ADVANCING THE NEUROSCIENCE OF ADHD

Attention-Deficit/Hyperactivity Disorder: A Selective

Overview
Joseph Biederman
Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial and clinically heterogeneous disorder that is associated with
tremendous financial burden, stress to families, and adverse academic and vocational outcomes. Attention-deficit/hyperactivity
disorder is highly prevalent in children worldwide, and the prevalence of this disorder in adults is increasingly recognized. Studies of
adults with a diagnosis of childhood-onset ADHD indicate that clinical correlates— demographic, psychosocial, psychiatric, and
cognitive features—mirror findings among children with ADHD. Predictors of persistence of ADHD include family history of the
disorder, psychiatric comorbidity, and psychosocial adversity. Family studies of ADHD have consistently supported its strong familial
nature. Psychiatric disorders comorbid with childhood ADHD include oppositional defiant and conduct disorders, whereas mood and
anxiety disorders are comorbid with ADHD in both children and adults. Pregnancy and delivery complications, maternal smoking
during pregnancy, and adverse family environment variables are considered important risk factors for ADHD. The etiology of ADHD
has not been clearly identified, although evidence supports neurobiologic and genetic origins. Structural and functional imaging
studies suggest that dysfunction in the fronto–subcortical pathways, as well as imbalances in the dopaminergic and noradrenergic
systems, contribute to the pathophysiology of ADHD. Medication with dopaminergic and noradrenergic activity seems to reduce ADHD
symptoms by blocking dopamine and norepinephrine reuptake. Such alterations in dopaminergic and noradrenergic function are
apparently necessary for the clinical efficacy of pharmacologic treatments of ADHD.

Key Words: Attention-deficit/hyperactivity disorder, comorbidity, pattern of psychologic dysfunction, psychosocial disability, psy-
dopamine, function, genetics chiatric comorbidity, and school failure that resembles the well-
known features of childhood ADHD (Biederman et al 2004).

T
he main purpose of this article is to provide a brief
overview of the salient aspects of attention-deficit/hyper- Prevalence and Persistence of ADHD
activity disorder (ADHD). Attention-deficit/hyperactivity
disorder is a highly prevalent, clinically heterogeneous disorder Attention-deficit/hyperactivity disorder is a worldwide and
that exacts an enormous burden on society in terms of financial highly prevalent disorder, estimated to affect 5%–10% of children
cost, stress to families, and adverse academic and vocational (Faraone et al 2003) and 4% of adults (Faraone 2004, Adult
outcomes (Biederman et al 2004). Attention-deficit/hyperactivity ADHD: A family-genetic perspective, presented at the Annual
disorder is a multifactorial disorder with complex etiology and Meeting of the American Psychiatric Association, May 1– 6, 2004;
strong genetic underpinnings (Faraone et al 2005). The inatten- Kessler 2004, Prevalence of adult ADHD in the United States:
tion component of ADHD is manifested as daydreaming, distract- Results from the national comorbidity survey replication (NCS-R),
ibility, and difficulty focusing on a single task for a prolonged presented at the Annual Meeting of the American Psychiatric
period, whereas the hyperactivity component is expressed as Association, May 1– 6, 2004). Although ADHD is perceived by
fidgeting, excessive talking, and restlessness. The symptoms of many to be an American disorder, its prevalence is in the same
ADHD predispose to accidents, create strain in interpersonal range in many other countries as in the United States (Faraone et
relationships, and disrupt the environment through interruptions al 2003). Varying rates in the worldwide prevalence of ADHD in
and inappropriate behavior. It is notable that the more overt school-age children might be attributed to methodologic differ-
symptoms of hyperactivity/impulsivity tend to wane early in life, ences in criteria used to define this disorder (Faraone et al 2003).
whereas the more covert symptom of inattention tends to persist Moreover, the evolving terminology and definitions assigned to
over time (Biederman et al 1996). ADHD in the Diagnostic and Statistical Manual of Mental
The areas of impairment associated with childhood ADHD Disorders—spanning DSM-II to DSM-IV— have influenced how
include academic and social dysfunction and skill deficits. The the characteristics of this disorder are conceptualized (Spencer
adolescent with ADHD is at high risk for academic failure, low et al 2002).
self-esteem, poor peer relationships, parental conflict, delin- Despite variability in rates of persistence of ADHD, several
quency, smoking, and substance abuse. Adults with retrospec- predictors of persistence have been identified, including family
tively defined childhood-onset and persistent ADHD show a history of ADHD, psychiatric comorbidity, and psychosocial
adversity (Biederman et al 1995b). In a study that used Rutter’s
indicators of adversity (i.e., severe marital discord, low social
From the Department of Pediatric Psychopharmacology Research, Massa-
class, large family size, paternal criminality, maternal mental
chusetts General Hospital, and Department of Psychiatry, Harvard Med- disorder, foster care placement) to predict ADHD-related psy-
ical School, Boston, Massachusetts. chopathology, the risk for ADHD was found to increase signifi-
Address reprint requests to Joseph Biederman, M.D., Massachusetts General cantly with each increase in the number of adversity indicators
Hospital and Harvard Medical School, Pediatric Psychopharmacology (Biederman et al 1995b).
Research, 15 Parkman Street – WACC 725, Boston, MA 02114; E-mail: Persistence of ADHD is not always associated with impaired
jbiederman@ outcome. In a study of normalized functioning in adolescents
partners.org. with persistent ADHD, using indices of emotional, educational,
Received June 18, 2004; revised September 21, 2004; accepted October 20, and social adjustments, Biederman et al (1998) found that
2004. although 20% of children functioned poorly at follow-up in all

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doi:10.1016/j.biopsych.2004.10.020 © 2005 Society of Biological Psychiatry
1216 BIOL PSYCHIATRY 2005;57:1215–1220 J. Biederman

Figure 2. Approximate prevalence of comorbid diagnoses in adults with

attention-deficit/hyperactivity disorder.
Figure 1. Approximate prevalence of comorbid diagnoses in children with
attention-deficit/hyperactivity disorder. 2004). Lifetime prevalence rates of comorbid anxiety disorders in
adults with ADHD approach 50%, whereas mood disorders,
three domains; 20% did well in all three domains; and 60% had antisocial disorders, and alcohol/drug dependency also show
intermediate outcomes. These findings suggest that the syn- substantial prevalence rates (Figure 2) (Biederman et al 1993,
dromic persistence of ADHD is not associated with a uniform 1994; Shekim et al 1990). Findings from a new, large sample of
functional outcome; rather, it leads to a wide range of emotional, male and female adults with and without ADHD provide com-
educational, and social adjustment outcomes that can be partially pelling evidence for the validity of adult ADHD and document
predicted. More work is needed, however, to disentangle the strikingly similar phenotypic features of the disorder in both
role of treatment on outcome. genders (Biederman et al 2004). Consistent with previous find-
ings, this study documented high rates of mood and anxiety
Comorbidity of ADHD disorders in adults with ADHD, with a female predominance.

Childhood ADHD Genetics and ADHD

Throughout the life cycle, a key clinical feature observed in
patients with ADHD is comorbidity. In children, psychiatric Familial Influence
disorders comorbid with ADHD include oppositional defiant Family studies of ADHD have consistently supported its
disorder, conduct disorder, mood disorders (both unipolar and strong familial nature (Faraone and Doyle 2001; Faraone and
bipolar), anxiety disorders, and learning disorders (Kessler 2004; Tsuang 1995). Despite nosologic changes, there is remarkable
Pliszka 1998). Although spurious comorbidity can occur due to agreement between early studies of children whose illness was
referral and screening artifacts (Caron and Rutter 1991), recent defined as hyperactivity (Cantwell 1972; Morrison and Stewart
reviews of the literature show that these artifacts cannot explain 1971) and subsequent studies using DSM-III and DSM-III-R
the high levels of psychiatric comorbidity observed for ADHD definitions of ADHD (Figure 3) (Biederman et al 1990; Faraone
(Angold et al 1999). Figure 1 illustrates the prevalence rates of et al 1992; Frick et al 1991; Schachar and Wachsmuth 1990). Most
common comorbid diagnoses of childhood ADHD and how family studies have identified a two- to eightfold increase in the
these diagnoses are affected with respect to gender (Biederman risk for ADHD in parents and siblings of children with ADHD
et al 1996, 1999; Pliszka 1998; Spencer et al 1999). (Biederman et al 1990; Cantwell 1972; Faraone et al 1992; Frick
In a systematic evaluation of the impact of gender on the et al 1991; Manshadi et al 1983; Morrison and Stewart 1971; Pauls
clinical features of ADHD, Biederman et al (2002) reported that et al 1983; Schachar and Wachsmuth 1990; Welner et al 1977). A
girls with ADHD were at less risk for comorbid disruptive study of siblings of adults with ADHD (Manshadi et al 1983) and
behavior disorder than boys with ADHD. Because disruptive
behavior disorder drives referral, this finding might explain the
substantial discrepancy in the male/female ratio between clinic-
referred (10:1) and community (3:1) samples of children with
ADHD (Biederman et al 2002). Furthermore, this gender discrep-
ancy suggests that girls with ADHD might be under-identified
and under-treated.

Adult ADHD
Follow-up studies have found that 5%– 66% of children with
ADHD persist with this disorder in adulthood (Biederman et al
1993). Current epidemiologic studies estimate the prevalence of
adult ADHD to be between 3% and 5% (Faraone 2004; Kessler
2004). Furthermore, studies of referred and nonreferred adults
with a clinical diagnosis of childhood-onset and persistent ADHD
revealed that clinical correlates— demographic, psychosocial,
psychiatric, and cognitive features—mirrored well-documented Figure 3. Family studies in attention-deficit/hyperactivity disorder
findings among children with ADHD (Biederman et al 1993, (ADHD).

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found in relatives of control probands. Biological relatives of

children with ADHD also perform more poorly on standardized
measures of attention than do adoptive relatives of children with
ADHD (Alberts-Corush et al 1986).

Molecular Genetics Studies

Two approaches are used to evaluate the genetic etiology of
ADHD: 1) the genome scan, which examines all chromosomal
locations without a priori guessing as to which genes underlie
ADHD; and 2) the candidate gene approach, which examines
one or more genes based on theory and empirical evidence
(Faraone et al 2005). A genomewide linkage scan in 204 nuclear
families (853 individuals and 270 affected sibling pairs) suggests
that regions 16p13 and 17p11 likely harbor risk genes for ADHD
(Ogdie et al 2003).
Cook et al (1995) observed an association between ADHD
and the 480-bp allele (or genotype) in the dopamine transporter
Figure 4. Heritability of attention-deficit/hyperactivity disorder (ADHD). gene (DAT). Additional polymorphisms in intron 9 and exon 9
were examined, with a trend for biased transmission of the
480-bp allele of VNTR polymorphism (Barr et al 2001). The
a study of children of adults with ADHD both documented very
dopamine transporter was found to be elevated by approxi-
high rates of ADHD in the families of adults with ADHD
mately 70% in adults with ADHD, according to single photon
(Biederman et al 1995a). These and other data suggest that
emission computed tomography (Dougherty et al 1999). By far,
persistent ADHD might be a useful phenotype for molecular
the gene most strongly implicated in ADHD is the 7-repeat allele
genetic studies (Faraone et al 2000).
of the human dopamine receptor D4 gene (DRD4), confirming a
Attention to comorbid psychiatric disorders in these family
strong dopamine component in the pathogenesis of ADHD
studies also provides evidence for the genetic heterogeneity of
(Faraone et al 2001b).
ADHD. Results of analyses from independent samples of chil-
dren with DSM-III attention-deficit disorder (Biederman et al
1990) and DSM-III-R ADHD (Biederman et al 1992) suggest that Other Factors Contributing to the Etiology of ADHD
1) ADHD and major depression share common familial vulner-
abilities (Biederman et al 1991b); 2) ADHD children with conduct Biological Adversity
disorders and bipolar disorders (Faraone et al 1991, 1997, 2001a; Several biologic factors have been proposed as contributors
Wozniak et al 1995) might be a distinct familial subtype of to ADHD, including food additives/diet, lead contamination,
ADHD; and 3) ADHD is familially independent from anxiety cigarette and alcohol exposure, maternal smoking during preg-
disorders (Biederman et al 1991a) and learning disabilities (Faraone nancy, and low birth weight. Although the Feingold Diet for
et al 1993; Goodman and Stevenson 1989). Thus, stratification by ADHD was popularized by the media and accepted by many
conduct and bipolar disorders might divide the universe of parents, systematic studies showed that this diet was ineffective
children with ADHD into more familially homogeneous sub- and that food additives do not cause this disorder (Conners
groups. On the other hand, major depressive disorder might be 1980). Several investigators have shown that lead contamination
a nonspecific manifestation of different ADHD subtypes. can cause distractibility, hyperactivity, restlessness, and lower
intellectual functioning; however, lead does not account for the
Twin and Adoption Studies majority of ADHD cases, and many children with high lead
Because ADHD is believed to be highly genetic, studies of exposure do not develop ADHD. An emerging literature docu-
twins have been used to establish its heritability, or the degree to ments that maternal smoking and alcohol exposure during
which this disorder is influenced by genetic factors (Coolidge et pregnancy, low birth weight, and psychosocial adversity are
al 2000; Edelbrock et al 1995; Gillis et al 1992; Gjone et al 1996; additional independent risk factors for ADHD (Biederman et al
Goodman and Stevenson 1989; Hudziak et al 2000; Kuntsi and 1995b; Mick et al 2002b).
Stevenson 2001; Levy et al 1997; Martin et al 2002; Nadder et al Pregnancy and delivery complications (i.e., toxemia, eclamp-
1998; Sherman et al 1997; Silberg et al 1996; Stevenson 1992; sia, poor maternal health, maternal age, fetal postmaturity,
Thapar et al 1995; Willcutt et al 2000; Willerman 1973). Based on duration of labor, fetal distress, low birth weight, antepartum
numerous studies of twins, which varied considerably in meth- hemorrhage) seem to predispose for ADHD (Sprich-Buckminster
odology and definitions of ADHD, the mean heritability for et al 1993). It is theoretically compelling to explore maternal
ADHD was shown to be .77 (Figure 4). smoking as a risk factor for ADHD, because nicotinic receptors
Adoption studies of ADHD also implicate a genetic etiology. modulate dopaminergic activity, and dopaminergic disruption is
Early studies showed that the adoptive relatives of hyperactive believed to be involved in the pathophysiology of ADHD.
children are less likely to have hyperactivity or associated Animal studies have shown a positive correlation between
disorders than are the biologic relatives of hyperactive children hyperactivity and chronic exposure to maternal nicotine intake
(Cantwell 1975; Morrison and Stewart 1973). In a recent study, during pregnancy (Fung and Lau 1989; Hagino and Lee 1985;
Sprich et al (2000) reported that the adoptive relatives of adopted Johns et al 1982; Richardson and Day 1994; Van De Kamp and
ADHD probands had rates of ADHD and other associated Collins 1994). Several studies documented that maternal smoking
disorders that were lower than those observed in the biological during pregnancy is an independent risk factor for ADHD
relatives of nonadopted ADHD probands, and similar to those (Biederman et al 1995b; Mick et al 2002a; Milberger et al 1996).

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Psychosocial Adversity concept that dysfunction in fronto–subcortical pathways occurs

Compelling work by Rutter et al (1975) in the classic Isle of in ADHD. Three subcortical structures implicated by the imaging
Wight studies revealed that the aggregate of adversity factors studies (i.e., caudate, putamen, and globus pallidus) are part of
(i.e., severe marital discord, low social class, large family size, the neural circuitry underlying motor control, executive func-
paternal criminality, maternal mental disorder, foster care place- tions, inhibition of behavior, and the modulation of reward
ment), rather than the presence of any single factor, led to pathways. These frontal–striatal–pallidal–thalamic circuits pro-
psychopathology. Findings of more recent studies support the vide feedback to the cortex for the regulation of behavior
previous work of Rutter and colleagues and stress the importance (Alexander et al 1986).
of adverse family– environment variables as risk factors for The fronto–subcortical systems pathways associated with
ADHD (Biederman et al 1995b, 1995c). In one of these, chronic ADHD are rich in catecholamines, which are involved in the
family conflict, decreased family cohesion, and exposure to mechanism of action of stimulant medications used to treat this
parental psychopathology (particularly maternal) were more disorder. Stimulants, such as methylphenidate, seem to reduce
common in ADHD families compared with control families core ADHD symptoms (i.e., inattention, hyperactivity, impulsiv-
(Biederman et al 1995b). It is important to note that, although ity) by inhibiting the dopamine transporter and blocking dopa-
many studies provide powerful evidence for the importance of mine and norepinephrine reuptake into the presynaptic neuron,
psychosocial adversity in ADHD, such factors tend to emerge as thereby increasing the release of these monoamines into the
universal predictors of children’s adaptive functioning and emo- extraneuronal space (Elia et al 1990). Changes in dopaminergic
tional health, rather than specific predictors of ADHD. As such, and noradrenergic function seem to be necessary for the clinical
they can be conceptualized as nonspecific triggers of an under- efficacy of pharmacologic treatments of ADHD. A plausible
lying predisposition or as modifiers of the course of illness. model for the effects of medications in ADHD suggests that,
through dopaminergic and/or noradrenergic pathways, these
agents increase the inhibitory influences of frontal cortical activ-
Neurobiology of ADHD ity on subcortical structures (Zametkin and Rapoport 1987). In
The neurobiology of ADHD is not completely understood, contrast, effects on serotonin metabolism seem to be marginally
although imbalances in dopaminergic and noradrenergic systems related to the clinical efficacy of anti-ADHD treatments (Zametkin
have been implicated in the core symptoms that characterize this and Rapoport 1987), and serotonergic drugs have little effects in
disorder (Pliszka 1998; Zametkin and Rapoport 1987). Inasmuch mitigating core symptoms of the disorder.
as there is great variation in the pervasiveness, frequency of Imaging studies also implicate the cerebellum and corpus
occurrence, and degree of impairment of symptoms of ADHD, callosum in the pathophysiology of ADHD. The cerebellum
the neurologic networks associated with it are highly heteroge- contributes significantly to cognitive functioning, presumably
neous. Although there are inconsistencies among studies, it is through cerebellar– cortical pathways involving the pons and
notable that the pattern of deficits that has emerged in neurobio- thalamus. The corpus callosum connects homotypic regions of
logic, neuroimaging, and neuropsychologic studies of ADHD the two cerebral hemispheres. Size variations in the callosum and
across the life cycle support the hypothesis that deficits in frontal volume differences in the number of cortical neurons might
lobe function and the connections between the frontal lobe and degrade communication between these two hemispheres, which
key subcortical regions underlie this disorder. Because of the might account for some of the cognitive and behavioral symp-
complexity of prefrontal circuitry (Cummings 1993), it is not yet toms of ADHD (Berquin et al 1998; Castellanos et al 2002).
clear whether the prefrontal abnormalities in ADHD are second-
ary to “lesions” of the prefrontal cortex or to brain areas with Summary
prefrontal projections. Thus, the term “fronto–subcortical” pro-
Attention-deficit/hyperactivity disorder is an early-onset,
vides a suitable neuropsychologic description of ADHD and
highly prevalent neurobehavioral disorder, with genetic, envi-
denotes a behavioral or cognitive dysfunction that looks frontal
ronmental, and biologic etiologies that persist into adolescence
but might be influenced by subcortical projections.
and adulthood in a sizable majority of afflicted children of both
Neuroimaging studies, ideal for testing hypotheses about the
genders. It is characterized by behavioral symptoms of inatten-
locus of brain dysfunction in ADHD, provide direct assessments
tion, hyperactivity, and impulsivity across the life cycle. Comor-
of brain structure and function. Structural imaging studies, with
bidity is a distinct clinical feature of both childhood and adult
computerized tomography or magnetic resonance imaging,
ADHD. Although its etiology remains unclear, emerging evi-
found evidence of structural brain abnormalities among ADHD
dence documents its strong neurobiologic and genetic underpin-
patients, with the most common findings being smaller volumes
nings. A pathophysiologic profile of ADHD has not been fully
in frontal cortex, cerebellum, and subcortical structures. One of
characterized, although structural and functional imaging studies
the most important neuroimaging studies of ADHD is the land-
consistently implicate dysfunction in the fronto–subcortical path-
mark study conducted by Castellanos et al (2002). These inves-
ways and imbalances in the dopaminergic and noradrenergic
tigators identified developmental trajectories for all structures
systems in the origin of core symptoms. Although not entirely
assessed (except caudate) that remained stable and parallel for
sufficient, changes in dopaminergic and noradrenergic function
ADHD subjects and controls during childhood and adolescence
seem to be necessary for the clinical efficacy of pharmacologic
that were independent of medication status. This work suggested
treatments for ADHD, supporting the hypothesis that alteration
that genetic or early environmental influences on brain develop-
of monoaminergic transmission in critical brain regions might be
ment in ADHD are fixed, nonprogressive, and unrelated to
the underlying factor for therapeutic action in ADHD.
stimulant treatment.
Functional studies are consistent with structural studies in
implicating the fronto–subcortical systems, yet there is a lack of Aspects of this work were presented at the conference, “Ad-
agreement on the locus or lateralization of the observed impair- vancing the Neuroscience of ADHD,” February 28, 2004, in
ments. Nevertheless, brain imaging studies fit well with the Boston, Massachusetts. The conference was sponsored by the

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J. Biederman BIOL PSYCHIATRY 2005;57:1215–1220 1219

Society of Biological Psychiatry through an unrestricted educa- functioning in adults with attention deficit hyperactivity disorder. Am J
tional grant from McNeil Consumer & Specialty Pharmaceuti- Psychiatry 150:1792–1798.
cals. Biederman J, Mick E, Faraone S (1998): Normalized functioning in youths
with persistent ADHD. J Pediatrics 133:544 –551.
Dr. Joseph Biederman receives research support from the Biederman J, Mick E, Faraone SV, Braaten E, Doyle A, Spencer T, et al (2002):
following sources: Shire Laboratories Inc and Eli Lilly & Com- Influence of gender on attention deficit hyperactivity disorder in chil-
pany, Pfizer Pharmaceutical, New River Pharmaceuticals, dren referred to a psychiatric clinic. Am J Psychiatry 159:36 – 42.
Cephalon Pharmaceutical, Janssen Pharmaceutical, Neuro- Biederman J, Milberger S, Faraone SV, Kiely K, Guite J, Mick E, et al (1995b):
search Pharmaceuticals, Stanley Medical Institute, the Lilly Family-environment risk factors for attention deficit hyperactivity disor-
Foundation, the Prechter Foundation, the National Institute of der: A test of Rutter’s indicators of adversity. Arch Gen Psychiatry 52:464 –
470.
Mental Health, the National Institute of Child Health and
Biederman J, Milberger SV, Faraone S, Kiely K, Guite J, Mick E, et al (1995c):
Human Development, and the National Institute on Drug Abuse. Impact of adversity on functioning and comorbidity in children with
He is a speaker for the following speaker’s bureaus: Eli Lilly & attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychia-
Company, Pfizer Pharmaceutical, Novartis Pharmaceutical, try 34:1495–1503.
Wyeth Ayerst, Shire Laboratories Inc, McNeil Pharmaceutical, Cantwell DP (1972): Psychiatric illness in the families of hyperactive children.
and Cephalon Pharmaceutical. He is on the advisory board for Arch Gen Psychiatry 27:414 – 417.
the following pharmaceutical companies: Eli Lilly & Company, Cantwell DP (1975): Genetics of hyperactivity. J Child Psychol Psychiatry 16:
261–264.
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ven Pharmaceutical, McNeil Pharmaceuticals, Janssen Pharma- issues and research strategies. J Child Psychol Psychiatry 32:1063–1080.
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