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Intensied testing for attention-decit hyperactivity disorder (ADHD) in girls

should reduce depression and smoking in adult females and the prevalence of
ADHD in the longterm
Elmar H. Pinkhardt
a
, Jan Kassubek
a
, Dagmar Brummer
b
, Michael Koelch
c
, Albert C. Ludolph
a
,
Joerg M. Fegert
c
, Andrea G. Ludolph
c,
*
a
Department of Neurology, University of Ulm, Germany
b
Department of Psychiatry III, University of Ulm, Germany
c
Department of Child and Adolescent Psychiatry, University of Ulm, Steinhoevelstrasse 5, 89075 Ulm, Germany
a r t i c l e i n f o
Article history:
Received 12 October 2008
Accepted 6 November 2008
s u m m a r y
Attention-decit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in youth.
About a third to one-half of the affected subjects continue to have symptoms in adulthood. Remarkably,
the prevalence numbers published for adult females are higher than for girls. The differences in the epi-
demiological data between the age groups clearly point to underdiagnosed ADHD in girls. Major depres-
sion, the most frequent psychiatric condition worldwide in adulthood, is twice as common in female as in
male adults. Anxiety and depression are also among the most common comorbidities in adults with
ADHD. Therefore, an undiagnosed ADHD may often underlie the psychopathology in depressive women.
Another possibly associated phenomenon is the increased frequency of smoking in adult females. Since
nicotine indirectly enhances the intrasynaptic dopamine level which presumably is too low both in ADHD
and in depression, smoking might be used as a self-medication in women with untreated ADHD and
consecutive depression. Furthermore, smoking during pregnancy is a major risk factor for ADHD in the
offspring, so the vicious circle is complete. Depression in mothers of children with ADHD is associated
with a higher rate of comorbidity in the children. Improved screening for ADHD in girls and treatment
in childhood might thus reduce the rate of depression and smoking in adult females. We hypothesize that
earlier identication and interventions might not only improve the lives of millions of girls and women
but might also reduce the prevalence rates in future generations or at least moderate the deviant behav-
iour in this highly heritable disorder in which the development and severity of symptoms and the
functional impairment depend to a high degree on epigenetic factors.
2008 Elsevier Ltd. All rights reserved.
Introduction
Attention-decit hyperactivity disorder (ADHD) is the most fre-
quently diagnosed neuropsychiatric disorder in childhood with an
estimated prevalence of 37% worldwide [1]. The three cardinal
symptoms are hyperactivity, inattention, and impulsivity [2]. Pre-
vious studies suggested that boys are more often affected than girls
with a male to female ratio of 3:1 up to 10:1 [3,4].
Although being so common in childhood, ADHD in adulthood
has long been considered as a rare phenomenon. Today, however,
the prevalence is estimated to be 15% [5] with a male to female
ratio of 3:2 in a US study [6] or 2:1 in a European study [7]. The
clinical symptoms in adults with ADHD are quite analogue to those
observed in children. Inattention might encompass a variety of
cognitive problems and difculties with tasks that require organi-
zation. The hyperactivity factor might not only be restricted to mo-
tor behaviour but also include inner restlessness, distractibility,
risk taking, and a tendency to become bored easily as mentioned
in the items of the Conners Adult ADHD Rating Scale (CAARS) [8].
The impulsivity/emotional lability factor resembles childhood
impulsivity but also includes impulsive verbal outbursts, stress
intolerance, irritability, and labile mood.
In untreated adults with ADHD, comorbidity is rather the rule
than the exception. An increased risk for the development of an
antisocial personality disorder, drug or alcohol misuse and high
rates of mood disorders has been reported [9]. Apart from illegal
drug consumption, untreated ADHD patients frequently seem to
use nicotine, alcohol and/or other drugs as self-medication to inu-
ence the dysregulated dopaminergic metabolism [10,11]. If the
alterations in the dopaminergic systemare the primary pathophys-
iological cause for ADHD symptoms or the sequelae of other neuro-
biological underpinnings such as hyperactivity in the glutamatergic
0306-9877/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2008.11.025
* Corresponding author. Tel.: +49 731 50061601; fax: +49 731 50061602.
E-mail address: andrea.ludolph@uni-ulm.de (A.G. Ludolph).
Medical Hypotheses 72 (2009) 409412
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system [12] or if other deciencies, e.g. in the serotonergic or
GABAergic system play a role is still unclear.
We hypothesize that untreated ADHD in childhood is a major
cause for depression and smoking habits especially in adult fe-
males and will give epidemiological and neurobiological clues for
this hypothesis in the following. Better identication and interven-
tion of ADHD in childhood, especially in girls, might thus signi-
cantly reduce the enormous costs for treating depression and the
sequelae of smoking in females. All the more, smoking in preg-
nancy and depression in mothers, often accompanied by insuf-
cient parenting, belong to the major environmental risk factors
for ADHD.
Epidemiology of ADHD, depression, and nicotine consumption
The prevalence rates of ADHD reported in the literature differ
widely [13]. A substantial part of this discrepancy in prevalence
may be explained by differences in the most common diagnostic
systems: the International Classication of Diseases, 10th edition
(ICD-10), by the World Health Organization, denes more restric-
tive diagnostic criteria for hyperkinetic disorders in comparison
to the criteria as dened by the Diagnostic and Statistical Manual
of the American Psychiatric Association fourth edition (DSM-IV).
Apart from the differences explained by diagnostic criteria, a
further bias may inuence prevalence data of children with ADHD.
Most studies report a signicant higher prevalence in boys than in
girls [13]. However, recent data show that the gender difference in
ADHD, as mentioned above, may be due to a referral bias. Froehlich
et al. [14] investigated the prevalence of ADHD in a national pop-
ulation-based sample of US children: A total of 3907 children aged
8 to 15 years were examined and 8.7% (51% boys and 49% girls) met
DSM-IV criteria for ADHD, so the sex ratio was nearly 1:1. Interest-
ingly, only 47% of these children had been diagnosed with ADHD
prior to the study, and girls were less likely to have their disorder
identied. Reports from the large NIMH Collaborative Multisite
Multimodal Treatment Study of children with ADHD (MTA study)
gave account that girls with ADHD showed less noticeable exter-
nalizing behaviour problems than boys [15].
Boys score higher on disruptive behaviour scales than girls,
also the higher level of teacher reported problem behaviour at
school may explain the high male to female ratio for ADHD in
clinical settings [16]. Biederman et al. [17] conclude from a study
with 140 boys and 140 girls with ADHD that girls with ADHD
were more likely than boys to have the predominantly inattentive
type which is not so annoying in the school setting for obvious
reasons. Wolraich et al. [18] reported a prevalence rate of ADHD
symptoms alone of 16.1% which was reduced to 6.8% when func-
tional impairment was also required as a diagnostic criterion.
Thus, the lower likelihood for girls with ADHD to be attributed
with functional impairment could result in referral bias unfavour-
able to girls.
In contrast to the above-named studies in childhood and ado-
lescent ADHD, Robison and colleagues [19] found that women with
ADHD were more impaired than men as rated on different ADHD
scales in a retrospective data analysis of two large multicenter
studies conducted in 2000 and 2001. More women than men
(75% versus 62%) had the combined type assessed with the DSM-
IV criteria, and women also scored higher on the Hamilton Rating
Scale for Depression since 18% of them fullled the diagnostic cri-
teria for major depression compared to 10% of men. The authors
concluded that the higher level of emotional symptoms as well
as the more complicated presentations of ADHD in women may
obscure the diagnosis of ADHD. In general, a higher prevalence of
depression and anxiety disorder in adults with ADHD is well de-
scribed [20]. In a meta-analytic review, Angold et al. [21] reported
a median odds ratio for the co-occurrence of ADHD and depression
of 5.5. In search of the main psychosocial risk factors for the
comorbidity of ADHD and depression, Drabick et al. [22] identied
social problems and a family environment characterized by con-
ict, low cohesion, and low marital satisfaction which might pro-
vide the link between these entities.
A recent comparison of adult undiagnosed ADHD subjects to
non-ADHD controls and diagnosed ADHD patients could demon-
strate signicantly higher rates of current depression, problem
drinking, lower educational level and greater emotional and inter-
personal difculties in the undiagnosed ADHD subjects [23].
ADHD in adults, especially when not diagnosed, poses a serious
burden with great functional and psychosocial impairment that
might contribute to the economic cost due to major depression
that in the US alone is estimated at $70 billion annually. The World
Health Organization (WHO) projects that by the year 2020, depres-
sion will be second only to heart disease as the leading cause of
disability worldwide [24].
In line with the generally accepted fact that ADHD is a strong
risk factor for substance use, Kollins et al. [25] observed signicant
relations between the number of retrospectively reported ADHD
symptoms and lifetime regular cigarette smoking in a sample of
young adults. Kalyva [26] reported that adolescents with ADHD
smoked more than adolescents with mild learning disabilities,
who in turn smoked more than adolescents not diagnosed with
any disability. According to Strong et al. [27] who presented com-
parable tobacco use prevalence estimates for the WHO European
region, male smokers had overall higher prevalence of daily smok-
ing (37.7%) and current smoking (43.1%) in 2002. The correspond-
ing rates for female smokers were 19.3% for daily smokers and
23.4% for current smokers. The global overall prevalence for tobac-
co use is even reported to be about four times higher among men
than women (48% male versus 12% female) [http://www.who.int/
tobacco/research/gender/about/en/]. In contrast to the overall
demographic data, individuals with ADHD smoke at higher rates
than the general population, and the male/female ratio is 1:1. Data
of a study conducted by Pomerleau et al. [28] showed 42% of
males and 38% of females to be smokers within a group of 71
adults diagnosed with ADHD. A recent study could show in addi-
tion that male and female smokers with ADHD manifest more se-
vere physical dependence on smoking compared with controls
[11].
The mechanisms underlying this increased vulnerability for nic-
otine addiction in individuals affected by ADHD are still not en-
tirely understood. Polymorphisms in the DRD2 gene and
among females the MAOA gene interacted with retrospective re-
ports of ADHD symptoms in contributing to risk for smoking in
1900 unrelated individuals, a subsample of the National Longitudi-
nal Study of Adolescent Health (Add Health in the US) [29].
Although a substantial fraction of the etiology of ADHD is due to
genes, the studies reviewed by Banerjee et al. [30] showed that
many environmental risk factors and potential geneenvironment
interactions also increase the risk for the disorder.
Neurobiological commonalities between ADHD and depression
ADHD is a highly heritable disorder (about 6080%) [31] as is
depression with about 40% [32]. However, neither of them is
monogenetically determined. Both, ADHD and depression are
complex phenomena with many genes possibly involved, resulting
in a vast number of possibilities for overlapping genes. On a neuro-
biological basis, a dysregulation of frontalstriatal circuits (lateral
prefrontal cortex, dorsal anterior cingulated cortex, caudate, puta-
men) is considered to play an essential role both in the develop-
ment of the core symptoms of ADHD and ADHD-associated
410 E.H. Pinkhardt et al. / Medical Hypotheses 72 (2009) 409412
neuropsychological impairments [33,34] as well as in the patho-
physiology of major depression [32]. These neurobiological data
have recently been conrmed by imaging studies [35]. An involve-
ment of the limbic system in the pathophysiology of ADHD has
been found, notably morphological alterations in hippocampus
and amygdala [36]. According to major depression, volume altera-
tions of limbic structures were detected in patients with the rst
episode of a major depression and in young female patients with
major depression [37]; moreover, recent studies have indicated
that hippocampal volume is reduced in major depressive disorder
[38,39].
Dopamine release abnormalities are considered as the integral
common underlying pathophysiological mechanism for the
above-named frontalstriatal dysregulation. Additionally, there is
also increasing evidence for alterations in the glutaminergic sys-
tem in ADHD [40]. Hence, an interaction between the dopaminer-
gic and glutaminergic systems is supposed to be an essential
pathogenetic mechanism of ADHD [41], since a hypofunction of
mesolimbic dopaminergic pathways induces decits in glutamate
signal transmission that is modulated via these dopaminergic cir-
cuits, resulting in attention response deciencies and poor behav-
ioural planning [42]. Russel and colleagues [43] detected
disturbances in glutamate, dopamine, and norepinephrine function
in the brain of a genetic animal model for ADHD.
In major depression, Nestler and colleagues demonstrated a
deciency in the mesolimbic dopaminergic transmission pathways
that play an important role in the rewarding system and are cru-
cially impaired in several symptoms of depression like anhedonia
and lack of motivation [44]. Moreover, glutamate, via activation
of its metabotropic glutamate receptor, is essential in ne tuning
of hypothalamic function that regulates the hypothalamic pitui-
tary adrenal (HPA) axis and is involved in depression and anxiety
disorders [45].
In conjunction with their role in the rewarding system, dopami-
nergic pathways are prone to exogenous stimulation as these cir-
cuits have a strong impact on addictive behaviour. Especially
untreated ADHD patients have a high vulnerability for developing
addictive behaviour [46]. Nicotine has to be named in the rst
place, as nicotine might be seen as a self-medication in untreated
ADHD subjects due to its inuence on the dopaminergic system,
as it indirectly enhances the intrasynaptic dopamine level which
presumably is too low in ADHD and also in depression [47]. This
explains the high prevalence of smokers in adult ADHD patients
[28]. Concerning pregnancy and nicotine consumption in adult fe-
males and given that ADHD adults smoke more, also in pregnancy,
nicotine directly stimulates nicotinic acetylcholine receptors in the
brain, inducing abnormalities in cell proliferation and cell differen-
tiation in the fetal brain [30]. Furthermore, it especially exerts ef-
fects on the fetal monoaminergic neurotransmitter system.
Dopaminergic and noradrenergic systems have been found to be
hypoactive and hyporesponsive to exogenous stimulation after
prenatal exposure to nicotine at postnatal day 30 [48].
Hypotheses that neurotrophic factors such as one of the most
prevalent ones, i.e. the brain-derived neurotrophic factor (BDNF),
also play a role in the pathogenesis for both disorders infer from
the observation that BDNF inuences the function of dopaminergic
neurons especially in the midbrain. BDNF knockout mice demon-
strate hyperactive behaviour. It was postulated that decreased cen-
tral BDNF, particularly in the midbrain region, might play a role in
the pathogenesis of ADHD [49]. A similar mechanism is proposed
for depression. Acute and chronic stress is a major risk factor for
developing depression, and also ADHD symptoms exacerbate un-
der stress. Stress decreases levels of BDNF expression in the den-
tate gyrus and pyramidal cell layer of hippocampus in rodents
[50]. Furthermore, BDNF expression is increased by chronic (but
not acute) treatment with antidepressants and even application
of BDNF itself seems to exert antidepressant-like effects in rodents
[51]. Chen et al. [52] could show that antidepressants also increase
BDNF levels in humans. The role of nicotine consumption in BDNF
metabolism has not yet been investigated in humans. However, re-
cent animal studies have suggested an association between nico-
tine and alterations in BDNF expression levels. Chronic nicotine
treatment markedly increased the basal levels of BDNF in other-
wise untreated rats. Additionally, nicotine reversed the stress-in-
duced decrease in the basal levels of BDNF [53].
Conclusions
The present article highlights the still underrated importance of
diagnosing female patients with ADHD in childhood and adoles-
cence and its relationship to adulthood ADHD, with special atten-
tion to the female ADHD patients comorbide conditions such as
affective disorders and smoking. It is evident that treated ADHD
in childhood persists into adulthood at a signicant rate [5], the
consequences of these ndings with respect to underdiagnosed
ADHD in girls compared with boys are little-known. The underly-
ing factors of the high prevalence of smoking and depression in
adulthood ADHD especially in women is still worth discussing.
We have shown that there are strong hints for an association be-
tween ADHD and a higher prevalence of depression and smoking
in adulthood, both on epidemiological and neurophysiological
grounds.
The basic link between ADHD and depression might be seen in
the essential role of the dopaminergic system in both disorders
that is crucially modied by altered glutaminergic pathways, neu-
rotrophic factors, and exogenous noxa (particularly smoking).
Hence morphological changes in the limbic system which plays
an essential role in ADHD as well as major depression and addic-
tive behaviour, can be postulated to be a result of the neurochem-
ical changes named above. Nevertheless, studies of limbic
pathways, e.g. by volumetric neuroimaging techniques, within
the subgroup of ADHD patients with depression in comparison to
ADHD patients without depression and patients with major
depression disorder have not been conducted up to now to our
knowledge.
On clinical grounds, the lower likelihood for girls to manifest
obvious psychiatric, cognitive, and functional impairment than
boys could be seen as confounding factor that results in gender-
based referral bias unfavourable to girls with ADHD.
ADHD is a highly heritably determined disorder, but as men-
tioned above, studies could also show that only the combination
of genetic predisposition and smoking leads to clinically relevant
ADHD symptoms. In a study by Kahn et al. [54], neither prenatal
smoke exposure alone nor a dopamine transporter polymorphism
alone was signicantly associated with increased scores of ADHD
symptoms but the combination of both. Given that maternal
smoking is regarded as a risk factor for ADHD [55,56], the
high prevalence of smoking women with ADHD gains in impor-
tance, particularly as smoking might be seen as a self-medication
in women with untreated ADHD, since nicotine by itself inu-
ences the dopaminergic, glutamatergic, and neurotrophic systems
[57].
We hypothesize that the prevalence of ADHD, respectively the
degree of functional impairment that consecutively leads to
depression and nicotine consumption, could be substantially low-
ered by more thorough diagnostics and therapy especially in girls.
For this, amended screening instruments should be developed and
eventually, ADHD diagnostics could be integrated in school-based
medical check-ups. Corequisite intensied research would lead to
improved therapy options for a patient group whose needs are still
too often inadequately recognized.
E.H. Pinkhardt et al. / Medical Hypotheses 72 (2009) 409412 411
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