Digital Comprehensive Summaries of Uppsala Dissertations

from the Faculty of Medicine 1353

Attention Deficit/Hyperactivity
Disorder in Adults
Prevalence, Psychiatric Comorbidities and Long-term
Outcome

DAN EDVINSSON

ACTA
UNIVERSITATIS
UPSALIENSIS ISSN 1651-6206
ISBN 978-91-513-0029-0
UPPSALA urn:nbn:se:uu:diva-327892
2017
Dissertation presented at Uppsala University to be publicly examined in Gunnesalen, Ing
10, Akademiska sjukhuset, Uppsala, Saturday, 30 September 2017 at 09:15 for the degree of
Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in Swedish.
Faculty examiner: Professor Bo Söderpalm (Sahlgrenska Akademin, Sektionen för psykiatri
och neurokemi vid Institutionen för neurovetenskap och fysiologi).

Abstract
Edvinsson, D. 2017. Attention Deficit/Hyperactivity Disorder in Adults. Prevalence,
Psychiatric Comorbidities and Long-term Outcome. Digital Comprehensive Summaries of
Uppsala Dissertations from the Faculty of Medicine 1353. 67 pp. Uppsala: Acta Universitatis
Upsaliensis. ISBN 978-91-513-0029-0.

Attention Deficit/Hyperactivity Disorder (ADHD) was originally thought to occur only in

children, but is increasingly recognised as causing functional impairment also in adulthood. The
overall aim of this thesis was to achieve a comprehensive understanding of ADHD in adulthood.
A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms,
reading and spelling problems, difficulties and suffering and general assessment of functioning
(GAF) was distributed to three samples: the general population (GP), outpatient psychiatry
(OPP) and female prison inmates. Symptoms consistent with ADHD were more than three times
higher in the OPP sample than in the GP sample (6.6 versus 2.1%). ADHD symptoms and related
problems occurred in 50% of the prison inmates.
A cohort of 168 patients diagnosed with ADHD in adulthood was interviewed about current
ADHD symptoms and psychiatric comorbidity on axis I and II. The lifetime prevalence of
psychiatric comorbidity on axis I was 92% and current comorbidity, including autism spectrum
disorders and Tourette’s syndrome, was 47%. The sex-specific pattern of the comorbid disor-
ders was similar to that in the general population. Forty-six per cent of the patients endorsed the
specific criteria for at least one personality disorder.
After a mean follow-up of six years, there was remission of adult ADHD in about 30% of the
patients, regardless of whether there was ongoing medication or not. There were no differences
in function and quality of life, except for global general improvement, which was better in
patients currently on medication.
The most prevalent long-term side effects of pharmacological treatment with mainly
stimulants were decreased appetite, dry mouth, anxiousness/restlessness and an increase in pulse
frequency. The discontinuation rate was about 50%: 29% discontinued because of a perceived
lack of effect, followed by elevated mood or hypomania (11%). No detectable evidence of
tolerance and increased need for dosage over time was observed.
To conclude, Symptoms of ADHD is highly overrepresented in OPP and in female inmates
compared with the GP. Furthermore, adults diagnosed with ADHD have a high lifetime
prevalence of psychiatric comorbidity. Long-term pharmacological treatment with stimulants is
safe with relatively mild and tolerable adverse effects. Continued medication, however, is not
related to remission.

Keywords: ADHD, adults, prevalence, inmates, psychiatric comorbidity, long-term outcome,

side effects, adverse events, stimulants, atomoxetine.

Dan Edvinsson, Department of Neuroscience, Psychiatry, University Hospital, Akademiska

sjukhuset, Uppsala University, SE-751 85 Uppsala, Sweden.

© Dan Edvinsson 2017

ISSN 1651-6206
ISBN 978-91-513-0029-0
urn:nbn:se:uu:diva-327892 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-327892)
With gratefulness and admiration, I
dedicate this thesis to the persons
who generously shared their life ex-
periences and participated in these
studies.
List of Papers

This thesis is based on the following papers, which are referred to in the text
by their Roman numerals.

I Edvinsson D, Bingefors K, Lindström E, Lewander T. (2010)

ADHD-related symptoms among adults in out-patient psychia-
try and female prison inmates as compared with the general
population. Ups J Med Sci, 115(1):30-40

II Edvinsson D, Lindström E, Lewander T, Bingefors K, Ekselius

L. (2013) Gender differences of axis I and II comorbidity in
subjects diagnosed with ADHD as adults. Acta Neuropsychiatr,
25(3):165-174.

III Edvinsson D, Ekselius L. (2017) Six-Year Outcome in Subjects

Diagnosed with Attention-Deficit/Hyperactivity Disorder as
Adults. Submitted for publication.

IV Edvinsson D, Ekselius L. (2017) Long-Term Tolerability and

Safety of Pharmacological Treatment of Adult Attention-
Deficit/Hyperactivity Disorder. Submitted for publication.

Reprints were made with permission from the respective publishers.

Papers I and II in this thesis, and a discussion on them, were the basis for a
licentiate degree in medicine at Uppsala University, defended on October 11,
2012.
Abbreviations

AD/HD Attention Deficit/Hyperactivity Disorder

ADD Attention Deficit Disorder
ASD Autism Spectrum Disorder
ASPD Antisocial Personality Disorder
ASRS Adult ADHD Self-Report Scale
AUDIT Alcohol Use Disorders Identification Test
BPD Borderline Personality Disorder
CAADID Conners’ Adult ADHD Diagnostic Interview for DSM-IV
CBT Cognitive Behavioural Therapy
CD Conduct Disorder
CGI-I Clinical Global Impression - Improvement
DAMP Deficits in Attention, Motor Control and Perception
DIP-I ICD-10 Personality Interview
DIVA Diagnostisk Intervju för ADHD hos vuxna
DSM Diagnostic Statistical Manual of Mental Disorders
DUDIT Drug Use Disorders Identification Test
ED Emotional Dysregulation
ESSENCE Early Symptomatic Syndromes Eliciting Neurodevelop-
mental Clinical Examination
EQ-VAS EuroQol-Visual Analogue Scales
EQ-5D EuroQol-5 Dimension Questionnaire
GAF Global Assessment of Functioning
HKD Hyperkinetic Disorder
HRQoL Health-related quality of life
ICD International Statistical Classification of Diseases and Re-
lated Health Problems
LD Learning disability
MTA-study The multimodal treatment study of children with ADHD
ODD Oppositional defiant disorder
PTSD Posttraumatic stress disorder
RCT Randomized controlled trial
SCID-I The Structured Clinical Interview for DSM-IV axis I
SCID-II The Structured Clinical Interview for DSM-IV axis II
SDS Sheehan Disability Scale
SUD Substance use disorder
Contents

Introduction ................................................................................................... 11
Background ................................................................................................... 12
Historical perspectives on ADHD ............................................................ 12
Current diagnostic criteria of ADHD ....................................................... 14
Prevalence and impairment of ADHD ..................................................... 14
Aetiology .................................................................................................. 15
Coexisting disorders and ADHD.............................................................. 16
ADHD in prison inmates .......................................................................... 17
Diagnostic assessment of ADHD in adulthood ........................................ 18
Multimodal treatment of ADHD .............................................................. 19
Pharmacological treatment of ADHD ...................................................... 20
Outcome predictors .................................................................................. 21
Aims and scope ............................................................................................. 22
Method .......................................................................................................... 23
Study design and participants ................................................................... 23
Procedures and measurements ................................................................. 25
Statistics ................................................................................................... 28
Ethics ........................................................................................................ 28
Results ........................................................................................................... 29
ADHD-related symptoms (Paper I).......................................................... 29
Sex differences (Paper II) ......................................................................... 31
Six-Year Outcome (Paper III) .................................................................. 33
Long-Term Tolerability and Safety (Paper IV)........................................ 37
Discussion ..................................................................................................... 41
Methodological considerations ................................................................ 41
General discussion and clinical implications ........................................... 45
Future aspects ........................................................................................... 51
Conclusions ................................................................................................... 52
Acknowledgements ....................................................................................... 53
References ..................................................................................................... 55
Introduction

At the turn of the century, the knowledge of adult ADHD within psychiatry
was almost non-existent, and sometimes even the existence of ADHD in
adulthood was outright put in question. To optimize resources to obtain,
assess and optimally use the new knowledge on ADHD in adulthood, and to
develop and implement procedures for accurate evaluation and treatment, a
specialized neuropsychiatric team was established within the Department of
Psychiatry at Uppsala University Hospital. The first part of this thesis is the
result of attempts to obtain relevant knowledge in order to ensure optimal
clinical practice. Therefore, the two first papers in this thesis investigate the
prevalence of adult ADHD in various settings and psychiatric comorbidity in
adults previously not diagnosed with ADHD.
Effectiveness and safety of pharmacological treatment as well as predic-
tors of favourable outcome are important issues to consider when planning
for scientifically based treatment programs. In an increasing number of sci-
entific publications, pharmacological treatment has been demonstrated to be
effective and safe in the short term. The long term outcome and safety of
pharmacological treatment is, however, still less well investigated. The se-
cond part of this thesis demonstrates the long-term outcome and safety of
pharmacological treatment of a clinical sample of subjects diagnosed and
treated for ADHD as adults.

11
Background

Historical perspectives on ADHD

The earliest description of attention difficulties in the medical literature, with
reference to the present concept of ADHD, is the publication by the German
physician Melkior Adam Weikard. In 1775, possibly even a few years earli-
er, he anonymously published the textbook Der Philosophische Artzt (Eng-
lish: The Philosophical Physician) [15]. In this textbook Weikard describes
the symptoms of inattention and distractibility – Attentio Volubilis, which
overlap part of the current inattentive ADHD diagnostic criteria. Interesting-
ly, his clinical examples included adults. Environmental factors such as up-
bringing were identified as the cause of inattention but Weikard also dis-
cussed the possibility of a neurological impact of these external causes. Fur-
thermore, he considered inattention to be more common in childhood than in
old people and that the symptoms described should be treated with a distrac-
tion-free environment and physical exercise, among other measures [15].
In 1798, the Scottish physician Alexander Crichton published a chapter
on inattention in his textbook An Inquiry into the Nature and Origin of Men-
tal Derangement [41]. Crichton states that a patient suffering from “disease
of inattention” is agitated by impressions and easily distracted, which causes
mental restlessness and “fidgets”. He concludes that a person with the disor-
der “may be either born with it or it may be the effect of accidental diseas-
es”. He further recommended special educational interventions in that physi-
cal punishment (“terrors of the rod”) seemed ineffective in these children.
Several descriptions of children with ADHD appeared later like the char-
acter Struwwelpeter (English: Shockheaded Peter) in the illustrated book
Lustige Geschichten und drollige Bilder (English: Funny stories and droll
pictures) by the German physician Heinrich Hoffman [72]. Since its appear-
ance in 1845, the character has constituted a prominent part of the literature
for children in German-speaking countries. Both the inattentive and the hy-
peractive/impulsive subtypes of ADHD can be clearly recalled from Hoff-
man’s poetic examples.
Until recently, the British physician Sir George Frederick Still was con-
sidered the first to present scientific descriptions of childhood ADHD. In a
series of lectures delivered in 1902 and later published in the Lancet, Still
describes a clinical panorama of children with a “defect of moral control”
[135]. Many of these children were described as hyperactive and today

12
would probably be considered to suffer from comorbid oppositional defiant
disorder (ODD). Of interest are Still’s observations of comorbid psychiatric
disorders and criminality among adult relatives of these children [14; 135;
136].
In 1947, the book Psychopathology and Education of the Brain Injured
Child was published by Alfred Strauss and Laura Lehtinen in which the con-
cept “minimal brain damage” was introduced [137]. The concept was based
on institutionalised children with distractibility, perseveration, hyperactivity
and motor and learning problems for whom specific educational plans were
later developed.
The concept of “minimal brain dysfunction” (MBD) appeared in an article
by Clements and Peters in 1962 describing school-age children with specific
learning, motor and coordination deficits together with “hyperkinesis”, im-
pulsivity, emotional lability, distractibility, “equivocal” neurological signs
and an EEG with a “6- and 14-per-second positive spiking pattern” [38].
DSM-II, published in 1968, included the entity “The hyperkinetic reaction of
childhood”, mainly implying that symptoms were a reaction to the environ-
ment and usually outgrown later in life with increased developmental ma-
turity [5].
In 1980, this concept was succeeded by the diagnostic entity “attention
deficit disorder” (ADD), which was introduced in DSM-III: diagnostics were
clarified by dividing the diagnosis into inattentional problems with and
without hyperactivity [6].
DSM-III-R, published in 1987, introduced the diagnosis “attention deficit
hyperactivity disorder (ADHD)”, with a unidimensional approach listing a
total of 14 symptoms with a diagnostic cut-off of ≥8 diagnostic criteria [7].
In 1982, Gillberg and Rasmussen separately introduced the concept “per-
ceptual, motor and attentional deficits” (PMAD) based on a survey of Swe-
dish seven-year-old children [60]. This concept was changed to “deficit in
attention, motor control and perception” (DAMP) in 1987 [58]. The DAMP
concept is used mostly in Scandinavia. In DSM-IV and DSM-5 it approxi-
mately corresponds to ADHD in combination with “developmental coordi-
nation disorder” (DCD) [58].
DSM-IV, published in 1994 [8], with a text revision, DSM-IV-TR in
2000 [9], lists nine symptomatic criteria of inattention and hyperactivi-
ty/impulsivity The cut-off for a diagnosis is set at ≥6 items in each domain,
resulting in the possibility of three subtypes: ADHD with predominantly
inattention, ADHD with predominantly hyperactivity/impulsivity and the
combined subtype (criterion A). The onset of symptoms causing impairment
should be present before the age of seven years (criterion B). Impairment
should be present in more than two settings (criterion C). There should be
clear evidence of clinically significant impairment in social, academic or
occupational functioning (criterion D). Symptoms that occur should not be
accounted for solely by another mental disorder (criterion E). Because the

13
DSM-IV diagnostic criteria were originally adopted for children, questions
were raised as to whether they are optimal for use in an adult population.
This issue will be further addressed regarding the DSM-5 criteria (i.e. the
current diagnostic criteria of ADHD).

Current diagnostic criteria of ADHD

DSM-5, published in 2013, presented some minor but important changes in
the diagnostic criteria of ADHD. The childhood symptom items of criterion
A are now supplemented by examples of how childhood symptoms can be
presented in adults. Furthermore, only ≥5 current items in each domain are
required for older adolescents and adults aged ≥17. Criterion B was changed
to childhood symptom presentation to before 12 years of age. Criteria C and
D were left unchanged. For criterion E, pervasive developmental disorders
(PDDs), such as previous autism spectrum disorder (ASD), were removed as
exclusion criteria [10].
The 10th revision of the International Statistical Classification of Diseases
and Related Health Problems (ICD-10) was published by The World Health
Organisation (WHO) in 1992 and has been in clinical use in Sweden since
1997 [161]. The ICD-10 uses a narrower definition of ADHD, namely hy-
perkinetic disorder (HKD). A diagnosis of HKD requires symptoms of hy-
peractivity/impulsivity, and accordingly, ICD-10 does not recognise the pre-
dominantly inattentive subtype of ADHD. Thus, in comparison with DSM-
IV (and partly DSM-5), HKD roughly corresponds to the combined and pre-
dominantly hyperactive/impulsive subtypes. The 11th Revision of the Inter-
national Classification of Diseases (ICD-11) has been announced to be due
out in 2018.
In addition, emotional dysregulation (ED) has been demonstrated to be
linked to ADHD, although not formally included in the diagnostic criteria of
DSM-5 and ICD-10. The "Wender Utah criteria" include ED as an important
part of ADHD. ED has been demonstrated to respond to treatment with
stimulants [118].

Prevalence and impairment of ADHD

ADHD is widely recognised as one of the most common psychiatric disor-
ders of school-age children, with a prevalence rate of 3-7%. Data indicate
that boys tend to be diagnosed [88] and treated more often than girls [11]. In
adulthood, research presents a much more differentiated picture, which has
been suggested to be explained by referral bias in combination with differ-
ences in assessment and methodology [154]. Although prospective studies
indicate a frequent decline of ADHD symptoms with increasing age, signifi-

14
cant loss of functioning may remain despite sub-threshold diagnostic status
[21; 50; 84]. Adult functioning after childhood ADHD varies but is generally
worse with persistence of ADHD symptoms [70]. Thus, the functional im-
pairment caused by ADHD in adulthood is increasingly acknowledged in a
broad variety of domains. For example, motor vehicle accidents among
adults with ADHD have been demonstrated to be substantially lower during
periods of medication [34]. In summary, the prevalence of adult ADHD in
the general population (GP) is estimated to be at least 2-4% [51; 83].

Aetiology
The aetiology of ADHD is still largely unknown, but it is widely recognized
that there is a substantial genetic component. Follow-up studies of monozy-
gotic and dizygotic twins report that persistent genetic influences explain
between 45 and 90% of the total genetic variance in hyperactivity-
impulsivity and inattention from childhood to adolescence [90]. The genetic
structure of ADHD has proven to be complex, although gene studies of
ADHD have produced evidence of the involvement of several genes in the
aetiology of the disorder. Meta-analyses are supportive of the involvement of
genes coding for serotonergic and dopaminergic receptors, together with
various proteins involved in dopamine transportation and membrane fusion
[104].
Environmental factors have also been reported to be important in ADHD.
An increased risk of ADHD has been demonstrated in children with prenatal
exposure to smoking [43], low birthweight [75], preterm birth [37], and low
Apgar scores [65]. Furthermore, nutritional factors [123], TV and computer
games have been discussed regarding ADHD [52; 140]. Severe institutional
deprivation has also been reported to be related to persistent symptomatolo-
gy of ADHD [80].
On a group level, ADHD children, regardless of sex, have been shown to
have smaller brain volume compared with controls [31]. The most frequently
replicated neuroanatomic deviations have been identified in brain areas in-
volved in executive functioning (e.g., the dorsolateral prefrontal cortex, cau-
date nucleus, globus pallidus, corpus callosum and cerebellum) [126]. Neu-
robiological deviations have been identified with functional magnetic reso-
nance imaging in boys with ADHD compared with age-matched non-ADHD
controls while performing visual go-stop tests. Relative underfunctioning of
the dorsomedial and left inferior frontal cortex, posterior cingulate and parie-
tal brain regions has been demonstrated in persons with ADHD, and has
been shown to be normalised with the use of methylphenidate, a central
stimulant used for ADHD treatment [122]. Finally, positron emission tomog-
raphy has demonstrated a decreased function in the dopamine reward path-

15
way in the brain in never previously medicated adults with ADHD [158],
and has been associated with motivation deficits in adult ADHD.

Coexisting disorders and ADHD

Coexisting disorders in childhood ADHD
To clarify the broad spectrum of disorders coexisting with ADHD in child-
hood and symptom sharing across disorders, the concept and acronym ES-
SENCE (early symptomatic syndromes eliciting neurodevelopmental clinical
examination) has been devised to cover children with impairing symptoms in
defined areas/domains before age 3 to 5 years [59]. Major problems in at
least one ESSENCE domain before age 5 years often signals major problems
in the same or overlapping domains years later. The ESSENCE perspective
is that one should not view neuropsychiatric symptoms in early childhood as
discrete disorders or syndromes, but from a perspective of early brain dys-
functions that goes beyond syndromes. ESSENCE refers to deviance in syn-
dromes included cover a wide spectrum comprising ASD and PPD, ADHD,
ODD, specific language impairment, learning disability (LD), non-verbal
LD, tic disorders, bipolar disorder, behavioural phenotype syndromes, epi-
lepsy syndromes and reactive attachment disorders. This broad ESSENCE
perspective is consistent with a report from the US on over 60 000 children
aged 6 to 17 years, which concluded that 46% of children with ADHD had a
LD, 27% a conduct disorder (CD), 18% an anxiety disorder, 14% depression
and 12% speech problems. Thirty-three per cent of the ADHD children had
at least one comorbid disorder, 16% two comorbid disorders and 18% three
or more comorbid disorders. Comorbidity widely exceeded that of persons
without ADHD [89].
Sex differences have been investigated in a study of 140 boys and 140
girls aged 6-17 years who were referred for and diagnosed with ADHD.
Compared with boys, girls were more likely to have the predominantly inat-
tentive subtype and less at risk for major depression, CD or ODD, whereas
the risk of substance use disorder (SUD) was higher in girls with ADHD
than in boys [22].

Coexisting disorders in adults with ADHD

Several studies have investigated psychiatric comorbidity in adult ADHD. In
a German study clinically referred adults with ADHD were reported to have
a lifetime comorbidity on axis I of 77% compared with 46% in age- and sex-
matched controls [130]. Affective and eating disorders, together with SUD,
were more frequently associated with adult ADHD, with a sex bias for SUD,
which was more prevalent in men. Slightly lower figures were reported in a

16
Canadian study with a current and lifetime axis I comorbidity of 47% in
adults with ADHD versus 27% in age- and sex-matched controls. Coexist-
ence of axis II comorbidity was reported to affect half of the individuals
[42]. Studies of subtype differences in comorbidity patterns have found ex-
ternalising disorders (e.g., ODD, CD, SUD) and antisocial personality disor-
der (ASPD) to be more frequently associated with the combined subtype. In
general, ADHD was more frequently associated with clusters B and C per-
sonality disorders, regardless of subtype, when compared with a non-ADHD
comparison group [101]. Another study reported the combined subtype to be
associated with significantly higher rates of lifetime CD, bipolar disorders
and psychosis compared with the inattentive and hyperactive/impulsive sub-
types [153]. Reversely, previously unidentified ADHD has been found to be
prevalent in samples of persons diagnosed with various psychiatric disorders
such as SUD [146], bipolar disorder [125], posttraumatic stress disorder
(PTSD) [93] and borderline personality disorder (BPD) [111]. Another im-
portant clinical issue is the frequency of sleeping disorders in adult ADHD,
which has been reported to be widely increased, especially in the combined
and hyperactive/impulsive subtypes [27]. The aetiology is poorly understood
but circadian rhythm disruption and an increased prevalence of restless legs
syndrome have been proposed as possible explanations [40; 128; 129]. In
accordance with the ESSENCE acronym, a high prevalence of learning disa-
bilities [28; 99] and reading difficulties has been reported in children, ado-
lescents, and adults with ADHD [45]. Studies have also indicated difficulties
in written language expression in persons with ADHD [134].

ADHD in prison inmates

Several studies have reported an increased prevalence of ADHD in incarcer-
ated men, affecting about 4 of 10 inmates [62; 120]. Female inmates have
been studied less frequently but a German study of 110 incarcerated females
found a lifetime prevalence of ADHD of 24.5% with 10% for persisting
diagnostic criteria according to DSM-IV. The subjects reported a decline in
the prevalence of persisting ADHD with age, from 17.9% (age ≤25 years) to
10% (age 26–45 years), and with none persisting above the age of 45 [121].
The coexistence of reading difficulties in male prison inmates has been re-
ported [116]. In a meta-analysis, the estimated general prevalence in incar-
cerated patients was 25.5%, with no significant differences for sex and age,
although with significant country differences [163]. Finally, pharmacological
treatment of inmates with ADHD has been linked to positive long-term func-
tional outcome [63].

17
Diagnostic assessment of ADHD in adulthood
Several screening instruments and diagnostic interviews are available for
adult ADHD. The World Health Organisation Adult ADHD Self-Report
Scale (ASRS) contains 18 items, one for each of the DSM-IV criteria, which
can be used for interviews, treatment evaluation, or both [82; 84; 145]. There
is also an abbreviated 6-item short screening version of current symptoms
based on selected DSM-IV criteria (50). This has been reported to have a
total classification accuracy of 97.9 % when applied to population survey
data (50) but is less specific when used in subsamples of diagnostic entities
such as subjects with SUD (51). The Brown ADD Scale concentrates on the
inattentive aspects of ADHD [124]. Conners’ Adult ADHD Rating Scale is
based on the 18 DSM-IV criteria with symptomatic descriptions adapted for
an adult population [2]. The Wender Utah Rating Scale [100]. is available
for a retrospective screening of childhood ADHD, including additional
symptoms often associated with ADHD (e.g., temper, affective lability and
emotional overreactivity). Finally, the parent questionnaire "Five to Fifteen"
is available for screening of symptoms and problems typical of ADHD and
its comorbidities [77].
To secure diagnostic accuracy after positive screening, semi-structured in-
terviews are available including the Conners’ Adult ADHD Diagnostic In-
terview for DSM-IV (CAADID) [47] and the Diagnostic Interview for
ADHD in adults (DIVA). CAADID is not available in an authorized Swe-
dish version and the original version in English is subject to copyright issues.
DIVA has been translated into several languages, including Swedish, and is
available free of charge on the Internet. The Spanish version of DIVA has
recently been validated against CAADID [48; 115].
Apart from past and present symptoms of ADHD, the influence of psy-
chiatric comorbidity, somatic disease, ongoing substance use and signs of
behavioural phenotype syndromes must be considered before a clinical diag-
nosis of adult ADHD is established. Neuropsychological testing with evalua-
tion of the cognitive level and profile often provides valuable information to
facilitate the diagnostic procedure. Sometimes computerized continuous
performance tests, e.g. QBtest [74], can be of value as part of the evaluation
process.
The European Network Adult ADHD was founded in 2002 to advance the
recognition and treatment of adult ADHD in Europe. An extensive review
article and consensus statement on the diagnostics and treatment of adult
ADHD was published by members of the network in 2010 and an updated
version is expected to be presented shortly [87].

18
Multimodal treatment of ADHD
A combination of pharmacological and non-pharmacological treatment, as
well as psychosocial and pedagogic interventions are often considered the
gold standard when treating subjects with ADHD. The multimodal treatment
study of children with ADHD (MTA study) constitutes a cornerstone in the
subsequent view on ADHD treatment [143]. The MTA group followed 597
children with the combined subtype over a period of 14 months. The chil-
dren were randomised to one of four treatment strategies: 1) carefully titrated
and monitored medication with stimulants, 2) intensive behavioural treat-
ment, 3) a combination of strategies 1 and 2, and finally 4) standard commu-
nity care (control group). The outcome demonstrated significantly greater
ADHD symptom reduction in groups 1 and 3 compared with groups 2 and 4.
There was no difference in symptom reduction when comparing groups 1
and 3, but combining carefully monitored treatment with stimulants with
behavioural treatment reduced parallel symptoms (e.g., aggressive/-
oppositional and internalising symptoms) known to be frequently associated
with ADHD in childhood.
Treatment of adults with ADHD has been the subject of several guide-
lines. The previously mentioned European Network has presented a treat-
ment algorithm of psychoeducation, pharmacotherapy, coaching, cognitive
behavioural therapy and family therapy. In this approach, the importance of
considering treatment of coexisting psychiatric comorbidity is underlined
[87]. The National Institute for Health and Care Excellence guidelines, pub-
lished in 2008 and updated in 2016, advocate pharmacotherapy to be the
first-line of treatment as a part of a comprehensive treatment programme
addressing interventions and treatment of psychological, behavioural and
educational or occupational needs [141]. Treatment recommendations of
ADHD by the Swedish Medical Products Agency (Swedish: Läke-
medelsverket) [98] underline pharmacological treatment as a component of a
multimodal approach including psycho-social and pedagogic interventions.
The effect of non-pharmacological treatment has been investigated in pa-
tients receiving treatment with stimulants or placebo undergoing either be-
havioural group psychotherapy or individual clinical management. After
three months of treatment, there was no difference in symptom reduction in
those treated with group psychotherapy or individual clinical management.
However, significantly decreased symptoms were found in patients treated
with stimulants compared with those treated with placebo. These results
were stable at a one-year follow-up [110].

19
Pharmacological treatment of ADHD
Mechanisms of action of stimulants and atomoxetine
Stimulants are thought to work primarily in dopamine and norepinephrine
pathways, especially in striatal areas of the brain by blocking the reuptake of
these neurotransmitters [155; 156; 157; 159].
The exact functional mechanism of atomoxetine remains unresolved but
is thought to be a selective inhibitor of the norepinephrine transporter in-
creasing norepinephrine causing α2-adrenergic receptor activation [56; 138].
In addition, atomoxetine appears to increase dopamine in the prefrontal cor-
tex through nonspecific action of the norepinephrine transporter [12].

Effectiveness and safety of pharmacological treatment of ADHD

in adulthood
Only a handful of randomised controlled trials (RCTs) of stimulants and
atomoxetine have been conducted for ≥24 weeks in adults with ADHD [76;
61; 1; 23; 121; 162]. Moreover, some short-term trials of stimulants have
been supplemented with open-label extensions confirming a similar pattern
of relatively mild side effects [3; 29; 64; 149; 150]. The most frequent side
effects reported for methylphenidate were headache, decreased appetite, dry
mouth/mucosal dryness, nasopharyngitis and difficulty falling asleep;
atomoxetine was linked to nausea, dry mouth, decreased appetite, headache
and fatigue.
Despite evidence of beneficial effect and treatment safety, the clinical rel-
evance of these short-term RCTs and/or open-label studies could be ques-
tioned since psychiatric comorbidity often excludes RCT participation. A
few prospective and/or naturalistic studies have been published up to date. In
a one-year study 30 % of participants experienced any side effect on
methylphenidate and 12 % terminated treatment on any ADHD drug due to
side effects [55]. Another study that included patients with a high degree of
psychiatric comorbidity found that half of the patients remained on treatment
with stimulants after two years. Only 15% discontinued treatment because of
lack of effect and 17% did so because of anxiety or depression. The most
frequently reported side effects during treatment were decreased appetite,
dry mouth and initial insomnia [17]. Finally, a four-year outcome question-
naire study of pharmacologically treated adults with ADHD reported a 37%
discontinuation rate at follow-up. Side effects were the most frequent reason
for cessation of medication, followed by lack of efficacy and misuse [95].
Because ADHD medication has been associated with a moderate mean
increase in blood pressure and pulse, questions on the long-term risks of
cardiovascular adverse events have been rightfully raised [68].

20
Outcome predictors
Outcome predictors in childhood
A six-year follow-up study of a European cohort of children diagnosed with
ADHD at a mean age of 11 years reported a correlation between younger
baseline age, higher ADHD symptom severity and higher impairment at
baseline and poorer overall functioning. Interestingly, pharmacological
treatment demonstrated no impact on either ADHD symptom severity or
overall functioning at follow-up [148]. Furthermore, a meta-analysis of stud-
ies on children identified ADHD severity, treatment for ADHD, comorbid
CD and comorbid major depressive disorder to be predictors in childhood for
ADHD persistence in adulthood [32]. In a longitudinal study of twins, adult
persistence was associated with more symptoms and lower IQ [4].

Outcome predictors in adulthood

With an increasing number of adults seeking evaluation and treatment of
ADHD, predictors at baseline for future outcome are clinically important to
identify and consider in clinical practice.
Patients diagnosed with ADHD in adulthood reported better outcome on
all measures when pharmacologically treated for two years or more com-
pared with those with a shorter treatment time after a mean observation peri-
od of 4.5 years and at a mean age of 36.5 years at follow-up. In this study,
comorbidity at baseline predicted poorer outcome [95]. A seven-year clinical
study of patients diagnosed with ADHD at a mean age of 34 years reported
that approximately 30% did not maintain ADHD criteria and 12% presented
full remission (defined as <4 symptoms at follow-up). Predictors of diagnos-
tic persistence were higher number of inattention and hyperactivi-
ty/impulsivity symptoms, previous ODD and social phobia at baseline [78].

21
Aims and scope

The overall aim of this thesis is to broaden the understanding of ADHD in

adulthood by screening for prevalence and investigating psychiatric comor-
bidity in adults with ADHD, as well as to demonstrate long-term outcome
and treatment safety in those diagnosed with ADHD as adults. The specific
aims of this thesis follow a stepwise pattern closely coupled to experienced
practical patient issues in everyday clinical practice.

The specific aims of this thesis are:

• To survey the frequency and severity of self-reported ADHD-related

symptoms, difficulties and suffering, functional impairment and reading
and spelling difficulties in patients seeking outpatient psychiatric care
and in female prison inmates in comparison with a sample of the GP.

• To examine prevalence and sex differences of axis I and II comorbidity

in a clinical sample of patients diagnosed with ADHD as adults. Specific
interest was focused on analysing the prevalence and gender differences
of personality disorders with and without fulfilment of the general diag-
nostic criteria.

• To assess long-term outcome with respect to symptom reduction and

function in a well-defined sample of patients first diagnosed with ADHD
as adults, to compare outcome in the patients who were still on medica-
tion versus those who discontinued medication, and also to identify po-
tential baseline predictors of favourable outcome.

• To evaluate tolerability and safety of long-term treatment in adults with

ADHD by assessing reasons for discontinuation as well as self-reported
side effects in patients under current long-term treatment. To assess
baseline predictors for adherence to treatment and to determine partici-
pants own perceived outcome since diagnosed with ADHD and subse-
quent treatment with stimulants and atomoxetine.

22
Method

Study design and participants

This thesis is based on cohort-studies performed in a piecemeal manner be-
cause of different and subsequent aims. An overview of the studies is given
in Table 1.
Paper I contains three studies investigating the prevalence of ADHD
symptomatology in three cohorts: the GP, adult psychiatric outpatients and
female prison inmates. The GP sample included of 1000 patients between 18
and 55 years of age who were randomly selected from the population regis-
try in Uppsala County by an independent company. The patients were re-
minded twice by mail after the initial request to participate. In all, 236 men
and 281 women were included, representing a participation rate of 52%. The
recruitment took place in autumn 2003. The psychiatric outpatient sample
was made up of adult psychiatric outpatients in Uppsala County seeking care
mainly for affective, anxiety, sleep and personality disorders, i.e. common
comorbid disorders in adult ADHD. The reception personnel were instructed
to inform every Swedish-speaking patient between 18 and 55 years of age
about the study, both orally and in writing, and to invite them to participate.
Four hundred and sixty-eight (n=468) patients were invited to participate in
the study and 400 (85%) volunteered to take part. Of the 400 patients, 369
(92%) completed the study. However, 20 patients were excluded because of
incomplete answers, leaving 77 men and 272 women for analysis, represent-
ing a participation rate of 75% (349/468). The recruitment took place in De-
cember 2003. The female prison sample comprised inmates from the Hinse-
berg Prison, which is the largest prison for women in Sweden with the high-
est security level. The prison is intended for female convicts from the entire
country who are sentenced to long-term (six years on average) imprison-
ment. The two most common crimes for which inmates were convicted were
severe drug-related crimes (44%) and murder/manslaughter (21%). At the
time of the study, there were 104 inmates; however, 17 had been transferred
to a special unit for treatment of alcohol and drug addiction, 18 had been
moved to an open-wing section because they had been convicted of minor
crimes and 4 had been admitted to hospital. Accordingly, 65 high-security
prisoners were available for the study and were invited to participate. Fifty
women gave informed consent and the overall participation rate was 77 %
(50/65). The recruitment took place in March-May 2004.

23
Table 1. An overview of the studies included in this thesis

Paper Sample Included Investigated sample Response rate (%) Females/males

I General population 1000 517 52 281/236
I Outpatient psychiatry 468 349 75 272/77
I Prison inmates 65 50 77 50/0

II Patients diagnosed with ADHD in adulthood 168 168 100 78/90

III Patients diagnosed with ADHD in adulthood 168 124 74 61/63

IV Patients diagnosed with ADHD in adulthood 168 112 67 57/55

with subsequent medication
 Paper II included adults diagnosed with ADHD in adulthood. In 2002, a
special outpatient clinic for referral of adult patients with suspected diagno-
ses of ADHD, ASD and Tourette’s syndrome was established at Uppsala
University Hospital. Of 233 consecutively referred patients, 168 (78 women
and 90 men) were diagnosed with adult ADHD and subsequently included in
this study. The recruitment took place in April 2002-October 2010.
Paper III is a follow-up study of participants included in paper II. Of the
168 eligible patients, 124 (74%) participated in the follow-up. The recruit-
ment took place in March-October 2013.
Paper IV included the same participants who took part in study II and III
who had been put on medication after being diagnosed with ADHD in adult-
hood. Of the 168 patients diagnosed with ADHD in adulthood, 112 (67%)
took part in the follow-up. The recruitment period was identical to paper III.

Procedures and measurements

In paper I, the first part of the study questionnaire covered the 18 symptoms
of ADHD according to DSM-IV. Each question was supplemented with a
short description of possible adult expressions of the symptoms. The re-
sponse format was four-fold, depending on current presence and burden of
symptoms of ADHD: “never/seldom”, “sometimes”, “often” and “very of-
ten”. Each answer corresponded to a score from 0 to 3. Thus, the scoring
system is based on a minimum total score of 0 points and a maximum total
score of 54 points (maximum score for hyperactivity-impulsivity=27 and
inattention=27). A score of ≥2 for at least six of nine symptoms of inatten-
tion or six of nine symptoms of hyperactivity-impulsivity was required to be
categorised as an inattentive or hyperactive type of adult ADHD. Questions
about ADHD symptoms during childhood, as reported to the participant by
parents or other informants, were asked separately. The GP sample and psy-
chiatric outpatient sample were asked about childhood hyperactivi-
ty/impulsivity only, whereas the female inmates were also asked about
childhood inattention. The first two samples were categorised as “hyperac-
tive” if they endorsed hyperactivity in childhood or adulthood. The inmate
sample was categorised as ADHD if they endorsed childhood hyperactivity
or inattention or six of nine DSM-IV criteria as adults. The second part of
the questionnaire contained questions on age and sex, as well as reading and
spelling difficulties (dichotomised answers: yes/no). Functional impairment
was assessed by asking the participants to rate difficulties and suffering
caused by the current ADHD-related symptoms, using two 100-mm visual
analogue scales (VASs) (end points: no difficulties/no suffering to totally
handicapped), as well as to self-rate their social, occupation and psychologi-
cal functioning using the Global Assessment of Functioning (GAF) scale
during the past year and the past two weeks [25; 114]. The psychiatric pa-

25
tients were also asked about reasons for seeking care and about ongoing
medication. The female prison inmates were screened for CD and ASPD by
using relevant subscales of the self-report version of the DSM-IV and the
ICD-10 personality questionnaire (DIP-Q) [8; 25].
In paper II, a multidisciplinary team made up of senior psychiatrists, clin-
ical psychologists, social workers and occupational therapists performed all
evaluations. The diagnostic procedure aimed at establishing best estimate
diagnoses was confirmed by all participating professionals reaching consen-
sus on the diagnostic outcome as well as on attributed impairment or suffer-
ing [92]. All patients underwent a physical examination that included basic
neurologic status, as well as routine laboratory testing, including urine
screening for drugs. All patients were interviewed about current symptoms
and behaviours associated with ADHD using a semi-structured interview
based on the 18 DSM-IV criteria [8]. The interview included realistic exam-
ples from everyday life that were obtained in clinical practice from adult
patients. The patients were encouraged to give their own examples of adult
ADHD with subsequent impairment in accordance with each diagnostic
item. The answers were evaluated and rated according to four categories,
depending on symptom frequency and impairment: “never”, “sometimes”,
“often”, and “very often”. An answer of “often” or “very often” was catego-
rised as a fulfilled criterion. Six or more of the maximum nine subtype crite-
ria were required to fulfil a diagnosis of adult ADHD. A social worker or
clinical psychologist collected and documented a developmental and social
history from childhood to the present. The clinical version of the Structured
Clinical Interview for DSM-IV axis I (SCID-I) [54], was administered by a
senior psychiatrist (author, DE) with training in the use of this instrument to
assess coexisting Axis I disorders. Evaluations of suspected ASD included
semi-structured developmental interviews, i.e. the Diagnostic Interview for
Social and Communication Disorders [94], and the Autism Diagnostic Inter-
view-Revised [91], which were performed by senior clinical psychologists
[91; 94]. Criteria for DSM-IV Axis II disorders were initially assessed by
means of the DSM-IV and ICD-10 Personality Interview (DIP-I) [108]. It
was later replaced by the Structured Clinical Interview for DSM-IV axis II
(SCID II) [53], which is very similar to the DIP-I and was used for half
(n=84) of the participating patients. ASPD was only considered if a previous
history of CD had been confirmed. All interviews relative to personality
disorders were performed by a senior psychiatrist (DE) with training in the
use of the respective instruments.
In paper III, questionnaires were sent to the participants with questions
about current symptoms of ADHD using a self-report version of the semi-
structured interview used at baseline. Current functioning was assessed by a
self-report version of the Global Assessment of Functioning Scale (GAF)
[25; 114]. Potential improvement since baseline was measured by the Clini-
cal Global Impressions Improvement scale (CGI-I). The CGI-I is a seven-

26
point scale from “very much improved” to “very much worse” [66]. Disabil-
ity and impairment were investigated by the Sheehan Disability Scale (SDS)
[96] a scale that covers three domains: work/school, social life and family
life/home responsibilities. The SDS has recently been psychometrically
evaluated in adult ADHD [39]. Health-related quality of life (HRQoL) was
measured by EQ-5D and EQ-VAS [44; 142]. Alcohol consumption was as-
sessed by the Alcohol Use Disorders Identification Test (AUDIT) [13] and
drug consumption by the Drug Use Disorders Identification Test (DUDIT)
[19]. When the questionnaires had been returned, a telephone interview was
conducted covering demographics as well as details of the participants’ past
and current medical condition. Participants’ information on previous medica-
tion periods was validated against data in their patient files if available. In
case of contradictory data, we choose to rely on patient file data.
In paper IV, data from paper III were supplemented with information
about each treatment period, defined as being of at least one month’s length
and with an intervening one-month period of non-medication or more before
another attempt of pharmacological treatment was considered. Patients’ in-
formation about previous medication periods and reasons for discontinuation
were validated against data in their patient records. In case of contradictory
data, we again choose to rely on patient record data. If there were several
treatment periods, the final reason for discontinuation was registered for
each pharmacological substance. In patients with ongoing medication, cur-
rent adverse effects were assessed by a form covering 31 adverse effects
which was used as part of the clinical routine in patients treated at the clinic
for neuropsychiatry at Uppsala University Hospital. The frequency of ad-
verse symptoms was categorised as “Never”, “Sometimes” (corresponding to
1-2 times/week), “Often” (corresponding to 3-6 times/week) and “Very of-
ten” (corresponding to daily/always). There were also questions on the pa-
tients’ experience of the effect of current medication, adherence and dosage
pattern. Finally, participants were asked to respond to five statements about
how their status had changed since baseline: “My quality of life has im-
proved”, “My level of functioning has improved”, “My understanding of my
way of functioning has increased”, “I have encountered greater understand-
ing from the environment of my way of functioning” and “I find it worthwhile
having been evaluated for ADHD”. Answers to the first four statements
were categorised in a four-step scale from “Not at all” to “Exactly correct”;
the last statement (...worthwhile having been evaluated...) was categorised in
the opposite order from “Yes, indeed” to “Not at all”. Data on deceased par-
ticipants’ cause of death among dropouts in paper III and their ongoing
pharmacological treatment at the time of death were supplied by The Swe-
dish National Board of Health and Welfare.

27
Statistics
All statistical analyses were performed using PASW Statistics, version
12.0.1 (paper I), version 18.0 (paper II) and version 23 (paper III and IV). P-
values ˂0.05 were considered statistically significant.
Dichotomous data were analysed using chi-square test statistics or Fisher’s
exact test when applicable with a cell count number of ˂5.
A Kolmogorov-Smirnov test was used to test for normality. When appro-
priate, the non-parametric Mann-Whitney U test was employed to determine
group differences; otherwise, the t-test was performed for continuous data.
Inter-rater reliability of continuous scale data was tested by single-
measure intraclass correlation and diagnostic agreement was tested using
Cohen’s kappa.
Because symptom and GAF scores in paper I were not normally distribut-
ed, differences in mean scores were analysed using the Mann-Whitney U test
for independent samples. Confounding by skewed sex proportions and a
higher prevalence of hyperactivity in the outpatient sample was corrected
using Mantel-Haenszel statistics. Because age was unevenly distributed
among men and in the number of diagnoses on axis I in both sexes, the
Mann-Whitney U test was used for analysis of sex differences in paper II.
All baseline variables (e.g., age, sex, ADHD subtype and score, psychiatric
comorbidity, sociodemographic data and treatment-related variables) were
tested for possible inclusion in univariate logistic regression models with
remission as the dependent variable in paper III and ongoing pharmacologi-
cal treatment in paper IV. None of these variables were significantly related
to either of the dependent variables, however.

Ethics
All studies included in this thesis were approved by the Regional Ethics Re-
view Board at Uppsala University: 02-452 (paper I), 2006/241 (paper II),
2012/544 (paper III and IV).

28
Results

ADHD-related symptoms among adults in outpatient

psychiatry and female prison inmates as compared with
the general population (Paper I)
This study aimed to compare the prevalence of symptoms consistent with
ADHD and related problems in adults in the GP, in outpatient psychiatry
(where females are in the majority) and in female convicts. Detailed infor-
mation concerning participating subject characteristics is given in paper I.

Prevalence of ADHD-symptomatology
One third (32.4%) of the participants in the outpatient psychiatry sample
reported hyperactivity versus about one sixth (15.1%) in the GP sample. All
three subgroups (childhood only, both childhood and adult and adult only)
were more prevalent in the outpatient sample than in the GP sample. The
prevalence of both adult and childhood hyperactivity/impulsivity was ap-
proximately three times higher among participants in the outpatient sample
compared with the GP sample (6.6 versus 2.1%).
Fifty per cent of the female inmates reported symptoms of ADHD in
childhood or as adults; 6 of the 50 participants (12%) reported inattention
only in childhood. Fifteen participants (30%) had both childhood inattention
and adult symptoms of ADHD. The frequencies of inmates endorsing the
criteria for CD and ASPD, self-rated GAF values and reading and spelling
difficulties in inmates, with and without symptoms of ADHD, are summa-
rised in Table 2.

Difficulties and suffering attributed to ADHD-related symptoms

The levels of difficulties and suffering due to ADHD-related symptoms in
the outpatient sample were significantly higher in those classified as hyper-
active and in those not classified as hyperactive as compared with the GP
sample. Within the GP sample, only the subgroup that reported both child-
hood and adult hyperactivity had significantly higher levels of difficulties
and suffering as compared with the non-hyperactive group. In the outpatient
sample, all subgroups had significantly higher levels of difficulties and suf-
fering as compared with the non-hyperactive group. There were no major
differences between men and women within the two samples. In the inmate

29
sample, difficulties and sufferings due to ADHD-related symptoms were
significantly higher in the group classified as ADHD (p<0.001).
Table 2. . The frequency of conduct disorder (CD) and antisocial personality disor-
der (ASPD), self-rated global assessment of function (GAF) values and reading and
spelling difficulties in the groups of inmates with and without attention-
deficit/hyperactivity disorder (ADHD) (from paper I).
ADHD group Non-ADHD group p-value
(n=25) (n=25)
CD (%) 84 (21/25) 28 (7/25) p<0.001 b
ASPD (%) 76 (19/25) 20 (5/25) p<0.001 b

GAF in the past year* 62±17 81±17 p<0.001 a

GAF in the past two 66±18 79±16 p<0.01 a
weeks*

Reading difficulties (%) 36 (9/25) 8 (2/25) p< 0.05 b

Spelling difficulties (%) 32 (8/25) 8 (2/25) ns
* n= 24 in each group; a Mann-Whitney U-test; confirmed by b Fisher’s exact test

Self-rated global assessment of function (GAF)

The GAF scores were significantly lower among participants in the outpa-
tient sample, both during the past year and during the past two weeks as
compared with the GP sample. In the inmate sample, the GAF self-ratings
for the past year and for the past two weeks were significantly lower in the
group classified as ADHD (Table 2).

Reading and spelling difficulties

There was a significantly higher prevalence of reading (p<0.001) and
spelling (p˂0.01) difficulties in the outpatient sample than in the GP sample.
This result was repeated in the non-hyperactive group (reading, p<0.001;
spelling difficulties, p˂0.05). In the GP sample, the subgroups with child-
hood hyperactivity as well as childhood and adult hyperactivity had signifi-
cantly higher frequencies of both reading (p<0.001 and spelling (p˂0.001)
difficulties than the non-hyperactive group . The data of the inmate sample
are presented in Table 2. The reading difficulties were significantly higher in
the group classified as ADHD than in the non-ADHD classified group
(p<0.05). Differences in spelling difficulties did not reach statistical signifi-
cance

30
Sex differences of axis I and II comorbidity in subjects
diagnosed with ADHD as adults (Paper II)
The aim of this study was to examine prevalence and sex differences of axis
I and II comorbidity in a clinical sample of patients diagnosed with ADHD
as adults.
Detailed patient characteristics are presented in paper II.
Of the 168 patients, 100 (60%) were diagnosed with an ADHD of com-
bined type and 61 (36%) of the inattentive type. The remaining seven (4%)
patients were diagnosed with ADHD (predominantly hyperactive-impulsive
ADHD). The inattentive type was more common in men than the combined
type and hyperactive type when compared with women (p<0.01).
ADHD symptom profiles by sex is depicted in Figure 1. The ADHD
items with the greatest difference between women and men were the hyper-
activity/impulsivity symptoms “talks excessively”, “blurts out answers” and
“interrupts and intrudes” (all ps<0.01).

Figure 1. Percentage of individual ADHD items fulfilled as a function of patient’s

sex (from paper II).

31
The lifetime prevalence of any comorbid axis I disorder was 95% in women
and 90% in men (Table 3). The mean number of lifetime diagnoses, includ-
ing ASD and Tourette’s syndrome, was 2.7±1.5 (range 1-7) in women and
2.7±1.8 (range 1-11) in men. Women were significantly more often diag-
nosed with mood and eating disorders, whereas men significantly more often
fulfilled criteria for SUD (Table 3).
The presence of at least one current Axis I disorder, including ASD and
Tourette’s syndrome was diagnosed in 47 % (45 % in the women and 49 %
in the men).
Table 3. Prevalence of psychiatric comorbidity on axis I in the clinical cohort of
patients investigated from paper II.
Prevalence
Disorder Women; n (%) Men; n (%) χ2 p-value1
Lifetime
Axis I disorders
Any mood disorder 71 (91.0) 60 (66.7) 14.44 <0.001
Any anxiety disorder 33 (42.3) 37 (41.1) 0.25 ns
Any somatoform disorder 2 (2.6) 1 (1.1) 0.50 ns
Any eating disorder 17 (21.8) 0 (0) 21.82 <0.001
Adjustment disorder 1 (1.3) 1 (1.1) 0.10 ns
Any psychotic disorder 1 (1.3) 2 (2.2) 0.21 ns
Any substance use disorder 26 (33.0) 45 (50.0) 4.76 <0.05
Comorbid neuropsychiatric disorders
Any autism spectrum disorder 6 (7.7) 11 (12.2) 0.94 ns
Tourette’s syndrome 2 (2.6) 6 (6.7) 1.55 ns

Any Axis I disorder, including comorbid 74 (94.9) 81 (90.0) 1.39 ns

neuropsychiatric disorder
Current
Any Axis I disorder, including comorbid 35 (44.9) 44 (48.9) 0,27 ns
neuropsychiatric disorder
1
women vs. men

When the general diagnostic criteria for a personality disorder were consid-
ered, only six women (8%) and 10 men (11%) were diagnosed with an Axis
II disorder. However, when only considering the specific criteria for at least
one personality disorder, 36 women (46%) and 41 men (46%) fulfilled spe-
cific criteria (Table 4). The only observable sex differences concerned ful-
filment of the specific criteria for histrionic personality disorder and for CD,
with the former more common in women (p<0.05) and the latter more com-
mon in men (p<0.01). In addition, men more often fulfilled specific criteria
for ASPD compared with women, but the difference was not statistically
significant (p=0.06).

32
Table 4. Comorbidity of personality disorders without considering the general diag-
nostic criteria in the investigated group of patients (from paper II).
Fulfilment of specific criteria
Women; n (%) Men; n (%) χ2 p-
value a
Cluster A 5 (6.4) 4 (4.4) 0.32 ns

Cluster B 20 (25.6) 26 (28.9) 0.22 ns

Antisocial 8 (10.3) 19 (21.1) 3.65 0.056
Conduct disorder 26 (33.3) 54 (60.0) 11.91 <0.01
Borderline 11 (14.1) 13 (14.4) 0.04 ns
Histrionic 4 (5.1) 0 (0) 4.23 <0.05
Narcissistic 0 (0) 3 (11.1) 2.64 ns

Cluster C 23 (29.5) 17 (18.9) 0.11 ns

Any cluster 36 (46.2) 41 (45.6) 0.01 ns

a
women vs. men.

Twenty-nine (17%) of the 168 patients were directly referred for evaluation
of ADHD. The remaining 139 patients had a previous history in adult psy-
chiatry (with a mean duration of 7.3±6.2 years, range 0-28) before being
identified as potential ADHD patients and subsequently referred for evalua-
tion by either adult psychiatry or primary health care. Twenty-seven women
(35%) and 35 men (39%) reported previous contact with child and adoles-
cent outpatient psychiatric clinics (one man had ongoing contact).
At the time of the evaluation, 110 (65%) of the patients were on medica-
tion. The five most common prescribed pharmaceuticals were medication for
somatic disorders: for example, hypertensives and antibiotics, analgesics
excluded, 25%), followed by antidepressants other than serotonin reuptake
inhibitors (SSRIs, 21%), SSRIs (18%), benzodiazepines (14%) and hypnot-
ics other than benzodiazepines (11%). Women were prescribed SSRIs more
frequently than men (p<0.01); no other sex differences were identifiable.

Six-Year Outcome in Subjects Diagnosed with

Attention-Deficit/Hyperactivity Disorder as Adults
(Paper III)
The study aimed to assess long-term outcome for symptom reduction and
function in a cohort of patients first diagnosed with ADHD as adults in rela-
tion to current medication (or not) and to identify potential baseline predic-
tors of favourable outcome. The primary outcome measure was remission,
which was defined as not fulfilling any ADHD subtype and a GAF score of
≥70 during the past year.

33
 Participants constitute a subgroup of patients presented in paper II and de-
tailed information of patient characteristics is presented in paper III.
Compared with baseline, there was a decrease in mean ADHD scores
from 36.8±7.8 to 25.5±11.1; 33% of the patients (41/123) were in remission.
There was also a similar decrease in the number of patients who fulfilled
each of the 18 DSM-IV ADHD criteria.
There was also an apparent change in ADHD subtype over time (Figure
2).

Figure 2. Number of patients with different ADHD-subtypes at baseline and at fol-

low-up. Presentation as in [46]. Numerals are numbers of patients; sizes of squares
and arrows represent approximate quantitative proportions.

34
In general, patients with a combined ADHD subtype at baseline remained as
a combined subtype, changed into an inattentive subtype, or did not fulfil the
criteria for a diagnosis of ADHD at follow-up Patients with an inattentive
ADHD subtype either maintained the diagnosis or did not fulfil criteria for a
diagnosis of ADHD. There was no decline in the number of patients with the
hyperactive type, whereas the number of patients with a combined ADHD
subtype decreased from 71 to 21 (i.e. with 70%) and the number of patients
with an inattentive ADHD subtype decreased from 47 to 31 (i.e. with 34%).
Patients in remission reported similar ADHD scores at baseline as those who
were not in remission (Table 5). Furthermore, there was no difference in
current medication between the groups (51 versus 43%). Patients in remis-
sion reported significantly better global functioning, less disability, better
quality of life (QoL) and better clinical improvement than those who were
not in remission. There was no difference in mean alcohol consumption, as
measured by AUDIT scores, and drug use, as assessed by DUDIT scores.
Scores above limits for harmful drinking [13] however, were observed in 7%
of those in remission versus 24% of those who were not (p=0.03), and risk
scores for potential drug-related problems [19] in 2% of those in remission
versus 11% of those who were not (p=0.16).
Reciprocally, there was no difference in remission rate between patients
in the current medication group, (37%) and in those not currently medicated
(30%). Medicated patients reported similar ADHD scores as those without
ongoing medication, both at baseline and at follow-up. They also reported
similar global functioning, disability and QoL than those not medicated,
although medicated patients showed better clinical improvement (Table 6).
All baseline variables and treatment-related variables were tested for pos-
sible inclusion in a regression model with remission as the dependent varia-
ble. None of these variables were significantly related to remission.

35
Table 5. Data for the patients that responded to the enquiry at follow-up by state of
remission (from paper III).
Remission Not remission p-value
(n=41) (n=82)
Time on treatment (months) 51±312 41±303 <0.0011
Time on treatment (per cent of follow-up) 65±352 55±353 <0.0011
ADHD score at baseline 35.8±7.74 37.2±7.85 0.411
ADHD score at follow-up 15.6±7.5 30.5±8.8 <0.0011
Current medication 21 (51%)2 35 (43%)3 0.44
CGI-improvement 2.2±1.3 3.2±1.7 <0.0011
GAF past year 84±10 61±14 <0.0011
GAF past two weeks 82±17 62±16 <0.0011
SDS
Work/school 1.7±3.1 4.5±3.8 <0.0011
Social life 1.7±3.4 4.5±3.5 <0.0011
Family life/home responsibilities 1.5±2.7 4.0±3.4 <0.0011
EQ-5D index 0.82±0.19 0.55±0.33 <0.0011
EQ-5D VAS 78±14 57±21 <0.0011
AUDIT score1 3.5±3.8 4.0±4.4 0.671
DUDIT score1 0.2±0.7 1.3±4.3 0.121
1
Mann-Whitney U test; 2 n=35; 3 n=76; 4 n=38; 5 n=80;

Table 6. Data for the patients that responded to the enquiry at follow-up by state of
medication (from Paper III).
Current medication
Yes (n=56) No (n=67) p-value
Time on treatment (months) 63±24 20±22 <0.0011
Time on treatment (percent of follow-up) 84±19 19±27) <0.0011
ADHD score at baseline 36.5±8.63 37.2±7.24 0.671
ADHD score at follow-up 24.5±11.03 26.4±10.9 0.671
Do not fulfil criteria for ADHD at follow-up 31(55 %) 33 (49 %) 0.50
Remission 21(37 %)3 20 (30 %) 0.44
CGI-improvement 2.4±1.53 3.3±1.6 <0.0011
GAF past year 69±163 68±17 0.901
GAF past two weeks 69±183 68±20 0.861
SDS
Work/school 3.2±3.73 3.8±3.8 0.411
Social life 3.4±3.63 3.7±3.8 0.741
Family life/home responsibilities 2.8±3.33 3.4±3.4 0.341
EQ-5D index 0.68±0.303 0.60±0.33 0.171
EQ-5D VAS 67±193 62±24 0.191
AUDIT score 4.1±4.53 3.6±4.0 0.501
DUDIT score 1.5±5.13 0.4±1.2 0.211
1 2 3 4
Mann-Whitney U test; The 55 who had discontinued their treatment; n=56; n=64;

36
Long-Term Tolerability and Safety of Pharmacological
Treatment of Adult Attention-Deficit/Hyperactivity
Disorder (Paper IV)
The aim of this study was to evaluate tolerability and safety of long-term
treatment in adults with ADHD by examining patient reasons for discontinu-
ation as well as self-reported side effects in patients currently on long-term
treatment. The study also assessed baseline predictors for adherence to
treatment and attempted to determine participants’ perceived outcome since
being diagnosed with ADHD.
Participants constitute a subgroup of patients presented in paper II and III.
Detailed information on patient characteristics is presented in paper IV. Data
on dropouts in paper III revealed that five persons had died since their
ADHD diagnosis and only one by way of natural causes.
Fifty-seven patients were currently on treatment and 55 had discontinued
treatment. There were no significant differences in baseline data between
current treatment and the off-treatment patients. Time on medication was
longer in patients on treatment compared with those who had discontinued
(63±24 versus 24±22 months).
Of the currently medicated patients, 46 were on treatment with
methylphenidate, 8 with amphetamine and 3 on a combination of
methylphenidate and atomoxetine. Of the eight patients currently treated
with amphetamine, seven had previously been on methylphenidate. Five
patients had previously been treated with atomoxetine but discontinued. Of
the currently medicated patients, 56 had a lifetime history of treatment with
methylphenidate, 13 with amphetamine and 8 with atomoxetine.
The maximum dosage during treatment was 84±37 mg for methylpheni-
date, 43±10 mg for amphetamine and 68±23 for atomoxetine. The current
dose was 60±32 mg for methylphenidate, 42±9 mg for amphetamine and
38±13 mg for atomoxetine.
Most patients on treatment with methylphenidate were treated with medi-
um- or long-acting agents All patients treated with amphetamine were on
short-acting tablets.
Seventy-eight per cent of the patients took their medication once or twice
daily. Eighty-four per cent of the patients stated that they took their medica-
tion in the exact dosage as prescribed, whereas 16% reported that they used a
lower dosage. Eighty-eight per cent reported daily adherence to treatment.
The total time on treatment was 61±24 months for stimulants, i.e. time of
treatment with methylphenidate and amphetamine added together; for
atomoxetine, the time was 9±17 months for the first treatment period. The
number of stimulant treatment periods was 2±1). When corrected for over-
lapping time of treatment with stimulants and atomoxetine, the total treat-
ment time increased to 63±24 months.

37
 Current adverse effects during pharmacological treatment of patients di-
agnosed with ADHD as adults are presented in Table 7. The most common
adverse effects related to methylphenidate were decreased appetite (28%),
dry mouth (24%) and anxiousness/restlessness, increased pulse frequency
(19%).
Finally, 81% of the patients reported a pronounced beneficial effect of
their ongoing medication and an additional 16% reported a moderate benefi-
cial effect.
The dosage at the time of discontinuation for those patients without cur-
rent medication was 68±42 mg for methylphenidate, 47±18 mg for amphet-
amine and 57±28 mg for atomoxetine. The total time on treatment with
stimulants was 22±21 months; the total time on treatment with atomoxetine
was 6±12 months. The number of treatment periods was 2±1 for stimulants
(no patients had been treated with atomoxetine more than once). When cor-
rected for overlapping time of treatment with stimulants and atomoxetine,
the total treatment time increased to 24±22 months.
The reasons for discontinuation of treatment are given in Table 8. The top
three reasons for discontinuation of treatment with methylphenidate were
lack of effect (29%), elevated mood or hypomania (11%) and not being able
to maintain contact with the prescriber (9%). None of the patients who dis-
continued methylphenidate or amphetamine because of elevated mood or
hypomania had been diagnosed with a bipolar disorder before medication.
One patient had been diagnosed with bipolar type II and one with bipolar
NOS at baseline; these two patients were treated with methylphenidate only.
In both these cases, depressive symptoms were the reason for discontinua-
tion. Fifteen patients had been treated with atomoxetine and the most com-
mon reason for discontinuation was, as with stimulants, lack of effect. Fur-
ther reasons for discontinuation were widespread, but in almost half of the
patients discontinuation was related to psychiatric side effects.
The statements, "My quality of life has improved", "My level of function-
ing has improved" and "Encountered increased understanding" were en-
dorsed to a higher degree among those patients still on medication.

38
Table 7. Current reported adverse effects during pharmacological treatment of 57
subjects diagnosed with ADHD as adults. Several symptoms could be reported sim-
ultaneously from each individual patient (from paper IV).
Adverse event1 MPH2 MPH+ATX3 AMPH4
Number of subjects; n (%) 46 3 8
Psychiatric
Anxiousness/restlessness 9(19)
Decreased sexual desire 8(17) 1
Depressed mood 5(11)
Elevated mood 3
Difficult getting to sleep 4
Increased need for sleep 3
Hyperactivity 3
Increased sexual desire 2
Apathy 1
Irritability 1

Dermatological
Perspirations 7(15) 1 2
Skin heating 3
Sensitive/dry mucous membranes 1 1
Pale skin 1
Cold hands/feet 4 1
Sensitive skin 1

Gastrointestinal
Decreased appetite 13(28) 1 1
Dry mouth 11(24) 1
Constipation 3
Nausea/vomiting 3
Abdominal pain 2
Diarrhea 1

Cardiovascular
Increased pulse frequency 9(19) 1
Hypertonia 4 1
Heart beats “strongly” 2 1
Hypotonia 1

Neurological 7 2
Headache 3
Sexual function problems 1 1
Vertigo/unsteadiness 1
Tics 1
Clumsiness 1
Difficult to accommodate (vision) 1
1 = Only those with symptom frequencies classified as “often” (3-6 times/week) or “very
often” (daily/always) are included. 2 = Methylphenidate, 3 = Methylphenidate + Atomoxe-
tine, 4 = Dexamphetamine,

39
Table 8. Reasons to discontinue pharmacological treatment in subjects diagnosed
with ADHD as adults (n=55; from paper IV).
Reason/Adverse effects MPH1 AMPH2 ATX3
Number of subjects; n (%) 55 11 15

Lack of effect 16(29) 4 3

No perceived need for further medication 1(2) 1
Lost contact with prescriber 5(9) 1

Psychiatric
Elevated mood or hypomania 6(11) 1
Depressed mood 4(7) 2
Aggressiveness 2(4) 1 2
Insomnia 2(4) 1 1
Fatigue 1(2) 1
Lethargy 1(2)
Increased obsessive-compulsiveness 1(2)
Drug abuse 1
“Mentally affected as influenced by drugs” 1

Dermatological
Rash 1(2) 1
Loss of hair 1(2)
Perspirations 1
Pruritus 1

Gastrointestinal
Nausea 3(6) 1
Weight gain 1(2)
Unspecific gastrointestinal symptoms 1

Cardiovascular
Hypertonia 3(6)
Palpitations/arrhythmia 3(6)

Neurological
Headache 2(4)
Dyskinesia 1(2)
Amnesia 1(2)
Unspecific pain 1
1
MPH = methylphenidate, 2AMPH = dexamphetamine, 3ATX = atomoxetine

40
Discussion

The principal aim of this thesis was to aid in the understanding of ADHD in
adulthood by screening for prevalence and investigating psychiatric comor-
bidity in adults with ADHD, as well as demonstrating long-term outcome
and treatment safety in persons diagnosed with ADHD as adults.

Methodological considerations
Design, samples and methods
For practical reasons, we decided in paper I to restrict participants in the GP
and outpatient sample to persons residing in Uppsala County and belonging
to a certain age group, which per se entails a selection bias. The age span of
18-55 years was arbitrarily chosen to diminish the risk for confounding dis-
orders occurring in older age groups. Uppsala County spans a widely diverse
geographic area that includes an expanding university city as well as less
populated areas with traditional industry, much like the rest of the country of
Sweden. This diversity would, to some extent, contribute to ensuring that
both the GP sample and the outpatient sample are representative of the Swe-
dish population.
Anonymous participation was chosen in all three samples to extract truth-
ful and honest answers as well as a high participation rate. This approach
unfortunately prevented attrition analyses. Concerning dropouts, ADHD-
related symptoms in combination with reading difficulties might be more
frequent in non-participants. Previous studies on attrition that examined oth-
er psychiatric disorders have reported a number practical issues [160], where
low income, low education level and a previous psychiatric diagnosis were
associated with lower participation rates [18]. From our own experiences in
the follow-up study, it cannot be ruled out that non-participants in paper I
may have had an even higher prevalence of ADHD symptomatology than the
patients included in the study.
Furthermore, it is important to stress that symptom reporting in paper I
did not include clinical evaluations, but describes patient self-reports of
symptomatology in accordance with ADHD. Self-report questionnaires, in
general, are easily administered and time-saving, but they have some inher-
ent issues that must be considered. Apart from various degrees of validity

41
and reliability of each instrument, systematic biases can be pronounced [36].
Another point to consider concerns issues such as who; the patient of next of
kin, in reality answered the questionnaires, how the questionnaires were
administered, and the fact that respondents used the questionnaires to freely
comment and communicate on symptom patterns and experiences. At the
time of Study I there were no validated screening instruments for current
symptoms of adult ADHD available for a Swedish population. The ADHD
questionnaire used by us in this study was constructed and based solely on
the DSM-IV diagnostic criteria but shared the disadvantage of not being
validated. The scale questions were, however, similar or almost identical to
the official WHO rating scale to evaluate adult ADHD, ASRS, that was pub-
lished later [82].
To optimise the length of the questionnaire, it only focused on present
symptoms of ADHD. Regarding childhood history, we chose to use a di-
chotomous Yes/No approach because we feared that an almost duplicated
questionnaire which also included questions on lifetime problems would
markedly increase attrition. The mixed sex samples of the GP and outpa-
tients were only asked about childhood hyperactivity as there was an initial
focus on the combined and hyperactive/impulsive subtypes according to
DSM-IV, which are equivalent to the HKD of ICD-10. In the all-female
prison inmate sample, a question on childhood inattention was supplement-
ed. It is regrettable that this was not done in the first two samples. To distin-
guish between shortcomings attributable to symptoms of ADHD and other
reasons for reduced functioning, the participants were asked to report about
difficulties and suffering exclusively caused by current ADHD symptoms.
For this purpose, we decided on a scale with a construction similar to the
GAF. Self-rated GAF scores have been shown to constitute a valid and relia-
ble instrument [114]. Outpatients and prison inmates with known ongoing
substance abuse, a feature which is recognised as being associated with high
prevalence rates of ADHD and related problems, were not included in the
present surveys and may have biased the observed prevalence rates. The
advantage of that decision was, however, that we could demonstrate that
ADHD and related problems among non-addicts and patients in abstinence
of drugs are common and need to be recognised. On the other hand, there
were no questions on SUD in any of the questionnaires, why it is possible
anyway that a number of unidentified patients with SUD were included.
Paper II is a descriptive study of a prospective sample of patients evaluat-
ed and diagnosed with ADHD as adults. The study design was based on in-
formation that could be extracted from the patient files. Selection bias may
have been introduced into the sample because the majority of the patients
were referred and had a previous history of psychiatric treatment, although
not diagnosed with ADHD. Still, by using consecutive inclusion, we hoped
to reduce the risk of further selection bias. All evaluations were performed in
the same outpatient clinic with a multi-professional neuropsychiatric team. A

42
reliable process to diagnose ADHD in adulthood in a scientific way was
complicated as there was no validated semi-structured interview available
for adults in Swedish in 2002 when the evaluations started. CAADID was
published in English in 2001 but was, and is, restricted to copyright law and
not available in Swedish. We chose to do the evaluation of adult ADHD
symptoms using a self-constructed and semi-structured interview according
to DSM-IV, which was similar to the questionnaire distributed in the previ-
ous studies. Because this interview had not previously been validated, diag-
nostic validity was ensured through interviews being videotaped and inde-
pendently and blindly rated by a second senior psychiatrist with long experi-
ence in clinical encounters with patients suffering from neuropsychiatric
disorders. Inter-rater reliability was excellent for individual ADHD items, as
well as the final diagnostic outcome (paper II).
Another potential problem concerns the possibility for patient recall bias,
particularly regarding retrospective assessment of lifetime axis I disorders.
This problem has been noticed in a previous study where a birth cohort was
followed from age 18 to 32 years, and where the prevalence of lifetime psy-
chiatric disorders almost doubled when assessed prospectively as compared
to when assessed retrospectively [102].
Another limitation was the lack of a specific assessment of overall func-
tioning (e.g. GAF) in the patient records. However, complete and extensive
demographic data were collected and analysed, indicating, at least indirectly,
some measure of overall social functioning. Only 34% of the participants
were working full or part time, which is lower than figures reported from
previous comorbidity studies [83; 132], where 61% and 72% respectively
were working.
Best estimate diagnoses were established by members of the professional
team who independently participated in the evaluation process. In general,
we consider the best estimate diagnostic process for all the participating
patients to provide reasonable evidence of functional impairment in accord-
ance with ADHD. Psychiatric comorbidity was investigated by SCID-I and
SCID-II interviews to secure validity of axis I and axis II disorders.
Paper III and IV included a follow-up of the sample described in paper II.
The follow-up was based across a broad spectrum of instruments. Being a
long-term follow-up study with a mean time of six years (range up to 11
years), the study design was subject to several practical and important issues.
Previously documented everyday difficulties which were presented by pa-
tients with ADHD were challenges to be considered in order to maximise
participation rate. The protocol was therefore designed to optimise data col-
lection. In addition, we assumed that a potential part of the participants
would have moved far away from the original catchment area and maybe
even abroad. We therefore decided on a two-step study design with initial
self-questionnaires to be followed by an interview and validation of the an-
swers given to the items in the questionnaires. In this way, missing infor-

43
mation, obvious misunderstandings and other potential problems in the first
step of the protocol could be resolved in the protocol’s second step. This
approach proved to be successful as it became clear that a number of partici-
pants needed assistance (e.g., telephone, a personal visit at the clinic or a
home visit) to complete the questionnaires. Another issue is that baseline
ADHD symptoms had been obtained using a semi-structured interview;
while the symptoms at follow up were obtained using a self-report question-
naire, although with the same questions. Here it must be considered that
adults with ADHD have been found to be their best informants regarding
their symptoms but tend to underreport the severity of their symptoms [86].
Adding informant reports from partners and significant others, as in the di-
agnostic process, would probably had accessed additional information.
To assess function apart from GAF, we choose to use the SDS because it
had recently been psychometrically evaluated in adult ADHD. This scale is a
comprehensive but short instrument measuring everyday functioning do-
mains applicable to any psychiatric as well as somatic disorder. The Weiss
Functional Impairment Rating Scale (WFIRS) [144] would probably have
yielded more detailed and specific information on impairment related to
ADHD but was omitted because our protocol already contained a large num-
ber of questionnaires.
We choose the ERQ-5D to assess HRQoL. EQ-5D is short and easy to
administer. We also choose AUDIT and DUDIT instruments for screening of
alcohol and substance abuse, respectively. These are regarded as the gold
standard for screening, and have been used for this purpose in numerous
studies.
The fact that there was no information on overall or cognitive functioning
at baseline might have influenced and biased the comparison in the different
groups at follow-up. Information from a parallel non-pharmacological treat-
ment and support arm, as well as an evaluation of psychiatric comorbidity at
follow-up would have contributed to more precise analyses. Obviously, an
RCT with a placebo treated control group would have been the most optimal
design to collect comparison data on long-term outcome. However, such a
design would be both practically impossible over a period of up to 11 years
and ethically extremely questionable. Another option, such as that used in
follow-up studies of the original MTA study, would be to attach a normal
matched control group to compare outcome [139]. This would have been a
more elaborate and extensive study design to demonstrate long-term out-
come of adult ADHD and would have facilitated interpretation of the data
obtained and demonstrated in papers III and IV.
Finally, no formal calculation of statistical power was performed before
designing any of the studies. In paper I, we assumed that a sample of 1000
patients in the GP would be sufficient based on a previously reported preva-
lence rate of ADHD in children of 3-7%. In the outpatient sample, we hy-
pothesised a potentially higher prevalence rate and thus restricted the num-

44
ber of distributed questionnaires to 400. The female inmates constituted all
high-security internees at the only prison available for investigation at the
time. Patients in paper II, III and IV were those that were consecutively
evaluated and diagnosed over a specific period. Nevertheless, it is highly
probable that a higher number of participants would have facilitated detailed
sub-analyses and identification of potential outcome predictors in the regres-
sion analyses in paper III and IV.

Ethical considerations
Because anonymous screening of psychiatric disorders can evoke the neces-
sity for psychiatric evaluation, all participants in paper I in the GP sample
and within outpatient psychiatry were invited to contact a specialised unit for
questions and assistance. The female inmates had access to health care facili-
ties within the prison for the same purpose. In preparation for paper II, it was
clearly stated in the application to the Ethics Committee that research on
data from patient files is an ethically delicate matter and must be carefully
considered based on the potential scientific outcome. To secure anonymity,
all study data were decoded from individual patient information before anal-
ysis. In paper III and IV, the principal ethical issue concerns evoking poten-
tial memories and emotional reactions when addressing and contacting pa-
tients who have undergone diagnostic procedures and long periods of treat-
ment. Generally, most participants expressed gratitude for being contacted.
Some participants conveyed a need for renewed medical contact and treat-
ment, and accordingly, were assisted with referrals to psychiatric outpatient
clinics in their residential area. Some of the participants had a need to ex-
press opinions and share their experiences with the interviewer since being
diagnosed with ADHD in adulthood. As many participants saw themselves
as being among the first individuals in the country to be diagnosed with
ADHD as adults, it was felt that many of the participants perceived them-
selves as "pioneers", a fact that probably contributed to the high participation
rate.

General discussion and clinical implications

The principal aim of this thesis was to expand our understanding of ADHD
by investigating prevalence, psychiatric comorbidity and long-term outcome
and safety of pharmacological intervention in persons diagnosed with
ADHD as adults.

45
Prevalence
Our data confirm the high prevalence of ADHD-related symptoms associat-
ed with increased difficulties and suffering, lower general functioning and
increased frequencies of reading and spelling difficulties in outpatient psy-
chiatry, regardless of sex. These findings were also observed in female pris-
on inmates. No major sex differences were identified in outpatient psychiatry
versus the GP. The high prevalence of reading difficulties in those with
ADHD symptoms was not unexpected and concurs with the ESSENCE con-
cept. Half of the female prison inmates reported symptoms of ADHD in
childhood or as adults, and approximately 30 % reported inattention in
childhood and symptoms of ADHD as adults. This is similar to the previous-
ly mentioned meta-analysis with an average ADHD prevalence rate of 25.5
% in prison inmates [163]. High prevalence rates of ADHD in both patients
and inmates prompt awareness of potential ADHD-related problems. Such
awareness should be beneficial in attaining optimal treatment, care and reha-
bilitation in patients who are in contact with outpatient psychiatry as well as
prison establishments [62; 106]. Currently, the awareness of ADHD as an
important factor for outcome in correctional treatment has increased substan-
tially. In addition, treating inmates diagnosed with ADHD has demonstrated
successful long-term outcome [63]. Finally, pharmacological treatment of
patients with ADHD has been linked to lower criminality rates in both men
and women compared with periods when patients are off medication [97].

Comorbidity
In our clinical sample of patients diagnosed with ADHD in adulthood, 9 out
of 10 patients had experienced at least one lifetime axis I disorder, and usu-
ally in the form of a mood disorder. This supports a published observation of
a genetic correlation of ADHD and bipolar disorder [147]. Thus, identifying
and treating potential coexisting mood disorders is an important part of adult
ADHD, especially as register data suggest that stimulant medication is relat-
ed to a decreased risk of suicide [35]. Our data reveal few sex differences for
an axis I disorder but confirm the results of previous studies in which mood
and eating disorders were more frequent in females [117; 119] and SUD
more common in males [20; 67; 117]. Accordingly, a recent study related to
the ESSENCE concept performed on adults with ADHD, ASD, or both con-
firmed that almost one fifth of the participants reported severely or moder-
ately disturbed eating behaviour [79].
The relatively low prevalence of ongoing substance use in our material
might be explained by compulsory drug screening and the request for drug
abstinence during the evaluation period. Although ADHD has been demon-
strated to be overrepresented in patients with SUD, a prospective study of
twins has linked the risk of alcohol problems during adolescence to external-

46
ising behaviour rather than to core ADHD symptoms [113]. Moreover, pro-
posed concerns of evoking SUD or provoking relapse of previous SUD by
treating ADHD with classified drugs has not been confirmed [33; 112].
In our sample, ASD and Tourette’s syndrome greatly exceeded the preva-
lence rates in the GP [16; 85]. Conversely, there is an increased risk for
ADHD in patients with ASD and their relatives [57] suggesting a genetic
overlap of the two disorders. This finding underscores the need to consider
coexisting symptoms of ASD and tics when treating patients diagnosed with
ADHD as adults.
Nearly half of the patients confirmed the specific criteria for one or more
personality disorders but only one tenth was considered to fulfil a best esti-
mate diagnosis. The low prevalence of personality disorders in the present
study is probably explained by the restrictive methodology applied, separat-
ing specific personality criteria from a best estimate diagnosis on axis II. The
diagnostic overlap between personality disorder criteria and ADHD has not
been sufficiently examined, especially in relation to cluster B disorders such
as ASPD and BPD. Borderline development in ADHD has been reported to
be related to certain environmental factors such as emotional abuse in child-
hood [111]. To elucidate and explain the variable extent of emotional lability
in ADHD, a gradient model of "cool" and "hot" executive functions with
different neuroanatomical correlations has been proposed [109]. The former
would be correlated to classical ADHD while the latter would be tied to anti-
social and borderline functioning. In parallel, non-emotional and emotional
processing would involve the basal ganglia with modulatory effects of the
dopamine system. In all, this dual concept would be a model to stepwise
integrate ADHD with emotional lability, ASPD and BPD.

The adult ADHD concept

Recently, data from a small number of studies have raised the question of
whether onset of ADHD could occur first in adulthood, an issue which
would further complicate the diagnostic procedure insofar as symptom re-
quirement before the age of 12 is still requested according to DSM-5 [4; 32;
49; 103]. Further studies are required to elucidate factors that influence age
of symptom onset and phenotypic expression of ADHD. Genetic research is
intense and several candidate genes have been proposed but still with limited
success in detecting common genetic variants for the diagnostic phenotype
of ADHD [26]. Accordingly, viewing ADHD as a dimensional rather than as
a categorical construct, together with increases in study sample sizes, have
been proposed for future genetic research [69]. In addition, to identify spe-
cific genetic correlations and biological markers predicting pharmacological
treatment response would be important to clinical practise. Polymorphism of
catechol-O-methyltransferase (COMT) has been linked to treatment response
to methylphenidate in children [81]. In adults, polymorphism in the gene

47
SLC6A3 has been reported to be associated to methylphenidate response
[86].

Long-term outcome
The principal outcome of the long-term follow-up is that one third of the
patients first diagnosed with ADHD as adults went into remission during a
mean observation period of six years. This result is consistent with findings
of a recently published seven-year longitudinal study of adults with ADHD
[78]. After being taken off medication and re-evaluated, one third of the
latter patients did not maintain ADHD criteria and 12% were in full remis-
sion. Another important finding in this thesis is that, despite a high percent-
age of psychiatric comorbidity at baseline, adult ADHD in general seems to
have a favourable long-term functional outcome as judged from the GAF
scores at follow-up, which were similar to scores reported from the GP in
paper I. Furthermore, the domain means on the SDS were below the cut-off
for significant functional impairment when assessed at follow-up, and inde-
pendent of ADHD remission. The EQ-5D index, a health status index related
to HRQoL, was similar to population sample scores [30] in patients in remis-
sion, but lower in those not. This finding must be given an interpretation
with caution, however, because substantial variability was noted between
individuals for these measures, indicating that some of the patients still per-
ceived substantial impairment in disability and HRQoL. Altogether, the re-
sults reflect the complexity of adult ADHD with all its nuances beyond core
symptomatology when evaluating aspects of treatment and treatment out-
come. A somewhat unexpected finding was that alcohol consumption (as
measured by AUDIT) in patients with ADHD was similar to that in the GP.
On the other hand, a DUDIT score which reflected any use of drugs was
reported in 14% overall, and in 17% of non-remitters, which is higher than
the 3% in the Swedish GP [19].
A noteworthy finding was that the remission rate and the ADHD scores
were similar in patients currently undergoing treatment with central stimu-
lants and in those not treated. Our data add to the present literature with
presently no accepted evidence based on longitudinal assessments, suggest-
ing that there are long-term benefits from medication in individuals first
diagnosed with ADHD as adults [71] Moreover, a six-year follow-up study
of participants with ADHD combined type in late adolescence and early
adulthood found no effect of pharmacological treatment on either ADHD
symptom severity or overall functioning despite an increasing rate of phar-
macological treatment over time [148]. In addition to that, time on medica-
tion did not predict persistence of ADHD in the previously mentioned study
[71]. This finding is, however, in contrast with those from another recent
study in adults with ADHD [95] which reported that 56% of the patients
currently on medication were below a cut-off for ADHD after a mean obser-

48
vation time of 4.5 years compared with 34% of those without ongoing medi-
cation, and also a better outcome on all measures in patients treated for two
years or more compared with those given shorter pharmacological treatment.
Although patients who were currently on medication did not report better
ADHD or SDS scores, they did report higher improvement as measured by
the CGI-I scale. This result may suggest that there are medication-related
improvements beyond core symptomatology of inattention and hyperactivi-
ty/impulsivity. It is also possible that the patients’ ratings contain a placebo-
related mechanism in the compliant patients as suggested and discussed in
reference [73]. There may also be differences in patient characteristics that
are not discerned, and also a variable amount and quality of psychoeduca-
tional measures and information that may have affected the tendency to dis-
continue medication. Psychiatric comorbidity at follow-up and data on the
participants’ cognitive level and profile, which were not assessed by us, are
also factors that could have influenced coping strategies and adherence to
medication.
It is particularly noteworthy that no baseline factors predicted outcome
six years after the patients were first diagnosed with ADHD in adulthood.
This observation is discordant with studies showing that psychiatric comor-
bidity at baseline is a negative prognostic factor [95; 78]. An explanation
could be that comorbidities are registered and diagnosed differently in dif-
ferent studies. Another issue can be that the primary outcome measure dif-
fered between studies. It has been recommended that clinical research in
ADHD should use remission as the primary outcome [133], which also was
used in this study. Our paper defined remission as not fulfilling any ADHD
subtype and a GAF value of ≥70 during the past year. Nevertheless, we also
calculated persistence of symptoms as performed and defined by Biederman
et al. [24] in the form of full or subthreshold ADHD based on the DSM-IV
diagnostic criteria, or failure to attain functional remission (GAF score ≤60).
Irrespective of how outcome was assessed there was no significant differ-
ence between patients who were on current medication and those who were
not (data not shown).

Pharmacological treatment
Half of the medicated patients were still on medication at follow-up, which
is consistent with previous data [17]. Most of these patients perceived a pro-
nounced or moderate effect on their ADHD, with a mean stimulant dosage
within recommended limits. Adherence to treatment was reported excellent
in this group, both with respect to dosage and to regularity of intake. Self-
reported adverse effects during treatment demonstrated a broad spectrum of
symptoms of the sort reported in previous studies: the five most common
complaints were decreased appetite, dry mouth, anxiousness, increased pulse
frequency and decreased sexual desire [76; 121]. The results indicate the

49
importance of a wide and systematic evaluation of adverse effects when
treating adults with ADHD. Most importantly, our data do not indicate that
there is tolerance or a need for increased dosage over time to the preserve
treatment effect, but rather the contrary. The reason for this could only be
speculative, but possibly long-term medication creates "a window" that ena-
bles and increases the possibility to profit by other non-medical interventions
and treatments. Further research will likely increase our knowledge of fac-
tors influencing the dose required for clinical effect over time. Nevertheless,
this thesis confirms that the long-term pharmacological treatment of patients
diagnosed with ADHD in adulthood, and who present a high degree of psy-
chiatric comorbidity at the time of the diagnostic evaluation, is safe and tol-
erable after a mean period of six years. Being based on a clinical sample
with no exclusion criteria attached, the present results seem representative of
a typical patient sample from an adult outpatient psychiatric clinic.
The other half of the participating patients had discontinued treatment at
follow-up. This observation is similar to observations made in other long-
term studies [17; 95]. We noticed a mean treatment time of two years in this
group, suggesting that there had been sufficient time to evaluate treatment
and to adjust dosage of the pharmaceuticals used to be in accordance with
dosage used in everyday clinical practice. It also raises the question of
whether the efficacy of treatment diminishes over time, or if, once again, the
non-pharmacological interventions that run parallel with medication, affects
the perceived need for pharmacological support. Furthermore, lack of effect
was the most common cause for discontinuation. Only one patient discontin-
ued methylphenidate and one amphetamine because they saw no need for
further medication.
Notably, none of the patients who had reported elevated mood or hypo-
mania had been diagnosed with a bipolar disorder at baseline, whereas those
two who had been diagnosed with a bipolar disorder at baseline discontinued
treatment because of depressed mood. This finding agrees with results of a
report suggesting that comorbidity of bipolar disorders and ADHD is more
frequently linked to depressive episodes than to manic episodes [125]. The
necessity of treating patients who present with comorbid bipolar disorder
and ADHD with mood stabilisers before stimulants has recently been
demonstrated [152]. It can also be discussed whether some patients with
SUD were offered optimal treatment in that data on patients with ADHD and
SUD indicate that dosage in the higher range may increase adherence to
treatment with methylphenidate [127].
Another important observation is that nearly one tenth of the participants
had discontinued treatment because of the perceived inability to stay in con-
tact with the prescribing physician. It cannot be ruled out that a change in the
panorama of comorbidity over the six-year period may have influenced ad-
herence to treatment as well as the reported adverse effects. Furthermore,
differences in non-pharmacological treatment or supporting interventions

50
since baseline are potential factors that could have biased the results. Con-
versely, combined data on pharmacological and non-pharmacological treat-
ment have demonstrated medication to be superior in outcome (at least for
one year) compared with supportive interventions and psychological treat-
ment [110].
Finally, patients’ own perception was that of an increased QoL, an in-
creased level of functioning and better understanding from the surroundings
in those with ongoing medication. This observation must not be underesti-
mated as an important feature of adult ADHD is the general effect of the
disorder on both the patients and their family members.

Future aspects
ADHD in adulthood may be a more complex diagnostic entity to evaluate
and treat than in childhood as it is associated with a wider spectrum of
comorbidity and also with secondary consequences of SUD and somatic
conditions.
The role of epigenetics in ADHD is still relatively unknown but has slow-
ly emerged over the past years. Taking this into account, ADHD in adult-
hood often displays a heterogeneous clinical presentation with aspects to
consider that go beyond the present categorical diagnostic system and core
symptomatology of inattention and hyperactivity/impulsivity. Reports on
possible adult onset of ADHD further complicates this issue. Future clinical
studies of ADHD in adulthood therefore need a wide spectrum of approaches
concerning genetics, diagnostics, treatment, and psychiatric as well as so-
matic comorbidity. Not to mention the link between cognitive impairment
and the clinical presentation and treatment outcome.
In the present study four persons had died of unnatural causes since diag-
nosed with ADHD, which is in line with the perspective that ADHD is relat-
ed to suicidal behaviour or other adverse health outcomes [105]. Key issues
to investigate are to further assess whether such an association is the effect
of comorbid psychiatric conditions, e.g. mood disorders and SUD, and if so,
to what extent a comorbid ADHD only acts as a risk amplifier.
A key issue is that the characteristics of ADHD as such contain elements
that affect adherence to structured treatment protocols negatively. Any
treatment protocol that only reaches half of those in need is in vain for a
substantial subgroup of patients. Research on how to organize care, and how
to effectively reach patients with psychoeducational interventions and coach-
ing in order to improve adherence to protocols is highly desired [107] The
rapid technological development allows for new approaches in such psy-
choeducational interventions and coaching. To date, some success has e.g.
been reported for Internet-based interventions and coaching [151; 131].

51
Conclusions

• There is a high prevalence of ADHD-related symptoms associated with

increased difficulties and suffering, lower general functioning and in-
creased frequencies of reading and spelling difficulties in psychiatric
outpatients, regardless of sex. These findings were also observed in fe-
male prison inmates.

• There was a high prevalence of psychiatric comorbidity in both women

and men diagnosed with ADHD as adults, with women more vulnerable
to mood disorders and men more at risk for substance-use disorders.

• Patients diagnosed with ADHD as adults report diagnostic remission in

about 3 of 10 cases after a mean period of six years, irrespective of on-
going pharmacological treatment at follow-up, and despite a high per-
centage of psychiatric comorbidity at baseline.

• Long-term pharmacological treatment (mainly with stimulants) of adults

with ADHD is safe with generally mild and tolerable adverse effects.
The discontinuation rate of about 50%, with almost a third of which due
to perceived lack of effect of methylphenidate, suggests that close sur-
veillance and a strategy to change drugs, drug combinations and dosages
should be assessed as a way to increase retention to treatment. Long-
term data do not indicate tolerance or a need for increased dosage over
time to preserve the treatment effect, but rather the contrary.

52
Acknowledgements

I would like to express my gratitude to all those who assisted me in the prac-
tical arrangements to make the respective studies, and finally the thesis, pos-
sible. I am particularly grateful to:

Lisa Ekselius, professor of psychiatry and my main supervisor, who "inherit-

ed" me as a PhD-student. I am most grateful to her for accepting the role as
my main supervisor. Without her this thesis would not have been possible.
She has always been available, encouraging, supporting and demanding in
the best possible way. I have especially appreciated her ability to swiftly
observe and focus on essential matters in this project which on many occa-
sions prevented me from losing track. Apart from a broad experience of clin-
ical psychiatry and research in general, her keen interest in and knowledge of
personality disorders, have been particularly stimulating in our discussions
during this project.

Tommy Lewander, associate professor of psychiatry, my co-supervisor, for

his accuracy in discussions, analyses and reviews of data, papers and manu-
scripts.

Lena Malmlöv Karlsson, RN and clinical collaborator, with admiration and

gratefulness for invaluable contribution in performing clinical interviews and
for impeccable logistics.

Eva Lindström, associate professor of psychiatry, my initial main supervisor,

for support and with admiration of her brightness in clinical psychiatric
evaluations.

Kerstin (Chris) Bingefors, PhD, lecturer, my co-supervisor, for her valuable

support on statistics and reviews of data.

Frits-Axel Wiesel, late professor of psychiatry and my previous senior su-

pervisor, who was the first to “inherit me” as a PhD-student and who gave
me generous support during a short period of time.

53
Ann-Mari Ahl, social worker and clinical collaborator. I am admired by ac-
curate clinical work and relevant, distinct and systematic documentation in
the patient files.

Hans Arinell, BA, for excellent statistical support.

Caisa Öster, RN, associate professor and lecturer and Josefin Bäckström,
RN, PhD and lecturer, for their valuable support with various practical and
theoretical issues including encouraging discussions at coffee breaks.

Ann-Charlotte Åslund, secretary at Uppsala University Hospital Department

of Psychiatry, together with Lottie Söder, Lena Bohlin and Ann-Charlotte
Fält, secretaries at the Department of Neuroscience, for never ending will-
ingness to assist with various practical issues.

Ing-Marie Wieselgren, Åsa Hagberg, Björn Milesson Fors, Gunilla

Svedström and Tarja-Leena Kirvesniemi, my clinical superiors over the
years at Uppsala University Hospital, for encouragement of clinical reseach
and priorites of time for research.

Ulf Durling, legendary criminal author and senior consultant in psychiatry,

for persuading me to become a psychiatrist. You are the still my role model
in everyday clinical practise.

And finally, to my mother Elisabeth and brother Björn. I am proud of you

both.

This project has been supported by grants from the Uppsala County Council,
The Märta and Nicke Nasvell Foundation and The Bror Gadelius Founda-
tion.

54
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