Flank, rs18000497 (TaqI), 1.65, 2.56, 0.11 [13];
T (A1 allele), reduced
DRD2 expression.
Meta-analysis (OR, 2, GWAS/ Neuropsychological
p value) CNVs endophenotypes
studies
-Sustained Attention: some
studies showed association
10R and higher commission
errors, more impulsive
responses, greater RTV on
CPT, SART. Other studies
Curr Psychiatry Rep (2014) 16:497
reported no association or
opposite results.
-Executive functions:
association 10R with
good performance on
TOL, SOPT, WISC-III,
digit span subtests.
-Response inhibition:
association 10R allele and
poorer response inhibition
on the Opposite Word Task;
-Association 10R and spatial
attentional bias [reviews 21,
22].
1.25, 3.35, 0.034 [13]
-Association haplotype
rs403636 (G)/rs463379 (C)/
rs393795 (C)/rs37020 (G)
and spatial working memory
[28].
-Association with alerting and
executive control
performance [29].
1.35, 5.10, <0.0001 -Association 7R with speed of
[13, 30] processing, set shifting, and
cognitive impulsiveness ;
-Association absence 7R with
high RTV ;
- no effect on response
inhibition [reviews 21, 22].
[34]
1.65, 2.18, 0.03 [30]
Page 3 of 20, 497
Table 1 (continued)

Systems Potential biomarker Gene function/rationale Location, polymorphism, Meta-analysis (OR, 2, GWAS/ Neuropsychological
risk allele, functionality p value) CNVs endophenotypes
studies
497, Page 4 of 20

nigra, ventral tegmental area,

and nucleus accumbens.
It plays a role in regulating Intron, rs2075654, Intron, -Association with greater
the mesolimbic reward rs1079596 commission error rates
pathways. [review 21].
Dopamine D5 receptor A member of the dopamine 5Flank, Dinucleotide 0.58, 2.13, 0.0329 [30]
(DRD5) D1-like receptors family. repeat, 136 bp
Expressed in amygdala, frontal 5Flank, Dinucleotide 1.26, 2.91, 0.0036 [30] -Association with commission
cortex, hippocampus, repeat, 148 bp errors, omission errors, RTs,
striatum, basal forebrain, RTV [36];
hypothalamus, cerebellum, -No association with cognitive
and thalamus. It is implicated tests (Stop-signal task,
in hippocampal memory Stroop task, TMT, FDI, IQ)
formation. [38].
Metabolomics Phenylethylamine (PEA) A DA receptor agonist,
synthesized by the
decarboxylation of
phenylalanine
Dopamine (DA) In ADHD the turnover is
reduced with excessive re-
uptake and intra-synaptic
monoamine concentrations
are decreased.
Homovanillic acid (HVA) Main DA metabolite.
Genomics Noradrenergic system Norepinephrine Codes for a protein responsible Exon 9, rs5569, A 1.06, 1.17, 0.279 [13] [34] -No association with CPT
transporter protein 1 for the reuptake of NE from performance [review 21].
NET (SLC6A2) the synaptic cleft back into
the presynaptic neuron.
Expressed in the frontal lobes. 5 Flank, rs28386840 -Association T allele with
(A-3081T), T allele, greater decrease in mean
reduced levels of NET commission errors scores
within the brain. [40, 41].
It is actively involved in both Intron, rs998424, Intron, -Association with high
noradrenergic and rs3785157 performance on the
dopaminergic reuptake and similarities subtest of the
regulation in this region. WISCIII [42].
Intron, rs3785155 -Association with RTV [43].
Metabolomics Norepinephrine (NE) It is released by noradrenergic
neurons located in the
specific central nervous
system apart from
dopaminergic neurons.
Normetanephrine (NM) Main metabolite of NE.
3-methoxy-4- Main metabolite of NE.
hydroxyphenyl glycol
(MHPG)
Curr Psychiatry Rep (2014) 16:497
Table 1 (continued)
Systems Potential biomarker Gene function/rationale
Neuropeptide Y (NPY) Colocalizes with catecholamine
systems. It participates in the
regulation of feeding, circadian
rhythms, reproduction and
thermoregulation.
Genomics Adrenergic system Alpha-2A-adrenergic
receptor (ADRA2A) Encodes alpha-2A-adrenergic
receptors regulating
neurotransmitter release from
sympathetic nerves and from
adrenergic neurons.
Metabolomics Influences executive functions
in the prefrontal cortex.
Epinephrine (EPI) Neuroimaging and animal
studies support alteration in
EPI in ADHD.
Metanephrine (M) Main metabolite of EPI.
Metabolism enzymes Catechol-O- Enzyme catalyzing the
methyltransferase inactivation of DA within the
(COMT) PFC. Expressed in frontal
lobe regions of brain.
It regulates synaptic DA levels.
Genomics/ Monoamine oxidase A Encodes a protein involved in
metabolomics (MAOA) the metabolism of DA, 5-HT,
and NE.
It is associated to impulsive,
aggressive behavior.
MAOA knockout mouse
showed increased levels of
aggressive behavior and
monoaminergic
neurotransmitter levels.
Dopamine Beta Catalyzes the conversion of DA
Hydroxylase (DBH) into NE.
Location, polymorphism,
risk allele, functionality
5 Flank, rs1800544 (MspI),
G, functional
3-UTR, rs553668 (DraI),
T in TMT [review 21].
Exon IV, rs4680 (158Val/
Met), valine, higher
activity
Promoter, 30-bp VNTR, 2-
and 3-R are considered
low-activity alleles
Intron, rs12843268, A,
Intron, rs3027400, T,
Exon, rs1137070, T
Intron V, rs2519152 (TaqI),
T/A2 allele, associated
with reduced DBH
activity
Meta-analysis (OR, 2, GWAS/
p value) CNVs
studies
[44]
0.99, 0.01, 0.542 [13];
1.077, 0.20, 0.65 [45]
0.94, 0.12, 0.638 [13]
-, 1.02, 0.7267 [48]
1.02, 0.01, 0.464 [13]
1.12, 0.43, 0.206 [13]
Neuropsychological
endophenotypes
-Association C allele with TOL,
Curr Psychiatry Rep (2014) 16:497
TMT, RTVon different tasks
[review 21].
-Association with performance
-interaction: COMT(val/val)-
MAOA(3R) and high
intelligence [49].
-Association 4- and 5R alleles
with more commission
errors [54];
-Interaction: COMT(val/val)-
MAOA(3R) and high
intelligence [49].
-Gender-specific association ATT
haplotype and poor motor
control (boys), visuo-spatial
working memory (girls) [55];
-Association of rs12843268
and symptoms and reward
deficiency or insufficient
response inhibition [56].
-Association A2/T allele with
poorer performances on
temporal order judgment
task, more commission and
omission errors and greater
RTV (on the SART), more
errors on the WCST
(problem-solving) and the
Page 5 of 20, 497
MFFT (cognitive
impulsiveness).
Table 1 (continued)

Systems Potential biomarker Gene function/rationale Location, polymorphism, Meta-analysis (OR, 2, GWAS/ Neuropsychological
risk allele, functionality p value) CNVs endophenotypes
studies
497, Page 6 of 20

Expressed in the PFC. [reviews 21, 22].

CNS development 5 Flank, rs1611115 (-1021 1.05, 0.16, 0.692 [13] -Executive function: Association
pathways C/T), T allele associated C allele and global executive
with reduced DBH function and more errors of
activity, reduction of commission and omission on
DA-to-NE conversion the CPT [57].
Genomics/ Brain-Derived Encodes a neurotrophin Promoter, rs6265, G, 1.01, 0.02, 0.406 [13] [34] -No association with Digit span
metabolomics Neurotrophic Factor promoting neurogenesis, allele Val associated with [review 21].
(BDNF) development, functional increased activity-
maintenance, and plasticity dependent secretion of
of neurons. BDNF
Expressed in pons, Intron, rs2049046, Intron, -No association with Digit span
hippocampus, frontal cortex, rs11030104 [review 21].
colliculi, and olfactory tract.
Genomics Synaptosomal-associated Encodes a protein involved in 3-UTR, rs3746544, 1.15, 4.71, 0.03 [13]
protein 25 (SNAP-25) axonal growth, synaptic unknown
plasticity, docking, and fusion
of synaptic vesicles in
presynaptic neurons.
Expressed in hippocampus. 3-UTR, rs1051312, T 1.06, 0.30, 0.298 [13]
Metabolomics Environmental risk Ferritin (iron store) Coenzyme of tyrosine
factors hydroxylase and MAO. Iron
deficiency is associated with
ADHD symptoms.
Zinc (Zn) Cofactor for metabolism
relevant to neurotransmitters,
and it affects DA metabolism.
Zinc deficiency is associated
with behavior problems in
ADHD.
Oxidative stress Some studies showed some
treatment efficacy for anti-
oxidant compounds.

Potential biomarker Neurophysiological Variations in brain anatomy Variations in brain function Biochemical/proteomics Gene expression Pharmacogenetics/drugs effect
endophenotypes (structural MRI finding) (functional MRI finding) endophenotypes

Dopamine transporter -Association 10R with -Association 10R and more -Association 10R and increased
(DAT1, SLC6A3) smaller caudate volumes activations corresponding to MPH response, but also
particularly in the left inhibition tasks [15]; contrasting results [reviews
than right hemisphere 16, 17];
[14]. -Association 10R and activation -No association 10R and MPH
in striatum and cerebellum response [meta-analysis
vermis [18]; [19].
-Association 10R and activation
Curr Psychiatry Rep (2014) 16:497

in left striatum, right dorsal

Table 1 (continued)

Potential biomarker Neurophysiological Variations in brain anatomy Variations in brain function Biochemical/proteomics Gene expression Pharmacogenetics/drugs effect
endophenotypes (structural MRI finding) (functional MRI finding) endophenotypes

premotor cortex, and bilateral

temporoparietal junction
[20];
-Association 9R and greater
neural activation [23];
-Association 9R and increased
Curr Psychiatry Rep (2014) 16:497

DAT activity in striatum [24];

-Neuroimaging/
Pharmacogenetics [review 25]:
a) Association 10R allele and
higher regional cerebral
blood flow and with poorer
MPH treatment response;
b) Association 10R and greater
DAT availability in basal
ganglia after treatment and
MPH poorer treatment
response.
-Haplotype studies:
a) Association 10/6 and
dopaminergic reward-
processing circuitry [26];
b) Association 10/3 and spatial
inattention [27];
-Haplotype studies:
a) Association 10/6 and
dopaminergic reward-
processing circuitry [26];
b) Association 10/3 and spatial
inattention [27];

Dopamine D4 receptor -Association 7R with - lower mRNA expression - Association 7R and increased
(DRD4) thinner prefrontal and levels [31]. MPH response, but also
parietal cortex; contrasting results;
-Association 7R with a -Association 4R and positive
delay in cerebral cortical linear improvement on
maturation [32, 33]. mathematics test outcomes
with increasing MPH dose,
absence 4R decreased
responses to higher MPH
doses;
-Association 4R and picking
behaviors, 7R with social
Page 7 of 20, 497
Table 1 (continued)

Potential biomarker Neurophysiological Variations in brain anatomy Variations in brain function Biochemical/proteomics Gene expression Pharmacogenetics/drugs effect
endophenotypes (structural MRI finding) (functional MRI finding) endophenotypes

withdrawal, with increasing

497, Page 8 of 20

MPH doses.
[reviews 16, 17].
Dopamine D2 receptor -No association with MPH
(DRD2) response [35].

Dopamine D5 receptor
(DRD5) -No association with MPH
response [37].
Phenylethylamine (PEA) -Reduced urine levels in ADHD -Normalization after AMP and
[meta-analysis 39]. MPH [39].
Dopamine (DA) -No alteration in urine levels in
ADHD [meta-analysis 39].
Homovanillic acid (HVA) -No alteration in urine levels in
ADHD [meta-analysis 39].
Norepinephrine -Small influence on MPH
transporter protein 1 response [review 17];
NET (SLC6A2) -Association G allele with
greater decrease in mean
omission error scores after
MPH administration
compared to A allele carriers
[40, 41].

-No association with the

cerebral volume or
thickness of the cortex
[42].
Norepinephrine (NE) -Higher urinary levels in ADHD -Normalization after polyphenol
[meta-analysis 39]. complex (Pyc), fenfluramine,
AMP [39].
Normetanephrine (NM) -No alterations in urinary
levels in ADHD after
Bonferroni correction
[meta-analysis 39].
3-methoxy-4- -Reduced urinary levels in -Greater reductions after MPH
hydroxyphenyl glycol ADHD [meta-analysis 39]. and AMP treatment [meta-
(MHPG) analysis 39].
Neuropeptide Y (NPY) -Association with gene dose- -Increased plasma
dependent increases in NPY concentrations in ADHD
and emotion processing [44]. [39].
Alpha-2A-adrenergic -Association G allele and MPH
receptor (ADRA2A) response [review 46];
Curr Psychiatry Rep (2014) 16:497
Table 1 (continued)

Potential biomarker Neurophysiological Variations in brain anatomy Variations in brain function Biochemical/proteomics Gene expression Pharmacogenetics/drugs effect
endophenotypes (structural MRI finding) (functional MRI finding) endophenotypes

-Haplotype studies: association

between GG haplotype and
non-remission of ADHD
symptoms with atomoxetine
treatment [47].
-Haplotype studies: association
between GG haplotype and
Curr Psychiatry Rep (2014) 16:497

non-remission of ADHD
symptoms with atomoxetine
treatment [47].
Epinephrine (EPI) -No peripheral alterations in
ADHD [meta-analysis 39].
Metanephrine (M) -Higher urinary levels in
ADHD, lost after bonferroni
correction [meta-analysis
39].
Catechol-O- -Association with -Association Val allele and MPH
methyltransferase antisocial and response [52, 53].
(COMT) aggressive
behaviors of
ADHD [50, 51].
Monoamine oxidase A -Reduced platelet levels in -Normalization after MPH
(MAOA) ADHD [meta-analysis [39]. treatment [39].

Dopamine Beta -Lower activities in serum/urine

Hydroxylase (DBH) in ADHD, [39].

Brain-Derived -Higher plasma levels in ADHD -Association Val allele and MPH
Neurotrophic Factor [58]; response [59].
(BDNF) -no alteration in serum levels in
ADHD [60].
Synaptosomal-associated -Association T allele with
protein 25 (SNAP-25) improved MPH responses;
-Association G allele with sleep
difficulties and irritability
[37].
-Association T allele and poorer
MPH response;
-Association C allele with tics
and other abnormal
movements [37].
Ferritin (iron store) -Reported reduced serum levels
in ADHD, lost after
Page 9 of 20, 497
497, Page 10 of 20 Curr Psychiatry Rep (2014) 16:497

Note: ADHD: Attention-deficit/hyperactivity disorder; OR: Odd Ratio; 2 : chi-square; VNTR: Variable number tandem repeat; UTR: Untranslated region; MPH: methylphenidate; DA: Dopamine;

SART: Sustained attention to response test; TOL: Tower of London test; WISC-III: Wechsler intelligence scale for children-III; SOPT: Self ordered pointing Test; FDI: Freedom from distractibility index;
WGAS: Genome Wide Association study; CNVs: Copy number variations; MRI: Magnetic resonance imaging; TMT: Trail making test; RTV: Reaction time variability; CPT: Continuous performance test;
Pharmacogenetics/drugs effect
treatment response in children with ADHD who completed 8 weeks
of MPH treatment. In particular only a 28.6% of the subjects with
10/10 genotype showed good response to MPH treatment [71].
Pharmacogenetic studies have demonstrated increased re-
sponse to MPH among homozygous 10R, but there are conflict-
ing results [16, 17]. However a recent meta-analysis [19]
shows that there is no significant association between this
VNTR and response to MPH treatment. The meta-analysis also
found no effects on dimensions of hyperactivity/impulsivity and
inattention. Thus this finding suggests that VNTR polymor-
phism is not a reliable predictor of MPH treatment success in
Gene expression

ADHD, neither in relation to these specific symptom subscales.

A DAT1 VNTR at intron-8 that contains common 5-repeat
(5R) and 6-repeat (6R) alleles has also been associated with
ADHD susceptibility [13]. Recent evidence suggests that joint
consideration in haplotypes may provide more information than
plasma/urine levels in ADHD
Bonferroni correction [meta-

-Normal levels of anti-oxidant

can be inferred from the analyses of single genetic markers. There

stress is insufficient [meta-
their response to oxidative
production in ADHD, but
-Reported reduced serum/

are some neurophysiological studies on the haplotypes of these

Biochemical/proteomics

[meta-analysis 39].

two DAT1 variants: the 10/6 haplotype (formed by the 10R allele
of the 3UTR VNTR and the 6R allele of the intron 8 VNTR) is
analysis 39].

analysis 61].
endophenotypes

associated with dopaminergic reward-processing circuitry whose

deficits are linked to ADHD [26]. The haplotype 10/3 (formed by
the 10R allele of the 3UTR VNTR and the 3R allele of the intron
8 VNTR) predicts spatial inattention suggesting a functional
effect of this haplotype on cognitive performance in ADHD [27].
Other variants of DAT1 have been studied. rs6350 was
Variations in brain function
(functional MRI finding)

associated to alerting and executive control performance using

the attention network test [29]. Moreover a haplotype
(rs403636 (G)/rs463379 (C)/rs393795 (C)/rs37020 (G)) was
associated with spatial working memory in ADHD [28].
IQ: Intelligence quotient; AMP: Amphetamine; MFFT: Matching familiar figures test

Dopamine D4 Receptor (DRD4)

Variations in brain anatomy

The DRD4 gene is a good candidate for ADHD because of its

(structural MRI finding)

high expression in brain regions implicated in attention and

inhibition such as anterior cingulate cortex [76]. DRD4 was
the first associated with novelty-seeking, a personality trait
which is a common in ADHD. It has been demonstrated that
mRNA expression levels of DRD4 were lower in ADHD [31].
DRD4 is located on chromosome 11p15.5. A highly poly-
morphic functional VNTR in the third exon has been frequent-
Neurophysiological

ly investigated in association studies. It comprises 11 copies of

endophenotypes

a 48-bp repeat sequence, where 4, 7, and 2R repeat alleles are

the most prevalent. A meta-analysis showed that the 7R allele
was associated with ADHD [13, 30].
Recent reviews on neuropsychological endophenotypes
[21, 22] concluded that, although more studies are needed,
the 7R allele is associated with some cognitive markers
Table 1 (continued)

Potential biomarker

such as speed of processing, set shifting, and cognitive

Oxidative stress

impulsiveness, but not with response inhibition (the stop

and go/no-go tasks). More robust evidence suggests that
Zinc (Zn)

the absence of this allele is linked to high reaction time

variability (RTV).
Table 2 Data extracted from endophenotypes studies to define a potential signature set of biomarkers useful for ADHD diagnosis
Potential biomarker
EEG Theta/Beta ratio (TBR)
Reaction time variability (RTV) Increased RTV in ADHD. [100]
Selective attention and vigilance/ Attention impairment in [6466].
sustained attention
Verbal and visuo-spatial
working memory
Caudate
Thalamus
Anterior cingulated
Prefrontal cortex
Premotor and SMA cortex
Superior parietal cortex
Precuneus, posterior cingulate,
lateral parietal cortex, medial
frontal cortex (default-mode
network)
Cerebellum (posterior inferior
vermis)
Corpus callosum (splenium/
isthmus)
Fasciculus longitudinalis
superior
Anterior corona radiate
Note: ADHD: Attention-deficit/hyperactivity disorder; MRI: Magnetic resonance imaging; SMA: Supplementary motor area
Rationale Meta-analysis
Elevated Theta/Beta ratio [62]
(TBR) in ADHD.
ADHD.
Anomalies in prefrontal [6467]
cortical regiones and
the basal ganglia in
ADHD. Alterations in
dopaminergic,
noradrenergic and
fronto-striatal systems.
Neuroimaging studies
supported dysfunction of
several areas of the brain.
Review Neuropsychological
endophenotypes
[63] -Prognostic
Stable feature of ADHD
but no specific.
[10] -Robust findings [10];
-No association [6466].
[10] -Robust findings
[10, 67, 68];
-No association [6466]
[102]
Neurophysiological Variations in brain anatomy
endophenotypes (structural MRI finding)
measure [62];
-potential
biomarker [63].
Reduced gray matter volume Reduced activity and
Reduced gray matter volume
Reduced gray matter volume,
reduced white matter integrity
Reduced gray matter volume,
reduced white matter integrity
Reduced gray matter volume
Reduced gray matter volume
Reduced gray matter volume,
reduced white matter integrity
Reduced white matter integrity
Reduced white matter integrity
Reduced white matter integrity
Variations in brain function
(functional MRI finding)
Curr Psychiatry Rep (2014) 16:497
functional connectivity
Reduced activity and
functional connectivity
Reduced activity and
functional connectivity
Reduced activity and
functional connectivity
Reduced activity and
functional connectivity
Reduced activity and
functional connectivity
Reduced activity and
functional connectivity
Reduced activity and
functional connectivity
Page 11 of 20, 497
497, Page 12 of 20
Neuroimaging studies found associations of 7R allele with
thinner prefrontal and parietal cortex as well as with delay in
cerebral cortical maturation [32, 33].
Pharmacogenetic studies suggest an enhanced response to
MPH among 7R carriers even though conflicting results have
been obtained [16, 17]. Moreover some studies have sug-
gested that different DRD4 genotypes exhibit different MPH
doseresponse curves [16, 17]. One study demonstrated that [79]. These studies support the rationale on the involvement of
individuals with one or two copies of the 4R allele had positive
linear improvement on mathematics test outcomes with increas-
ing MPH dose, while those lacking a copy showed greater
improvement at lower doses, and deterioration at higher doses.
A second study found that those lacking any 4R allele had
decreasing responses to higher MPH doses compared with other
genotypes. Both these studies are consistent with the idea
that the 7R codes for a defective dopamine receptor that
responds less effectively at higher doses, an idea with some
potential for clinical relevance if replicated in larger samples.
One interesting finding suggests that DRD4 might play a
role in predicting susceptibility to medication side effects. In
the Preschool ADHD Treatment Study, MPH treated ADHD
children homozygous for the 4R were three-times more
likely to develop picking behaviors, while those with at least
one copy of the 7R were four-times more likely to develop
social withdrawal with increasing doses. Thus, 7R carriers
appear to be a distinct subgroup of ADHD patients which
experiences differential medication effects.
Other variants in the promoter region have also been stud-
ied, focusing on a 120-base pair duplication (120-bp dup),
521C/T (rs1800955), 616C/G (rs747302), 615A/G, and
376C/T, located in the 5 untranslated region. However two
meta-analyses conducted on 120-bp dup and 521C/T
showed no association with ADHD [13, 30].
Dopamine D2 receptor (DRD2)
The DRD2 gene is located at chromosome 11q23.1. The
rationale for its involvement in ADHD is based on the evi-
dence that it is expressed in those brain areas relevant for the
pathology and it is implicated in the regulation of mesolimbic
reward pathways [77]. A recent genome wide association
study reported a nominal association of this gene with
ADHD susceptibility [34]. The TaqIA (rs1800497) variant
of DRD2 was believed to connect with urinary level of the
DA metabolite homovanillic acid (HVA) and DRD2 expres-
sion levels. According to Wu et al.s meta-analysis, an asso-
ciation of this polymorphism was reported [30]. However,
due to excessive heterogeneity, the authors concluded that this
result was invalid. Pharmacogenetic studies have found no
association of this variant with MPH response [35]. Two
other DRD2 variants, rs2075654 and rs1079596, have
been associated with greater commission error in ADHD
[21].
Curr Psychiatry Rep (2014) 16:497
Dopamine D5 Receptor (DRD5)
DRD5 maps to chromosome 4p15.3. In situ hybridization
studies demonstrated that the expression of the gene is higher
in hippocampus, a brain area involved in ADHD pathogenesis
[78]. Moreover functional studies showed that DRD5 is impli-
cated in synaptic strength in hippocampal memory formation
DRD5 gene in ADHD. The association between ADHD and a
highly polymorphic dinucleotide repeat of DRD5 ((CA)n),
located in 18.5 kb at the end of the 5 flanking region, has been
the most studied. This variant comprises 12 alleles ranging from
134 to 156 bps in length, among which the 148-bp and 136-bp
alleles are the most common. The 148-bp allele was a risk
factor for ADHD according meta-analyses, while that of 136-
bp allele was a protective factor for ADHD [13, 30].
Interestingly, the 148 bp allele associated to commis-
sion errors, omission errors, RTs, and RTV [36], whereas
no association was detected with cognitive test scores [38].
Pharmacogenetic studies found no association of MPH
response with the 148-bp allele, whereas the 151-bp allele
has been linked to a favorable MPH response [37].
Metabolomics
Phenylethylamine (PEA)
In dopaminergic neurons of the nigrostriatal system, the dopamine
(DA) receptor agonist PEA is synthesized by the decarboxylation
of phenylalanine. PEA stimulates the release of DA and, accord-
ing to a meta-analysis [39], urinary levels of PEA are signifi-
cantly lower in patients with ADHD compared with controls.
Interestingly decreased levels of PEA have also been associated
with symptoms of inattentiveness and administration of AMP and
MPH markedly increased urinary excretion of PEA [39].
DA and HVA
DA and its main metabolite HVA showed no difference in urine
excretion in ADHD patients compared with controls [39].
Potential Noradrenergic Biomarkers for ADHD
Genomics
Norepinephrine Transporter Gene (NET1, SLC6A2)
The SLC6A2 gene codes for the norepinephrine transporter,
which is responsible for the reuptake of norepinephrine (NE)
from the synaptic cleft back into the presynaptic neuron and is
targeted by atomoxetine, a medication for ADHD. NET1 is
most highly expressed in the frontal lobes where it plays a role
Curr Psychiatry Rep (2014) 16:497
in noradrenergic and dopaminergic reuptake [80]. A frequent-
ly studied SNP (rs5569 or G1287A) located in exon 9 was not
significant in a meta-analysis of candidate gene studies [13],
but a nominal association was observed in a genome-wide
association study [34]. No association was found between this
variant and CPT performance [21]. A recent review on phar-
macogenetics concluded that NET1 influence on response to
MPH is small [17], although a recent genome-wide associ-
ation study found two SNPs in SLC6A2 gene associated with
MPH response [81]. In a study rs3785143 was associated with
atomoxetine response [47].
Moreover children with the G/G genotype at G1287A showed
a greater decrease in mean omission error scores after MPH
administration compared to A allele carriers. Another polymor-
phism A-3081T at 5flank, demonstrated to be functional, was
associated with T allele with greater decrease in mean commis-
sion errors scores, meaning improved impulsive behavior [40,
41]. Other variants such as rs998424 and rs3785157 were linked
to high performance on the similarities subtest of the WISCIII,
but not with the cerebral volume or thickness of the cortex [42].
Another SNP rs3785155 was associated to RTV [43].
Metabolomics
Norepinephrine (NE)
Concerning NE levels, a meta-analysis [39] indicated higher
urinary levels in ADHD compared with controls, and a nor-
malization of NE concentrations has been observed after
treatment with polyphenol complex and with fenfluramine
and AMP [39].
3-Methoxy-4-Hydroxyphenylglycol (MHPG)
MHPG is the main metabolite of NE. Its urinary levels
were lower in ADHD patients and stimulant trials
showed that decreases in ADHD symptoms with treat-
ment were associated with greater reductions in urinary
MHPG excretion [39].
Neuropeptide Y (NPY)
NPY frequently colocalizes with catecholamine systems. It
participates in the regulation of feeding, circadian rhythms,
reproduction, and thermoregulation. Oades et al. found in-
creased plasma NPY concentrations in ADHD children com-
pared with controls [82]. Moreover a recent genome-wide
copy number variation analysis [44] found that NPY was
included in a rare 3 Mb duplication on chromosome 7p15.2
to 15.3 and an association of this duplication was found with
increased NPY plasma concentrations. Moreover an associa-
tion was observed between gene dose-dependent increases in
NPY and emotion processing [44].
Page 13 of 20, 497
Potential Adrenergic Biomarkers for ADHD
Genomics
Alpha-2A-adrenergic receptor (ADRA2A)
ADRA2A in the prefrontal cortex influences executive func-
tions impaired in ADHD [83]. It is also a target for two ADHD
medications: guanfacine and clonidine. A-1291 C>G creates
an MspI site in the promoter region and it is a functional
polymorphism. Two meta-analyses confirmed no association
with ADHD [13, 45]. However the C allele was associated
with TOL, trail making test (TMT), and RTV on the stop-
signal task as well as the CC genotype was associated with
high RTV on the CPT test [21]. A recent pharmacogenetic
review [17] summarized some studies reporting that G allele
is associated with greater reduction of inattentive symptoms
over time. Froehlich et al. also found a main effect of this
genetic variant on MPH response [46]. However, the G allele
was associated with hyperactive-impulsive symptoms on pla-
cebo and across doses.
Another variant rs553668, for which the disorder meta-
analysis was negative [13], was associated with the perfor-
mance on TMT suggesting an involvement of this gene on
executive functions [21]. Yang et al. described an association
between GG haplotype (rs1800544/rs553668) and non-
remission of ADHD symptoms with atomoxetine treatment
[47].
Metabolomics
Epinephrine (EPI) and Metanephrine (M)
EPI and its main metabolite M levels, according to a recent
meta-analysis [39], were respectively no different or higher
in ADHD patients. The difference for M was lost after
Bonferroni correction.
Potential Metabolism Enzymes as Biomarkers for ADHD
Genomics/Metabolomics
Catechol-O-Methyltransferase (COMT)
COMT is an enzyme responsible for the degradation of DA
and NE. It is highly expressed in frontal lobe where it regu-
lates synaptic DA levels [84]. Studies examining the associa-
tion between COMT and ADHD have largely focused on a
functional SNP in exon 4 that creates an amino acid substitu-
tion (valine/methionine). This variant affects COMT enzyme
activity, such that homozygotes for the valine allele shows 34
times greater activity than homozygotes for the methionine
497, Page 14 of 20
allele. However meta-analysis [48] indicates no association
between ADHD and the 158Val/Met.
A review summarized studies on 158Val/Met and neuropsy-
chological endophenotypes [21]. While no association was
observed between this variant and performance on cognitive
tasks, a significant finding was reported between the Met allele
and impairment in sustained attention and fewer commission
errors. In the neurophysiological studies, this variant was asso-
ciated with antisocial and aggressive behaviors of ADHD [50,
51]. Pharmacogenetic studies reported a positive association
between Val allele and response to MPH [52, 53].
Monoamine Oxidase A (MAOA)
The MAOA gene encodes a protein involved in the metabolism of
DA, 5-HT, and NE. It has been associated with impulsive,
aggressive behavior [85]. Moreover an MAOA knockout mouse
showed increased levels of aggressive behavior and monoamin-
ergic neurotransmitter levels [86]. Recent studies have focused
largely on a functional 30-bp VNTR 1.2 kb upstream of the gene,
previously associated with impulsivity and aggression. According
the classification system [87], the 2- and 3R are considered low-
activity alleles, the others are high-activity alleles. A recent
meta-analysis reported no association with ADHD [13].
According to neuropsychological studies, the 4 and 5R alleles
are associated with commission errors on the TOVA test, and a
MPH administration attenuated this association [54].
Moreover a gender-specific association has been reported with
the ATT haplotype (rs12843268/rs3027400/rs1137070) [55]. In
boys, the ATT haplotype was associated with motor control; in
girls with visuo-spatial working memory. This suggests that
MAOA genotype influences cognitive and motor functioning in
ADHD and sex moderates these effects. This may be related to
biological differences between males and females in serotonin
neurotransmission. Finally Nymberg et al. reported a sex-specific
association between ADHD symptomatology and reward defi-
ciency or insufficient response inhibition depending on
rs12843268 genotype [56]. Concerning blood levels, a recent
meta-analysis indicated reduced levels in ADHD compared with
controls [39]. MAO levels were associated with impulsiveness
and MPH treatment normalized the reduced levels.
Dopamine Beta Hydroxylase (DBH)
The DBH gene encodes an enzyme that catalyzes the conversion of
DA into NE which is particularly expressed in the prefrontal cortex
[88]. A1021C/T variant (rs1611115) accounts for up to 50 % of
the variation of plasma DBH activity, but it is the intron 5 TaqI
variant (rs2519152) that has been most often tested. A meta-
analyses of these variants reported no association with ADHD [13].
Two recent reviews of neuropsychological endophenotypes
summarized studies of DBH [21, 22]. In particular the A2/T
allele was found associated with poorer performances on a
Curr Psychiatry Rep (2014) 16:497
temporal order judgment task, more commission and omission
errors and greater RTV on the SART, more errors on the
Wisconsin Card Sorting Test (WCST) (problem-solving) and
the Matching Familiar Figures Test (MFFT) (cognitive
impulsiveness).
Finally an association between neuropsychological mea-
sures of executive function in children with ADHD and the
1021C/T variant has been reported [57].
A meta-analysis [39] found that ADHD patients showed
lower activities of DBH in serum and urine and it was sug-
gested that decreased DBH levels correlate with ADHD
symptoms [39, 89, 90].
Potential CNS Development Biomarkers for ADHD
Genomics/Metabolomics
Brain Derived Neurotrophic Factor (BDNF)
BDNF has been mapped to chromosome 11p13. It belongs to a
family of neurotrophins, involved in promoting neurogenesis,
neuronal survival, and synaptic plasticity [91]. A genome wide
study supported a nominal association with ADHD susceptibil-
ity [34]. A common variant resulting in a valine to methionine
amino acid substitution at codon 66 (Val66Met; rs6265) regu-
lates the intracellular tracking and activity-dependent secretion
of BDNF in brain. A meta-analysis found no association of this
variant with ADHD [13]. This variant and two others,
rs2049046 and rs11030104, were not associated with the Digit
Span test [21]. Moreover better MPH response in ADHD chil-
dren who are Val/Val homozygous was reported [59].
Concerning peripheral levels, higher plasma concentrations
were observed in ADHD patients as compared with controls
[58], whereas no alterations were observed in serum levels [60].
Synaptosomal-Associated Protein 25 (SNAP-25)
SNAP-25 codes for a protein involved in axonal growth,
synaptic plasticity, and in the docking and fusion of synaptic
vesicles in presynaptic neurons necessary for the regulation of
neurotransmitter release [92]. The major variants studied were
rs362987 (intron 4), rs363006 (intron 6), rs3746544 (3UTR),
and rs1051312 (3UTR). A main effect on ADHD suscepti-
bility was observed only with rs3746544 [13].
Concerning pharmacogenetic studies, homozygotes for
the T allele of T1065G had moderately improved MPH
responses, whereas homozygotes for the G allele developed
sleep difficulties and irritability. Moreover, homozygotes for
the T allele at T1069C exhibited poorer MPH response,
whereas homozygotes for the C allele developed tics and
other abnormal movements [37].
Curr Psychiatry Rep (2014) 16:497
Potential Biomarkers for Environmental Risk factors
Metabolomics
Iron
It is a coenzyme of tyrosine hydroxylase and MAO, which are
critical in the synthesis and degradation, respectively. Ferritin
is a major intracellular iron storage protein and serum ferritin
levels are an indication of iron stores in the body and brain.
Children with iron deficiency exhibited ADHD symptoms,
such as inattention, hyperactivity, and/or impulsivity [review
90]. A meta-analysis indicated that serum ferritin levels were
lower for ADHD patients compared with controls, although
the finding was lost after Bonferroni correction [39].
Zinc
Zinc is another essential cofactor for neurotransmitter me-
tabolism which affects DA metabolism. Zinc deficiency is
associated with behavior problems in children with ADHD
[review 90]. Although a systematic review of randomized
controlled clinical trials demonstrated that using zinc, either
alone or in combination with stimulants, did not improve
ADHD symptoms [93], a meta-analysis reported reduced
serum/plasma/urine levels in ADHD [39].
Oxidative Stress
The normal oxidation-reduction reactions that create energy in the
cell create toxic oxidants or reactive oxygen species. These by-
products of normal oxidation-reduction reactions are highly un-
stable. Antioxidants counteract the effects of oxidants. When
antioxidants are not sufficient, oxidative stress occurs and dam-
ages cellular proteins, lipids, carbohydrates, and nucleic acids.
Brain tissue is especially susceptible to oxidative stress. Indirect
evidence for oxidative stress in ADHD comes from studies show-
ing some treatment efficacy for anti-oxidant compounds such as
omega-3 fatty acids, pycnogenol and N-acetylcysteine [9497].
A meta-analysis of oxidative stress in ADHD suggested
that patients with ADHD have normal levels of anti-oxidant
production but that their response to oxidative stress is insuf-
ficient, leading to oxidative damage [61].
Potential Endophenotypes as Biomarkers for ADHD
Besides indentifying a genetic marker involved in neurophysio-
logical/neuropsychological, neuroimaging, pharmacogenetics,
biochemical features, a putative signature set of biomarkers
could be integrated with a research on endophenotypes
(Table 2).
Page 15 of 20, 497
EEG Theta/Beta Ratio (TBR)
TBR is a measurement of the power (wave amplitude squared)
produced by brain waves altering between 3.5 and 28.0 Hz in
children with ADHD [98]. A genetic overlap between ADHD
symptoms and EEG theta power has been reported [99] and
this supports a recent review suggesting TBR as a potential
biomarker for ADHD [63]. However a recent meta-analysis
concluded that excessive TBR cannot be considered a reliable
diagnostic measure of ADHD but it could have a prognostic
value [62]. In June 2013 FDA approved Neuropsychiatric
EEG-Based Assessment Aid (NEBA) System, a test recording
the type and number of brain waves that nerve cells give off
each second.
In summary, as also reported in Thome et al. the neurophys-
iological markers must be viewed as promising candidates for
biomarkers of ADHD but further studies are needed [10].
Reaction Time Variability (RTV)
Individuals with ADHD are described frequently as ubiqui-
tously slower and more variable than their unaffected peers,
and ADHD-related RTV is considered by many to reflect a
unique, stable, and etiologically important characteristic of the
disorder. Results of a recent meta-analysis indicate that, con-
trary to contemporary characterizations of individuals with
ADHD as slower and more variable, ADHD individuals
may be better characterized as more variable but not slower
after accounting for their increased response variability.
However RTV lacks specificity among clinical disorders,
and thus is not a viable diagnostic marker of ADHD [100].
Selective Attention and Vigilance/Sustained Attention
A prominent multidimensional model of attention differentiates
between alertness, divided attention, selective attention,
vigilance/sustained attention and shifting. According to
Thome et al. the most robust findings indicated that children
with ADHD displayed difficulties in measures of selective
attention and vigilance/sustained attention [10]. Impairments
of vigilance/sustained attention are the most replicated neuro-
psychological finding in ADHD. However a considerable num-
ber of investigations were unable to find difference between
ADHD patients and controls [6466]. In addition effect sizes
indicated only small to moderate differences between ADHD
patients and controls.
Executive Functions
They are an umbrella term encompassing various functions of
higher cognitive functioning including planning, problem
solving, concept formation, fluency, cognitive flexibility, and
working memory. The most consistent finding in the domain
497, Page 16 of 20
of executive functions is that patients with ADHD display
impairments in working memory. Working memory measures
appear therefore to be the most sensitive indicator of executive
dysfunctioning in ADHD [10]. Additional studies support
this finding [67, 68]. However, as for vigilance/sustained
attention, no difference was found between patients and con-
trols with small to moderate effect sizes [6466].
In summary, although promising results were obtained for
selective attention and vigilance/sustained attention and work-
ing memory, no sensitive or specific profile based on neuro-
psychological tests assessing cognition in ADHD has as yet
been found [101].
Brain Differences in ADHD
Kasparek et al. reported alterations in several areas of the
brain, particularly the anterior cingulum, the dorsolateral as
well as ventrolateral prefrontal cortex, the orbitofrontal cortex,
the superior parietal regions, the caudate nucleus, the thala-
mus, the amygdala and the cerebellum. Imaging studies point
to the persistence of changes in both brain structure and
function into adulthood, although there might be a tendency
for improvement of caudate nucleus pathology. Growing ev-
idence suggests that MPH treatment can lead to improvement
of brain changes seen in neuroimaging by its positive effect on
neuroplasticity [102].
Fig. 1 Hypothetical pyramid representation of possible signature sets of
biomarkers for ADHD diagnosis. Starting from the literature, we built an
hypothetical pyramid describing a putative set of biomarkers where, at
the top, variants in DAT1 and DRD4 genes are the best candidates as
useful biomarkers, for their associations to neuropsychological tasks,
activation in specific brain areas, methylphenidate response and gene
expression levels. A further level is represented by the noradrenergic
system (Norepinephrine transporter, Norepinephrine, 3-methoxy-4-
hydroxyphenylglycol, Monoamine Oxidase, Neuropeptide Y) for their
altered peripheral levels, their association with neuropsychological
tasks, symptomatology, drugs effect and brain function. Other minor
putative genetic biomarkers could be Dopamine Beta Hydroxylase and
Curr Psychiatry Rep (2014) 16:497
Conclusion
The study of psychiatric biomarkers is very complex because
of the heterogeneous nature of psychiatric disorders which are
often referred to as syndromes with several subtypes, not
uniform problems. Therefore, a single biomarker is very un-
likely to provide enough information to identify cellular and
metabolic pathways involved in a particular individual.
Identification of a signature set of biomarkers for disorder
subtypes each based on their underlying biological pathways
will be the most effective for diagnosis and treatment
selection.
Starting from the literature, we have built an hypothetical
pyramid representing a putative set of biomarkers where at the
top there are potentially useful biomarkers for ADHD and at
the bottom those that are probably not useful (Fig. 1).
Following Pies et al.s [12] example, a potential genetic-
biomarker could be represented by the variants in DAT1 and
DRD4 genes as the best candidates as biomarkers for ADHD.
Indeed the 10R allele at the 3UTR of SLC6A3, is associated
with specific neuropsychological tasks [21, 22], generates
more activation in specific brain areas [33], and is associated
to MPH response [16, 17]. Similarly the 7R allele at exon 3
of DRD4 is involved in specific neuropsychological tasks [21,
22], brain structure [32, 33], MPH response [16, 17], and
expression levels of DRD4 [31].
Catechol-O-methyltransferase. In the bottom, we placed endophenotype
biomarkers. In particular working memory, selective attention vigilance/
sustained attention, Theta/beta ratio, Reaction Time Variability and
neuropsychological endophenotypes are, in this order, probably not
useful biomarkers for ADHD diagnosis. Notes: Dopamine Transporter
gene (DAT1, SLC6A3); Dopamine D4 receptor (DRD4);
Norepinephrine transporter (NET1, SLC6A2); Norepinephrine (NE);
3-methoxy-4-hydroxyphenylglycol (MHPG); Monoamine oxidase
(MAO); Neuropeptide Y (NPY); Dopamine beta hydroxylase (DBH);
Catechol-O-methyltransferase (COMT); Theta/beta ratio (TBR);
Reaction time variability (RTV)
Curr Psychiatry Rep (2014) 16:497
Interesting data also come from the noradrenergic system.
In fact, according to metabolomic studies, NET1, NE, its
metabolite MHPG and MAO along with NPY could represent
good candidates as biomarkers for ADHD, based on their
peripheral levels altered in ADHD [39], their association
with neuropsychological tasks [21, 4043, 5456], symptom-
atology, drugs effect [39], and brain function [44].
Other minor putative genetic biomarkers could be the two
enzymes DBH and COMT. Although the meta-analyses of
Taq1 and -1021 T/C in DBH gene and 158Val/Met in
COMT gene have not identified susceptibility alleles, variants
of these genes are associated with neuropsychological perfor-
mance [21, 22, 57], neurophysiological features [50, 51], brain
function [103], peripheral levels [39, 89], and MPH re-
sponse [52, 53].
Concerning the identification of endophenotype
biomarkers, to date it is not possible to characterize an accu-
rate biomarker for ADHD. As described in [10, 101, 104],
no biomarker has sufficiently high specificity and sensitivity
for the ADHD diagnosis. Currently proposed biomarkers are
limited by age, gender, and drug effects and studies have been
limited by small sample sizes and poor control for multiple
testing.
This work supports the necessity to take into account the deep
integration of omics sciences such as pharmacogenomics,
phenomics, epigenomics, proteomics, transcriptomics, 8. Singh I, Rose N. Biomarkers in psychiatry. Nature. 2009;460(7252):
and metabolomics. In fact, a better understanding of the
interaction network of genes, proteins, and biochemical pro-
cesses in relation to more accurate clinical profiles, by using
new high-throughput computational methods, will allow us
to identify a list of biomarkers both for the optimization of
diagnostic assessment as well as for the personalization of
therapies.
Acknowledgments This research was supported by grants from the
Fondazione Mariani (RF2006) and from the Italian Ministry of Health
(Ricerca Corrente).
Compliance with Ethics Guidelines
Conflict of Interest Cristian Bonvicini Ph.D., Catia Scassellati declare
that they have no conflict of interest.
In the past year, Stephen V. Faraone received consulting income,
travel expenses and/or research support from Ironshore, Shire, Akili
Interactive Labs, Alcobra, VAYA Pharma, and SynapDx and research
support from the National Institutes of Health (NIH). His institution is
seeking a patent for the use of sodium-hydrogen exchange inhibitors in
the treatment of ADHD. In previous years, he received consulting fees or
was on Advisory Boards or participated in continuing medical education
programs sponsored by: Shire, Alcobra, Otsuka, McNeil, Janssen,
Novartis, Pfizer and Eli Lilly. Dr. Faraone receives royalties from books
published by Guilford Press: Straight Talk about Your Childs Mental
Health and Oxford University Press: Schizophrenia: The Facts.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Page 17 of 20, 497
References
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