1. health and fitness
2. disorders
3. mental disorder
4. a.d.d.

Meeting Report
Changing paradigms in the treatment
of ADHD: adults are important too
This report was commissioned following a promotional Eli Lilly meeting on 25–27 September 2013 and
represents a summary of the data presented
Prescribing information appears on pages 11 and 12
ADHD in adults
Introduction
A
tomoxetine was recently approved for the treatment of adults with attention deficit hyperactivity
disorder (ADHD). This is an important milestone as,
outside of Germany, it is currently the only licensed
medication for ADHD treatment initiation in adults.
Welcoming adult psychiatrists and other mental health
specialists from 13 European countries to London
for the Lilly-sponsored meeting, Changing paradigms
in the treatment of ADHD: adults are important too,
Professor David Nutt (Professor of Neuropsychopharmacology, Imperial College London) said we are
now seeing a new approach to treatment after years
of struggling against negative attitudes, misdiagnosis
and underinvestment.
Speakers
Professor David Nutt, Professor of Neuropsychopharmacology, Imperial College London
Professor Philip Asherson, Professor of Clinical and Molecular Psychiatry, Institute of Psychiatry and Consultant
Psychiatrist, Adult ADHD Clinic, Maudsley Hospital, London
Professor István Bitter, Chair, Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest
Dr James Kustow, Consultant Psychiatrist, Barnet, Enfield and Haringey Mental Health Trust, London
Dr Chris Bushe, Senior Medical Advisor, Eli Lilly & Co
Professor David Heal, Visiting Professor in Pharmacy and Pharmacology, University of Bath and Executive Director,
RenaSci Ltd
Medical writer in attendance: Steve Chaplin
2
ADHD in adults
Changing paradigms in the
treatment of ADHD: adults
are important too
Diagnosing ADHD: the
European perspective
Prevalence per 1000 patients
ADHD in adults is a common
disorder with clearly negative
outcomes – but it is treatable,
said Professor Philip Asherson
(Professor of Clinical and
Molecular Psychi atr y, Institute
of Psychiatr y and Con sultant
Psychiatrist, Adult ADHD Clinic,
Maudsley Hospital, London). The
main clinical issues are recognising
the impact that ADHD has on adult
mental health and discerning the
degree of impairment, a prerequisite for treatment.
Estimates of the prevalence
of ADHD in adults range from
2.5–4.4%.1–3 Around 15% of children with ADHD continue to
meet the full diagnostic criteria at
age 25 and a further 50% are in
partial remission with continued
impairments from the symptoms
as adults. 4 ADHD symptoms
persist in many young adults,
Professor Asherson said. The
nature of the disorder, however,
can change with age – while inattentiveness remains unchanged
or becomes more impairing
in adult life, hyperactivity and
impulsivity tend to become less
severe.5 Nevertheless, Professor
Asherson pointed out that some
of the most impaired adults with
ADHD continue to have high levels of impulsivity, restlessness and
emotional instability, sometimes
associated with criminal behaviour or substance use disorders.
14
12
2006 12.77
10
2005
8
2004
6
4
2
9.08
2003
5.64
2002
2001
2000
1999
3.18
1.92
1.07
0.64
0
15
16
17
18
Age (years)
19
20
21
Figure 1. Prevalence of prescribing methylphenidate, dexamphetamine, and
atomoxetine to male patients aged 15–21 years, 1999–2006.6 Reproduced with
permission from the Royal College of Psychiatrists
The most typical problems for
adults with ADHD include difficulty with time management and
organisation, forgetfulness and
difficulty focusing on and completing tasks that interfere with
educational and occupational
activities. Despite these continued
difficulties, the proportion of adolescents who remain in treatment
as adults is far below expected
levels and, although prescribing
rates have been increasing in children, they remain low after age 18
(Figure 1).6
ADHD in adults is further complicated by the prevalence of comorbidities. The risk of mood disorders
(mainly depression but also bipolar
disorder) is increased by a factor of
5 in adults with ADHD, they have a
3.7-fold increased risk of anxiety
disorders and a 3-fold increased risk
of substance use disorder.2 Even in
the absence of comorbidities, adults
with ADHD have a high prevalence
of subthreshold psychopathology
including forgetfulness, fatigue,
sleep problems, irritability and
worry.7 It is now recognised that
ADHD and its comorbidities cause
significant impairment in many
aspects of life.8,9 This can complicate the presentation, Professor
Asherson said, and ADHD is often
misdiagnosed or unrecognised in
adults, often because of the presence of emotional dysregulation or
mood instability.
To complicate matters further,
sceptical and negative attitudes
towards ADHD by some healthcare professionals still obstruct
the diagnosis and access to
3
ADHD in adults
Key points
l The main clinical issues are
recognising ADHD in adults,
understanding its impact on
adult mental health and discerning ADHD-related impairment.
l Most children with ADHD will
continue to have some symptoms
and functional impairment as
adults. In a significant subset this
is severe.
l Adults with ADHD are at high
risk of mood disorders and
substance misuse.
l Negative attitudes and mis understanding of the needs of
adult ADHD are common.
Diagnosing ADHD:
the tools and the
challenges
The number of adults with
ADHD who are diagnosed will
increase with the introduction of
the DSM-V diagnostic criteria,
said Professor István Bitter
(Chair, Department of Psychiatry
and Psychotherapy, Semmelweis
University, Budapest). Fewer
symptoms are now required to
meet the diagnosis (only five
symptoms in either the inattentive or hyperactive-impulsive
domain are required at age ≥17)
4
and the age of onset for ‘noticeable inattentive or hyperactiveimpulsive symptoms’ has now
been raised from 7 to 12 years.
Additionally, autism spectrum
disorder is no longer an exclusion
criterion.11 That said, the DSM-V
still has shortcomings. Specifi cally, like the DSM-IV, it focuses
on core symptoms (inattention,
overactivity, impulsiveness) without including the associated
problems with which the patient
is more likely to present and
be impacted, eg mood lability,
many forms of executive dys functioning, stubbornness, failing
to reach potential and unstable
relationships.12,13
To further complicate matters,
a number of clinical issues remain
unresolved. Specifically, it is
dif ficult to differentiate between
ADHD and a number of the
comorbidities with which these
patients so commonly suffer, and
there is uncertainty about treating
people with ADHD who are ‘highly
functioning’ despite (or because
of) their disruptive behaviour.
Not surprisingly, adults may be
known to health services but not
diagnosed with ADHD, Professor
Bitter continued. In one study, the
prevalence of undiagnosed ADHD
among adults attending psychiatric
clinics in the UK was 22%.14 A
Hungarian study (n=161) in primary care further showed that,
with age, women account for an
increasing proportion of patients:
the male:female ratio falls from 3:1
to 1:1 after age 40 (Figure 2).15
Widely used instruments to
assist in diagnosis include the
Conners Adult ADHD Diagnostic
Interview (CAADID),16 mainly in
research settings, and the Diagnostic Interview for ADHD in
Adults (DIVA),17 which is available
in many European languages.
DIVA is available free of charge at
www.divacenter.eu. Of the available
screening tools, symptom checklists are the easiest to use. The
World Health Organization’s Adult
ADHD Self-Report Scale (ASRS)
Screener18 is quick and simple and,
although false positives can occur,
false negatives are rare.
Key points
l The number of adults with
ADHD who are diagnosed will
increase with the introduction of
the DSM-V diagnostic criteria.
l The DSM-V focuses on core
symptoms without including the
4
Male
Female
3
Prevalence (%)
services,10 although this is starting
to improve. Unfortunately, due to
the lifelong impairments associated with ADHD, a diagnosis late
in life can lead to considerable
distress and leave adults with a
chronic sense of failure.
Clearly, adults with ADHD
have substantial unmet needs
and there is a wide gap between
clinical practice and policy, but
Professor Asherson concluded on
a note of optimism, expressing his
strong belief that ser vices are
changing for the better.
2
1
0
≤40 years
>40 years
Figure 2. The proportion of women among adults with ADHD increases after
age 40.15 Reproduced with permission from Springer
ADHD in adults
associated problems with which
patients most often present.
l There is still uncertainty about
treating people with ADHD
who are ‘highly functioning’.
l The Diagnostic Interview for
ADHD in Adults (DIVA) and the
World Health Organization’s
Adult ADHD Self-Report Scale
(ASRS) Screener are available in
many European languages and
are free of charge.
Treatment strategies
for adult ADHD: new
perspectives
Services for adults with ADHD are
still limited and most focus on
assessment, diagnosis and pharmacological management, said
Dr James Kustow (Consultant
Psychiatrist, Barnet, Enfield and
Haringey Mental Health Trust,
Lon don). He described a new
approach of titration-aligned
psycho-education (TAP) that
can be integrated into current
service provision.
After diagnosis, follow-up
consultations with patients tend
to focus on dose titration and a
review of medication response
and adverse effects. In contrast,
TAP entails making time during
these appointments to introduce
a structured psycho-educational
approach (Table 1).19
Clinicians tend to think of
deficits and weaknesses and try
to reduce problems, Dr Kustow
noted, with the result that many
adults with ADHD do not think
they have any strengths. Instead,
they can be encouraged to develop
effective strategies to deal with
ADHD and aim to master the
things they are good at, leaving the
things they are not good at to others
or identifying other work-around
strategies appropriate for them.
Adjustment to the
diagnosis
Education about
Empowerment and
the disorder and
engagement
treatment approaches
Lifestyle modification
Help normalise the
emotional reaction
(and adjustment
stages)
Simple key messages
about the disorder
and its management
Promotion of adaptive
lifestyle changes
Help address
unhelpful schemas
and beliefs and
allow reframing
Identification of
strengths, skills and
talents (emphasising
positives)
Introduction of targeted
behavioural strategies
Building the
relationship; optimising
engagement and
adherence
Table 1. Domains of titration-aligned psycho-education
Key points
l TAP is a new approach that
integrates psycho-education
into the structure of follow-up
appointments for patients with
ADHD.
l TAP covers adjustment to the
diagnosis, education, empowerment and engagement, and
lifestyle modification.
Atomoxetine: efficacy
and safety trial data
from adult population
Atomoxetine is the only medication approved across most of
Europe for the initiation of treatment for ADHD in adults (except
Germany where Medikinet® is also
licensed). It has been available in
some countries since 2002, where
11 years of real-world prescribing
to over three million adult ADHD
patients complement a clinical
trial programme involving 4829
patients, said Dr Chris Bushe
(Senior Medical Advisor, Eli Lilly &
Co). The clinical trial programme
provided robust data to demonstrate that atomoxetine is the only
ADHD medication licensed in the
EU for which not only efficacy has
been demonstrated but also a
maintenance of that response. This
is important for patients to know.
The main clinical trial
programme
Most adults in the clinical trial programme (mean age 35) had severe
ADHD. As is usual with registration
trials, inclusion criteria were highly
selective, but Dr Bushe highlighted
evidence from studies more representative of daily clinical practice
where comorbidities were not
totally excluded.20–22 It was further
emphasised that the clinical
response in all studies was consistent
with an early onset of some efficacy
at one to two weeks, with incremental improvement over time
evidenced throughout all studies.
In one 12-week, placebocontrolled trial in 445 young adults
(age 18–30), atomoxetine significantly improved symptoms compared with placebo (p<0.001). The
difference was statistically significant from two weeks, with continued improvement throughout the
study and a final effect size of 0.40
(Figure 3).20
None of the long-term studies
have reported any definitive
plateau of effect with atomoxetine
– it is not clear when maximal
efficacy is reached, Dr Bushe said.
Patients continue to improve with
ongoing treatment with atomoxetine,23,24 reaching an effect size of
0.57 versus placebo after 24 weeks
in one study (Figure 4).23 The
5
CAARS-Inv:SV
Least-squares mean change
ADHD in adults
Atomoxetine (n=220)
–1
Placebo (n=225)
–6
***
–11
***
***
***
***p≤0.001
–16
0
1
2
3
4
5
6
7
8
Weeks on therapy
9
10
11
12
13
CAARS-Inv:SV
Least-squares mean change
Figure 3. Atomoxetine has an effect size of 0.40 versus placebo in young adults.20
Reproduced with permission from Wolters Kluwer Health
0
–2
–4
–6
–8
–10
–12
–14
–16
–18
–20
Atomoxetine (n=268)
Placebo (n=234)
***
***
***
***
***
***
***p<0.001
0 1 2
4
8
12
16
Weeks on therapy
***
***
20
24
12-week effect size 0.41; 24-week effect size 0.57.
≥25% reduction in CAARS-Inv: atomoxetine 68%; placebo 42%.
≥40% reduction in CAARS-Inv: atomoxetine 47%; placebo 28%.
Mean change from baseline
Figure 4. Long-term efficacy of atomoxetine versus placebo over 24 weeks.23
Reproduced with permission from Wolters Kluwer Health
20
15
*p<0.05
**p<0.01
**
**
Atomoxetine (n=250)
Placebo (n=251)
*
*
10
5
0
Total score
Life outlook
Life
Psychological Relationships
productivity
health
Adult ADHD Quality of Life Scale
Figure 5. Functional outcomes in adults after long-term treatment with atomoxetine.24
Reproduced with permission from Wolters Kluwer Health
6
response rate using a highly robust
definition of response (CAARSINV:SV ≥30% and CGI-ADHD-S ≤3)
in the pooled population from
short-term trials was 34.8%
with atomoxetine (versus 22.3%
with placebo, p<0.001), but this
increased to 43.4% (versus 28%,
p<0.001) in long-term trials.25,26
Post hoc analyses showed that
atomoxetine was equally effective
in all relevant patient subgroups,
including those defined by age,
gender, baseline severity and
ADHD subtype.26 It also improved
ADHD-related quality of life scores,
with gains in life outlook, life
productivity, psychological health
and relationships domains compared with placebo (Figure 5).24 In
a real-world setting, the improvement in ADHD symptoms with
atomoxetine has matched the
results achieved in clinical trials,
and treatment has also been shown
to improve driving skills.27
Long-term maintenance
of response
Dr Bushe described a trial of
long-term maintenance therapy
with atomoxetine in adults with
ADHD.28 No other licensed ADHD
medication in the UK has comparable data, he commented.
Patients with a robustly defined,
clinically meaningful response
after 24 weeks of treatment were
randomised to continue treatment
with atomoxetine or were switched
blindly to placebo. The proportion
of patients maintaining a clinically
meaningful response after six
months was significantly greater
with atomoxetine (64.3 versus
50.0% with placebo, p=0.001).
Dr Bushe further noted the good
continued (placebo) response after
only six months of atomoxetine
treatment and emphasised that
treatment with atomoxetine need
not be indefinite.
ADHD in adults
Atomoxetine versus
methylphenidate
The important question for clinicians is not whether atomoxetine
is superior to methylphenidate
but which is more suitable for
the patient, Dr Bushe commented.
Responder rates in placebocontrolled trials26,29 and effect sizes
are similar, but the trajectory of
response differs. Methylphenidate
has a faster onset of response with
maximum efficacy around four to
five weeks, whereas the efficacy of
atomoxetine is incremental over
24 weeks with no clear evidence of
when maximal efficacy may be
reached, making efficacy comparisons between the drugs difficult.
One study in which atomoxetine
and modified-release methylphenidate were included as active controls found similar improvements
in ADHD symptom scores over six
weeks.30 A second study over eight
to ten weeks reported similar
improvements in core symptoms,
quality of life and functioning
with atomoxetine and immediaterelease methylphenidate.31
Adverse events
The adverse events reported in the
clinical trials in adults were consistent with the pharmacology and
what was known from studies in
children. Nausea was the most
common adverse event in clinical
trials (Table 2).26 This occurs early
in the course of treatment then
declines; it can be reduced in some
patients by gradual dose titration
or dose reduction. Erectile dysfunction associated with atomoxetine
(in around 9%) occurs early in the
course of treatment, but resolves
within three months in 50% of
men and within six months in
80%.26 Sexual dysfunction does
not occur in women to a greater
extent than placebo. Overall, the
adverse events associated with
Adverse event
%
Adverse event
%
Nausea
Dry mouth
Headache
Decreased appetite
Insomnia
Fatigue
Erectile dysfunction
(male patients only)
26.7
18.4
16.3
14.9
11.3
10.8
9.0
(of n=2820)
Dizziness
Nasopharyngitis
Constipation
Hyperhidrosis
Somnolence
Irritability
8.7
7.8
6.6
6.5
6.0
5.4
Table 2. Adverse events reported in ≥5% of atomoxetine-treated clinical trial adults
(n=4892)26
Adverse event
OROSmethylphenidate
Atomoxetine
Treatment-emergent adverse
event (TEAE)
Serious adverse event
Frequency of TEAE leading to
discontinuation
Sleep-related TEAE
Cardiovascular-related TEAE
Nausea
Mean weight change
Suicidal ideation
Erectile dysfunction
Decreased libido
82.4%
83.8%
1
8.8%
0
10.8%
36.8%
11.8%
10.3%
–1.47kg
1
2.9%
5.9%
21.6%
6.8%
35.1%
–0.56kg
0
8.1%
2.7%
Table 3. Adverse events associated with atomoxetine and methylphenidate30
methylphenidate and atomoxetine
are similar (Table 3).30
Dr Bushe summarised the prescribing precautions for atomoxetine and other ADHD medications,
advising caution for patients with
potential risk factors for cardiovascular disorders in accordance
with the summary of product characteristics.32 However, a US analysis
of healthcare records for 150 359
adults in real-world prescribing
showed that medication for
ADHD, including atomoxetine,
has not to date been associated
with an increased risk of serious
cardiovascular events in adults.33
Key points
l Atomoxetine is the only medication for ADHD treatment
initiation in adults licensed in
the EU (except Germany where
Medikinet® is also licensed).
l Atomoxetine is a non-stimulant
with no abuse potential; it is not
a controlled substance.
l The efficacy of atomoxetine
is similar to that of methyl phenidate.
l The response to treatment with
atomoxetine is slower in onset
than with methylphenidate but
does not show a definitive
plateau, even after 24 weeks.
l Atomoxetine is the only ADHD
medication licensed in the UK
to show that its clinical benefit
can be maintained.
l The profile of adverse effects
associated with atomoxetine is
consistent and predictable.
7
ADHD in adults
Dopamine, striatum
Noradrenaline, prefrontal cortex
7000
*** ***
***
*** ***
400
*
***
***
*
***
***p<0.001
5000
4000
***
3000
***
***
2000
1000
**
1200
d-Methylphenidate (10mg/kg ip)
d-Methylphenidate (3mg/kg ip)
d-Methylphenidate (1mg/kg ip)
Saline (ip)
1000
800
600
*********
***
******
******
******
*********
***************
******
*** ** ** * ** ****** **
**
*
*
400
200
0
*
***
*p<0.05
**p<0.01
***
1000
***p<0.001
***
***
800
600
***
400
***
***
***
***
*** ***
200
***
***
***
***
***
**
***
***
***
***
** ** ** *
**
*
** *
* *
0
–4
5
–3
0
–1
5
0
15
30
45
60
75
90
10
5
12
130
5
15
0
16
5
18
0
19
5
21
0
22
5
24
0
–4
5
–3
0
–1
5
0
15
30
45
60
75
90
10
5
12
0
13
5
15
0
16
5
18
0
19
5
21
0
22
5
24
0
Time (min)
450
Time (min)
700
Atomoxetine (3mg/kg ip)
Atomoxetine (1mg/kg ip)
Atomoxetine (0.3mg/kg ip)
Saline
400
350
300
250
*
200
*
*
150
100
50
*p<0.025
0
Dopamine efflux (% of baseline)
Noradrenaline efflux (% of baseline)
C
** ***
* *
Time (min)
Dopamine (% of baseline)
Noradrenaline (% of baseline)
1200
**
***
*** *** ** * *
Time (min)
B
***
***
0
75
90
10
5
12
0
13
5
15
0
16
5
18
0
*** *** **
*** *
* **
* **
45
60
0
15
30
–4
5
–3
0
–1
5
0
**
6000
75
90
10
5
12
0
13
5
15
0
16
5
18
0
800
*p<0.05
**p<0.01
0
15
30
1200
***
45
60
d-Amphetamine (3mg/kg ip)
d-Amphetamine (1mg/kg ip)
d-Amphetamine (0.3mg/kg ip)
Saline (ip)
–4
5
–3
0
–1
5
1600
Dopamine (% of baseline)
Noradrenaline (% of baseline)
A
Prefrontal cortex
Striatum
Nucleus accumbens
600
500
400
Atomoxetine
300
*
200
100
*p<0.05
0
–60
–30
0
30
60
90
120 150 180 210 240
Time (min)
–60
–30
0
30
60
90
120 150 180 210 240
Time (min)
Figure 6. Effects of (A) amphetamine,34 (B) methylphenidate35 and (C) atomoxetine36 on synaptic level of noradrenaline in the
prefrontal cortex and dopamine in the striatum (microdialysis studies in freely moving rats). Reproduced with permission from
Elsevier and Macmillan Publishers Ltd
8
ADHD in adults
The pharmacology
of medications used
in ADHD
The effects of methylphenidate
and amphetamines on synaptic
levels of dopamine and noradrenaline underlie both their therapeutic
properties and their risk of recreational abuse, said Professor
David Heal (Visiting Professor in
Pharmacy and Pharmacology,
University of Bath and Executive
Director, RenaSci Ltd).
He said that ADHD is associated with a functional imbalance
of noradrenaline and dopamine.
The brain region primarily responsible for ADHD is probably the
prefrontal cortex, but the striatum,
parietal lobes and the cerebellum
also appear to be involved.
Stimulants such as the
amphetamines act predominantly
by promoting the release of
dopamine and noradrenaline from
the presynaptic nerve terminal.
This causes a rapid but short-lived
increase in synaptic levels of
neurotransmitters, raising levels
of noradrenaline and dopamine
in the prefrontal cortex and of
dopamine in the striatum. The
effect on striatal dopamine is
particularly marked, with levels
increasing by a factor of several
thousand in vivo (Figure 6).34–36
There is no ceiling to this effect.
The properties of methylphenidate resemble those of amphetamine, raising striatal dopamine
levels 1000-fold. It is this rise that
is thought to be responsible for
its abuse potential. By contrast,
atomoxetine increases noradrenaline levels in the prefrontal
cortex more modestly and has
no effect on striatal dopamine.
This probably explains why atomoxetine has no known potential
for abuse.
Professor Heal challenged
the view that methylphenidate
acts as a conventional reuptake
inhibitor: it should be described
as a monoamine reuptake transporter inverse agonist, he said.
Like cocaine,37 methylphenidate
increases the efflux of dopamine
into the synapse (release), but it
does not delay the clearance of
dopamine (reuptake inhibition).
He proposed that methylphenidate
and cocaine produce this effect
as a consequence of binding to
the ‘cocaine binding site’ on the
dopamine reuptake transporter.
A similar mechanism also applies
to the effect of methylphenidate on
noradrenaline and this outweighs
its inhibitory effects on reuptake.
By promoting the release of
dopamine and noradrenaline,
Professor Heal said, methylphenidate is acting in a similar way
to the amphetamines.
Rapid increases in synaptic
noradrenaline and dopamine, with
no response ceiling, underpin the
early onset and large effect size of
the stimulants in treating ADHD,
Professor Heal concluded, and it
also accounts for their potential for
recreational abuse. Atomoxetine
does not increase synaptic
dopamine, but causes sustained
enhancement of noradrenaline in
the prefrontal cortex. With continued treatment this may be associated with neuro-adaptation, he
suggested, and helps to explain its
long-term efficacy.
Key points
l The effects of methylphenidate
and the amphetamines on synaptic levels of dopamine and noradrenaline underlie both their
therapeutic properties and many
of their side-effects.
l Methylphenidate
and the
amphetamines have powerful
enhancing effects on synaptic
levels of dopamine and this
underpins their risk for recreational abuse.
l Stimulants such as the amphetamines act predominantly by
promoting the release of dopamine and noradrenaline from
the neurone terminal; it is rapid
in onset and there is no ceiling
to this effect.
l The properties of methyl phenidate resemble those of
amphetamine.
l Atomoxetine has no effect
on striatal dopamine; this may
explain why it does not have the
potential for abuse.
Summary
Most children with ADHD continue to have symptoms and
impairment into adulthood; however, ADHD in adults is underrecognised and under-treated,
with individuals still experiencing
negative attitudes. Outside of
Germany, atomoxetine is currently
the only licensed medication for
ADHD treatment initiation in
adults and is also the only ADHD
medication to show a sustained
maintenance of response in clinical
trials. Evidence from clinical trials
and real-world settings shows that
it is as effective as methylphenidate,
but that improvement does not
plateau within the first six months.
In addition, it is well tolerated and
has no potential for abuse.
References
1. Simon V, Czobor P, Bálint S, et al.
Prevalence and correlates of adult attention-deficit hyperactivity disorder: metaanalysis. Br J Psychiatry 2009;194:204–11.
2. Kessler RC, Adler L, Barkley R, et al. The
prevalence and correlates of adult ADHD
in the United States: results from the
National Comorbidity Survey Replication.
Am J Psychiatry 2006;163:716–23.
3. Fayyad J, De Graaf R, Kessler R,
et al. Cross-national prevalence and
correlates of adult attention-deficit
9
ADHD in adults
hyperactivity disorder. Br J Psychiatry
2007;190:402–9.
4. Faraone SV, Biederman J, Mick E. The
age-dependent decline of attention
deficit hyperactivity disorder: a metaanalysis of follow-up studies. Psychol
Med 2006;36:159–65.
5. Larsson H, Lichtenstein P, Larsson JO.
Genetic contributions to the development of ADHD subtypes from childhood
to adolescence. J Am Acad Child
Adolesc Psychiatry 2006;45:973–81.
6. McCarthy S, Asherson P, Coghill D,
et al. Attention-deficit hyperactivity
disorder: treatment discontinuation in
adolescents and young adults. Br J
Psychiatry 2009;194:273–7.
7. Skirrow C, Asherson P. Emotional
lability, comorbidity and impairment in
adults with attention-deficit hyperactivity
disorder. J Affect Disord 2013;147:80–6.
8. Asherson P. Clinical assessment and
treatment of attention deficit hyper activity disorder in adults. Expert Rev
Neurother 2005;5:525–39.
9. National Institute for Health and Care
Excellence. Attention deficit hyperactivity
disorder. Diagnosis and management of
ADHD in children, young people and
adults. Clinical Guideline 72. London:
NICE; September 2008 (http://guidance.
nice.org.uk/CG72; last accessed 31
January 2014)
10. Matheson L, Asherson P, Wong IC,
et al. Adult ADHD patient experiences
of impairment, service provision and
clinical management in England: a qualitative study. BMC Health Serv Res
2013;13:184.
11. American Psychiatric Association.
Diagnostic and Statistical Manual of
Mental Disorders, 5th edn. Washington
DC: APA, 2013.
12. Asherson P, Chen W, Craddock B,
et al. Adult attention-deficit hyperactivity
disorder: recognition and treatment in
general adult psychiatry. Br J Psychiatry
2007;190:4–5.
13. Kooij SJ, Bejerot S, Blackwell A, et al.
European consensus statement on diagnosis and treatment of adult ADHD: The
European Network Adult ADHD. BMC
Psychiatry 2010;10:67.
14. Rao P, Place M. Prevalence of ADHD
in four general adult outpatient clinics
in North East England. Prog Neurol
Psychiatry 2011;15:7–11.
15. Bitter I, Simon V, Bálint S, et al. How
do different diagnostic criteria, age and
gender affect the prevalence of attention
deficit hyperactivity disorder in adults?
10
An epidemiological study in a Hungarian
community sample. Eur Arch Psychiatry
Clin Neurosci 2010;260:287–96.
16. Epstein J, Johnson DE, Conners CK.
Conners Adult ADHD Diagnostic
Interview for DSM IV. North Tonawanda,
NY: Multi-Health Systems Inc, 1999.
17. DIVA Foundation. Diagnostic
Interview for Adult ADHD 2.0 (www.diva
center.eu; accessed 31 January 2014).
18. Kessler RC, Adler LA, Gruber MJ,
et al. Validity of the World Health
Organization Adult ADHD Self-Report
Scale (ASRS) Screener in a representative sample of health plan members. Int
J Methods Psychiatr Res 2007;16:52–65.
19. Young S, Bramham J, Gray K, et al.
The experience of receiving a diagnosis
and treatment of ADHD in adulthood: a
qualitative study of clinically referred
patients using interpretative phenomenological analysis. J Atten Disord 2008;
11:493–503.
20. Durell TM, Adler LA, Williams DW,
et al. Atomoxetine treatment of attentiondeficit/hyperactivity disorder in young
adults with assessment of functional
outcomes: a randomized, double-blind,
placebo-controlled clinical trial. J Clin
Psychopharmacol 2013;33:45–54.
21. Adler LA, Liebowitz M, Kronenberger
W, et al. Atomoxetine treatment in adults
with attention-deficit/hyperactivity disorder and comorbid social anxiety disorder.
Depress Anxiety 2009;26:212–21.
22. Wilens TE, Adler LA, Weiss MD, et al.
Atomoxetine treatment of adults with
ADHD and comorbid alcohol use
disorders. Drug Alcohol Depend 2008;
96:145–54.
23. Young JL, Sarkis E, Qiao M, et al.
Once-daily treatment with atomoxetine
in adults with attention-deficit/hyper activity disorder: a 24-week, randomized,
double-blind, placebo-controlled trial.
Clin Neuropharmacol 2011;34:51–60.
24. Adler LA, Spencer T, Brown TE, et al.
Once-daily atomoxetine for adult
attention-deficit/hyperactivity disorder:
a 6-month, double-blind trial. J Clin
Psychopharmacol 2009;29:44–50.
25. Asherson P, Bushe C, Saylor K, et al.
Response rates of adults with ADHD
in multicenter placebo controlled trials
of atomoxetine: an integrated analysis.
4th World Congress on ADHD: from
Childhood to Adult Disease, 6–9 June
2013, Milan, Italy.
26. MHRA. Strattera Public Assessment
Report 2013.
27. Sobanski E, Sabljic D, Alm B, et al.
Driving performance in adults with
ADHD: results from a randomized, waiting list controlled trial with atomoxetine.
Eur Psychiatry 2013;28:379–85.
28. Upadhyaya H, Ramos-Quiroga JA,
Adler LA, et al. Maintenance of response
after open-label treatment with atom oxetine hydrochloride in international
European and non-European adult outpatients with attention-deficit/hyper activity disorder: a placebo-controlled,
randomised withdrawal study. Eur J
Psychiatry 2013;27:185–205.
29. Rösler M, Fischer R, Ammer R, et al.
A randomised, placebo-controlled, 24week, study of low-dose extendedrelease methylphenidate in adults with
attention-deficit/hyperactivity disorder.
Eur Arch Psychiatry Clin Neurosci 2009;
259:120–9.
30. Weisler RH, Pandina GJ, Daly EJ, et
al. Randomized clinical study of a histamine H3 receptor antagonist for the
treatment of adults with attention-deficit
hyperactivity disorder. CNS Drugs 2012;
26:421–34.
31. Ni HC, Lin YJ, Gau SS, et al. An
open-label, randomized trial of methylphenidate and atomoxetine treatment in
adults with ADHD. J Atten Disord 2013
[Epub ahead of print].
32. Eli Lilly & Co. Strattera Summary of
Product Characteristics. December 2013.
33. Habel LA, Cooper WO, Sox CM, et al.
ADHD medications and risk of serious
cardiovascular events in young and
middle- aged adults. JAMA 2011;306:
2673–83.
34. Heal DJ, Cheetham SC, Smith SL.
The neuropharmacology of ADHD drugs
in vivo: insights on efficacy and safety.
Neuropharmacology 2009;57:608–18.
35. Heal DJ, Smith SL, Kulkarni RS,
et al. New perspectives from microdialysis
studies in freely-moving, spontaneously
hypertensive rats on the pharmacology
of drugs for the treatment of ADHD.
Pharmacol Biochem Behav 2008;90:
184–97.
36. Bymaster FP, Katner JS, Nelson DL,
et al. Atomoxetine increases extra
cellular levels of norepinephrine and
dopamine in prefrontal cortex of rat:
a potential mechanism for efficacy in
attention deficit/hyperactivity disorder.
Neuro psychopharmacology 2002;27:
699–711.
37. Wu Q, Reith ME, Kuhar MJ, et al.
Preferential increases in nucleus accumbens dopamine after systemic cocaine
administration are caused by unique
characteristics of dopamine neurotransmission. J Neurosci 2001;21:6338–47.
ADHD in adults
STRATTERA® ABBREVIATED PRESCRIBING INFORMATION
(ATOMOXETINE)
Presentation Hard capsules: 10mg, 18mg, 25mg, 40mg, 60mg, 80mg, or
100mg atomoxetine. Uses Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children 6 years of age and older, in adolescents, and in adults
as part of a comprehensive treatment programme. Treatment must be initiated
by a specialist in the treatment of ADHD. In adults, the presence of symptoms
of ADHD that were pre-existing in childhood should be confirmed. Third-party
corroboration is desirable and Strattera should not be initiated when the
verification of childhood ADHD symptoms is uncertain. Based on clinical
judgment, patients should have ADHD of at least moderate severity, as
indicated by at least moderate functional impairment in 2 or more settings.
Diagnosis should be made according to current DSM criteria or the guidelines
in ICD. Treatment with Strattera need not be indefinite. Re-evaluation of the
need for continued therapy beyond 1 year is recommended, particularly when
the patient has reached a stable and satisfactory response. Dosage and
Administration For oral use, administered as a single daily dose in the morning, with or without food. Some patients may benefit from taking it twice daily
in divided doses. Can be discontinued without dose tapering. Dosing of
children/adolescents up to 70 kg body weight: Initiate at a total daily dose of
approximately 0.5mg/kg and maintain for a minimum of 7 days prior to upward
dose titration according to clinical response and tolerability. The recommended
maintenance dose is approximately 1.2mg/kg/day. The safety of single doses
over 1.8mg/kg/day and total daily doses above 1.8mg/kg have not been systematically evaluated. Dosing of children/adolescents over 70 kg body weight:
Initiate at a total daily dose of 40mg and maintain for a minimum of 7 days
prior to upward dose titration according to clinical response and tolerability.
The recommended maintenance dose is 80mg. Dosing of adults: Strattera
should be initiated at a total daily dose of 40mg. The initial dose should be
maintained for a minimum of 7 days prior to upward dose titration according
to clinical response and tolerability. The recommended maintenance daily dose
is 80mg to 100mg. The maximum recommended total daily dose is 100mg.
The maximum recommended total daily dose in children and adolescents over
70 kg and adults is 100mg. The safety of single doses over 120mg and total
daily doses above 150mg have not been systematically evaluated. Prior to prescribing it is necessary to take an appropriate medical history and conduct a
baseline evaluation of a patient’s cardiovascular status, including blood pressure and heart rate. This should be recorded after each dose adjustment and
then at least every 6 months. Special Populations Doses may need to be modified in patients with hepatic insufficiency or renal disease. For patients with a
known poor metaboliser genotype (CYP2D6 poor metabolisers), a lower starting dose and slower up titration of the dose may be considered. Atomoxetine
should not be used in children under 6 years of age. The use of atomoxetine
in elderly patients over 65 years of age has not been systematically evaluated.
Contra-indications Hypersensitivity to the active substance or any of the
excipients. Should not be used in patients with narrow angle glaucoma. Should
not be used in patients with phaeochromocytoma or a history of the condition.
Should not be used in combination with monoamine oxidase inhibitors (MAOIs)
and should not be used within 2 weeks of discontinuing therapy with a MAOI.
Treatment with a MAOI should not be initiated within 2 weeks of discontinuing
atomoxetine. Should not be used in patients with severe cardiovascular or
cerebrovascular disorders. Warnings and Special Precautions Suiciderelated behaviour (suicide attempts and suicidal ideation) has been reported
in patients treated with atomoxetine. In double-blind clinical trials, suiciderelated behaviours were uncommon but occurred more frequently in atomoxetine-treated patients, with no events in the placebo group. In adult doubleblind clinical trials there was no difference in frequency of suicide-related
behaviour between atomoxetine and placebo. Sudden death has been
reported in patients with structural cardiac abnormalities who were taking atomoxetine at usual doses. Although some serious structural cardiac abnormalities alone carry an increased risk of sudden death, use only with caution in
patients with known serious structural cardiac abnormalities and in consultation with a cardiac specialist. Atomoxetine can affect heart rate and blood pressure. Most patients experience a modest increase that may not be clinically
important. However, as some patients do experience clinically relevant
changes in BP and HR (eg, 15 to 20mmHg/20 beats per minute), use with
caution in patients with hypertension, tachycardia, cerebrovascular or other
cardiovascular disease, or conditions that predispose to hypertension or
abrupt changes in heart rate or blood pressure. In some cases changes are
progressive or sustained. Pulse and blood pressure should be measured and
recorded before treatment is started and, during treatment, after each adjustment of dose and then at least every 6 months. Patients who develop symptoms such as palpitations, exertional chest pain, unexplained syncope,
dyspnoea, or other symptoms suggestive of cardiac disease during treatment
should undergo prompt specialist cardiac evaluation. Long-term sustained
changes in blood pressure may potentially contribute to clinical consequences
such as myocardial hypertrophy. Use with caution in patients with congenital
or acquired long QT or a family history of QT prolongation. Patients with risk
factors for cerebrovascular conditions should be assessed at every visit for
neurological signs and symptoms. Very rare cases of severe liver injury, including acute liver failure, have been reported. Discontinue in patients with jaundice
or laboratory evidence of liver injury, and do not restart. Treatment emergent
psychotic or manic reactions, eg, hallucinations, delusional thinking, mania,
and agitation, can be caused by atomoxetine at usual doses. If such symptoms
occur, consideration should be given to a possible causal role of atomoxetine,
and discontinuation of treatment should be considered. Hostility and emotional
lability were more frequently observed in clinical trials among children and adolescents treated with atomoxetine compared to those treated with placebo.
Patients who are being treated for ADHD should be carefully monitored for the
appearance or worsening of suicide-related behaviour, aggressive behaviour,
hostility, or emotional lability. Uncommonly, allergic reactions, including anaphylaxis, have been reported. Introduce with caution in patients with a history
of seizure. Discontinuation of atomoxetine should be considered in any patient
developing a seizure or if there is an increase in seizure frequency where no
other cause is identified. Growth and development should be monitored in children and adolescents during treatment with atomoxetine. Consideration
should be given to dose reduction or interrupting therapy in children and adolescents who are not growing or gaining weight satisfactorily. Patients requiring
long-term therapy should be carefully monitored. Patients being treated for
ADHD should be monitored for the appearance or worsening of anxiety symptoms, depressed mood and depression, or tics. Interactions Atomoxetine
should not be used with MAOIs. Dose adjustment and slower titration of atomoxetine may be necessary in those patients who are also taking CYP2D6
inhibitor drugs (eg, SSRIs, quinidine, terbinafine). Caution is advised when
combining atomoxetine with potent inhibitors of cytochrome P450 enzymes
other than CYP2D6 in patients who are poor CYP2D6 metabolisers. Atomoxetine should be administered with caution to patients being treated with high
dose nebulised or systemically administered (oral or intravenous) salbutamol
(or other beta2 agonists) because the action of salbutamol on the cardiovascular system can be potentiated. Attention should be paid to monitoring heart
rate and blood pressure, and dose adjustments may be justified for either atomoxetine or salbutamol (or other beta2 agonists) in the event of significant
increases in heart rate and blood pressure during co-administration of these
drugs. There is the potential for an increased risk of QT interval prolongation
when atomoxetine is administered with other QT prolonging drugs (such as
neuroleptics, class IA and III anti-arrhythmics, moxifloxacin, erythromycin,
methadone, mefloquine, tricyclic antidepressants, lithium, or cisapride), drugs
that cause electrolyte imbalance (such as thiazide diuretics), and drugs that
inhibit CYP2D6. Caution is advised with concomitant use of medicinal drugs
which are known to lower the seizure threshold (such as antidepressants or
SSRIs, neuroleptics, phenothiazines or butyrophenone, mefloquine, chloroquine, bupropion or tramadol). Atomoxetine should be used cautiously with
antihypertensive drugs, pressor agents, and drugs that affect noradrenaline.
Review of therapy may be justified in the case of significant change in blood
pressure. Pregnancy and Lactation Should not be used during pregnancy
unless the potential benefit justifies the potential risk to the foetus. Due to lack
of data, atomoxetine should be avoided during breast-feeding. Driving, etc
Use caution when driving or operating hazardous machinery. Undesirable
Effects (Clinical Trial Reporting) Children and Adolescents Headache,
abdominal pain, and decreased appetite are the most common adverse events
but seldom lead to drug discontinuation; abdominal pain and decreased
appetite are usually transient. Some patients experienced growth retardation
early in therapy in terms of both weight and height gain. With continued longterm treatment both height and weight normalised to baseline. In adult and
11
paediatric clinical trials, patients experienced increases in heart rate and blood
pressure. The following is based on adverse event reporting and laboratory
investigations from clinical trials and post-marketing spontaneous reports in
children and adolescents: Very common (≥10%): Headache, somnolence,
appetite decreased, abdominal pain, vomiting, nausea, blood pressure and
heart rate increased (based on measured vital signs). Common (≥1-<10%):
Anorexia, insomnia, irritability, mood swings, agitation, anxiety, depression and
depressed mood, tics, dizziness, mydriasis, constipation, dyspepsia, dermatitis, pruritus, rash, fatigue, lethargy, chest pain, weight decreased. Uncommon
(≥0.1-<1%): Suicide-related events, aggression, hostility, emotional lability,
psychosis (including hallucinations), syncope, tremor, migraine, paraesthesia,
hypoaesthesia, seizure, palpitations, sinus tachycardia, QT interval prolongation, dyspnoea, blood bilirubin increased, hyperhidrosis, allergic reactions,
asthenia. Rare (≥1-<0.1%): Raynaud’s phenomenon, abnormal/increased liver
function tests, jaundice, hepatitis, liver injury, acute hepatic failure, urinary
hesitation, urinary retention, priapism, male genital pain. In trials lasting up to
ten weeks, weight loss was more pronounced in poor metabolisers. Adults In
adult ADHD clinical trials, the following system organ classes had the highest
frequency of adverse events during treatment with atomoxetine: gastro-intestinal, nervous system, and psychiatric disorders. The most common adverse
events (≥5%) reported were appetite decreased (14.9%), insomnia (11.3%),
headache (16.3%), dry mouth (18.4%), and nausea (26.7%). The majority of
these events were mild or moderate in severity and the events most frequently
reported as severe were nausea, insomnia, fatigue, and headache. A complaint
of urinary retention or urinary hesitancy in adults should be considered potentially related to atomoxetine. The following is based on adverse event reporting
and laboratory investigations from clinical trials and post-marketing spontaneous reports in adults: Very common (≥10%): Appetite decreased, insomnia,
headache, dry mouth, nausea, blood pressure and heart rate increased (based
on measured vital signs). Common (≥1-<10%): Agitation, libido decreased,
sleep disorder, depression and depressed mood, anxiety, dizziness, dysgeusia,
paraesthesia, somnolence (including sedation), tremor, palpitations, tachycardia, flushing, hot flush, abdominal pain, constipation, dyspepsia, flatulence,
vomiting, dermatitis, hyperhidrosis, rash, dysuria, pollakiuria, urinary hesitation,
urinary retention, dysmenorrhoea, ejaculation disorder, erectile disturbance,
prostatitis, male genital pain, asthenia, fatigue, lethargy, chills, feeling jittery,
irritability, thirst, weight decreased. Uncommon (≥0.1-<1%): Suicide-related
events, aggression, hostility and emotional lability, restlessness, tics, syncope,
migraine, hypoaesthesia, QT interval prolongation, peripheral coldness, dyspnoea, allergic reactions, pruritus, urticaria, muscle spasms, micturition urgency,
ejaculation failure, menstruation irregular, orgasm abnormal, feeling cold, chest
pain. Rare (≥1-<0.1%): Psychosis (including hallucinations), seizure, Raynaud’s
phenomenon, abnormal/increased liver function tests, jaundice, hepatitis,
liver injury, acute hepatic failure, blood bilirubin increased, priapism. For full
details of these and other side-effects, please see the Summary of Product
Characteristics, which is available at http://www.medicines.org.uk/emc/. Legal
Category POM Marketing Authorisation Numbers 00006/0375 00006/0376
00006/0377 00006/0378 00006/0379 00006/0615 00006/0616 Basic NHS
Cost £15.62 per pack of 7 (10mg, 18mg, 25mg, 40mg) £62.46 per pack of 28
(10mg, 18mg, 25mg, 40mg, 60mg) £83.28 per pack of 28 (80mg) £83.28 per
pack of 28 (100mg) Date of Preparation or Last Review December 2013
Full Prescribing Information is Available From Eli Lilly and Company Limited,
Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL Telephone:
Basingstoke (01256) 315 000 E-mail: [email protected] Website: www.lillypro.co.uk
STRATTERA® (atomoxetine) is a registered trademark of Eli Lilly and Company.
Adverse events should be reported. Reporting forms and further
information can be found at www.mhra.gov.uk/yellowcard.
Adverse events and product complaints should also be reported
to Lilly: please call Lilly UK on 01256 315 000.
The meeting was developed, organised and funded by Eli Lilly. This meeting report, sponsored by Eli Lilly, is based on the meeting and the
speakers and publisher retained final editorial control of the content. The opinions expressed in the report are not necessarily those of the
publisher or Eli Lilly.
Printed and published by John Wiley & Sons, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ
© John Wiley & Sons 2014
Pr.1472
Date of preparation March 2014
UKSTR00960