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CNS Drugs 2006; 20 (2): 107-123
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THERAPY IN PRACTICE
© 2006 Adis Data Information BV. All rights reserved.
Attention-Deficit Hyperactivity
Disorder in Girls
Epidemiology and Management
Jud Staller and Stephen V. Faraone
SUNY Upstate Medical University, Syracuse, New York, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
1. Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
2. Sex Ratios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
3. Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
4. Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
4.1 School . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
4.2 Behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
4.3 Social . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
4.4 Self-Esteem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
4.5 Intelligence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
4.6 Executive Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
5. Psychiatric Comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
6. Substance Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
7. Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
7.1 Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
7.2 Acquired Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
8. Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
9. Neurophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
10. Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
11. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
12. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
12.1 Non-Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
12.2 Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
13. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Abstract
Attention-deficit hyperactivity disorder (ADHD) in girls is a topic of growing
research and clinical interest. For many years, girls with ADHD have been
ignored and overshadowed by hyperkinetic and impulsive boys, but they are now
attracting interest in an effort to understand the similarities and differences in the
prevalence, symptoms, familial risk, comorbidities and treatment of ADHD in the
108
Staller & Faraone
two sexes. A review of past and current literature finds that the symptoms of
ADHD are not sex specific, but that identification of girls with ADHD is
hampered by parental and teacher bias, and confusion. Girls are more likely to be
inattentive without being hyperactive or impulsive, compared with boys. Girls and
boys share the same familial risk patterns, as well as similar, although not
identical, comorbidity or impairment patterns. The risk of non-treatment is as
great in girls as it is in boys; up to 70–80% of identified children will have
persistent symptoms and impairment that extends into adolescence and adulthood.
Treatment modalities are equally effective in girls and boys. Stimulants,
non-stimulants and behavioural modalities are the mainstays of effective treatment.
Attention-deficit
hyperactivity
disorder
(ADHD), as we now know it, has a lengthy history
of nosological and conceptual evolution that, in
some respects, underlies and reflects the gender bias
that often leads to confusion and uncertainty when
considering the diagnosis in females. In the 1930s,
the term “minimal brain dysfunction” was adopted
to connote abnormal hyperactivity and impulsivity
levels, based on a clinical assumption that there
must be some brain damage to explain these symptoms that were so often manifest in mentally retarded and brain injured children.[1] The “hyperkinetic
reaction of childhood” was another iteration of the
concept that became formalised in the DSM-II.[2]
With the publication of DSM-III came a significant
but temporary shift in the conceptualisation of the
disorder – “Attention Deficit Disorder with, or without hyperactivity” – where the emphasis was on
inattention, rather than the activity level.[3] During
the last 10 years, since the inception of DSM-IV,
psychiatry has shifted back to incorporating ‘hyperactivity’ into the primary nosology – ‘ADHD’ –
with three subtypes – predominantly hyperactive/
impulsive, predominantly inattentive, or mixed.[4]
Considering that boys are more likely than girls
to exhibit motoric hyperactivity and behavioural
impulsivity, and the predominant theme of hyperkinesis or hyperactivity in the nosology of the past 70
years, the potential for under-recognition, un© 2006 Adis Data Information BV. All rights reserved.
der-diagnosis and under-treatment of females with
attention deficit disorder becomes apparent.[5-7]
Throughout the past 70 years, research has been
conducted almost exclusively in boys, or in mixed
groups of youths with few efforts to distinguish sex
differences in symptoms or response, further blurring the concept of possible sex differences in children with ADHD.[8] Type II error (false negative
findings) is a major potential problem in the clinical
studies that have been typified by small numbers of
females compared with males.
1. Prevalence
Reports of prevalence rates of ADHD can vary
widely from study to study due to differences in
assessment methodology, but a review of this literature suggests that the worldwide prevalence of
DSM-IV-defined ADHD is between 8% and 12%.[9]
Several factors can influence prevalence rate results; sample source, rater type and number, sample
age, interview and rating scale method, and diagnostic criteria. For example, prevalence rates diminish
with age and increase when samples shift from
school, to community, to clinic.[9,10] Estimates of
prevalence are also greater when the diagnostic approach does not address impairment, as is the case
with many rating scales.[9] Another example pertains
to the assignment of greater or lesser importance to
CNS Drugs 2006; 20 (2)
ADHD in Girls
specific symptoms. In particular, some British studies emphasised defiant and antisocial behaviour as
core aspects of hyperkinesis, whereas American and
other studies focused on restlessness and distractibility. When these variations were reconciled, previously reported lower rates in British children were
found to be comparable to US prevalence rates.[11,12]
2. Sex Ratios
Male-to-female ratios for ADHD vary from 9 : 1
to 3 : 1, depending on whether the sample is clinicreferred or community based.[6] More recent studies
of patients with ADHD indicate a narrowing gap in
the sex ratio.[13,14] Assuming a conservative overall
prevalence of ADHD (3%) and a mid-range, but
likely, conservative sex ratio of 5 : 1, there are at
least 1 million women and girls in the US and 32
million females worldwide who have ADHD. Thus,
the impact of ADHD in girls is a major international
health concern.
In view of the substantial discrepancy between
clinic-referred samples, where the prevalence ratio
of females is low, and community-based samples,
where prevalence rates are closer to those in males,
questions arise regarding the generalisability of
prevalence data obtained in clinic settings, from
which many studies are derived. It appears that
overtly, severely behaviourally symptomatic youngsters are most likely to be referred to a psychiatric
treatment setting and that they are more likely to be
male, thus perpetuating the view that ADHD is
much more common among boys than girls.[6,7,15,16]
Furthermore, diagnostic criteria have been derived
from predominantly male cohorts, thus potentially
skewing the inclusion/exclusion criteria in favour of
male-dominated symptom expression and possibly
underestimating the actual prevalence of ADHD in
girls, particularly for girls with less severe and less
overt behavioural symptoms. Efforts to determine
the prevalence of subtypes of ADHD in girls have
found lifetime estimates of 4% for inattentive, 2.2%
© 2006 Adis Data Information BV. All rights reserved.
109
for hyperactive-impulsive and 3.7% for combined
type, for a total of 9.9%.[17]
3. Symptoms
Presently, the diagnosis of ADHD, like every
disorder in psychiatry, is symptom based, without
biological tests to confirm clinical decisions. DSMIV is a categorically-based system, in which a specified number of criteria must be present in order to
confirm a diagnosis, but there is a growing body of
research that indicates a shift in the conceptualisation of the disorder from a categorical schema to a
dimensional continuum.[17] Within a dimensional
schema, impairment criteria become highly significant when determining the level of disturbance, the
prognosis and treatment.[18-20] Hyperactivity, impulsivity and inattention are considered core symptoms
of ADHD, with subtypes separated according to
which set of features predominate. Hudziak et al.[17]
confirmed, in a large female adolescent twin study,
that girls do fit the criteria for DSM-IV subtypes,
and that symptoms are manifest on separate continua of inattention, hyperactivity-impulsivity and
combined type.
For the past 75 years, hyperactivity has been
considered a cornerstone symptom of ADHD. Examples of hyperactivity, such as fidgeting, talking
excessively, running or climbing excessively, difficulty playing quietly, and leaving one’s seat in the
classroom, are cited in DSM-IV and have been
validated as core symptoms of the disorder.[4] Associated with hyperactivity is the symptom of impulsivity, with examples such as difficulty with turn
taking, blurting out answers, or interrupting or intruding on others.[4] Several studies have concluded
that the symptoms of hyperactivity and impulsivity
are indeed present in girls with ADHD and that there
are no sex-based differences.[6,21,22] However, some
would argue that sex-specific modifications in the
severity of symptoms required for diagnosis should
be implemented because girls, whether identified
CNS Drugs 2006; 20 (2)
110
Staller & Faraone
with ADHD or non-clinical controls, generally have
a lower intensity of these symptoms than boys (table
I). Research has confirmed that girls have lower
ratings for externalising behaviours than boys, with
perhaps the most salient difference being lower rates
of conduct disorder among girls with ADHD.[6,7,15]
Inattention in patients with ADHD has been scrutinised more carefully in recent years than previously; it was not always considered a prominent feature
of this disorder – as in ‘hyperkinetic syndrome’– nor
is it considered a necessary condition for the diagnosis of ADHD today, as in ‘predominantly hyperactive-impulsive type’. Inattention is exemplified by
carelessness in work or schoolwork; difficulty sustaining attention to tasks or play; not listening when
spoken to; failing to follow through with instructions and schoolwork, chores or work; disorganisation; avoidance of tasks requiring sustained mental
effort; being easily distracted; and being forgetful.[4]
Table I. Comparison of the disease characteristics of boys and girls
with attention-deficit hyperactivity disorder
Parameter
Boys vs girls
Occurrence of impairment
general
>
hyperactive/impulsive
>
inattentive
<
Deficit in academic performance
objective assessment
=
teacher attribution
>
4. Impairment
Occurrence of behaviours
overall
>
aggression
>
hyperactivity
>
conduct disorders
>
oppositional defiant disorder
>
Deficit in social skills
=
Occurrence of diminished esteem
=
Deficit in IQ
?>
Deficit in executive function
?
Occurrence of comorbidities
externalising disorders
>
internalising disorders
?=
substance use disorders
<
Treatment response
? indicates tentative or inconclusive.
The inattentive symptom complex is a central issue
in the sex-based arguments surrounding ADHD. If
the historical development of the criteria for the
diagnosis of ADHD were skewed, based on
predominantly male subjects who were hyperactive
and impulsive, then inattentive symptoms may have
been under-appreciated and under-studied. Recent
research has found that girls are 2.2-fold more likely
than boys to have inattentive subtype ADHD.[15]
Furthermore, the onset of symptoms (or their recognition) in the inattentive subtype often occurs after
the age of 7 years (currently a cutoff age for the
DSM-IV criteria).[23,24] Thus, the number of girls
with ADHD who may be undiagnosed may be substantial, whether due to less severe hyperactive,
externalising and impulsive symptoms compared
with boys, to a greater likelihood of having the
inattentive subtype of this disorder, or to manifesting inattentive symptomatology after the cutoff age
of 7 years. In fact, when the linkage between symptoms and impairment is studied, most symptoms,
with the exception of inattention, show poor correlations (see section 4), and researchers are now questioning the primacy of hyperactivity over inattention
in ADHD.[17,25] This correlation and shift may ultimately enhance the awareness and treatment of
ADHD in girls.
=
© 2006 Adis Data Information BV. All rights reserved.
Symptoms alone are insufficient to diagnose
ADHD. DSM-IV criteria (somewhat vaguely) specify the need for significant impairment in at least two
separate domains in order to make a diagnosis.
However, recent research has found a surprisingly
weak link between most symptoms and impairment
in youths with ADHD, challenging long-held assumptions about the primacy of hyperactive and
impulsive symptoms, which, as has been discussed,
are most severe in boys.[25] Several studies have
confirmed that the prevalence rates of ADHD are
significantly impacted by whether impairment criteCNS Drugs 2006; 20 (2)
ADHD in Girls
ria are required for diagnosis,[9,26,27] and that failure
to consider impairment may lead to over-inflated
prevalence rates. On the other hand, researchers
have found that significantly impaired youths may
not always meet the (categorical) criteria for diagnosis, but that they will often seek treatment.[18] Lastly,
although sex differences in impairment domains
have been inconsistent, the study cohorts are typically clinic based, where the greatest impairment is
likely to be seen for both sexes. In earlier population-based studies, nonreferred boys with ADHD
appeared to be more impaired than nonreferred girls
with the disorder.[6] A recent Australian populationbased study, which assessed subtypes of ADHD and
their correlation with impairment (social, schoolwork, self-esteem) found that boys with hyperactive-impulsive or combined-type ADHD were more
impaired than girls with these subtypes, but that girls
with inattentive-type ADHD had more impairing
effects compared with boys within the inattentive
group.[22]
111
tom of inattention and impairment in school function.[25] Considering that the inattentive subtype of
ADHD is most prevalent in girls, the degree of
impairment in school experienced by girls with
ADHD attributable to inattentive type ADHD may
be misunderstood, further adding to type II error.
4.2 Behaviour
Internalising and externalising behavioural
symptoms characterise girls with ADHD.[28,30] Compared with unaffected girls, those with ADHD are
more likely to have symptoms related to mood,
anxiety and conduct disorders.[21] However, although affected girls have more behavioural symptoms than unaffected girls, when compared with
affected boys, disruptive behaviours, aggression and
hyperactivity are of lesser severity.[6,7] Furthermore,
the prevalence rates of conduct disorder and oppositional defiant disorder are half of those seen in
boys.[16]
4.3 Social
4.1 School
Compared with girls without ADHD, girls with
ADHD have more impaired academic function; they
have lower achievement scores; and they are more
likely to repeat a grade.[21,28] The academic performances of girls with ADHD and boys with ADHD are
comparable.[6] In fact, academic success in girls
does not preclude the diagnosis of ADHD.[17] However, teachers tend to attribute greater impairment
on measures of inattention, hyperactivity and impulsivity to boys with ADHD compared with girls with
ADHD,[6] and the vast majority believe that ADHD
is more prevalent in boys.[29] Thus, there is a risk of
under-diagnosing ADHD in girls, as teacher reports
and ratings are considered a significant source of
information relevant to the formulation of a diagnosis. Added to this are the aforementioned recent
findings correlating symptoms with impairment, in
which the strongest correlation is between the symp© 2006 Adis Data Information BV. All rights reserved.
Greene et al.[16] found that interpersonal deficits,
irrespective of sex and comorbidity, are a major
correlate of ADHD, and that peer interactions may
be a particularly important measure to assess in this
domain. Compared with unaffected girls, those with
ADHD showed more aggressive responses, fewer
negotiated responses and more anticipated negative
peer responses in a study measuring responses to
hypothetical peer interactive vignettes.[31] Impairment regarding social relationships in girls with
ADHD was most prevalent in those with the severe
combined type, and notably less in inattentive and
hyperactive-impulsive subtypes. Similarly, Hinshaw[28] found that girls with the inattentive subtype
were more socially isolated but less rejected by
peers, compared with those with the combined type.
Social impairment associated with ADHD is strongly predictive of later substance abuse and other longterm sequelae, irrespective of sex.[16] Greene et al.[16]
CNS Drugs 2006; 20 (2)
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Staller & Faraone
reported that Social Adjustment Inventory for Children and Adolescents (SAICA) results were similar
for boys and girls with ADHD with two exceptions –
girls were more impaired in leisure time activity
(thought to be associated with anxiety) and less
impaired on the School Behavior subscale. Once
again, there is the potential for under-identification
of girls with ADHD in the school environment when
the assessment is based primarily on high profile
behavioural observations.
those in children with ADHD.[41] Some studies suggest that executive function deficits are primarily
associated with inattention, while others suggest that
poor inhibitory control underlies deficits in executive function;[24,42] conclusive resolution of this
question will require further study. With regard to
possible sex differences in executive function in
children with ADHD, deficits were of comparable
magnitude in boys and girls.[40]
5. Psychiatric Comorbidity
4.4 Self-Esteem
ADHD-affected boys and girls tend to suffer
from lower self-esteem than unaffected peers.[32,33]
In addition, they tend to overestimate their performance and competence levels more than non-ADHD
peers in an apparent self-protective effort; the domains with the greatest deficits are the ones that are
the most distorted.[34,35]
4.5 Intelligence
Compared with female controls, girls with
ADHD were, from a statistical point of view, significantly more likely to have a lower IQ as well as
lower achievement scores.[7,21] Compared with boys
with ADHD, there is some support for greater intellectual impairment in girls with ADHD, although
the differences are of limited clinical significance.[6,15,16] All of the studies were based on clinicreferred samples, increasing the likelihood of overestimating this difference.[36]
4.6 Executive Function
Neuropsychological testing in children with
ADHD has found impaired vigilance and inhibition
of motor responses, organisation, planning, learning
and recall of verbal information, and other tasks
regulated by the frontal cortex.[37-40] Evaluation of
children at increased genetic risk for ADHD has
shown executive function deficits that are similar to
© 2006 Adis Data Information BV. All rights reserved.
Once thought to be exceptional, psychiatric
comorbidity has become a predominant factor in the
psychiatric evaluation and treatment of adults[43] and
children with ADHD.[44] The presence of one or
more comorbid disorders, regardless of sex, results
in significantly greater social impairment.[16] Studies
of boys with ADHD found a co-aggregation of
depressive disorders and conduct disorders, as well
as bipolar disorder.[6] Studies of comorbidity in girls
with ADHD compared with boys have produced
contradictory results to date. Some found no sex
differences in comorbidity patterns.[45-47] Others
have found that overall comorbidity in girls was
more severe than in boys,[10] and some have found a
lower prevalence of conduct disorders and a higher
prevalence of internalising disorders in girls with
ADHD compared with boys.[6,15,30] A recent study of
subtypes of conduct disorder in ADHD, comparing
covert conduct disorder (clandestine, stealthy, nonconfrontational behaviour, such as burglary and lying) with overt conduct disorder (confrontational
and overt, such as fighting and violence), found
evidence that females exhibited more covert symptoms than males.[48] This finding is consistent with
other studies, in which aggression in girls is more
likely to be verbal and relational, as opposed to
directly physical.[49,50] These findings may help to
explain the lower prevalence rate for diagnosed conduct disorder and ADHD in girls – overt aggression
is more likely to quickly become the focus of adult
CNS Drugs 2006; 20 (2)
ADHD in Girls
and peer attention and concern than covert scheming
and manipulative social behaviour.
6. Substance Abuse
In general, ADHD and substance use disorders
occur together significantly more frequently than
chance would predict: (i) 50% of adults with ADHD
have a history of substance use disorders; (ii) onset
of substance use disorders occurs earlier in adolescents with ADHD than in matched controls; and (iii)
persistent ADHD is likely to increase substance
use.[51-55] The treatment of ADHD with stimulants
does not increase the risk for substance use or
abuse.[56] When sex-specific data are reviewed, evidence indicates that girls with ADHD carry a higher
risk for substance use compared with female controls.[57,58] More surprisingly, ADHD and substance
use correlate more strongly in girls than boys,[57,59]
even though significantly fewer girls with ADHD
have comorbid conduct disorder than boys;[16] conduct disorder is a well known risk factor for substance use in all teens.[60-64]
7. Aetiology
7.1 Genetic Factors
Family studies are fraught with potential
problems rooted in the conundrum of diagnostic
accuracy. Prevalence rates among relatives can be
influenced by inaccuracy of retrospective parental
self-reports, a lack of corroborating sources, secondary gain, suggestibility, and overidentification with
the child. In spite of these limitations, ADHD family
studies indicate a very high rate of heritability,
among the highest of any psychiatric disorder, irrespective of sex – about 0.8.[65-68] Family studies have
shown a greater incidence of ADHD among first and
second degree relatives and siblings of probands.[69-72] Twin studies reflect a 50–80% concor© 2006 Adis Data Information BV. All rights reserved.
113
dance among monozygotic twins and up to 33%
between dizygotic twins.[73]
Sex does not appear to alter the risk associated
with the familial transmission of ADHD or
comorbid psychopathology.[45,74] However, there is
evidence to suggest that the heritability of inattentive versus hyperactive or impulsive subtypes may
differ. In a recent ADHD twin study, inattention was
heritable irrespective of level of hyperactivity and
impulsivity; and hyperactivity and impulsivity were
strongly correlated with inattention in the ADHD
twin.[75] If confirmed in future studies, this finding
could further alter our understanding of the fundamental role of inattention, as opposed to hyperactivity and impulsivity, in ADHD, and it could, once
again, underscore the need for recognition of the
inattentive subtype in girls.
A multitude of molecular genetic studies of
ADHDhave been conducted in recent years, but a
significant advance in the effort to delineate familial
risk has been elusive. Small sample size, contradictory results and varied techniques have slowed progress. However, evidence is beginning to point to
several genes that may be involved in the aetiology
of ADHD; these include DRD4 (dopamine receptor
D4), SLC6A3 (a dopamine transporter), SLC6A4 (a
serotonin transporter), DRD5 (dopamine receptor
D5), DRD2 (dopamine receptor D2), SNAP25
(synaptosomal-associated protein of 25kd) and
HTR1B (serotonin receptor 1B).[37,68]
7.2 Acquired Factors
Although genetic inheritance accounts for 80%
of all cases of ADHD, there is a small, but important, contribution from acquired factors. Insults to
the intrauterine environment can affect brain development and result in ADHD.[76] Maternal factors,
such as smoking, as well as metabolic disorders,
such as phenylketonuria, can lead to ADHD in children.[77-79] Perinatal complications, such as anoxia,
and later environmental insults, such as head trauCNS Drugs 2006; 20 (2)
114
ma, stroke, meningitis, post-infection autoimmune
reactions, lead exposure and iron deficiency, have
also been implicated in the aetiology of ADHD.[80-88]
Although sex-specific data regarding acquired
ADHD are currently unavailable, considering that
family heritability studies alone indicate sex parity,
acquired ADHD may account for the apparently
higher overall prevalence rates of ADHD in boys
compared with girls.
8. Neuroanatomy
Anatomical neuroimaging of individuals aged
4.7–17.8 years with ADHD using magnetic
resonance imaging (MRI) during the last 10 years
has established that, compared with controls, patients with ADHD have a total brain volume that is
reduced by 5%.[89,90] Several studies have reported
that this volumetric reduction is diffuse, affecting
multiple cerebral regions,[91,92] whereas other studies
have found that more specific areas of volumetric
deficit appear and that these are related to
dopamine-rich pathways in the fronto-striatal region
and cerebellum.[89-93] No reports of significant sex
differences have been published.
9. Neurophysiology
Quantitative electroencephalographic studies
have found that children with ADHD have excessive
slow-wave activity, reflecting underarousal, as well
as other patterns suggesting less developed differentiation and specialisation of the cortex.[94,95] There
are indications of possible sex-based differences in
the EEG patterns of children with ADHD, although
these findings need replication.[96,97]
Functional neuroimaging – positron emission tomography, single photon emission computed tomography, functional MRI and magnetic resonance
spectroscopy – has detected differences between
children with ADHD and control children. These
include diminished global cerebral glucose metabolism, diminished activation of frontostriatal net© 2006 Adis Data Information BV. All rights reserved.
Staller & Faraone
works, and diminished activity of the cerebellum
and temporal lobe.[98-102]
Efforts to elucidate sex differences in neurophysiology have been limited, but have suggested that
the findings of reductions in cerebral metabolism are
more specific to females with ADHD (adolescents
and adults) than males with the disorder.[100,103]
10. Pharmacogenomics
Although the field of pharacogenomics is in its
infancy, the potential clinical implications of integrating specific, individualised genetic profiles with
detailed knowledge of different drug effects in the
CNS are significant. For example, children with
ADHD who respond poorly to methylphenidate
have been found to be homozygous for the 10-repeat
allele at the dopamine transporter gene[104,105] and
the DRD4 7-repeat allele has been shown to predict
methylphenidate response.[106] Although preliminary, this type of information could be used in the
future to help determine medication algorithms for
ADHD, subtypes of ADHD and comorbid ADHD.
11. Evaluation
Early identification of ADHD is important, irrespective of sex, for a number of reasons. First,
parental stress and family dysfunction are common
when a child manifests symptoms of ADHD.[107]
Secondly, academic and social challenges can become insurmountable, leading to underperformance
and underachievement in these areas. Thirdly, the
sequelae of persistent underachievement can include
comorbid depression, externalising behavioural
problems, substance abuse and anxiety disorders.[6,108]
Given that hyperactive and impulsive behaviours
are typically more severe and attention-getting in
boys, and that girls are more likely to have an
inattentive subtype of ADHD, identifying girls with
ADHD early in their development becomes a notable challenge.[6,15,30] Careful history taking from parCNS Drugs 2006; 20 (2)
ADHD in Girls
ents, teachers and patients, as well as the utilisation
of standardised rating scales for each of these
sources of information, can clarify symptoms of
ADHD, as well as other psychiatric symptoms and
disorders that may underlie or coexist with and
complicate the presentation of ADHD. Assessment
for language and learning disorders is important
because of the frequent comorbid association of
these disorders with ADHD and the need to specifically address those disorders when they exist.[109,110]
12. Treatment
As delineated above, children with ADHD, irrespective of sex, are likely to experience significant
dysfunction in school, with interpersonal relationships, and intrapsychically. The trajectory of ADHD
into adolescence and adulthood indicates a high risk
of persistent symptoms and impairment, with adverse effects on social, emotional and vocational
development and adjustment.[111-114] Cantwell[115]
has described the natural history of ADHD, wherein
up to 70% of children with ADHD continue to
manifest functionally impairing ADHD symptomatology in adulthood; nearly half of these will develop more serious comorbid psychopathology, including substance abuse and antisocial personality disorder. There is some evidence to suggest that girls
with ADHD are at greater risk for adult psychiatric
admission than boys, and that comorbid conduct
disorder in girls (and boys) further intensifies the
risk.[116] Thus, there are considerable risks associated with the non-treatment of children with ADHD.
Questions have persisted for the past 50 years
pertaining to the most appropriate and effective interventions for ADHD in children and adults. Sexspecific ADHD treatment research has been limited.
There are hundreds of studies on the treatment of
ADHD, but most have assessed and confirmed the
short-term efficacy of stimulants. Few have systematically compared different psychological, psychosocial and educational interventions to one an© 2006 Adis Data Information BV. All rights reserved.
115
other or to medication, combined treatments to a
single intervention strategy, or long-term interventions of any kind.
12.1 Non-Pharmacological Treatment
There is a lack of consensus regarding the role of
non-pharmacological treatments in children with
ADHD. In a 2-year multisite study of 103 children
with ADHD, subjects were randomly assigned to
methylphenidate alone or in combination with
psychosocial intervention, academic assistance, psychotherapy, social skills training and parent training.[117-120] Combination treatment provided no additional benefit over medication alone for ADHD
symptoms, academic functioning or social functioning.[117-120] Other studies have found a similar lack of
superiority of combined non-pharmacological treatment and medication over medication alone.[121-123]
In contrast, the 14-month MTA (Multimodal
Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder Cooperative Group)
study of 579 children with ADHD found some benefit of combined treatment.[13] The study involved
four treatment groups. The medication management
group received methylphenidate three times daily,
adjusted for the most effective dosage, and other
drugs were used if necessary. The medication dosage was managed by an expert pharmacotherapist.
The intensive behavioural treatment group received
parent training, structured teacher consultations, an
8-week full-time summer treatment programme, 12
weeks with a behavioural specialist being present
for half the time the child spent in class, and individual case management. The combined treatment
group received both medication management and
intensive behavioural treatment. The communitybased care group was blindly assessed by the study
team (as were the other groups) but they received
whatever care they sought in the community. A
major finding of the study was the relative strength
of medication-based treatment, which is addressed
CNS Drugs 2006; 20 (2)
116
in section 12.2. Combined treatment showed a significant, small to medium effect-size advantage over
medication management alone for core ADHD and
disruptive symptoms. In addition, in combined treatment groups, lower dosages of medication were
prescribed with comparable effects. For those children with comorbid anxiety disorders, behavioural
treatment alone was as effective as medication or
combined treatment for ADHD-related and anxiety
symptoms. In the MTA follow-up report at 24
months, no significant additional beneficial effects
of non-pharmacological treatments were found.[124]
Other investigators have found support for
psychosocial and behavioural interventions, such as
active, ongoing parent and teacher involvement.[125]
Parent training and counselling is indicated to enhance consistency and structure in the child’s life,
and to optimise environmental management and
planning.[126] Close monitoring of compliance, including ignoring negative behaviour when possible,
and reinforcing prosocial, compliant and on-task
behaviour with praise and interesting, changeable,
tangible rewards, in conjunction with a time-out
plan for serious behavioural offenses, are fundamental principles of management at home and in school.
Maintaining routines and schedules, such as mealtimes and chores, providing simple written routines
and task lists coupled with appropriate reminders
and the breaking down of large tasks into smaller
units, are also integral to behavioural management.[114] Sleep, hygiene, diet and exercise are potentially very important, but understudied, parameters in children with ADHD.[127]
Educating patients and families about the
neurobiology of ADHD can be a significant factor in
adaptation, and treatment of ADHD-affected parents
may be necessary before they can be effective managers themselves.[128]
Alternatives to traditional educational settings,
materials and expectations are being advanced and
assessed to enhance educational success and self© 2006 Adis Data Information BV. All rights reserved.
Staller & Faraone
esteem in children with ADHD through programmes such as Teaching Every Student (TES).[129]
Eliminating television viewing in the first 3 years
of life may reduce ADHD symptoms. More specifically, recent studies have found a correlation between television exposure in the first 3 years of life
and impairments in attention, hyperactivity and
reading at age 7 years.[130,131]
Sex effects are difficult to assess. In both large
studies cited above, the majority of subjects were
boys, making specific inferences about girls and
non-pharmacological treatment unreliable. If girls,
as suggested previously,[6,15,30] are more likely to
have internalising symptoms, then their need for
psychosocial interventions that can specifically address anxious and/or depressed symptoms may be
higher than for boys. In fact, the MTA study indicated that non-pharmacological interventions were of
significant benefit to children with comorbid anxiety disorders.[13] Lastly, if girls are more often inattentive than boys, then their parents will need a
different training approach to parenting skills than
one designed for typically hyperactive and disruptive boys.
In summary, these findings suggest that
behavioural therapy combined with medication
treatment is not routinely needed for children with
uncomplicated ADHD, but that it can enhance overall treatment response. In individual children, for
example those with certain comorbid disorders,
behavioural treatments appear to be an effective and
important component of multimodal care.
12.2 Pharmacological Treatment
Medications that enhance dopamine and/or
noradrenaline (norepinephrine) release have been
found to be effective for the treatment of
ADHD.[132-134] Increasing dopamine release
presynaptically, as with dexamfetamine (dextroamfetamine) and mixed amfetamine salts, or inhibiting the dopamine transporter, as with
CNS Drugs 2006; 20 (2)
ADHD in Girls
117
Table II. Pharmacological treatments for attention-deficit hyperactivity disorder
Drug
Dose (mg)
Duration (h)
Comments
Methylphenidate preparations
Methylphenidate (Ritalin®)a
5, 10, 20
3–4
Sustained-release methylphenidate (Ritalin® SR)
20
5–8
Extended-release methylphenidate (Ritalin® LA)
20, 30, 40
6–8
Extended-release methylphenidate (Metadate® ER)
10, 20
5–8
Fixed-combination immediate- and extended-release
methylphenidate (Metadate® CD)
10, 20, 30
8–9
Methylphenidate (Methylin™)
5, 10,20
4–5
Extended-release methylphenidate (Methylin™ ER)
10, 20
Extended-release methylphenidate (Concerta™)
18, 27, 36, 54
Dexmethylphenidate
2.5, 5, 10
4
Dexamfetamine (dextroamfetamine) [Dexedrine®]
5
4–6
Sustained-release dexamfetamine capsules (Dexedrine®
Spansule®)
5, 10, 15
8–12
Granules can be sprinkled on
apple sauce
Granules can be sprinkled on
apple sauce
6–8
12
Twice the potency of
methylphenidate
Amfetamine preparations
Dexamfetamine (Dextrostat®)
5, 10
4–6
Mixed amfetamine salts (Adderall®)
5, 7.5, 10, 12.5, 15,
20, 30
4–6
Extended-release mixed amfetamine salts (Adderall® XR)
5, 10, 15, 20, 25, 30
12
Other
Atomoxetine
10, 18, 25, 40, 60
6–12
SNRI that increases DA and NA
neurotransmission
Antidepressants
Sustained-release bupropion
75, 100, 150, 200
Imipramine
10, 25, 50, 100
ECG monitoring
Desipramine (desimipramine)
10, 25, 50, 75, 100,
150
ECG monitoring
a
The use of trade names is for product identification purposes only and does not imply endorsement.
DA = dopamine; NA = noradrenaline (norepinephrine); SNRI = serotonin-noradrenaline reuptake inhibitor.
methylphenidate
and
dexamfetamine/mixed
amfetamine salts, are the mechanisms most commonly employed for activating certain neural networks.[135,136] Several long-acting preparations of
these compounds are now available that can enhance
duration of action and patient compliance compared
with the previously available short-acting formulations (see table II).
Several alternatives to stimulants are available,
should a patient be intolerant of or poorly responsive
to stimulants. Atomoxetine and bupropion increase
noradrenaline and dopamine neurotransmission, and
are considered to be second-line alternatives to stimulants.[137-140] TCAs have also been found to be
© 2006 Adis Data Information BV. All rights reserved.
possible alternatives to stimulants in patients who
are poorly tolerant or poorly responsive to stimulants; they act primarily through enhancement of
noradrenaline pathways.[140,141] α-Adrenergic agonists (clonidine and guanfacine), alone or in combination with stimulants, are sometimes useful in reducing hyperactive and aggressive behaviour and
insomnia associated with ADHD.[142-144] Pemoline,
once a popular alternative to methylphenidate and
dexamfetamine, had come to be rarely used because
of concerns over hepatotoxicity[145] and was recently
withdrawn from the market. Modafinil is currently
under study as a potential agent for the treatment of
ADHD.[146]
CNS Drugs 2006; 20 (2)
118
Overall, more than 80% of children and adolescents with correctly diagnosed ADHD respond
favourably to stimulants.[147] Comorbid psychophathology and environmental factors can have
a significant impact on drug effectiveness. There are
limited data suggesting that female patients may
require higher doses of methylphenidate due to more
extensive first-pass metabolism compared with
boys.[147] However, there is no evidence to suggest a
sex-based difference in drug treatment response.
Girls with ADHD respond favourably to stimulant
drugs, both methylphenidate and dexamfetamine, in
a robust manner indistinguishable from the response
of boys with ADHD.[36,148,149]
Few studies have addressed the long-term effectiveness of pharmacological treatment for ADHD.
The MTA study was 14 months in duration, and it
concluded that the medication management and
combined non-pharmacological and pharmacological treatments were equally effective and both were
superior to behavioural treatment alone and community care.[13] In a recent review of the long-term
safety and efficacy of stimulant treatment,
Hechtman and Greenfield[139] concluded that children treated for as long as 2 years continued to
safely benefit from treatment with regards to several
domains, including ADHD symptoms, the presence
of comorbid oppositional defiant disorder and academic and social functioning. Furthermore, stimulant treatment in childhood had modest positive
effects on adult social skills and self-esteem. With
regard to long-term safety, growth suppression has
long been the focus of concern. In a recent review of
this topic, it was concluded that a modest (1 cm/year
for the first 3 years) impact on adult stature is
possible.[150] There are no data pertaining to sexspecific growth suppression.
In summary, psychostimulants and other agents
are considered to be safe and effective for the treatment of ADHD in girls and boys. Very few research
© 2006 Adis Data Information BV. All rights reserved.
Staller & Faraone
data exist relating to sex-specific pharmacological
treatment.
13. Conclusions
ADHD in girls, once thought to be infrequent or
less impairing, is now being recognised worldwide
as a significant disorder affecting millions of females. Often under-recognised, under-diagnosed
and under-treated, ADHD in girls requires increased
attention and awareness on the part of parents,
teachers and clinicians, because girls have the same
risks as boys for morbidity and impairment, as well
as comorbidity. Careful assessment in multiple domains, and the awareness of a greater likelihood of
the inattentive subtype occurring in girls, should
reduce the number of girls with ADHD who go
undiagnosed.
Individualised treatment planning, with the
utilisation of pharmacological treatment as a central,
and possibly unitary, intervention will enhance outcomes for girls (and boys) with ADHD. The addition of non-pharmacological treatment, utilising
behavioural, educational and/or psychosocial interventions, should be considered on a case by case
basis.
Acknowledgements
This paper was not funded. Dr Staller has received research support from AstraZeneca Pharmaceuticals. Dr
Faraone has received honoraria and research support from
Shire, McNeill and Eli Lilly.
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Correspondence and offprints: Dr Jud Staller, SUNY Upstate Medical University, 750 East Adams Street, Syracuse,
New York 13210, USA.
E-mail: [email protected]
CNS Drugs 2006; 20 (2)