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JPPT

Review Article

A Review of Pharmacological Management of


Attention-Deficit/Hyperactivity Disorder
Leslie Briars, PharmD1 and Timothy Todd, PharmD2

1
Department of Pharmacy Practice, The University of Illinois at Chicago College of Pharmacy, Chicago, Illinois; 2Department
of Pharmacy Practice, Midwestern University, Downers Grove, Illinois

Attention-deficit/hyperactivity disorder (ADHD) is a common psychological diagnosis in children. This disorder


impacts children and adolescents in all areas of life, including academic performance, extracurricular activi-
ties, and social interactions. ADHD can continue into adulthood where unemployment and substance abuse
has been described. Although behavioral therapy is recommended for all patients with ADHD, medication
management typically is initiated soon after diagnosis. Psychostimulants remain the primary medication of
choice. This review focuses on the clinical use of psychostimulant medication in children and adolescents.
The pharmacodynamic and pharmacokinetic differences between the newest long-acting formulations as
well as commonly encountered adverse drug reactions, with suggested management strategies, will be
highlighted. Non-stimulant therapy with atomoxetine or alpha2-adrenergic agonists is also reviewed. These
agents may be warranted for patients who cannot tolerate psychostimulant therapy or have a comorbid
condition. Finally, the 8-year multimodal treatment study results are also discussed.

INDEX TERMS: adolescent, alpha2-agonist, amphetamine, atomoxetine, attention deficit disorder with hy-
peractivity, central nervous system stimulants, child, clonidine, methylphenidate, pediatric

J Pediatr Pharmacol Ther 2016;21(3):192–206

INTRODUCTION rather to highlight the common regimens and


challenges seen within the community.
Attention-deficit/hyperactivity disorder
(ADHD) is one of the most common neurobe- Prevalence
havioral disorders in childhood. ADHD can The prevalence of ADHD in any specific popu-
impact not only school performance, but also lation is difficult to determine owing to differ-
social interaction. If untreated, this could lead ences in diagnostic criteria and access to health
to poorer grades and isolation from friends, and care. In the United States, it is estimated that 5%
in adolescence there is increased drug abuse and to 9% of children aged 5 to 12 years have ADHD,
delinquent behavior. Pharmacological treatment which is similar to the estimated worldwide
is highly effective, and ongoing, long-term stud- prevalence of 5.29%.1-3 Male children are twice as
ies are starting to reveal more evidence to help likely to be diagnosed as similarly aged females;
providers discern proper therapy duration, po- however, this may be due to males expressing
tential side effects, and more specific outcomes more hyperactive symptoms, while females
to monitor. Many agents are available and clini- demonstrate inattentiveness often, which may
cians need to be aware of the pharmacokinetic be more difficult to identify.4,5 ADHD impacts
and pharmacodynamic differences so that an patients of all ethnic backgrounds, but there is a
appropriate, patient-specific regimen can be slightly higher prevalence noted in non-Hispanic
offered. This review will discuss the common Caucasians.4 Approximately 70% of patients di-
medication therapy used for ADHD patients agnosed with ADHD as a child will continue to
along with strategies to help manage common have significant symptoms during adolescence
side effects. This article is not meant to encom- and more than half of them will have impairment
pass all comorbidities associated with ADHD but into adulthood.6
192 J Pediatr Pharmacol Ther 2016 Vol. 21 No. 3 • www.jppt.org
Common ADHD Medications JPPT
Etiology egory to be diagnosed with ADHD. Patients 17
The exact cause of ADHD is unknown, but years of age or older only require 5 symptoms
many potential risk factors have been identi- for the diagnosis. Additionally, to be diagnosed,
fied, including biological and environmental the patient must have expressed the symptoms
risks. Both norepinephrine and dopamine play of ADHD for a minimum of 6 months and have
a critical role in modulating attention in ADHD. a history of developing several of the symptoms
Norepinephrine may have more effect on execu- before the age of 12 years. Symptoms also must
tive functioning (deficits in executive functioning be present in 2 or more settings, such as home
manifest as having difficulty solving problems, and school, and there must be clear evidence
remembering tasks, and planning for a future that the symptoms interfere with functioning. In
task),7 whereas dopamine may be more impor- addition to the diagnosis of ADHD, a presenta-
tant in maintaining attention.8 Genomic studies tion subtype is described for each patient, based
have identified a variety of dopamine and sero- on the number of symptoms found within each
tonin receptors (i.e., dopamine 4 and 5, serotonin category. If the patient has 6 or greater symptoms
1B) having significant association with ADHD. in both the inattention and the hyperactivity/
A genetic component to ADHD has mount- impulsivity categories, they are designated as
ing evidence, too, stemming from a twins study having combined presentation ADHD. If the
completed in Europe, Australia, Scandinavia, and patient has 6 or greater symptoms in the inatten-
the United States, showing a mean heritability tive category only, they are designated as having
of 76%. This means that 76% of the etiology of predominantly inattentive presentation ADHD,
ADHD can be explained by genes.9 Some envi- whereas if they have 6 or greater symptoms in
ronmental factors that have been associated with only the hyperactive/impulsive category, they
ADHD include low birth weight and maternal are considered to have predominantly hyperac-
smoking.1 Thus, there is a multitude of factors tive/impulsive presentation ADHD.
that need to be taken into account when consid- A number of rating scales have been created to
ering a diagnosis of ADHD. assist the clinician in the diagnosis of ADHD and
in the monitoring of therapy. The Conners Rat-
Symptoms and Diagnosis ing Scales and the Vanderbilt ADHD Diagnostic
There are 3 hallmark symptoms of ADHD: inat- Scales are the 2 most commonly used in clinical
tention, hyperactivity, and impulsivity. Inatten- practice. The Conners Parent Rating Scale–Re-
tion presents as difficulty paying close attention vised asks the parent or adolescent patient ques-
to details in schoolwork or other activities, lack tions to elucidate information that helps deter-
of attention to partners in verbal communica- mine the relative degree of presence or absence
tion, and inability to follow through on tasks. of the hallmark ADHD symptoms. The Conners
In contrast, impulsivity is seen as the inability Teacher Rating Scale–Revised is similar in nature
to remain seated in situations where it would but evaluates the symptoms in a separate setting
be expected (e.g., school, work), blurting out re- and is used if the parents allow information to be
sponses to questions, completing other people’s obtained from the patient’s school. The Vander-
sentences, or acting without thinking through the bilt ADHD Diagnostic Parent and Teacher Scales
consequences first. Hyperactivity often presents evaluate for ADHD symptoms and additionally
as fidgeting when attempting to remain seated assess for common comorbid conditions.1 Further
or excessive movement throughout the day. The detailed information about each rating scale can
presence of any of these symptoms in a patient be found in the article by Pliszka et al.1
justifies being evaluated for ADHD.
The Diagnostic and Statistical Manual of Mental PHARMACOTHERAPY OF ADHD
Disorders (DSM-5)10 is used to officially diagnose
a patient with ADHD. The DSM-5 separates Psychostimulants have been the medications
the hallmark symptoms into 2 categories: inat- of choice for treating ADHD for more than 60
tention and hyperactivity/impulsivity. Within years. About 75% to 80% of children with ADHD
each category there is a list of symptoms, and a will benefit from the use of psychostimulants.
pediatric patient (younger than 17 years) must Methylphenidate, dexmethylphenidate, dex-
have 6 or more of these symptoms in either cat- troamphetamine, lisdexamfetamine, and the

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JPPT L Briars, et al

mixed amphetamine salts (dextro- and levo- chostimulants inhibit monoamine oxidase and
amphetamine) constitute the psychostimulants thus coadministration may cause a hypertensive
currently on the market. They have similar clini- crisis.14,15
cal benefits; however, the pharmacokinetic and
pharmacodynamic profiles vary greatly. Tables 1 Methylphenidate
and 2 list the common ADHD medications avail- Methylphenidate is the medication most
able as of January 2016. widely used as first line treatment for ADHD.
In general, the psychostimulants have similar Methylphenidate exerts its action on both dopa-
common adverse reactions including decreased mine and norepinephrine transporters, thus it is
appetite, stomach pain, sleep disturbances, and believed to increase dopamine and norepineph-
headaches. Less common adverse reactions rine in the prefrontal cortex.16 There are various
include labile mood and growth suppression. formulations available. The immediate-release
Data are conflicting regarding the effect of psy- formulations are usually started for younger
chostimulants on growth. There are long-term and smaller children (i.e., <16 kg) who are naïve
data available discussing height loss of 1 to 2 to psychostimulants.1 The dose is usually given
cm that is sustained but dependent upon dose twice daily, about 4 hours apart (i.e., before school
and duration of therapy.11 However, a more and at lunchtime) and can be given up to three
recent longitudinal study12 was published that times a day. There are liquid formulations avail-
disputes this variation in growth. Patients born able if the child cannot swallow the tablets whole,
between 1976 and 1982 were retrospectively as is recommended. Food does not change the
evaluated to assess final adult height and peak overall benefit of methylphenidate administra-
height velocity and the association between tion; however, with the long-acting, solid dosage
psychostimulant use and duration. There was formulations, a high-fat meal eaten at the same
no significant change in height between those time of administration may delay the onset of
patients treated for ADHD versus non-treated action.16 Titration to maximum effective dose can
controls. Results also did not show any differ- occur quite quickly, since the clinical benefit can
ence even in patients treated for >3 years.12 New be seen within a few days to 1 week. Thus, clini-
warnings of sudden cardiac death are described cians can titrate doses every 7 days. Once patients
within the psychostimulants’ product informa- are titrated to an appropriate dose, clinicians may
tion. Table 3 discusses more recent primary consider once-daily formulations.
literature highlighting strategies for managing Methylphenidate once-daily formulations
potential cardiovascular risk. There is no uni- vary in pharmacodynamic effect even though,
versal requirement about obtaining a baseline pharmacokinetically, the dose is listed as once
electrocardiogram; however, the American daily for all sustained-release formulations. Con-
Academy of Pediatrics and the American Heart certa (McNeil Pediatrics, Titusville, NJ), Focalin
Association state that an electrocardiogram XR (Novartis Pharmaceutics Corporation, East
can be considered in children with risk factors, Hanover, NJ), Metadate CD (UCB Inc, Smyrna,
such as a family history of heart disease or an GA), and Ritalin LA (Novartis Pharmaceutics
individual history of chest pain or dizziness.6,13 Corporation, East Hanover, NJ) are the newest
Drug-drug interactions are not common with long-acting formulations available. Ritalin SR
the psychostimulants; however, amphetamine (Novartis), Metadate ER (UCB), and Methylin
products have more potential for interactions ER (Mallinckrodt Inc, Hazelwood, MO) are in-
than methylphenidate, since amphetamines termediate-acting formulations and may require
are metabolized through cytochrome P450 2D6. either twice-daily dosing or an addition of an im-
However, caution is to be taken if methylpheni- mediate-release preparation midday to achieve
date is administered with tricyclic antidepres- adequate benefit. When considering once-daily
sants, phenobarbital, phenytoin, or warfarin, dosing, the clinician needs to take into account
since increased concentrations of these agents when the symptoms occur and the duration of
has been shown. The exact mechanism of this effect that is warranted. The timing of peak con-
interaction is unknown.14 Methylphenidate and centrations and overall “coverage” vary greatly
amphetamine products are contraindicated with from product to product. With Ritalin LA and
monoamine oxidase inhibitors, since the psy- Focalin XR, the spheroidal oral drug absorption

194 J Pediatr Pharmacol Ther 2016 Vol. 21 No. 3 • www.jppt.org


Table 1. Commonly Prescribed Psychostimulant Medications for ADHD14,15,17-23,26,54-58

Duration
Brand Formulation Dosage Information of Activity Comments
Starting Maximum
Methylphenidate – Short Acting
 Ritalin Tablet: 5, 10, 20 mg 10 mg/day 60 mg/day 2-4 hr Daily doses may be divided into two to three times a day, usually
giving last dose of day in afternoon.
Common ADHD Medications

 Methylin Tablet: 5, 10, 20 mg


 Methylin Chewable tablet: 2.5, 5, 10 mg
 Methylin Solution: 5 and 10 mg/mL
 Focalin Tablet: 2.5, 5, 10 mg 5 mg/day 20 mg/day 3-5 hr
Methylphenidate – Intermediate Acting
  Ritalin SR Tablet: 20 mg 10-20 mg/ 60 mg/day 6-8 hr Pharmacodynamics vary between formulations. SR tablets given once
  Methylin ER Tablet: 10, 20 mg day daily may not provide the same duration of action, compared to CD or
  Ritalin LA Capsule: 10, 20, 30, 40 mg LA capsules.
Addition of short-acting formulation may be necessary in certain
cases.
Capsule formulations can be opened and contents placed on soft

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food.
Methylphenidate – Long Acting
  Focalin XR Capsule: 5, 10, 15, 20, 30 mg 5 mg/day 30 mg/day 9-12 hr Capsule formulations can be opened and contents placed on soft
food.
  Quillivant XR Suspension: 25 mg/5 mL 20 mg/day 60 mg/day Suspension formulation needs to be reconstituted by pharmacist.
Once suspended, the liquid can be stored at room temperature and
must be vigorously shaken before administration.
  Quillichew ER Tablet: 20, 30, 40 mg

 Concerta Tablet (OROS): 18, 27, 36, 54 mg 18 mg/day Children: The OROS tablets cannot be chewed or broken. The shell of the tablet
54 mg/day may be found in the stool. As of November 2014, the FDA rating
Adolescents: of generic Concerta manufactured by Mallinckrodt & Kudco is not
72 mg /day AB rated and thus cannot be automatically substituted for brand
Concerta.54
  Aptensio XR Capsule55: 10, 15, 20, 30, 40, 50, 10 mg/day 60 mg/day Aptensio was released in 2015; capsules may be opened and
60 mg sprinkled on applesauce.
 Daytrana Patch: 10, 15, 20, 30 mg 10 mg/day 30 mg/day The patches may cause a rash and pruritus.
ADHD, attention-deficit/hyperactivity disorder; BID, two times a day; CD, controlled delivery; ER, extended release; FDA, United States Food and Drug Administration; LA, long acting; ODT, orally disin-
tegrating tablet; OROS, osmotic-controlled release oral delivery system; qd, one time daily; SR, sustained release; XR, extended release; yr, years old

195
JPPT
JPPT L Briars, et al

system (SODAS; Elan Corpora-

ADHD, attention-deficit/hyperactivity disorder; BID, two times a day; CD, controlled delivery; ER, extended release; FDA, United States Food and Drug Administration; LA, long acting; ODT, orally disin-
tion, Allegan, MI) formulation

Current long-acting amphetamine formulations approved for >6 yr


is used, which provides 2 peaks
in concentration, mimicking the
administration of twice-daily
immediate-release prepara-
tions. Fifty percent of the drug
is immediately released and
50% is released 4 hours later.17,18
The Metadate CD drug deliv-
Comments

ery system is a timed release


bead formulation (Diffucaps,
Adare Pharmaceuticals, Law-
renceville, NJ) that releases

tegrating tablet; OROS, osmotic-controlled release oral delivery system; qd, one time daily; SR, sustained release; XR, extended release; yr, years old
30% of the dose as immediate
release and 70% of the dose as
extended release.19 Focalin XR,
Metadate CD, and Ritalin LA
are capsules that can be opened
and sprinkled onto soft food,
which aids administration,
although the beads should not
be chewed. The longest acting
of Activity
Duration

of the formulations is Concerta,


8-12 hr
4-6 hr

which is the osmotic-controlled


Table 1. Commonly Prescribed Psychostimulant Medications for ADHD14,15,17-23,26,54-58 (cont.)

release oral delivery system


(OROS; ALZA Corporation,
18.8 mg/day;

12.5 mg/day
40 mg/day

30 mg/day
40 mg/day
70 mg/day
Maximum

Mountain View, CA) formula-


13-17 yr:
6-12 yr:
Dosage Information

tion that delivers 22% of the


drug as immediate release and
then by osmotic pressure, the
remaining drug is released at
20-30 mg qd
10 mg daily
once to BID

5-10 mg qd
>6 yr: 5 mg

3.1 mg qd

a controlled rate.20 This tablet


3-5 yr: 2.5
<3 yr: 2.5
Starting

mg daily
mg/day

needs to be swallowed whole


and not crushed or broken and
the outer shell may be seen in
Capsule: 5, 10, 15, 20, 25, 30 mg

the stool. Quillivant XR (Tris


  Adzenys XR-ODT Tablet: 3.1, 6.3, 9.4, 12.5, 15.7,
Capsule: 20, 30, 40, 50, 60, 70
Tablet: 5, 7.5, 10, 12.5, 15, 20,

Tablet: 2.5, 5, 7.5, 10, 15, 20,

Pharma Inc, Monmouth Junc-


tion, NJ) is a once-daily suspen-
Formulation

Capsule: 5, 10, 15 mg

sion, available for patients who


Solution: 5 mg/5 mL

cannot take the solid dosage


Tablet: 5, 10 mg
Tablet: 5, 10 mg

formulations.21 The suspension


delivers methylphenidate as
Amphetamine – Short Acting

Amphetamine – Long Acting

18.8 mg

20% immediate release and


30 mg

30 mg

80% extended release. Similar


mg

to the other extended-release


formulations already discussed,
a high-fat meal will delay the
  Dexedrine SR
  Adderall XR
 DextroStat
Brand

 Dexedrine

peak concentration by up to
 Procentra
 Adderall

 Vyvanse
 Zenzedi

1 hour. Specific instructions


for reconstitution of the oral
powder formulation by the

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Common ADHD Medications JPPT
Table 2. Commonly Prescribed Non-Psychostimulant Medications for ADHD29,42,43
Generic Formulation Dosage Information Duration of Comments
(Brand) Starting Maximum Activity
Selective norepinephrine reuptake inhibitor
Atomoxetine Capsule: 10, If <70 kg give Dose: 1.4 mg/ 10-12 hr After initiation, wait a minimum
(Strattera) 18, 25, 40, 60, 0.5 mg/kg/ kg/day up to (variable and of 3 days before titrating to usual
80, 100 mg day; if >70 kg 100 mg/day dependent maintenance dose to evaluate
give 40 mg/ Given daily or on patient for tolerability. For patients with
day divided BID metabolism) CYP2D6 polymorphisms or those
taking strong CYP2D6 inhibitors,
initial titration should occur at 4
weeks.
Dose adjustment required in
hepatic impairment.
Alpha2-agonists
Clonidine ER Tablet: 0.1, 0.1 mg/day 0.4 mg/day 12-24 hr Patients converting from immediate
(Kapvay) 0.2 mg given at divided BID release formulations cannot be
bedtime converted on a 1:1 ratio.
Full efficacy of dose is evident at
7-14 days post initiation. Do not
Guanfacine Tablet: 1, 2, 3, 0.05-0.08 mg/ 6-12 yr: 4 mg/ break, crush or chew ER tablets.
ER 4 mg kg/dose or 1 day; 13-17 yr: Dose adjustments required with
(Intuniv) mg given one 7 mg/day guanfacine and concomitant use
time daily of strong CYP3A4 inhibitors or
inducers.
ADHD, attention-deficit/hyperactivity disorder; BID, two times a day; CYP, cytochrome P450; ER, extended release; yr, years old

pharmacist before dispensing are available in the may need a short course of topical corticosteroids
product information.21 and possibly a change to oral methylphenidate.
Dexmethylphenidate is the isomeric form of The used patch should be disposed of properly,
methylphenidate and is available as an immedi- by folding it in half with the sticky sides stuck
ate-release Focalin (Novartis), and long-acting together to avoid abuse potential or accidental
Focalin XR formulation.22 The dose is about one- ingestion by a small child or pet.
half of the racemic methylphenidate formula-
tions. The long-acting formulation is the bimodal Amphetamine
release system described above (SODAS). Even though the mechanism of action is
Methylphenidate also is available as a trans- believed to be similar for methylphenidate
dermal patch, Daytrana (Noven Pharmaceuticals and amphetamine products, the amphetamine
Inc, Miami, FL).23 The patch is applied to the hip products also increase dopamine release. The am-
area every day, typically for 9 hours. The fam- phetamine products also have more potential for
ily should apply the patch onto the child in the decreased appetite.25 There are immediate-release
morning, 2 hours before the desired time of effect, tablets, extended-release capsules, and liquid
and remove it after 9 hours; however, it should available. The capsule formulations of Adderall
be noted that the drug’s effect may continue for XR (Shire US Inc, Wayne, PA), Dexedrine Span-
up to 2 to 3 hours after taking off the patch. The sules (Catalent Pharma Solutions, Winchester,
patch may be removed earlier than 9 hours if KY), and Vyvanse (Shire US) can be opened and
a shorter duration of effect is desired or if the placed on soft foods.15,22,26 As with methylphe-
patient is experiencing side effects later in the nidate, food does not affect the overall benefit
day. The patch is known to produce a rash and of amphetamines; however, there is a delay in
irritation at the application site in upwards of absorption of about 2.5 hours if a high-fat meal is
40% of patients.24 The application site should be eaten with the mixed amphetamine salts.15 When
rotated every day to try and limit the potential comparing the immediate-release preparations of
for rash; however, if irritation appears, the patient amphetamine/dextroamphetamine and methyl-

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JPPT L Briars, et al

Table 3. Management of ADHD Medication Side Effects59,60

Medication Side Effect Strategies to Manage


Psychostimulants: Decreased appetite, Administer medication with food/after meal or switch to short-
side effects nausea, vomiting, acting agent. Monitor height and weight every 6 months. Drug
common to the headache holidays may be beneficial if significant decrease in growth is
class noted.
Sleep disturbances Avoid late afternoon and evening dosage. Use short-acting
agent or switch to atomoxetine. Decrease bedtime stimuli and
consider addition of melatonin.

Labile mood, irritability Decrease dose or consider discontinuation of medication with


further evaluation of potential comorbid conditions.
Psychiatric symptoms Evaluate comorbid conditions before starting therapy.
Development of symptoms is rare (<0.1%); however, if new
psychiatric symptoms emerge once a psychostimulant is started,
consider changing therapy.
Tic disorder ADHD is a common comorbidity with tic disorders. Although
ADHD medications do not cause tics, in some cases they may
exacerbate an underlying tic disorder. Alternative therapies
for ADHD should be considered, if tics worsen while on
psychostimulants include alpha2 agonists or atomoxetine.
Cardiovascular risk Baseline evaluation of BP, HR, and family/patient history of
heart disease should occur. There is a possible increased risk of
cardiovascular event when decreasing psychostimulant dose60;
however, further investigation is needed.
Priapism May occur while on therapy, but has been reported after
discontinuation of therapy. This is considered a medical
emergency and should be treated immediately.
Daytrana Leukoderma Loss of skin pigmentation has been reported and may persist
after discontinuation. Discontinue patch use if leukoderma is
noted.
Atomoxetine Abdominal pain, vomiting, To assist with tolerance, use recommended dose titration when
decreased appetite initiating therapy. May give with food. Administration BID;
divided dose may help decrease side effects.

Somnolence, fatigue, Administer once daily at bedtime.


dizziness
Priapism Considered a medical emergency and patient should seek care
immediately.
Psychiatric symptoms, Development of new psychiatric symptoms is rare (<0.2%).
including suicidal Suicidal ideations (0.4%) have been noted, but no completed
thoughts or behaviors suicides have been reported.
Alpha2 agonists Somnolence, fatigue, Administer at bedtime.
dizziness
Blood pressure changes Titrate slowly to maximum effective dose to avoid lowering
of BP. Avoid abrupt discontinuation and taper slowly to avoid
rebound hypertension.
ADHD, attention-deficit/hyperactivity disorder; BID, two times a day; BP, blood pressure; HR, heart rate

phenidate, Pelham et al25 reported that amphet- methylphenidate. However, dosing needs to be
amine/dextroamphetamine seemed to have a individualized by symptom response. Vyvanse
longer, sustained effect at about half the dose of (lisdexamfetamine dimesylate) is a prodrug that
198 J Pediatr Pharmacol Ther 2016 Vol. 21 No. 3 • www.jppt.org
Common ADHD Medications JPPT
is converted to the active metabolite dextroam- least 2 weeks before the start of school in order to
phetamine in the gut, which may reduce the achieve maximum benefit. In any case, however,
potential for abuse. these “drug holidays” are less often implemented,
owing to the chronic nature of ADHD. The medi-
Clinical Use of Psychostimulants cation may be discontinued temporarily during
Selection of psychostimulants depends upon the school year once the student is established
duration of coverage desired, formulation within his/her class to determine whether or
required, and cost. As mentioned earlier, the not the medication is at the proper dose or if it is
pharmacodynamic profile differs among the necessary to continue the medication. During any
various agents. If a child or adolescent only needs change in dose or trial off of medication, evalua-
help during school, the product chosen should tions should be completed so as to discern if medi-
provide about 6 to 8 hours of action, whereas if cation continues to be needed. If a child reaches
a child or adolescent needs benefit to maintain the maximum daily dose recommended without
after-school activities, including homework and clinical benefit, consider changing to a different
driving, a 12-hour product should be consid- psychostimulant, especially if no adverse reac-
ered.16,27 The usual initial regimen starts with an tions occurred. An example might be in a child
immediate-release psychostimulant adminis- who has been on Concerta at maximum daily
tered twice daily (e.g., 5 mg two times daily) for doses with minimal clinical benefit, but has had
those that are smaller in weight (i.e., <16 kg),1 and no adverse reactions. A clinician may consider
then the dose is titrated to a maximum effective switching to an amphetamine-based product,
dose producing minimal side effects. In children e.g., Adderall (Teva Select Brands, Horsham,
who are older and larger, and adolescents, the PA). However, if adverse drug reactions occur
smallest effective dose should be initiated and (i.e., decreased appetite, headache), the isomeric
titrated upwards. Many of the sustained-release formulation of methylphenidate, dexmethylphe-
formulations are available in lower strengths nidate, could be considered. If side effects persist
and may be used as initial therapy. In clinical or if psychostimulants have not provided optimal
practice, with the newer once-daily formulations benefit, non-psychostimulant therapy should be
now available, most providers will start with a considered.
once-daily, long-acting formulation (e.g., Con-
certa, Ritalin LA, or Metadate CD). If sustained- Atomoxetine
release formulations are not providing adequate As noted above, psychostimulants are consid-
coverage, an immediate-release formulation is ered to be the first-line medications for the treat-
added in the afternoon. Unlike other medications ment of ADHD. However, some patients may
used in pediatrics, weight-based dosage is not not be able to take agents from this class owing
used routinely with these agents. These medi- to their inability to tolerate the side effect profile
cations should be taken daily to gain complete or the presence of a contraindicating factor, such
clinical benefit. At least monthly follow-up is as an allergy to a psychostimulant product or a
recommended with face-to-face interviews and comorbid tic condition (e.g., Tourette’s disorder).
completion of teacher and parent evaluations to Additionally, anywhere from 10% to 30% of
determine effectiveness of the regimen. patients will not respond to psychostimulants.28
Drug holidays may be used in a variety of Atomoxetine is an alternative agent for these pa-
situations. For example, in patients experiencing tients. Atomoxetine is theorized to be a selective
weight loss, a period off of drug may provide time norepinephrine reuptake inhibitor.29 As a result of
for a child to gain some weight. Another common the inhibition, concentrations of norepinephrine
drug holiday that families request is time off of and dopamine are increased in the prefrontal
medication during the summertime. If a child cortex of the brain, which is believed to control
ends a school year on medication and the family behaviors. The localization of this effect limits the
chooses to not administer medication during the impact of the medication on the remaining areas
summer, it is highly recommended to restart the of the brain and may explain why atomoxetine
medication at the end of summer break so that the lacks abuse potential.30 Therefore, unlike the
child can start the new school year with medica- psychostimulants, atomoxetine is not a controlled
tion. Restarting of the medication should be at substance.

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JPPT L Briars, et al

Unlike psychostimulants, the initial dosage Atomoxetine is relatively well tolerated by


for atomoxetine in younger children is based patients. 34 Somnolence, dry mouth, nausea,
on weight and is then titrated after a minimum constipation, dizziness, and decreased appetite
of 3 days to allow the patient time to adjust are often seen early in the treatment course and
to the medication’s impact and adverse drug tend to subside significantly over time.29 Insom-
reactions.29 For young children and adolescent nia may develop over time and may be worse in
patients weighing less than or equal to 70 kg, the those patients with evening doses. Atomoxetine
initial dose is 0.5 mg/kg/day given once daily in may mildly increase both heart rate and blood
the morning. After the recommended 3-day ad- pressure, and may produce orthostatic hypoten-
justment period to assess for tolerability, the dose sion, but does not impact growth.29,35
can be increased to 1.2 mg/kg/day, if needed for Two potentially fatal issues can be seen in
efficacy. Doses larger than 1.4 mg/kg/day or 100 patients taking atomoxetine, and pharmacists
mg/day have not been found to improve results should counsel the patients and their families
and should be avoided owing to increased risks about monitoring for these reactions. 29,33 As
for adverse reactions. Children 6 years of age or with other medications that impact the central
older, adolescent patients weighing greater than nervous system neurotransmitters, atomoxetine
70 kg, and adults are not dosed by weight, but in- has the potential to increase suicidal ideation in
stead have a standard initial dose of 40 mg daily. patients and this is listed as a Black Box warning
The dose can be titrated to 80 mg after the rec- in the product information. However, it is not
ommended 3-day adjustment period if needed. considered a contraindication. The risk for this
If this dose fails to control the patient’s ADHD reaction is greatest when initially starting the
symptoms, it can be titrated to 100 mg after 2 to medication or when dose adjustments are made.
4 weeks.31 In both age groups, total daily doses The patients and their families should be warned
can be given as a single dose in the morning or to watch for these types of thoughts or significant
can be split evenly between a morning dose and changes in behavior or mood and to report them
an early evening dose.29 Splitting the daily dose immediately to a health care provider for close
into 2 doses does not impact daytime results of management. Similarly, patients and families
the agent, but may decrease side effects experi- will need to monitor for any evidence of liver
enced by the patient and improve symptoms in failure, such as change in urine color or jaundice.
the home setting after school.32 This is most likely If these symptoms appear, the medication should
due to the product’s duration of action, which is be stopped immediately and liver function tests
limited to near 9 hours, as noted in research and performed.
review articles by Wigal.31 The exact duration of Atomoxetine has been proven effective when
action is variable between patients and may be compared to placebo in a number of double-
due to alterations in metabolism, which will be blind, placebo controlled trials.36,37 Slightly less
discussed in the next paragraph. In contrast to clear is the comparative efficacy of atomoxetine
the near immediate effects of the psychostimu- and psychostimulants. In 2010, May and Kratoch-
lants, atomoxetine may take 1 to 2 weeks before vil38 published an evaluation comparing all psy-
manifesting an initial response; after reaching the chostimulants to atomoxetine and indicated that
recommended maximum daily dose for his/her in most trials the psychostimulants performed
weight, a patient’s symptoms may continue to better than atomoxetine. However, when looking
improve for up to 2 months.32 If the patient fails at individual agents, the results can differ. For
to respond to atomoxetine or develops intolerable example, immediate-release methylphenidate
adverse reactions, the medication can be stopped demonstrates similar efficacy to atomoxetine,
abruptly without tapering.29 but when comparing Concerta to atomoxetine, a
Atomoxetine is metabolized in the liver by the clear advantage is observed with Concerta.39 As
cytochrome P450 2D6 pathway.28,29 Approximate- of 2013, only 1 small pilot study formally evalu-
ly 7% of the Caucasian population are poor me- ated using atomoxetine with methylphenidate.
tabolizers within this pathway and may require Although the pilot study had promising results,
dose adjustments. Similarly, patients using other this combination cannot be recommended at
medications that are known inhibitors of the 2D6 this time owing to the limited amount of data
pathway will need to be followed up closely.33 available.40

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Common ADHD Medications JPPT
Alpha2-Agonists been found to be more effective than smaller
Before the release of atomoxetine in 2002,29 doses and increases the side effect potential of
there were no Food and Drug Administration the drug. Doses can be taken in the morning or at
(FDA) approved alternatives to psychostimu- bedtime, but should consistently be given at the
lants for the management of ADHD symptoms. same time each day.42 Improvement in symptoms
Immediate-release clonidine and guanfacine, is typically observed when the dose reaches 0.05
alpha2-agonists used for blood pressure control, to 0.08 mg/kg/day.42
were used off-label as second-line agents for pa- Extended-release clonidine, Kapvay (Shiongi
tients failing 2 psychostimulants or as adjunctive Inc, Florham Park, NJ), is initiated at 0.1 mg at
therapy for patients with suboptimal results with bedtime. At weekly intervals the daily dose can
a psychostimulant alone.1,33,34 These agents were be titrated by 0.1 mg. Doses larger than 0.1 mg
also used if the patient had a comorbid condi- should be split into equal morning and evening
tion resulting in tics, such as Tourette’s disorder, doses. If equal doses are not possible, the larger
which could be exacerbated by psychostimulant dose should be at night.
therapy.35 However, these agents could be dif- The full impact of these agents on ADHD
ficult for the patient to tolerate owing to their symptoms may not be seen until 7 to 14 days
side effect profile and they may place the patient have elapsed.44 If it becomes necessary to stop
at a significant risk for rebound hypertension either of these agents, it is important to taper the
if abruptly discontinued. Recently, extended- medication slowly to avoid rebound hyperten-
release versions of each drug have become sion. Doses of extended-release guanfacine can
available, which minimize the initial drop in be decreased by 1 mg every 3 to 7 days. Doses of
blood pressure and are better tolerated than their extended-release clonidine are decreased by 0.1
immediate-release counterparts.34 These agents mg every 3 to 7 days.42,43
should be considered for patients that have failed Extended-release clonidine is metabolized in
psychostimulant monotherapy or atomoxetine the liver to inactive metabolites. In terms of drug
or require treatment for comorbid psychiatric interactions, this metabolism is beneficial, since
conditions. Additionally, patients exhibiting serum concentrations are not impacted. How-
aggression may benefit from alpha2-agonist ever, health care providers should remember
therapy owing to its subtle sedative effect.41 The that this agent will still exhibit drug interactions
alpha2-agonists can be used as monotherapy or by potentiating adverse reactions, such as seda-
as adjunctive therapy in patients with suboptimal tion or hypotension, or antagonizing the effects
response to psychostimulants.42,43 of other therapies. In contrast, extended-release
The exact mechanism of action for the alpha2- guanfacine is metabolized by the cytochrome
agonists in ADHD is not known.34 The predomi- P450 3A4 pathway, and dose adjustments will
nant theory is that these agents work by directly be needed when using guanfacine with strong
mimicking norepinephrine effects at the alpha2A inducers or inhibitors of this pathway.42,43
adrenoreceptors in the prefrontal cortex. Guan- In the long term, the alpha2-agonists are gen-
facine is selective for the alpha2A adrenorecep- erally well tolerated. Upon initiation of either
tors, while clonidine is active at the alpha2A,B, agent, the patient may experience some transient
and C
adrenoreceptors. Theoretically, this implies adverse drug reactions. The most common of
that guanfacine and clonidine will have similar these reactions are dizziness, drowsiness, fatigue,
efficacy via stimulation of the alpha2A adrenore- and headache. It should be noted that the alpha2-
ceptors, but guanfacine may have less sedation agonists may exacerbate depression and they
and impact on blood pressure owing to its lack should not be used in patients with pre-existing
of effect on the alpha2B and C adrenoreceptors.34 depression.42,43 These agents pose a risk for hy-
Each product has its own unique dosing regi- potension, orthostatic hypotension, and brady-
men. Extended-release guanfacine, Intuniv (Shire cardia; therefore, patients should be monitored
US), is approved for patients older than 6 years closely at initiation, at subsequent evaluations,
and is initiated at a dose of 1 mg per day. At and with each dose adjustment. Over time, the
weekly intervals the daily dose can be increased patient will develop tolerance to the blood pres-
by 1 mg until a response is seen or the daily dose sure change.34,42,43 Guanfacine has been shown
reaches 4 mg. Doses larger than 4 mg have not to be less sedating and less potent in decreasing

J Pediatr Pharmacol Ther 2016 Vol. 21 No. 3 • www.jppt.org 201


JPPT L Briars, et al

blood pressure and may be tolerated better by pa- Multimodal Treatment Study of Children With
tients sensitive to these issues.38 When comparing Attention-Deficit/Hyperactivity Disorder
the alpha2-agonists to the psychostimulants as The MTA study was started in 1992 and is fol-
monotherapy for ADHD, the alpha2-agonists do lowing up 579 children long term with ADHD.
not perform nearly as well. Assessments indicate There is now a published 8-year follow-up study
that Intuniv and Kapvay are approximately 40% in which school-aged children (7-9 years old) have
to 75% as effective as the psychostimulants in been evaluated after initial intensive randomized
managing the primary symptoms of ADHD.45,46 therapy with either behavioral-based treatment
However, these agents can be used along with a alone, medication alone, a combination of behav-
psychostimulant to provide better results if the ior therapy plus medication or community care.49
patient has suboptimal response to the psycho- The initial intensive treatment phase was for 14
stimulant alone.38,47,48 months. Thereafter, the children were followed
up “naturally” and without randomization. In
Non-Standard Therapies a 14-month interim analysis, there was more
The American Academy of Pediatrics guide- clinical improvement in the combination therapy
line for the diagnosis, evaluation, and treatment group (behavior plus medication therapy). How-
of ADHD in children and adolescents recognizes ever, it was noted that the children in the MTA
the role of the psychostimulants, atomoxetine, medication treatment arms received larger doses
and the alpha 2 -adrenergic agonists in the of medication for a longer period of time and
management of patients with ADHD.44 Other medication management by a clinical pharmacist
agents (e.g., venlafaxine, monoamine oxidase occurred monthly, compared to the community-
inhibitors) have been studied for the potential treated group where this did not occur.11,52,53 In
management of ADHD symptoms; however, the 8-year follow-up study, there appears to be
these options are not currently FDA-indicated a loss of sustained effects of medication after 2
for the condition or suggested for use within the years. Since the long-term follow-up was done
major guidelines. “naturally” and without randomization, it is very
difficult to know if sustained clinical benefit may
BEHAVIORAL-BASED THERAPY have been maintained with intensive medication
management plus behavioral therapy. The one
There is still a lot of discussion as to where outcome that does seem to hold true, though, is
behavioral therapy fits into the armamentarium that patient’s initial symptoms and severity of ill-
for ADHD treatment. Should behavior therapy ness better predict future outcome than type and
be used as first-line therapy for all patients or intensity of therapy initiated. Children diagnosed
only those who are younger or with milder with ADHD do poorer overall than their peers
symptoms? Is medication plus behavior therapy without ADHD.49
the best plan for all patients? Many studies have
looked at these questions, and guidelines and rec- SUMMARY
ommendations are available from the American
Psychiatric Association, the American Medical Despite the multitude of pharmacological
Association, and the American Academy of Child agents for the treatment of ADHD, there are
and Adolescent Psychiatry. Unfortunately, all 3 many questions remaining regarding the treat-
organizations have slightly different opinions. ment algorithm that will provide the most clinical
With more recent studies (e.g., the multimodal benefit with the least side effects. In particular, it
treatment study of children with ADHD [MTA]), is important to consider long-term efficacy of psy-
there is evidence suggesting that researchers chostimulant use and protection or lack thereof
have not been identifying and monitoring for the for delinquent behavior and substance abuse.
correct outcomes.49 Looking more at functional Despite small studies showing some “protection”
outcomes versus the DSM listing of symptoms against these adolescent behaviors, it is still un-
may be more beneficial in the long term. Some known if ADHD medications will decrease sub-
of these functional outcomes include activities of stance use. The MTA study looked at substance
daily living, peer and parent relationships, and use and overall concluded that nicotine and mari-
academic achievement.50-51 juana use is increased in children with an ADHD

202 J Pediatr Pharmacol Ther 2016 Vol. 21 No. 3 • www.jppt.org


Common ADHD Medications JPPT
diagnosis, but current standard pharmacological 3. Polanczyk G, de Lima MS, Horta BL, et
treatment has not conclusively demonstrated al. The world-wide prevalence of ADHD:
decreases or “protection” against this behavior.61 a systematic review and metaregression
Psychostimulants remain the agents of choice, analysis. Am J Psychiatry. 2007;164:942-948.
with atomoxetine, a non-controlled substance, 4. Frochlich TE, Lamphear BP, Epstein JN, et
as an alternative option for those patients un- al. Prevalence, recognition, and treatment
able to tolerate or having failed psychostimulant of attention-deficit/hyperactivity disorder
therapy. Alpha2-agonists offer another option for in a national sample of U.S. children. Arch
those patients with comorbid conditions such as Pediatr Adolesc Med. 2007;161(9):857-864.
tics or aggression. Non-standard therapies, in- 5. Ramtekkar UP, Reiersen AM, Todorov
cluding antidepressants and monoamine oxidase AA, Todd RD. Sex and age differences in
inhibitors, have been studied, but their place in attention-deficit/hyperactivity disorder
therapy has yet to be determined. Questions still symptoms and diagnosis. J Am Acad Child
remain as to the exact duration of therapy, but Adolesc Psychiatry. 2010;49(3):217-228.
trials off of medication, i.e., drug holidays, may 6. Dopheide JA, Pliszka SR. Attention-deficit-
be warranted to determine continued need for hyperactivity disorder: an update. Pharma-
medication. Thus, choice of medication, dose, cotherapy. 2009;29(6):656-679.
monitoring, and drug holiday options need to 7. Willcutt EG, Doyle AE, Nigg JT, et al. Va-
be individually tailored. lidity of the executive function theory of
attention-deficit/hyperactivity disorder:
Disclosure The authors declare no conflicts or financial a meta-analytic review. Biol Psychiatry.
interest in any product or service mentioned in the 2005;57:1336-1346.
manuscript, including grants, equipment, medications, 8. Hunt RD. Functional roles of norepi-
employment, gifts, and honoraria.
nephrine and dopamine in ADHD. Med-
Abbreviations ADHD, attention-deficit/hyperactivity dis-
scape Psychiatry & Mental Health. March
order; DSM-5: Diagnostic and Statistical Manual of Mental 2006;11(1). http://www.medscape.org/
Disorders, fifth edition; FDA, The United States Food and viewarticle/523887. Accessed April 19,
Drug Administration; MTA, multimodal treatment study 2016.
of children with attention-deficit/hyperactivity disorder; 9. Faraone SV, Perlis RH, Doyle AE, et al.
OROS, osmotic-controlled release oral delivery system; Molecular genetics of attention-deficit/
SODAS, spheroidal oral drug absorption system hyperactivity disorder. Biol Psychiatry.
2005;57:1313-1323.
Correspondence Leslie Briars, PharmD, 833 S Wood St,
10. American Psychiatric Association. Diagnos-
Mail Code 886, The University of Illinois at Chicago Col-
lege of Pharmacy, Chicago, IL 60612, email: las@uic.edu
tic and Statistical Manual of Mental Disorders.
5th ed. Arlington, VA: American Psychiatric
REFERENCES Association; 2013.
11. MTA Cooperative Group. National Institute
1. Pliszka SR, Bernet W, Bukstein O, et al; for of Mental Health multimodal treatment
the American Academy of Child and Ado- study of ADHD follow-up: changes in
lescent Psychiatry Work Group on Quality effectiveness and growth after the end of
Issues. Practice parameter for the assess- treatment. Pediatrics. 2004;113(4):762-769.
ment and treatment of children and ado- 12. Harstad EB, Weaver AL, Katusic SK,
lescents with attention-deficit-hyperactivity et al. ADHD, stimulant treatment, and
disorder. J Am Acad Child Adolesc Psychiatry. growth: a longitudinal study. Pediatrics.
2007;46(7):894-921. 2014;134:e935-e944.
2. Willcut EG. The prevalence of DSM-IV 13. Perrin JM, Friedman RA, Knilans TK.
attention-deficit/hyperactivity disorder: Cardiovascular monitoring and stimulant
a meta-analytic review. Neurotherapeutics. drugs for attention-deficit/hyperactivity
2012;9(3):490-499. disorder. Pediatrics. 2008;122:451-453.

J Pediatr Pharmacol Ther 2016 Vol. 21 No. 3 • www.jppt.org 203


JPPT L Briars, et al

14. Ritalin, Ritalin SR [product information]. 24. Anderson VR, Scott LJ. Methylphenidate
East Hanover, NJ: Novartis Pharmaceu- transdermal system in attention-deficit
ticals Corporation; April 2015. http:// hyperactivity disorder in children. Drugs.
pharma.us.novartis.com/product/pi/pdf/ 2006;66(8):1117-1126.
ritalin_ritalin-sr.pdf. Accessed April 1, 2016. 25. Pelham WE, Aronoff HR, Midlam JK, et
15. Adderall XR [product information]. Wayne, al. A comparison of Ritalin and Adderall:
PA: Shire US Inc. April 2015. http:// efficacy and time-course in children with
pi.shirecontent.com/PI/PDFs/Adderal- attention-deficit/hyperactivity disorder.
lXR_USA_ENG.PDF. Accessed April 1, Pediatrics.1999;103:1-14.
2016. 26. Vyvanse [product information]. Wayne,
16. Markowitz JS, Straughn AB, Patrick KS. PA: Shire US Inc; January 2015. http://
Advances in the pharmacotherapy of pi.shirecontent.com/PI/PDFs/Vyvanse_
attention-deficit-hyperactivity disorder: USA_ENG.pdf. Accessed April 1, 2016.
focus on methylphenidate formulations. 27. Swanson JM, Wigal SB, Wigal T, et al. A
Pharmacotherapy. 2003;23(10):1281-1299. comparison of once-daily extended-release
17. Ritalin LA [product information]. East methylphenidate formulations in children
Hanover, NJ: Novartis Pharmaceuticals with attention-deficit/hyperactivity disor-
Corporation; July 2015. http://www. der in the laboratory school (The Comacs
pharma.us.novartis.com/product/pi/pdf/ Study). Pediatrics. 2004;113(3):e206-e216.
ritalin_la.pdf. Accessed April 1, 2016. 28. Mohammadi MR, Akhondzadeh S. Phar-
18. Focalin XR [product information]. East macotherapy of attention-deficit/hyper-
Hanover, NJ: Novartis Pharmaceuticals activity disorder: nonstimulant medica-
Corporation; April 2015. http://www. tion approaches. Expert Rev Neurother.
pharma.us.novartis.com/product/pi/pdf/ 2007;7(2):195-201.
focalinXR.pdf. Accessed April 1, 2016. 29. Straterra [product information]. Indianapo-
19. Metadate CD [product information]. lis, IN: Lilly USA LLC; April 2015. http://
Smyrna, GA: UCB Inc. June 2009. http:// pi.lilly.com/us/strattera-pi.pdf. Accessed
www.ucb.com/_up/ucb_com_products/ March 31, 2016.
documents/Metadate%20CD%2011E%20 30. Banaschewski T, Roessner V, Dittmann
04-2012.pdf. Accessed April 1, 2016. RW, et al. Non-stimulant medications in
20. Concerta [product information]. Titusville, the treatment of ADHD. Eur Child Adolesc
NJ: McNeil Pediatrics – a division of Ortho- Psychiatry. 2004;13:102-116.
McNeil-Janssen Pharmaceuticals Inc; No- 31. Wigal SB. Efficacy and safety limitations
vember 2010. http://www.concerta.net/ of attention-deficit hyperactivity disorder
prescribing-information.html. Accessed pharmacotherapy in children and adults.
April 1, 2016. CNS Drugs. 2009;23(suppl 1):21-31.
21. Quillivant XR [product information]. 32. Waxmonsky JG, Waschbusch DA, Akinnusi
Monmouth Junction, NJ: Tris Pharma Inc; O, Pelham WE. A comparison of atomox-
February 2016. http://labeling.pfizer.com/ etine administered as once versus twice
ShowLabeling.aspx?id=965. Accessed April daily dosing on the school and home func-
1, 2016. tioning of children with attention-deficit/
22. Dexedrine [product information]. Win- hyperactivity disorder. J Child Adolesc Psy-
chester, KY: Catalent Pharma Solutions; Feb- chopharmacol. 2011;21(1):21-32.
ruary 2015. https://dailymed.nlm.nih.gov/ 33. Kaplan G, Newcorn JH. Pharmacotherapy
dailymed/drugInfo.cfm?setid=a37b6ef9- for child and adolescent attention-deficit
78b4-4b18-8797-ecb583502500. Accessed hyperactivity disorder. Pediatr Clin North
April 1, 2016. Am. 2011;58:99-120.
23. Daytrana [product information]. Miami, FL: 34. Martinez-Raga J, Knect C, Szerman N,
Noven Pharmaceuticals Inc; August 2015. Martinez MI. Risk of serious cardiovascular
https://dailymed.nlm.nih.gov/dailymed/ problems with medications for attention-
drugInfo.cfm?setid=2c312c31-3198-4775- deficit hyperactivity disorder. CNS Drugs.
91ab-294e0b4b9e7f. Accessed April 1, 2016. 2013;27:15-30.

204 J Pediatr Pharmacol Ther 2016 Vol. 21 No. 3 • www.jppt.org


Common ADHD Medications JPPT
35. Spencer TJ, Kratochvil CJ, Sangal RB, et 46. Jain R, Segal S, Kollin SH, Khayrallah M.
al. Effects of atomoxetine on growth in Clonidine extended-release tablets for
children with attention-deficit/hyperac- pediatric patients with attention-deficit/
tivity disorder following up to 5 years of hyperactivity disorder. J Am Acad Child
treatment. J Child Adolesc Psychopharmacol. Adolesc Psychiatry. 2011;50(2):171-179.
2007;17(5):689-699. 47. Burkstein OG, Head J. Guanfacine ER
36. Cheng JY, Chen RY, Ko JS, et al. Efficacy for the treatment of adolescent attention-
and safety of atomoxetine for attention- deficit/hyperactivity disorder. Expert Opin
deficit/hyperactivity disorder in children Pharmacother. 2012;13(15):2207-2213.
and adolescents: meta-analysis and meta- 48. Sallee FR. The role of alpha2-adrenergic
regression analysis. Psychopharmacology. agonists in attention-deficit/hyperactivity
2007;194(2):197-209. disorder. Postgrad Med. 2010;122(5):78-87.
37. Kratochvil CJ, Mitlon DR, Vaughan BS, 49. Molina BSG, Hinshaw SP, Swanson JM, et
Greenhill LL. Acute atomoxetine treatment al. The MTA at 8 years: prospective follow-
of younger and older children with ADHD: up of children treated for combined-type
a meta-analysis of tolerability and effi- ADHD in a multisite study. J Am Acad Child
cacy. Child Adolesc Psychiatry Ment Health. Adolesc Psychiatry. 2009;48(5):484-500.
2008;2:25-34. 50. Pelham WE, Fabiano GA. Evidence-based
38. May DE, Kratochvil CJ. Attention-deficit psychosocial treatments for attention-
hyperactivity disorder. Drugs. 2010;70(1):15- deficit/hyperactivity disorder. J Clin Child
39. Garnock-Jones KP, Keating GM. Atomox- Adolesc Psychol. 2008;37(1):184-214.
etine: a review of its use in attention-deficit 51. Creating a daily report card from home;
hyperactivity disorder in children and ado- 2002. How to establish a daily report card
lescents. Pediatr Drugs. 2009;11(3):203-226. (school-home note); cited 2013 April 24
40. Carlson GA, Dunn D, Kelsey D, et al. A pilot [treatment materials]. New York: Univer-
study for augmenting atomoxetine with sity of Buffalo Center for Children and
methylphenidate: safety of concomitant Families. http://ccf.buffalo.edu/resourc-
therapy in children with attention-deficit/ es_downloads.php#PT. Accessed May 19,
hyperactivity disorder. Child Adolesc Psy- 2016.
chiatry Ment Health. 2007;1:10-17. 52. Jensen PS, Arnold LE, Swanson JM, et
41. Hunt RD, Capper L, O’Connell P. Clonidine al. 3-year follow-up of the HIMH MTA
in child and adolescent psychiatry. J Child study. J Am Acad Child Adolesc Psychiatry.
Adolesc Psychopharmacol. 1990:1(1):87-102. 2007;46(8):989-1002.
42. Intuniv [product information]. Wayne, 53. Murray DW, Arnold E, Swanson J, et al.
PA: Shire US Inc; February 2013. http:// A clinical review of outcomes of the mul-
pi.shirecontent.com/PI/PDFs/Intuniv_ timodal treatment study of children with
USA_ENG.pdf. Accessed January 31, 2016. attention-deficit/hyperactivity disorder
43. Kapvay [product information]. Florham (MTA). Curr Psychiatry Rep. 2008;10:424-431.
Park, NJ: Shiongi Inc; February 2013. 54. United States Department of Health and
http://kapvay.com/pdf/kapvay-conc-v1- Human Services. US Food and Drug
USPI.pdf. Accessed July 9, 2015. Administration. Questions and answers
44. American Academy of Pediatrics. ADHD: regarding methylphenidate hydrochloride
clinical practice guideline for the diagnosis, extended release tablets (generic Con-
evaluation, and treatment of attention-def- certa) made by Mallinckrodt and Kudco.
icit/hyperactivity disorder in children and http://www.fda.gov/drugs/drugsafety/
adolescents. Pediatrics. 2011;128(5):1007- ucm422569.htm. Accessed April 1, 2016.
1022. 55. Aptensio XR [product information]. Green-
45. Sallee FR, Eaton K. Guanfacine extended- ville, NC: Patheon Manufacturing Services
release for attention deficit/hyperactiv- LLC; April 2015. http://aptensioxr.com/
ity disorder. Expert Opin Pharmacother. resources/full-prescribing-information.
2010;11(15):2549-2556. pdf. Accessed April 1, 2016.

J Pediatr Pharmacol Ther 2016 Vol. 21 No. 3 • www.jppt.org 205


JPPT L Briars, et al

56. Zenzedi [product information]. Atlanta, 59. Cortese S, Holtmann M, Banaschewski T, et


GA: Arbor Pharmaceuticals LLC; January al. Practitioner review: current best practice
2014. http://zenzedi.com/docs/PIand- in the management of adverse events dur-
MedicationGuide.pdf. Accessed February ing treatment with ADHD medications in
2, 2016. children and adolescents. J Child Psychol
57. Quillichew ER [product information]. Psychiatry. 2013; 54(3):227-246.
Monmouth Junction, NJ: Tris Pharma Inc; 60. Dalsgaard S, Kvist AP, Leckman JF, et al.
December 2015. http://labeling.pfizer. Cardiovascular safety of stimulants in chil-
com/ShowLabeling.aspx?id=2577#page2. dren with attention-deficit/hyperactivity
Accessed February 2, 2016. disorder: a nationwide prospective cohort
58. Adzenys XR-ODT [product information]. study. J Child Adolesc Psychopharmacol.
Grand Prairie, TX: Neos Therapeutics LP. 2014;24(6):302-310.
January 2016. http://www.adzenysxrodt. 61. Molina BSG, Hinshaw SP, Arnold LE, et
com/files/PI-Adzenys-XR-ODT-FDA.pdf. al. Adolescent substance use in the multi-
Accessed February 2, 2016. modal treatment study of attention-deficit/
hyperactivity disorder (ADHD) (MTA) as
a function of childhood ADHD, random
assignment to childhood treatments, and
subsequent medication. J Am Acad Child
Adolesc Psychiatry. 2013;52(3):250-263.

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NIH Public Access
Author Manuscript
Wiley Interdiscip Rev Cogn Sci. Author manuscript; available in PMC 2016 January 01.
Published in final edited form as:
NIH-PA Author Manuscript

Wiley Interdiscip Rev Cogn Sci. 2015 ; 6(1): 39–52. doi:10.1002/wcs.1324.

ADHD, Multimodal Treatment, and Longitudinal Outcome:


Evidence, Paradox, and Challenge
Stephen P. Hinshaw1, L. Eugene Arnold2, and For the MTA Cooperative Group
Stephen P. Hinshaw: hinshaw@berkeley.edu
1Department of Psychology, Tolman Hall, University of California, Berkeley CA 94720
2Departmentof Psychiatry, 395E McCampbell Hall, 1581 Dodd Dr., Ohio State University,
Columbus, OH 43210

Abstract
Given major increases in the diagnosis of attention-deficit hyperactivity disorder (ADHD) and in
NIH-PA Author Manuscript

rates of medication for this condition, we carefully examine evidence for effects of single versus
multimodal (i.e., combined medication and psychosocial/behavioral) interventions for ADHD. Our
primary data source is the Multimodal Treatment Study of Children with ADHD (MTA), a 14-
month, randomized clinical trial in which intensive behavioral, medication, and multimodal
treatment arms were contrasted with one another and with community intervention (treatment-as-
usual), regarding outcome domains of ADHD symptoms, comorbidities, and core functional
impairments. Although initial reports emphasized the superiority of well-monitored medication for
symptomatic improvement, reanalyses and reappraisals have highlighted (a) the superiority of
combination treatment for composite outcomes and for domains of functional impairment (e.g.,
academic achievement, social skills, parenting practices); (b) the importance of considering
moderator and mediator processes underlying differential patterns of outcome, including comorbid
subgroups and improvements in family discipline style during the intervention period; (c) the
emergence of side effects (e.g., mild growth suppression) in youth treated with long-term
medication; and (d) the diminution of medication’s initial superiority once the randomly assigned
treatment phase turned into naturalistic follow-up. The key paradox is that whereas ADHD clearly
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responds to medication and behavioral treatment in the short term, evidence for long-term
effectiveness remains elusive. We close with discussion of future directions and a call for greater
understanding of relevant developmental processes in the attempt to promote optimal, generalized,
and lasting treatments for this important and impairing neurodevelopmental disorder.

Attention-deficit hyperactivity disorder (ADHD) is a highly impairing neurodevelopmental


disorder that originates in childhood. This condition is newsworthy on many fronts,
particularly its fast-rising rates of diagnosis and of medication treatment across recent
years.1 Contrary to the myth that ADHD is merely a label for bothersome, fidgety behavior
in boys, this disorder, whether defined categorically or dimensionally, is highly impairing,
clearly present in girls (although at lower rates than in boys), and strongly heritable.2,3 Still,

Correspondence to: Stephen P. Hinshaw, hinshaw@berkeley.edu.


No disclosures.
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ADHD is “revealed” most saliently in the context of achievement and vocational pressures,
meaning that biological underpinnings and contextual factors are inseparable in terms of
gaining full understanding of this clinical condition.1 Given the extent to which problems of
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focus, inhibitory control, and self-regulation provide windows on both brain mechanisms
and current cultural contexts, intensified basic and clinical research on ADHD remains a
core priority. At the same time, this disorder mandates careful assessment and diagnosis, to
differentiate it from normative behavior patterns, child maltreatment, or a number of other
child/adolescent disorders.1 Moreover, given the serious academic, social, familial, and
accidental-injury consequences of ADHD, as well as its risk for incurring comorbid
conditions and later substance abuse, the need for development and dissemination of
efficacious and effective treatments is pressing.1,2

Two decades ago a landmark, randomized clinical trial for children with ADHD took place.
This investigation, known as the Multimodal Treatment Study of Children with ADHD
(MTA), directly contrasted, in a large and carefully diagnosed sample of children aged 7–9.9
years—all with the “combined” presentation of ADHD (i.e., high rates of both inattention
and hyperactivity/impulsivity)—the following intervention strategies: (1) systematic
medication procedures, involving an initial titration to establish the optimal medication and
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dosage, followed by monthly pharmacotherapy visits; (2) an intensive behavioral treatment


package including home, school, and summer treatment components; (3) the combination of
the first two interventions; and (4) treatment as usual in community settings. Treatments
spanned 14 months; systematic, naturalistic, longitudinal follow-up then occurred for 15
years after the study treatments ceased.4

Although high levels of symptom-related improvement were yielded by the study’s


medication algorithm—without statistically or clinically significant increment from the
addition of intensive behavioral intervention5,6—additional analyses revealed that for
composited outcomes of adult-rated symptoms, and particularly for functional impairments
(i.e., academic achievement, peer-related social skills, and parenting practices),
combination/multimodal treatment was optimal.7,8 Furthermore, cost-benefit analyses
suggested strongly that for complex cases with substantial comorbidities, the addition of
behavioral treatment to medication was justified.9 Moreover, moderator analyses highlighted
that treatments were far less than optimal for children with pre-existing parental depression,
severe child ADHD symptoms, and subaverage child cognitive skills.10 At the same time,
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mediator analyses revealed that when accompanied by clinically significant improvements


in parenting style, multimodal treatment yielded not just improvement but even
normalization of school-reported behavior patterns.11 Finally, and crucially, the initial
superiority of medication with respect to symptom improvement gradually abated after the
randomly assigned interventions ceased, becoming nonsignificant two years later.12,13,14 At
the same time, certain side effects (e.g., a slight diminution of ultimate adult height)
persisted in some cases, leading to additional questions about the long-term advantages and
disadvantages of pharmacologic intervention for ADHD.15

In all, inattentive and hyperactive-impulsive symptomatology and its functional


consequences exact huge personal, familial, and economic costs. As a result, there is great
need to analyze and discuss the promise and limitations of existing treatment strategies and

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to prioritize high levels of investment in developing sustained, generalized, evidence-based


interventions for the condition known as ADHD. Without such concerted efforts, high levels
of suffering (for individuals, families, schools, and communities) and low rates of
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productivity are likely to persist.

ADHD: A BRIEF OVERVIEW


The subject of voluminous research, ADHD remains a fascinating and complex syndrome.
Defined by developmentally extreme and impairing symptoms in the domains of inattention/
disorganization and hyperactivity impulsivity,16 ADHD—when diagnosed carefully—is
associated with highly impairing outcomes in the core domains of academic performance,
social relationships, parent-child interactions and family stress, and risk for serious
accidental injury.2,17,18,19 Thus, ADHD is not simply a societal or psychiatric label for
fidgety, bothersome behavior or a sign of a society’s intolerance of behavioral
nonconformity. Instead, it represents a lack of full development of self-regulation,
frequently accompanied by deficits in key executive functions (e.g., inhibitory control,
working memory, planning, and the like) and highly likely to be accompanied by a variety
of comorbid conditions (e.g., excessive aggression, depression and anxiety, learning
disorders).1,2,16 Understanding and treating this syndrome is a priority for both mental
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health and public health.

The unevenness of performance of individuals with ADHD is both puzzling to and


frustrating for peers and other social partners. People showing high rates of relevant
symptomatology can be quite engaging but seemingly oblivious to social cues, cognitively
sharp but unable to complete tasks or manage their time, resourceful and full of ideas but
without the inner resources to sustain intrinsic motivation or refrain from outbursts of pique
or frustration. Academic underachievement is prevalent; over time, rates of substance abuse,
delinquency, poor relationship functioning, and (particularly for girls) self-injurious
behavior during adolescence and adulthood are alarming, occurring at far-beyond-normative
levels and signaling the serious impairments accruing to this condition.2,20 By adulthood,
associate problems in close relationships and in vocational endeavors are rampant.
Moreover, even though childhood ADHD is highly likely to be accompanied by comorbid
psychiatric conditions, core ADHD symptomatology is typically responsible for much of the
functional impairment accruing from this disorder.
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The symptom domains linked to ADHD are highly heritable.21 Yet, as with all other
psychiatric syndromes, the effects of any specific risk alleles are quite small, and gene-
environment interplay is likely to be of major significance for exacerbation of symptoms and
impairments.17 Additional risk factors include low birthweight, maternal ingestion of
noxious substances (e.g., alcohol or nicotine), and other toxins (e.g., lead; pesticides).3
Except in cases of severe physical and emotional deprivation, relevant symptomatology does
not appear to stem from aberrant parenting practices per se, although overly harsh or lax
parenting can be highly relevant for predicting developmental course.22

Current models of ADHD include disrupted attention, deficits in response inhibition, poor
executive function/cognitive control more generally, and problems in arousal and reward

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sensitivity. These models implicate neurotransmitter systems linked to dopamine and


norepinephrine, with multiple pathways likely to be involved in the most severe cases.2,23,24
At the same time, despite the clear neurophysiological roots of ADHD, it is in the context of
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family interactions, school demands, and (by adulthood) vocational settings and intimate
relationships that the problems related to ADHD are elicited, maintained, and magnified. In
other words, when work demands get harder, when emotion regulation is required, and when
self-control is at a premium, ADHD tends to rear its head most explosively.

Typically revealing itself in early to middle childhood, ADHD extends into adolescence and
adulthood in a majority of individuals.25 Across these developmental periods, childhood
ADHD portends problems in delinquency and antisocial behavior, substance abuse, risk for
accidental injury (including risky driving), and (particularly in females) internalizing
disorders and self-injurious behavior.26 Indeed, when comorbid disorders, family
dysfunction, and peer problems accompany ADHD-related symptomatology, the risk for
poor outcome substantially intensifies, signaling the importance of (a) differential diagnosis
and (b) ascertaining the comorbid conditions that may legitimately accompany ADHD. As
noted above, thorough assessments are necessary in order to rule out competing conditions,
including response to trauma; account for comorbid disorders; and differentiate symptoms
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from normal-range behavior patterns.1

TYPES OF TREATMENTS
Many treatments for ADHD have been implemented over the years. However, no consistent
evidence exists that one-on-one therapy with the child (still a common intervention strategy
with many youth) provides meaningful benefit, even though for adults with ADHD,
cognitive-behavioral therapy has shown real promise.27,28 In addition, despite periodic
surges in popularity, dietary interventions typically yield small effects; neurofeedback
training (in which individuals learn to control their brain waves toward the end of enhancing
self-regulation) has not received unequivocal support from controlled trials despite some
promise; and specific cognitive training (e.g., exercises to enhance working memory) does
not appear to provide generalized or lasting change.29,30,31 Coaching for adolescents and
adults has proliferated as well, but it remains relatively unspecified and unevaluated.
Whereas some families and some individuals give testimonials to these kinds of treatment
modalities—as well as far more esoteric alternatives that often crowd web pages with
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glowing case reports—to date the gold standard of randomized clinical trials has been met
mainly by behavior therapy and pharmacotherapy. Specifically, the consistently evidence-
based treatments for this condition involve (a) behavioral interventions (and for adults,
cognitive-behavioral treatments, as noted),32,33 and (b) medications, chiefly those that target
dopaminergic and noradrenergic neurotransmitter systems.34,35

Behavioral Intervention
For youth with ADHD, direct contingency management programs in school or summer
camp programs can motivate improved behavior, but more common are clinical behavior
therapy interventions, which target parents and teachers as the recipients of intervention.
These adults learn to break tasks down into component parts, provide regular reinforcement
(including clear and non-emotional consequences for misbehavior), and strive, over time, to

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promote the child’s self-regulation. Peer groups, if highly structured, may provide important
social benefits as well. A host of controlled studies reveal positive benefits of parent
management and teacher consultation, which admittedly require substantial time and energy
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on the part of the adults who deliver prompts and reinforcement.36,37,38

Medication
The main types of medications used to treat ADHD are called stimulants, which facilitate
actions of dopamine, in particular. Noradenergic agonists are also evidence-based
interventions for this condition. Hundreds of controlled trials reveal the behavioral and
cognitive benefits yielded by stimulants for individuals with ADHD—particularly when a
proper dosage is administered and potential side effects (e.g., appetite suppression, sleep
disruption) are avoided. Such effects may be sustained over at least two years.39,40,41 Of
course, however, medications alone cannot teach skills and competencies. Furthermore,
although pharmacologic intervention is helpful for youth with ADHD even when comorbid
conditions are present, the presence of conduct disorder, internalizing disorders, and
learning disabilities mandates the use of concerted psychosocial treatment strategies to
supplement treatments directed toward ADHD per se.42 In short, it’s not just a matter of
reducing problem behavior but of facilitating problem solving, planning, error correction,
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academic performance, and social skills to yield real impact on the lives of individuals
grappling with ADHD. It may well be that deficient dopamine neurotransmission underlies
the need for regular, tailored rewards to assist managing this condition.

Combination Treatments
In theory, the effects of behavioral and medication interventions should at least be additive:
the brain’s “fine tuning” via dopmanergic and/or noradrenergic enhancement may set the
stage for better “take” of reward-based programs designed to teach skills and reduce
problem behavior. Initial trials during the 1970s and 1980s showed trends along these lines,
although in other cases the symptom reduction provided by medication alone produced a
limit on any added benefit from behavioral intervention.43,44,45 In addition, controlled trials
of behavioral treatment, medication, and their combination were almost uniformly of
relatively short duration (several months at longest), precluding definitive information on
the potential for potentiation of pharmacologic with psychosocial treatment. Thus, a strong
rationale came to exist, during the 1990s, for trials that would allow inference about the
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additive benefits of pharmacologic and psychosocial treatments over relatively long periods
of time. Since then, in addition to the MTA study (the trial under discussion), other long-
term trials have provided mixed information about whether behavior therapy and social
skills interventions provide a significant increment over medication alone in terms of
improving core outcomes.41

SPECIFICS OF MTA DESIGN AND CORE FINDINGS


Design Considerations
After a competitive request for applications and review of submitted proposals, the National
Institute of Mental Health, which provided the bulk of funding for the initial years of the
MTA, stipulated that the selected investigators would need to meet, face to face, once per

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month for a year and a half to design a collaborative, parallel intervention across the six sites
represented. The final MTA protocol was forged across an intensive set of such meetings.
Following considerable discussion and debate, the design involved a between-subject
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randomized clinical trial for children aged 7.0–9.9 years of age who had been carefully
diagnosed with ADHD-Combined type. (Indeed, the baseline assessment battery spanned
nearly 10 hours, a far cry from the extremely quick assessments that all too often lead to
designations of ADHD status at present.1) In other words, each participant had to show
clinically impairing symptoms of both inattention and hyperactivity/impulsivity, yielding
problems in both home and school settings.16 Moreover, most of the common comorbidities
accompanying ADHD (e.g., oppositional and aggressive behavior patterns, anxiety
disorders, learning disabilities) were allowed. Funds were available to support a 14-month
trial, to test whether the skill-building approach inherent in behavioral treatments could
compete with (or significantly increment) the expected gains from medications.

In short, the MTA Study was clearly designed as an effectiveness trial, involving treatments
in real-world settings such as schools, with highly comorbid participants rather than mildly
impaired cases treated in laboratory settings. Yet it also included core elements of efficacy
trials, including random assignment of participants to treatment conditions, in order to
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bolster causal claims about the relative benefits of medication and behavioral treatments.
Via a between-group design, conducted in parallel at the six sites, children and families were
randomly assigned to one of the four following intervention conditions after parents had
given thorough consent for participation, with rigorous cross-site training and monitoring
performed throughout the trial to ensure that a unified set of claims could be made at the end
of treatment.4,46,47

Behavioral Treatment—Here, intensive clinical behavior therapy was deployed. Thirty-


five parent training sessions were offered, mostly in groups of six families but also including
periodic individual sessions. In addition, twice-monthly teacher consultation was performed
by the same psychologist who conducted the parent training, focused on integrating the
home and school interventions. Next, children participated in an 8-week summer treatment
program featuring direct contingency management. To promote generalization, a classroom
aide (in the form of a counselor from the summer program) spent three hours per day in the
classroom of the child’s second school year of participation. In short, this treatment arm was
designed to be intensive, exemplifying the kinds of behavior management and skill building
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that might stand up to a medication approach. Each treatment component was scrupulously
manualized.48

Medication Management—Children and families assigned to this condition first


underwent a 4-week medication titration trial, with daily switches of three stimulant (mainly
methylphenidate) doses and placebo, intended to ascertain optimal dosage on the basis of
regular parent and teacher ratings of symptoms, target behaviors, and side effects. Once the
initial dose was selected, participants saw their pharmacotherapist for thirty minutes each
month; information from the child’s teacher helped to guide ongoing dosage monitoring and
adjustment. Moreover, the child was seen alone at the end of each session, to promote
adherence. This level of monitoring was intended to be far more intensive than usual care.

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The recommendation of three doses per day (of the then-available short-acting formulations
of stimulants), along with the recommendation for weekend doses, was made to ensure
continuous waking coverage with medication. Formal behavior therapy was not permitted,
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to prevent overlap with our behavioral-treatment conditions; but common pediatric


behavioral techniques were allowed, such as a star chart for dry nights if enuresis came up in
the session. If we had excluded what physicians would commonly do in the course of
medication management, it would not have given a fair chance for medication treatment to
“work.” Again, a detailed manual guided the MTA pharmacotherapy protocol, including
needed psychotherapeutic aspects of pharmacotherapy.49

Combined Treatment—Here, families received the multimodal combination of the first


two conditions. Because of the more frequent contact with study professionals in this
treatment arm, it was conceivable that medication dosage would be adjusted upward
frequently. Thus, the design specifications were such that any adjustments in treatment had
to initially involve the behavioral aspects of intervention rather than medication. As it turned
out, the final medication dosages were significantly lower in Combined treatment than in
Medication Management.6
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Community Comparison—A major design issue related to the composition of our


“community comparison” group: it would have been impractical and even unethical to insist
on no intervention across 14 months for the remaining 25% of families in the MTA trial.
Thus, this condition comprised treatment as usual in the community: families received a full
report of the study’s assessment findings and a list of general sources of referral in the
community but were not treated by MTA practitioners. As it turned out, 68% of the
Community Comparison families procured stimulant medications for their children during
the 14-month intervention period. Yet periodic service utilization interviews during the
course of the trial revealed that such medication treatment was far less intensive than in our
own Medication Management and Combination Treatment conditions, comprising, on
average, brief visits with a pediatrician every six months, without afternoon dosing or school
contact to guide medication adjustments.6

Core Findings
Outcomes were measured at 3 months and 9 months into the treatment period and again at
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post-treatment (14 months). They spanned six core domains: ADHD, externalizing, and
internalizing symptoms, and the important functional outcomes of academic achievement,
parent-child interactions, and peer relations/social skills.50 Given the six domains of
outcome, with multiple measures per domain, stringent per-comparison alpha adjustments
were made within domain to reduce Type I errors in interpretation of findings.

After the 14 months of active intervention, the core symptoms of ADHD showed
significantly greater improvement in the Medication Management and Combinaton
conditions than in Behavioral Treatment or Community Comparison conditions.5 Indeed,
symptom reduction was virtually identical in the first two conditions, a finding that received
substantial media attention in the aftermath of the treatment phase of the investigation. For
the other symptom areas and the domains of functional impairment, treatment differences

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were smaller, with the most prevalent outcome that Combination Treatment was
significantly superior to Community Comparison but with the other five contrasts not
showing as consistent a pattern. Furthermore, one-fourth of the Behavioral Treatment
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participants required medication before the 14-month treatment period ended—either going
back on medication if they had received pharmacologic intervention prior to the study or
taking it for the first time if their symptoms and impairments worsened during the course of
the study.6

In short, the core outcome paper5 discussed the within-subject improvements, on average,
for participants in all four randomly assigned treatments as well as the relative superiority of
well-delivered medication treatment for ADHD, contrasted with intensive behavioral
intervention or with far-less-rigorous medication intervention in the community. On the
basis of these data, U.S. treatment guidelines for ADHD came to feature medication as a
first-line treatment,51,52 whereas parallel European guidelines did not.53 Still, the MTA
results were instrumental in increasing medication use and respectability, even in Europe.

ADDITIONAL ANALYSES AND LONGITUDINAL FOLLOW-UP


Composited Outcomes
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When secondary analyses were published several years after the initial publications,
composite outcome measures were featured. First, parent and teacher ratings of ADHD were
combined and then dichotomized, yielding an index of “excellent response” (ER),
comprising post-treatment scores that were below ‘just a little’ on the rating-scale metric,
trending toward rates found in normative samples. With this outcome measure, the rate of
ER in the Combined condition was 68%, significantly better than the rate of 56% in
Medication Management (Behavioral treatment yielded a rate of 34%, with Community
Comparison trailing the pack at 25%).7 A separate outcome analysis featured a factor score
as the primary outcome, which amalgamated the three symptom domains of ADHD,
externalizing (i.e., aggressive), and internalizing (i.e., anxious/depressed) plus three domains
of functional impairmemt: objectively measured reading and math scores, parent-reported
discipline practices at home, and teacher-rated social skills at school. Here again, the
sharpest rate of improvement occurred with Combined treatment, followed respectively by
Medication Management, Behavioral, and Community Comparison (all pairwise contrasts
were significantly different).8 In short, with composite outcome measures, including those
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tapping functional impairment, a significant increment over medication alone (of small
effect) was found for multimodal intervention.

Recall that, in our Community Comparison condition, over two-thirds of the children
received stimulant medications—the same intervention featured in the MM and Comb
treatments. An important mediator analysis, however, revealed the following:6 (a)
medication in the Community Comparison group was dispensed with infrequent monitoring
and at probably inadequate dosages; (b) outcomes of the medicated subgroup of Community
Comparison participants were superior to those CC children who did not receive medication;
and (c) the Behavioral Treatment results were statistically comparable, at post-intervention,
to those of the medicated Community Comparison participants. Crucially, however, well-
delivered medication—with accurate dosing, frequent monitoring, dosages spanning after-

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school hours, contact with teachers, and clinical time with the child during each visit (to
discuss issues of medication adherence, etc.)—in our Medication Management and
Combined Treatment conditions proved far superior to medication practices in the
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community. Quality of delivery of pharmacologic intervention is crucial for optimal effects.


The same is doubtless true for psychosocial interventions as well, although we did have the
means for such a comparison in the MTA database.

The bottom line is that the planned comparisons related to the MTA’s primary hypotheses
showed clear benefits for medication, when rigorously dosed and monitored, for symptom
reduction, even though alternative analyses including more reliable outcomes featuring
functional impairment indicated significant superiority for multimodal intervention—i.e.,
significant incremental benefit of adding behavioral treatment to medication. Yet these latter
findings appeared several years after publication of the core findings, with far less attention
in the media.

Moderators and Mediators


Moderators of Treatment Response—In a clinical trial, a moderator is a pretreatment
(baseline) variable that distinguishes the treatment response of individuals in the trial’s
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different conditions.54 (Predictors are associated with better or worse outcome across the
treatments, for the whole sample.) Importantly, several potential moderator variables did not
yield significant findings in the MTA. For example, boys versus girls showed similar
patterns of response, as did those youth who entered the study with versus without histories
of receiving stimulant medication. In addition, and somewhat surprisingly, the 54% of the
MTA sample who entered the study with comorbid diagnoses of aggressive behavior
patterns (i.e., oppositional defiant disorder or conduct disorder) did not show an appreciably
different response to any of the four randomly assigned treatments.6

Second, however, the presence of a comorbid anxiety disorder (all DSM categories except
for specific phobias)—which comprised just over a third of the sample at pre-treatment—
signaled important treatment-condition differences in response to intervention, particularly
with regard to behavioral treatment. Specifically, the subgroup with ADHD plus any
comorbid anxiety disorder showed a better response to Behavioral Treatment and Combined
Treatment than did those lacking such comorbidity. Indeed, for youth with comorbid anxiety
disorders, (a) response to Behavioral Treatment was comparable to response to Medication
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Management, and (b) response to Combined Treatment was even better.6 Finer-grained
examination of such response patterns revealed that children with ADHD plus anxiety
disorder (but without disruptive behavior disorder comorbidity) were the ones who
responded equally well all three MTA treatments. For those with both anxiety disorders and
oppositional defiant or conduct disorders, multimodal (Combined) intervention was better
than either unimodal treatment.55,56 Although underlying mechanisms are not certain—for
example, do youth with ADHD showing anxiety disorders respond better to contingencies?
or are their parents better able to adhere to parent management training?—practitioners
would be advised to evaluate for the presence of anxiety disorders in children with ADHD
and consider behavioral treatment as a first-line approach for such youth and families. We

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lacked sufficient sample size to assert, with confidence, precisely which anxiety disorders
might be at play in this regard.
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Another moderator finding was that for the one family in five who participated in the MTA
trial who received public assistance—that is, those families in the lowest socioeconomic
strata who required welfare support of one kind or another—only Combined Treatment
yielded meaningful benefit with respect to the outcome of teacher-reported social skills.6
Thus, for the study’s most disenfranchised families, it took both well-delivered and
systematically monitored medication plus intensive home and school behavior therapy to
yield important gains in the social/peer domain. Furthermore, in an examination of the
interactive influence of a several moderator variables considered simultaneously, Owens and
colleagues found that, for children receiving either Medication Management or Combined
Treatment, (a) caregiver symptoms of depression and (b) more severe initial ADHD
symptomatology in the child predicted worse outcome than for those with less-depressed
parents or only moderate levels of ADHD severity. For children with subaverage IQ scores
as well, this pattern was intensified. In short, once a child has been diagnosed with ADHD,
difficulties at home (parental depression), more severe symptoms, and worse-than-average
intelligence predict a less robust response to intervention (in this case, pharmacologic
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treatment).10 It may be that early preventive nonmedical intervention—before symptoms


have yielded sufficient impairment to consolidate into a diagnosis—may be particularly
crucial for children with ADHD, especially those from lower-SES families, as highlighted in
recent professional treatment guidelines.52

Mediators of Treatment Response—Unlike moderators, mediators are those variables


defining processes that occur during the period of active intervention, with potential
explanatory power for how treatments exert their effects.54 One basic mediator process is
participation in treatment: It may well be the case that families who attend more sessions
encourage more gains in their children’s behavior over time. Intriguingly, however, we
found that attendance patterns at parent training sessions in the Behavioral Treatment and
Combined Treatment conditions were not associated with differential patterns of outcome.
On the other hand, attendance at pharmacotherapy sessions was clearly linked to child
outcome.6 Indeed, without regular participation in such sessions, families could not receive
medication prescriptions.
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One possible speculative explanation here may relate to the intensity of the MTA behavioral
treatment package: perhaps the full dose was not necessary for optimal effect. That is,
parents who felt their child had already achieved sufficient improvement declined what they
perceived as “overdosage.” Also, benefits of behavioral intervention may continue through
missed visits, whereas medication only works while taken.

We tested another key mediator process, related to whether changes in family interactions
and family discipline style during the course of intervention would explain or mediate
important school-related outcomes. Before examining relevant results, we first raise the
point of whether parental discipline could actually be an important explanatory variable for
differential outcome in relation to ADHD, which has been established as a highly heritable
condition. Wouldn’t it be the case for such a biologically mediated, neurodevelopmental

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disorder that environmental and contextual factors are relatively unimportant? Yet it’s
mistaken to think that mental disorders with high genetic liability are impervious to
environmental input. In fact, recent work utilizing genetically informative designs reveals
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that family processes (particularly parental hostility) are important for the developmental
course of this condition, independent of potential genetic mediation of such traits.57
Moreover, investigators have been interested in parental discipline styles not so much as a
causal factor related to the onset of the relevant symptoms but instead as an important
contextual set of variables that may shape (or maintain) symptom expression and, in
particular, comorbidity19,58 For example, there may be a vicious cycle in which the child’s
symptoms exasperate and perturb the parent, who reacts hostilely, exacerbating symptoms in
a child who needs extra support (in biological families, such processes would exemplify
gene-environment correlation).

In sum, we hypothesized that for those parents who showed clear improvements in parenting
during the MTA treatment period, in the form of reductions in ineffective and negative
discipline practices, their children would demonstrate the greatest responses to intervention,
particularly for participants receiving behavioral treatment. The key outcome was teacher-
reported social skills and impulsive/disruptive/aggressive behavior patterns (note that we
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chose teacher-reported outcomes in order not to confound the source of information on


parenting with the source of information on child outcomes).

The key finding was that for families in the Combined Treatment condition who
demonstrated the largest improvements in negative/ineffective discipline, their children’s (a)
social skills improved dramatically and (b) disruptive and aggressive behavior was reduced
into the normal range by the end of treatment—a pattern not found in Combined Treatment
when parenting did not show such improvements, nor in Behavioral Treatment alone.11 This
finding suggests that the improvement in parental discipline facilitated the child’s response
to medication in school. In other words, the crucial mechanism whereby children receiving
the multimodal combination of pharmacologic and psychosocial treatment promoted
normalization of school-related outcomes was through major improvements in parental
discipline style. Thus, a strongly heritable condition like ADHD is malleable with respect to
clinically significant improvements in parenting, further signaling the transactional
pathways underlying the developmental course of children with impairing attention and
impulse-control problems.
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We note, as well, that later publications utilizing objectively observed parenting behavior as
the outcome measure revealed the clear superiority of Behavioral and Combined Treatment
over Medication Management and Community Comparison conditions.59 Medication alone,
which reduced children’s problem behavior, was not sufficient for change in parenting skills
and practices per se. Clearly, to teach and motivate more adaptive parenting, active
psychosocial strategies are needed. The parent has to be taught to “shift gears” to reinforce
the child’s medication-linked behavioral improvement. It is undoubtedly the case that
bidirectional processes are at work in families of children with ADHD: early problem
behavior, linked to difficult temperament, elicits combinations of lax and harsh parenting,
which in turn promote worse child behavior. Intervening at the level of parenting, in

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addition to pharmacologic treatment for the child, is essential in promoting meaningful


change.
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Cost Benefit Analyses


The MTA investigators teamed with health economists to ascertain whether, for “simpler”
cases of ADHD without comorbidities versus more complex cases with impairing comorbid
disorders, single-modality versus multi-modal treatments would be viewed as cost-
effective.9,60 In an intriguing analysis, based on levels of overall impairment following
intervention, Foster and colleagues found that, for non-comorbid youth with ADHD,
Medication Management was effective clinically as well as cost effective. However, for
youth with comorbid anxiety disorders or comorbid disruptive behavior disorders, payers
willing to spend more to justify eventual savings would be likely to prefer behavioral
strategies, usually in combination with medication.9 In short, it may well be that
transcending symptoms of ADHD to include comorbid conditions and levels of life
impairment reveals the importance of multimodal treatment over pharmacologic intervention
alone, particularly in terms of long-range cost offset (e.g., preventing juvenile justice-related
outcomes).
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Side Effects
Any treatment, whether pharmacologic or psychosocial, incurs the risk of “treatment
emergent symptoms” (commonly termed side effects). In the MTA the typical short-term
side effects linked to stimulant medication (appetite reduction, sleep disruption) were
typically managed adequately by alterations of dosage or timing of pill delivery. However,
there has been a longer-term question of whether, over time, stimulants may suppress the
ultimate stature (height) of a child. Initial analyses revealed that previously medication-
naïve children who were medicated throughout the MTA treatment trial—as well as during
the initial two-year follow-up—showed a reduction of height of approximately one inch.61
This same level of growth suppression was noted, more recently, across a 10-year follow-up
interval.15 That is, intensive, consistent stimulant treatment causes, on average, a nearly 1-
inch growth lag the first year that is not caught up over the next 10 years if medication is
continued. The underlying message is that positive versus negative effects of treatments
must be weighed by clients as well as those funding those interventions.
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Naturalistic Follow-up
As noted in passing within the previous section on side effects, the MTA investigators
prioritized longitudinal follow-up beyond the 14-month period of active intervention, to
explore the persistence of any initial benefits or the potential emergence of “sleeper” effects
across time. In effect, all participating families became members of the Community
Comparison condition after the formal period of intervention ended, in that MTA staff no
longer provided treatment—and families needed to fend for themselves in terms of
procuring services for their children. (Of course, a given family’s experiences during the
trial may have influenced their subsequent treatment decisions, revealing the complexities
involved in making inferences about lasting gains, plus the need for equally complex
statistical strategies for analyzing follow-up data.) In sum, after the clinical trial per se, the
MTA entered a 15-year phase of naturalistic follow-up.

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Ten months after the end of formal treatment, the relative advantage of the Medication
Management and Combined Treatment conditions over Behavioral Treatment and
Community Comparison with respect to ADHD symptomatology had been reduced by half.
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Specifically, participants in Behavioral Treatment (a third or more of whom were now


receiving medication) continued to show some improvement but the initially medicated
participants (some of whom had stopped medication) had begun to backslide. In another
year’s time participants across all four randomly assigned treatments were in an essential
dead heat with respect to nearly all core outcomes: The initial advantages for optimally
medicated participants had dissipated.12,62,63,64 This pattern—of initial superiority of
medication-based treatments that tapered and then evaporated once intensive, manualized
treatments had ended—has continued across all years subsequent follow-up.65 Still, this
convergence of results is at a level significantly improved from baseline, at least for ADHD
symptoms.

In the absence of a multi-year randomized trial, of course, it is impossible to assert with


certainty whether the tapering of the effectiveness of medication is related to the lack of a
continued, intensive medication treatment, to the tendency for participants with the highest
severity of symptoms to remain medicated, or to some other selection-related factors.
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However, careful propensity analyses showed that such selection biases were not likely
explanations,66 leaving open the possibility that medications targeting dopamine and
norepinephrine neurotransmission may, at least in some cases, have an “expiration date”
with respect to their effectiveness over the course of continuous administration. Medication
may not be an extended, hoped-for panacea in all individuals,67 despite the multiple short-
term randomized clinical investigations showing significant benefit compared to placebo in
children, adolescents, and adults.

In short, just like behavioral treatments, which are known to lack continued benefit once the
contingencies are lifted, medication for ADHD may not always be a viable lifelong option
(for detailed discussion of the intricacies of the MTA as it transformed from a randomized
clinical trial to naturalistic follow-up investigation, see Swanson and colleagues68,69). The
core question, therefore, is which intervention strategies, delivered at which time intervals
and at what levels of intensity, are optimal in promoting maintained change for different
subgroups of youth with ADHD.
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DISCUSSION
Key Findings
The initial reported findings of the MTA related to medication’s superiority were highly
influential in the press, in subsequent published treatment recommendations, and
undoubtedly in much clinical practice. Even though alternative analyses of outcomes,
reports of moderator and mediator processes, cost-benefit analyses, and follow-up findings
(see above sections) provided a far more complex picture of effectiveness than the early
publications had revealed, medication as a treatment has continued to soar in popularity.70
Indeed, even if behavioral and multimodal treatments are sought, too few practitioners are
skilled in their use, and reimbursements are usually far from adequate.1 Graduate and
professional training in evidence-based interventions is a major priority.

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Against the backdrop of soaring rates of ADHD diagnoses and medication treatment, and
given additional information about the limitations of medication as a sole treatment
modality, reconsideration of the MTA findings has been brewing, including many of the
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study’s primary investigators.71 ADHD is far from a set of symptoms that, when lowered, is
“cured.” Despite the clear benefits of medication in most cases of ADHD, initial gains may
not sustain, and side effects such as growth suppression must be taken into account. For
comorbid cases, in particular, it is apparent that several channels of intervention are
mandated; the presence of anxiety disorders with ADHD should steer practitioners to
behavioral/psychosocial interventions. The complex, transactional nature of biological
vulnerability, discordant family interactions, peer rejection, and classroom struggles faced
by far too many youth with this condition requires a fundamental reconceptualization of
needed intervention, which might include direct support for parental depression and ADHD-
related symptomatology,72 academic remediation, peer and friendship coaching,73
organizational skills training,74 well-coordinated parent-teacher interchange, and attention to
nutritional support.75 In addition, despite recent evidence that specific cognitive training for
ADHD (e.g., working memory training) does not lead to generalized gains, it may well be
the case that combining skills- and reinforcement-based behavioral interventions with
neurocognitive intervention holds promise.76 Moreover, the stunning mediator finding that
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parents in multimodal treatment the largest improvements in reducing negative/ineffective


discipline were precisely those whose children were normalized in terms of school behavior

Paradox
Despite the clear evidentiary base for medication and behavioral treatments related to
ADHD and despite suggestions that medication treatment may actually be neuroprotective
for individuals with ADHD (despite prevalent fears and stereotypes that they will disrupt
brain functioning),77 the effects of each dissipate rapidly when (a) the medication is
terminated or (b) the contingencies are lifted. Thus, both behavioral and medication
treatments are best viewed as palliative rather than curative. The paradox is that, despite
their proven short-term benefits, no clinically significant and enduring intervention (or
intervention combination) exists for this condition, as of yet. Perhaps this fact should come
as no great surprise, given the complex etiological pathways linked to its emergence and
maintenance of this condition.17,23,78 It will take advances in basic science—related to the
formation of synaptic pathways underlying attention, response inhibition, intrinsic
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motivation, and self-regulation—and (a) extending efficacious treatments and (b)


developing new treatments altogether to meet the considerable challenge ahead (indeed, see
Abikoff for cogent discussion of the challenges of promoting generalization in the treatment
of ADHD79). Intervention for ADHD must be viewed as a lifelong enterprise, with a major
need to implement developmental extensions of evidence-based treatments into adolescence
and adulthood, as well as development of new treatments appropriate for each age. The
clinical picture of ADHD’s trajectory is devastating in far too many cases, with outcomes of
academic and vocational failure, low levels of organizational skills and executive functions,
substance abuse, self-injury, and interpersonal tumult, demanding a concerted effort to
rethink our fundamental attitudes and approaches toward this condition.

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Hinshaw et al. Page 15

Conclusion
For a number of important reasons, clinical trials should be preregistered, with hypotheses
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and primary outcome measures publicized in advance of presentation of outcomes and with
data analyses emphasizing such procedures as “intent to treat,” meaning that once a
participant is randomized to a particular condition, he or she should always be analyzed with
respect to that condition.80 In other words, clinical trials should not typically be subject to an
“infinite regress” of alternative analyses, which may encumber the risk of promotion of
chance-level, after-the-fact conclusions. Still, there is good reason to consider that the
primary outcomes of the MTA, presented separately by domain and informant, yielded
experimentwise alpha correction procedures that overlooked the clinical significance of
multimodal treatment, particularly for measures linked to functional impairment.
Composited outcome measures, potentially more difficult to interpret clinically but
presumably more reliable and robust, provided evidence for preferential benefit from
combined treatment. In addition, understanding of moderator and mediator analyses
emphasizing the stronger response of comorbidity-defined or SES-linked subgroups (or of
parenting/discipline as a key mediator) with respect to multimodal intervention is essential
for full appreciation of the overall, average effects of the randomly assigned treatments. In
addition, and crucially, comprehending the differences between immediate response to
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treatments, even as intensive as those in the MTA trial, and longer-term outcomes into
adolescence and beyond presents a challenge to the assumption that ADHD is amenable to
significant long-range alteration from childhood-focused treatments alone. Finally, as
effective as medications are for promoting symptom change, it may well take skill building
and positive-habit-forming approaches related to behavioral and other forms of psychosocial
intervention to produce needed long-term improvements in the too-often dismal trajectories
related to ADHD.

The challenge ahead is therefore great. Even when stigma is overcome81 and an appropriate
diagnosis is made—and evidence-based treatment initiated—far more remains to be done.
Most saliently, the field needs to rethink the ways, beyond altering individual
neurochemistry per se, in which families, schools, and peer groups must be included in the
effort to foster self-regulation and age-appropriate competencies across the lifespan. Given
the increasing evidence for long-range impairments in the clear majority of individuals with
ADHD, such reconceptualization and renewed effort is of paramount importance.
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Acknowledgments
Dr. Arnold has received research funding from Curemark, Forest, Lilly, Neuropharm, Novartis, Noven, and Shire
(as well as NIH and Autism Speaks) and has consulted with or been on advisory boards for Gowlings, Neuropharm,
Novartis, Noven, Organon, Otsuka, Pfizer, Roche, Seaside Therapeutics, Sigma Tau, Shire, and Tris Pharma and
received travel support from Noven.

References
1. Hinshaw, SP.; Scheffler, RM. The ADHD Explosion: Myths, Medication, Money, and Today’s Push
for Performance. New York: Oxford University Press; 2014.
2. Barkley, RA., editor. Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and
Treatment (4th ed). New York: Guilford Press; in press

Wiley Interdiscip Rev Cogn Sci. Author manuscript; available in PMC 2016 January 01.
Hinshaw et al. Page 16

3. Nigg, JT. What Causes ADHD? Understanding What Goes Wrong and Why. New York: Guilford
Press; 2006.
4. Richters JE, Hinshaw SP. Psychiatry's turbid solution. Clin Psychol: Science and Practice. 1997;
NIH-PA Author Manuscript

4:276–280.
5. MTA Cooperative Group. Fourteen-month randomized clinical trial of treatment strategies for
attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1999; 56:1073–1086. [PubMed:
10591283]
6. MTA Cooperative Group. Moderators and mediators of treatment response for children with
ADHD: The MTA Study. Arch Gen Psychiatry. 1999; 56:1088–1096. [PubMed: 10591284]
7. Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, Clevenger W,
Davies M, Elliott G, Greenhill LL, et al. Clinical relevance of the primary findings of the MTA:
Success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Amer Acad
Child Adolesc Psychiatry. 2001; 40:168–179. [PubMed: 11211365]
8. Conners CK, Epstein JN, March JS, Angold A, Wells KC, Klaric J, Swanson JM, Abikoff HB,
Arnold LE, Elliott GR, et al. Multimodal treatment of ADHD in the MTA: An alternative outcome
analysis. J Am Acad Child Adolesc Psychiatry. 2001; 40:159–167. [PubMed: 11211364]
9. Foster EM, Jensen PS, Schlander M, Pelham WE, Hechtman L, Arnold LE, Swanson JM, Wigal T.
Treatment for ADHD: Is more complex treatment cost effective for more complex cases? Health
Services Research. 2007; 42:165–182. [PubMed: 17355587]
10. Owens EB, Hinshaw SP, Kraemer HC, Arnold LE, Abikoff HB, Cantwell DP, Conners CK, Elliott
G, Greenhill LL, Hechtman LT, et al. Which treatment for whom for ADHD? Moderators of
NIH-PA Author Manuscript

treatment response in the MTA. J Consult Clin Psychol. 2003; 71:540–552. [PubMed: 12795577]
11. Hinshaw SP, Owens EB, Wells KC, Kraemer HC, Abikoff HB, Arnold LE, Conners CK, Elliott G,
Greenhill LL, Hechtman L, et al. Family processes and treatment outcome in the MTA: Negative/
ineffective parenting practices in relation to multimodal treatment. J Abn Child Psychol. 2000;
28:555–568.
12. MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of
ADHD follow-up: 24-month outcomes of treatment strategies for attention-deficit hyperactivity
disorder. Pediatrics. 2004; 113:754–761. [PubMed: 15060224]
13. Jensen PS, Arnold LE, Swanson JM, Vitiello B, Abikoff HB, Greenhill LL, Hechtman L, Hinshaw
SP, Pelham WE, Wells KC, et al. Follow-up of the NIMH MTA study at 36 months after
randomization. J Am Acad Child Adolesc Psychiatry. 2007; 46:988–1001.
14. Molina BSG, Hinshaw SP, Swanson JM, Arnold LE, Vitiello B, Jensen PS, Epstein JN, Hoza B,
Hechtman L, Abikoff HB, et al. The MTA at 8 Years: Prospective follow-up of children treated
for combined type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry. 2009;
48:484–500. [PubMed: 19318991]
15. Swanson JM, Greenhill LL, Arnold LE, et al. kStimulant treatment and growth suppression in the
MTA trial: Long term effects. Unpublished manuscript.
16. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed).
Washington DC: American Psychiatric Press; 2013.
NIH-PA Author Manuscript

17. Nigg, J. Attention-deficit/hyperactivity disorder. In: Beauchaine, TP.; Hinshaw, SP., editors. Child
and Adolescent Psychopathology (2nd ed). Hoboken NJ: Wiley; 2013. p. 377-409.
18. Hoza B, Mrug S, Gerdes AC, Hinshaw SP, Bukowski JM, Gold J, Kraemer HC, Pelham WE,
Wigal T, Arnold LE. What aspects of peer relationships are impaired in children with ADHD? J
Consul Clin Psychol. 2005; 73:411–423.
19. Johnston C, Mash EJ. Families of children with attention-deficit/hyperactivity disorder: Review
and recommendations for future research. Clin Child Fam Psychol Rev. 2001; 4:183–207.
[PubMed: 11783738]
20. Hinshaw SP, Owens EB, Zalecki C, Huggins SP, Montenegro-Nevado A, Schrodek E, Swanson
EN, et al. Prospective follow-up of girls with attention-deficit hyperactivity disorder into young
adulthood: Continuing impairment includes elevated risk for suicide attempts and self-injury. J
Consult Clin Psychol. 2012; 80:1041–1051. [PubMed: 22889337]

Wiley Interdiscip Rev Cogn Sci. Author manuscript; available in PMC 2016 January 01.
Hinshaw et al. Page 17

21. Faraone SV, Perlis RH, Doyle AE, Smollar JW, Goralnick JJ, Holmgren MA, Sklar P. Molecular
genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005; 57:1313–1323.
[PubMed: 15950004]
NIH-PA Author Manuscript

22. Campbell, SB. Behavior Problems in Preschool Children (2nd ed). New York: Guilford Press;
2002.
23. Sonuga-Barke EJ. The dual pathway model of AD/HD: An elaboration of neuro- developmental
characteristics. Neurosci Biobeh Rev. 2003; 7:593–604.
24. Sjowall D, Roth R, Lindqvist S, Thorell LB. Multiple deficits in ADHD: Executive dysfunction,
delay aversion, reaction time variability, and emotional deficits. J Child Psychol Psychiatry. 2013;
54:619–627. [PubMed: 23061803]
25. Barkley, RA.; Murphy, K.; Fisher, M. ADHD in Adults: What the Science Says. New York:
Guilford Press; 2008.
26. Mannuzza S, Klein RG. Long-term prognosis in attention-deficit/hyperactivity disorder. Child
Adolesc Psychiatr Clin N Am. 2000; 9:711–726. [PubMed: 10944664]
27. Safren SA, Sprich S, Mimiaga MJ, Surman C, Knouse L, Groves M, Otto MW. Cognitive
behavioral therapy vs relaxation with educational support for medication-treated adults with
ADHD and persistent symptoms. JAMA. 2010; 304:875–880. [PubMed: 20736471]
28. Solanto, MV. Cognitive-behavioral Therapy for Adult ADHD: Targeting Executive Dysfunction.
New York: Guilford Press; 2011.
29. Sonuga-Barke EJ, Brandeis D, Cortese S, Daley D, Ferrin M, Holtmann M, Stevenson J,
Danckaerts M, van der Oord S, Dopfner M, et al. Nonpharmacological interventions for ADHD:
NIH-PA Author Manuscript

Systematic review and meta-analyses of randomized controlled trials of dietary and psychological
treatments. Am J Psychiatry. 2013; 170:275–289. [PubMed: 23360949]
30. Lofthouse N, Arnold LA, Hersch S, Hurt E, DeBeus R. A review of neurofeedback treatment for
pediatric ADHD. J Atten Disord. 2012; 16:351–372. [PubMed: 22090396]
31. Rutledge KJ, van den Bos W, McClure SM, Schweitzer JB. Training cognition in ADHD: current
findings, borrowed concepts, and future directions. Neurotherapeutics. 2012; 9:542–558.
[PubMed: 22911054]
32. Hinshaw, SP.; Klein, R.; Abikoff, H. Nonpharmacologic treatments and their combination with
medication. In: Nathan, PE.; Gorman, JM., editors. A Guide to Treatments that Work (3rd ed).
New York: Oxford University Press; 2007. p. 3-27.
33. Pelham WE, Fabiano GA. Evidence-based psychosocial treatment for attention deficit/
hyperactivity disorder: An update. J Clin Child Adolesc Psychol. 2008; 37:185–214.
34. Paykina, N.; Greenhill, LL. Pharmacological treatments for attention-deficit/ hyperactivity
disorder. In: Nathan, PE.; Gorman, JM., editors. A Guide to Treatments that Work (3rd ed). New
York: Oxford University Press; 2007. p. 29-70.
35. Wilens, TE. Straight Talk About Psychiatric Medications for Kids (3rd ed). New York: Guilford
Press; 2008.
36. Pelham, WE.; Hinshaw, SP. Behavioral intervention for attention-deficit hyperactivity disorder. In:
Turner, SM.; Calhoun, KS.; Adams, HE., editors. Handbook of Clinical Behavior Therapy (2nd
NIH-PA Author Manuscript

ed). New York: Wiley; 1992. p. 259-283.


37. Miller, M.; Hinshaw, SP. Attention-deficit/hyperactivity disorder. In: Kendall, PC., editor. Child
and Adolescent Therapy: Cognitive-behavioral Procedures (4th ed). New York: Guilford Press;
2011. p. 61-91.
38. Pfiffner LJ, Hinshaw SP, Owens EB, Zalecki C, Kaiser N, Villodas M, McBurnett K. A two-site
randomized clinical trial of integrated psychosocial treatment for ADHD-inattentive type. J
Consult Clin Psychol. 2014 online first.
39. Cascade E, Kalali AH, Wigal SB. Real-world data on attention deficit hyperactivity disorder
medication side effects. Psychiatry (Edgmont). 2010 Apr.4:3–15.
40. Garnock-Jones KP, Keating GM. Atomoxetine: a review of its use in attention-deficit hyperactivity
disorder in children and adolescents. Paedtr Drugs. 2009; 11:203–226.
41. Abikoff H, Hechtman L, Klein RG. Symptomatic improvement in children with ADHD treated
with long-term methylphenidate and multimodal psychosocial treatment. J Am Acad Child
Adolesc Psychiatry. 2004; 43:802–811. [PubMed: 15213581]

Wiley Interdiscip Rev Cogn Sci. Author manuscript; available in PMC 2016 January 01.
Hinshaw et al. Page 18

42. Hinshaw, SP. Psychosocial intervention for ADHD and comorbidities. In: Brown, TE., editor.
ADHD Comorbidities: Handbook for ADHD Complications in Children and Adults. Washington
DC: American Psychiatric Press; 2009. p. 385-398.
NIH-PA Author Manuscript

43. Klein RG, Abikoff H. Behavior therapy and methylphenidate in the treatment of children with
ADHD. J Atten Disord. 1997; 2:89–114.
44. Hinshaw SP, Henker B, Whalen CK. Cognitive-behavioral and pharmacologic interventions for
hyperactive boys: Comparative and combined effects. J Consult Clin Psychol. 1984; 52:739–749.
[PubMed: 6501659]
45. Hinshaw SP, Henker B, Whalen CK. Self-control in hyperactive boys in anger-inducing situations:
Effects of cognitive-behavioral training and of methylphenidate. J Abnorm Child Psychol. 1984;
12:55–77. [PubMed: 6715694]
46. Arnold LE, Abikoff H, Cantwell DP, Conners CK, Elliott GR, Hechtman LT, Hinshaw SP, Hoza
B, Jensen PS, Kraemer H, et al. National Institute of Mental Health Collaborative Multimodal
Treatment Study of Children with ADHD (MTA): Clinical design challenges and choices. Arch
Gen Psychiatry. 1997; 54:865–870. [PubMed: 9294378]
47. Arnold LE, Abikoff H, Cantwell DP, Conners CK, Elliott G, Greenhill LL, Hechtman LT,
Hinshaw SP, Hoza B, Jensen PS, et al. NIMH Collaborative Multimodal Treatment Study of
Children with ADHD (MTA): Design, methodology, and protocol evolution. J Atten Disord. 1997;
2:141–158.
48. Wells KC, Pelham WE, Kotkin RA, Hoza B, Abikoff H, Abramowitz A, Arnold LE, Cantwell DP,
Conners CK, Del Carmen R, et al. Psychosocial treatment strategies in the MTA Study: Rationale,
methods, and critical issues in design and implementation. J Abnorm Child Psychol. 2000;
NIH-PA Author Manuscript

28:483–505. [PubMed: 11104313]


49. Greenhill LL, Abikoff HB, Arnold LE, Cantwell DP, Conners CK, Elliott G, Hechtman L,
Hinshaw SP, Hoza B, Jensen PS, et al. Medication treatment strategies in the MTA Study:
Relevance to clinicians and researchers. J Am Acad Child Adolesc Psychiatry. 1996; 35:1304–
1313. [PubMed: 8885584]
50. Hinshaw SP, March JS, Abikoff H, Arnold LE, Cantwell DP, Conners CK, Elliott GR, Halperin J,
Greenhill LL, Hechtman LT, et al. Comprehensive assessment of childhood attention-deficit
hyperactivity disorder in the context of a multisite, multimodal clinical trial. J Atten Disord. 1997;
1:217–234.
51. American Academy of Child and Adolescent Psychiatry Work Group on Quality Issues. Practice
parameter for the assessment and treatment of children and adolescents with attention-deficit/
hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007; 46:894–921. [PubMed:
17581453]
52. American Academy of Pediatrics. ADHD: Clinical practice guideline for the diagnosis, evaluation,
and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics.
2011; 128:1007–1022. [PubMed: 22003063]
53. National Institute for Health and Clinical Excellence. Attention Deficit Hyperactivity Disorder:
Diagnosis and Management of ADHD in Children, Young People, and Adults. London: British
NIH-PA Author Manuscript

Psychological Society and Royal College of Psychiatrists; 2009.


54. Kraemer HC, Wilson GT, Fairburn CG, Agras WS. Mediators and moderators of treatment effects
in randomized clinical trials. Arch Gen Psychiatry. 2002; 59:877–883. [PubMed: 12365874]
55. March JS, Swanson JM, Arnold LE, Hoza B, Conners CK, Hinshaw SP, Hechtman L, Kraemer
HC, Greenhill LL, Abikoff H, et al. Anxiety as a predictor and outcome variable in the Multimodal
Treatment of Children with ADHD (MTA). J Abnorm Child Psychol. 2000; 28:527–541.
[PubMed: 11104315]
56. Jensen PS, Hinshaw SP, Kraemer HC, Lenora N, Abikoff HB, Conners CK, Elliott G, Hechtman
L, Hoza B, March JS, et al. ADHD comorbidity findings from the MTA study: Comparing
comorbid subgroups. J Amer Acad Child Adolesc Psychiatry. 2001; 40:147–158. [PubMed:
11211363]
57. Harold GT, Leve LD, Elam KK, Thapar A, Neiderhiser JM, Natsuaki NM, Shaw DS, Reiss D. The
nature of nurture: Disentangling passive genotype-environment correlation from family
relationship influences on children's externalizing problems. J Fam Psychol. 2013; 27:12–21.
[PubMed: 23421830]

Wiley Interdiscip Rev Cogn Sci. Author manuscript; available in PMC 2016 January 01.
Hinshaw et al. Page 19

58. Hinshaw, SP. Psychosocial intervention for childhood ADHD: Etiologic and developmental
themes, comorbidity, and integration with pharmacotherapy. In: Cicchetti, D.; Toth, SL., editors.
Rochester Symposium on Developmental Psychopathology (Vol. 9): Developmental approaches to
NIH-PA Author Manuscript

prevention and intervention. Rochester, NY: University of Rochester Press; 1999. p. 221-270.
59. Wells KC, Chi TC, Hinshaw SP, Epstein J, Pfiffner L, Nebel-Schwalm M, Owens EB, Arnold LE,
Abikoff H, Conners CK, et al. Treatment-related changes in objectively measured parenting
behaviors in the Multimodal Treatment Study of Children with ADHD. J Consult Clin Psychol.
2006; 74:649–657. [PubMed: 16881772]
60. Jensen PS, Garcia JA, Glied S, Crowe M, Schlander M, Hinshaw SP, Vitiello B, Arnold LE, Elliott
G, Hechtman L, et al. Cost-effectiveness of ADHD treatments: Findings from the Multimodal
Treatment Study of Children with ADHD. Am J Psychiatry. 2005; 162:1628–1636. [PubMed:
16135621]
61. Swanson JM, Elliott GR, Greenhill LL, Wigal T, Arnold LE, Vitiello B, Hechtman L, Epstein J,
Pelham W, Abikoff HB, et al. Effects of stimulant medication on growth rates across 3 years in the
MTA follow-up. J Amer Acad Child Adolesc Psychiatry. 2007; 46:1014–1022.
62. MTA Cooperative Group. Differential change in efficacy from post-treatment to initial follow-up
of MTA treatment strategies. Pediatrics. 2004; 113:762–770. [PubMed: 15060225]
63. Jensen PS, Arnold LE, Swanson JM, Vitiello B, Abikoff HB, Greenhill LL, Hechtman L, Hinshaw
SP, Pelham WE, Wells KC, et al. Follow-up of the NIMH MTA study at 36 months after
randomization. J Am Acad Child Adolesc Psychiatry. 2007; 46:988–1001.
64. Molina BSG, Flory K, Hinshaw SP, Greiner AR, Arnold LE, Swanson J, Hechtman L, Jensen PS,
Vitiello B, Hoza B, et al. Delinquent behavior and emerging substance use in the MTA at 36-
NIH-PA Author Manuscript

months: Prevalence, course, and treatment effects. J Am Acad Child Adolesc Psychiatry. 2007;
46:1022–1032.
65. Molina BSG, Hinshaw SP, Arnold LA, Swanson JM, Pelham WE, Hechtman L, Hoza B, Epstein
JN, Weal T, Abikoff HB, et al. Adolescent substance use in the MTA as a function of childhood
ADHD, random assignment to childhood treatments, and subsequent medication. J Am Acad
Child Adolesc Psychiatry. 2013; 52:260–263.
66. Swanson JM, Hinshaw SP, Arnold LE, Gibbons R, Marcus S, Hur K, Jensen PS, Vitiello B,
Abikoff H, Greenhill LL, et al. Secondary evaluations of MTA 36-month outcomes: Propensity
score and growth mixture model analyses. J Am Acad Child Adolesc Psychiatry. 2007; 46:1002–
1013.
67. Wang G-J, Volkow ND, Wigal T, Kollins SH, Newcorn JH, Telang F, Logan J, Jayne M, Wong
CT, Han H, et al. Long-term stimulant treatment affects brain dopamine transporter level in
patients with attention deficit hyperactive disorder. PLoS One. 2013:e63023. [PubMed: 23696790]
68. Swanson J, Arnold LE, Hechtman L, Molina B, Hinshaw SP, Vitiello B, Jensen P, Steinhoff K,
Lerner M, Greenhill L, et al. Evidence, interpretation, and qualification from multiple reports of
long-term outcomes in the Multimodal Treatment Study of Children with ADHD (MTA): Part I:
Executive summary. J Atten Disord. 2008; 12:4–14. [PubMed: 18573923]
69. Swanson J, Arnold LE, Hechtman L, Molina B, Hinshaw SP, Vitiello B, Jensen P, Steinhoff K,
NIH-PA Author Manuscript

Lerner M, Greenhill L, et al. Evidence, interpretation, and qualification from multiple reports of
long-term outcomes in the Multimodal Treatment Study of Children with ADHD (MTA): Part II:
Supporting details. J Atten Disord. 2008; 12:15–43. [PubMed: 18573924]
70. Visser SN, Danielson ML, Bitkso RH, Holbrook JR, Kogan MD, Ghandour RM, Perou R,
Blumberg SJ. Trends in the parent report of health care provider-diagnosed and medicated
attention deficit hyperactivity disorder: United States, 2003–1011. J Amer Acad Child Adolesc
Psychiatry. 2014; 53:34–46. [PubMed: 24342384]
71. Schwarz, AADHD. experts re-evaluate study’s zeal for drugs. New York Times. 2013 Dec 29.
retrieved from http://mobile.nytimes.com/2013/12/30/health/adhd-experts-re-evaluate-studys-zeal-
for-drugs.html?smid=tw-nytimeshealth&seid=auto&_r=0
72. Chronis AM, Chacko A, Fabiano A, Wymbs BT, Pelham WE. Enhancements to the behavioral
parent training paradigm for families of children with ADHD: Review and future directions. Clin
Child and Fam Psychol Rev. 2004; 7:1–27. [PubMed: 15119686]

Wiley Interdiscip Rev Cogn Sci. Author manuscript; available in PMC 2016 January 01.
Hinshaw et al. Page 20

73. Mikami AY, Lerner MD, Griggs MS, McGrath A, Calhoun CD. Parental influence on children
with attention-deficit/hyperactivity disorder: II Results of a pilot intervention training parents as
friendship coaches for children. J Consult Clin Psychol. 2010; 38:737–749.
NIH-PA Author Manuscript

74. Abikoff H, Gallagher R, Wells KC, Murray DW, Huang L, Lu F, Petkova E. Remediating
organizational functioning in children with ADHD: Immediate and long-term effects from a
randomized controlled trial. J Consult Clin Psychol. 2013; 81:113–128. [PubMed: 22889336]
75. Rucklidge JJ, Frampton CM, Gorman B, Boggis A. Vitamin-mineral treatment of attention-deficit
hyperactivity disorder in adults: double-blind randomised placebo-controlled trial. Br J Psychiatry.
2014 online ahead of print.
76. Chacko A, Kofler M, Jarrett M. Improving outcomes for youth with ADHD: A conceptual
framework for combined neurocognitive and skill-based treatment approaches. Clin Child Fam
Psychol Rev. 2014 online first.
77. Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J.
Effect of psychostimulants on brain structure and function in ADHD: A qualitative literature
review of magnetic resonance imaging-based neuroimaging studies. J Clin Psychiatry. 2013;
74:902–917. [PubMed: 24107764]
78. Volkow ND, Wang G, Kollins SH, Wigal TL, Newcorn JH, Telang F, Fowler JS, Zhu W, Logan J,
Ma Y, et al. Evaluating dopamine reward pathway in ADHD: Clinical implications. JAMA. 2009;
302:1084–1091. [PubMed: 19738093]
79. Abikoff H. ADHD psychosocial treatments: Generalization reconsidered. J Atten Disord. 2009;
13:207–210. [PubMed: 19553560]
NIH-PA Author Manuscript

80. Fisher LD. Advances in clinical trials in the twentieth century. Annu Rev Public Health. 1999;
20:109–124. [PubMed: 10352852]
81. Hinshaw, SP. The Mark of Shame: Stigma of Mental Illness and an Agenda for Change. New
York: Oxford University Press; 2007.
NIH-PA Author Manuscript

Wiley Interdiscip Rev Cogn Sci. Author manuscript; available in PMC 2016 January 01.
HHS Public Access
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Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
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Published in final edited form as:


Res Dev Disabil. 2014 June ; 35(6): 1412–1424. doi:10.1016/j.ridd.2014.03.006.

A Review of Atomoxetine Effects in Young People with


Developmental Disabilities
Michael G. Amana, Tristram Smithb, L. Eugene Arnolda, Patricia Corbett-Dickb,
Rameshwari.Tumuluruc, Jill A. Hollwaya, Susan L. Hymanb, Marissa Mendoza-Burchammc,
Xueliang Pand, Daniel W. Mruzekb, Luc Lecavaliera, Lynne Levatob, Laura B. Silvermanb,
and Benjamin Handenc
Author Manuscript

aTheNisonger Center UCEDD, Ohio State University, McCampbell Hall, 1581 Dodd Dr.,
Columbus, OH, 43210
bDivision of Neurodevelopmental and Behavioral Pediatrics at the University of Rochester, Box
671, 601 Elmwood Ave., Rochester, NY, 14642
cDepartment of Psychiatry at the Western Psychiatric Institute and Clinic, Thomas Detre Hall,
3811 O'Hara St., Pittsburgh, PA, 15213
d Center for Biostatistics, Ohio State University, 2012 Kenny Rd., Columbus, OH, 43221

Abstract
This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties,
common side effects, and clinical advantages and disadvantages associated with atomoxetine
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(ATX) treatment in typically developing children and adults with ADHD. Then the clinical
research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is
summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled
randomized clinical trials, and both focused on a single DD population (ASD). All trials but one
indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge
the magnitude and validity of reported improvement in the absence of placebo controls. Effects of
ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite
decrease, nausea, and irritability were the most common adverse events reported among children
with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much
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Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
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Conflict of Interest
Dr. Aman has received research contracts, consulted with, or served on advisory boards of Biomarin Pharmaceuticals, Bristol-Myers
Squibb, Confluence Pharmaceutica, Coronado Bioscience, Forest Research, Hoffman LaRoche, Johnson & Johnson, MedAvante Inc.,
Novartis, Pfizer, and Supernus Pharmaceutica.
Dr. Arnold has received research funding from CureMark, Forest, Lilly, and Shire, advisory board honoraria from Biomarin, Novartis,
Noven, Roche, Seaside Therapeutics, and Shire, consulting fees from Tris Pharma, and travel support from Noven. Dr. Handen has
received research funding from CureMark, Lilly and Roche. Dr. Hollway has received research funding from Forest Research
Institute.
The following authors have no disclosures to make: Patricia Corbett-Dick, PNP, Susan l. Hyman, M.D., Luc Lecavalier, Ph.D., Lynne
Levato, Ph.D., Marissa Mendoza-Burchamm, Ph.D., Daniel W. Mruzek, Ph.D., Xueliang Pan, Ph.D., Laura B. Silverman, Ph.D.,
Tristram Smith, Ph.D., Rameshwari Tumuluru, M.D.
Aman et al. Page 2

more commonly in persons with DD than in typically developing individuals. Splitting the dose
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initially, starting below the recommended starting dose, and titrating slowly may prevent or
ameliorate side effects. Patience is needed for the slow build-up of benefit. Conclusions: ATX
holds promise for managing ADHD symptoms in DD, but properly controlled, randomized
clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and
researchers should be vigilant for emergence of irritability with ATX treatment. Effects of ATX
on cognition in DD are virtually unstudied.

Keywords
Atomoxetine (Strattera); Review; Developmental Disabilities; Autism Spectrum Disorders

1. Introduction
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Overactivity and inattention are among the most common behavioral concerns for
individuals with developmental disabilities (DD; Emerson, 2003). The prevalence of
attention-deficit hyperactivity disorder (ADHD) in this population has been estimated at
9-16% (Emerson, 2003; Strømme & Diseth, 2000), substantially exceeding the rate of
ADHD in typically developing (TD) individuals. Stimulants such as methylphenidate are the
most extensively studied treatment for ADHD in individuals with DD (Handen & Gilchrist,
2006). Findings indicate that individuals with DD are less likely to show therapeutic benefit
and more likely to experience negative side effects from stimulants than are TD individuals
(Aman, Farmer, Hollway, & Arnold, 2008; Handen & Gilchrist, 2006; Research Units on
Pediatric Psychopharmacology Autism Treatment Network [RUPP], 2005). Thus, there
remains a need to identify additional treatment options for this common and impairing set of
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symptoms in individuals with DD.

Atomoxetine (ATX; Strattera) is a nonstimulant medication of considerable interest.


Although ATX only received Food and Drug Administration approval in 2002 for treatment
of ADHD, there is a large literature base on effectiveness in TD children, adolescents, and
adults (Cheng, Chen, Ko, & Ng, 2007; King et al., 2006; Kratochvil, Milton, Vaughan, &
Greenhill, 2008). Not surprisingly, because of the difficulties in recruiting and testing
individuals with DD, the research on any therapeutic agent tends to lag behind that of the
TD population. Comparatively speaking, the literature on ATX in people with DD is very
small. Moreover, as illustrated by the research on methylphenidate (Research Units on
Pediatric Psychopharmacology Autism Treatment Network [RUPP], 2005), medication
effects for individuals with DD may differ from effects seen in TD individuals. It is essential
that, to the extent possible, clinical decision making is based on findings on the population
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with DD. We conducted this review in an effort to summarize the available findings in
patients with DD and to compare some of these findings relative to TD patients (e.g., data on
adverse events [AEs]). Our aims in this paper were to: (a) provide a general context for
assessing ATX in individuals with DD by first providing pharmacological data
(pharmacodynamics, pharmacokinetics, side effects) from the general/TD population, (b)
comment on general advantages and disadvantages of ATX relative to other ADHD
medicines, (c) critically review the existing literature on ATX therapeutic effects in DD, (d)

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characterize the side effects observed in DD samples to determine if they differ from those
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seen in the TD population, and (e) provide an overall summary and conclusion about the
status quo of ATX research in the field of DD. To the best of our knowledge, there is no
similar published review to date.

1.1 Atomoxetine Pharmacodynamics


ATX enhances norepinephrine (NE) activity by selectively and potently blocking its
reuptake through transporter inhibition and increasing presynaptic concentrations in
noradrenergic pathways (Hammerness, 2009). In the rat, ATX increases NE in regions such
as the occipital cortex, lateral hypothalamus, dorsal hippocampus, and cerebellum
(Swanson, 2006). Increased NE neurotransmission in the prefrontal cortex (PFC) is
associated with enhanced attention and higher cognitive processes (Bymaster, 2002). ATX
increases DA in the PFC because, in contrast to other areas of the brain, DA is taken up by
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NE transporters in that location. Dopamine is increased in the PFC in animals and is


attributed to a common regional uptake inhibition of monoamines (Hammerness, 2009;
ATX has relatively low affinity for other dopamine and serotonin uptake sites. ATX does
not increase the dopamine levels in the nucleus accumbens and associated reward pathways
or in the striatum. As a result, it has limited abuse potential and is not associated with tics
(Garnock-Jones & Keating, 2009).

1.2 Atomoxetine Pharmacokinetics


Pharmacokinetics are well established in TD children and adults, have been found to be
similar after adjusting for body weight, and are linear after 6 years of age, yielding plasma
levels predictably proportional to mg/kg dose (Sauer et al., 2005; Witcher et al., 2003). ATX
is highly water soluble with high membrane permeability; hence it is rapidly and well
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absorbed after oral administration. The extent of absorption is unaffected by food, and the
manufacturer recommendation is that it may be taken with or without food (Sauer et al.,
2005).

Atomoxetine clearance is achieved through three metabolic pathways: aromatic ring-


hydroxylation, benzylic hydroxylation and N-demethylation (Hammerness et al., 2009).
Primary metabolism occurs via CYP450-2D6, with extensive first-pass liver metabolism via
oxidative processes to equipotent primary metabolite 4-hydroxyATX. Further
transformation occurs via glucoronidation, resulting in 4-hydroxyATX-O-glucoronide
(Sauer et al., 2005). ATX is metabolized to a much lesser degree via CYP2C19 to N-
desmethylATX, an active metabolite which exerts minimal pharmacologic activity.
Differences in ATX pharmacokinetics are noted between genetically determined CYP2D6
extensive metabolizers (EMs) (over 90% of the population) and CYP2D6 slow metabolizers
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(SMs) (approximately 7% of population) (Sauer et al., 2005). Plasma clearance of ATX in


both EMs and SMs occurs primarily via oxidative pathways, though this occurs at a much
slower rate in SMs, yielding higher peak plasma concentrations for the slower metabolizing
subgroup (Sauer et al., 2005). Individuals with slow metabolism are at risk for higher serum
ATX levels even at lower drug doses, though these pharmacokinetic differences have not
been found to be clinically relevant, and dose recommendations are consistent across
CYP2D6 genetic subtypes (Sauer et al., 2004), Bioavailability ranges from 63% in EMs and

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94% in SMs. Peak plasma levels are typically achieved in 1-2 hours in EMs and in 3-4 hours
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in SMs. A high-fat meal reduces the peak plasma concentration, and delays the time it takes
to reach peak plasma concentration by 3 hours, but does not affect the extent of absorption
(Sauer et al., 2005). The volume of distribution into total body water is 0.85 L/kg after an IV
dose, and it is well distributed in both EMs and SMs (Sauer et al., 2005). In EMs, twice-
daily dosing was not associated with elevated peak plasma concentrations (Witcher, et al,
2003). ATX is 98% bound to plasma proteins, primarily to albumin, and does not affect the
protein binding of other highly plasma-bound drugs (e.g., warfarin, acetylsalicylic acid,
phenytoin, diazepam) to albumin, nor do these drugs affect the protein binding of ATX to
albumin ( Sauer et al., 2005). Since ATX is highly protein-bound, systemic clearance may
be reduced in hepatic insufficiency, and dosage adjustments are advised (Hammerness,
2009).

Mean plasma elimination half-lives vary considerably between EMs and SMs. Half-lives of
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ATX and its metabolites, in EMs, are: (a) ATX, 5.2 hours; (b) 4-hydroxyATX, 6-8 hours;
and (c) N-desmethylATX 6-8 hours. Half-lives of ATX and its metabolites in SMs are: (a)
ATX, 21 hours; (b) 4-hydroxyATX, 19 hours and (c) N-desmethylATX 34-40 hours. (Sauer
et al., 2003). While the primary ATX metabolism is similar in both EMs and SMs, specific
metabolite amounts, and rates of formation vary between the subgroups (Sauer et al., 2005).

Excretion of ATX occurs primarily in the urine, with less than 3% of an oral dose excreted
unchanged and 80% as 4-hydroxyATX-O-glucoronide; the remaining 17% is excreted in
feces (Sauer et al., 2005). ATX does not significantly account for inhibition or induction of
metabolism of other CYP-2D6 medications, though drugs that inhibit CYP-2D6, such as
paroxetine and fluoxetine, cause slower elimination and increases in peak plasma
concentrations (Hammerness et al, 2009).
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1.3 Side Effects, Typically Developing Patients


Clinical Trials sponsored by Eli Lilly indicated that , serious potential side effects of ATX
may include suicidal thoughts, hepatotoxicity, sedation, and weight loss or slowed growth.
Common side effects in TD children include upset stomach, decreased appetite, nausea or
vomiting, dizziness, tiredness, and mood swings. This was further confirmed by later
reviews in the literature Cheng et al. (2007) and Schwartz and Correll (2013). A more
detailed review of the literature is reported as follows.Though there was no incidence of
completed suicide, the incidence of suicidal ideation was 5/1337 (.0037) compared to 0%
taking placebo (Bangs et al., 2008). Patients with DD were not included in the review of
Bangs et al.. The review did not report incidents of QTc changes or hepatotoxicity.
According to Wernicke et al. (2003), ATX caused no QT interval prolongation and minimal
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changes in diastolic blood pressure in TD children and a minimal increase in pulse rate.
Kratchovil et al. (2006) reported a notable change in growth early in treatment, which
increased after 18 months indicating that, though there is an early decrease in growth, there
was no significant change at 2-year follow-up. Many common side effects reported could be
explained as common childhood illnesses (Kratchovil et al., 2006). Wilens et al. (2006)
monitored TD children and adolescents and reported that children experienced higher rates
of somnolence and headaches than adolescents. There also appears to be a difference in side

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Aman et al. Page 5

effects experienced based on titration method. Greenhill et al. (2007) reported that TD
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children who were titrated slowly experienced headaches as a common side effect, whereas
those who were titrated quickly reported a decrease in appetite and somnolence. This may be
pertinent for children with autism spectrum disorder ASD (and perhaps other children with
DD) who are notoriously picky eaters. Appetite suppression is often a concern for parents of
these children.

1.4 Potential Advantages and Disadvantages of ATX


Until now, the focus of this paper has been on ATX effects in TD patients; henceforth, we
consider individuals with DD (including ASD) as well. Although further research is
obviously needed to elucidate the role of ATX in management of ADHD symptoms in the
presence of DD, we have enough information for tentative conclusions about its advantages
and disadvantages relative to other FDA-approved options. Some of these are based on
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clinical experience and knowledge of the pharmacological properties of ATX (e.g.,


pharmacokinetics), whereas others have literature bearing on the issue.

1.4.1 Advantages of ATX—These include the following: (a) ATX may reduce anxiety,
an important issue in children with ASD and potentially other DD (Gabriel & Violato, 2011;
Dell'Agnello et al., 2009; Ravindran, Kim, Letamendi, & Stein, 2009). (This advantage is
shared with alpha-2 agonists such as guanfacine.) (b) ATX may have some benefit for
depression, although one trial with neurotypical adults was negative (Young, Sarkis, Qiao,
Wietecha, 2011). (c) ATX's longer duration of action provides a smoother effect over time,
without the ups and downs of stimulants. (d) Timing of ATX doses is not as critical as with
other ADHD medications. (e) ATX appears to have less “rebound irritability” (i.e.,
disruptive behavior occurring at the end of the day, when the effects of many stimulants
wear off) than stimulants. (f) ATX does not interfere with sleep as do stimulants, often
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important in ASD and other DD (Hollway & Aman, 2011). (g) ATX does not induce or
exacerbate tics. (h) There may be less limitation by side effects for ATX than for stimulants
if titration proceeds slowly and if doses are split initially. (i) ATX is not a Schedule II drug,
allowing refills and phone prescriptions. (j) ATX has little or no abuse potential.

1.4.2 Disadvantages of ATX—These include the following: (a) ATX takes longer than
stimulants to reach an effective level; maximal benefit may be delayed a month or two. (b)
The ATX response rate may be lower than for stimulants, at least in TD children. (c) If there
are limiting side effects, they may take longer to wash out given the longer half-life of ATX
compared with stimulants. (d) Initial split doses to prevent side effects can be inconvenient.
(e) Side effects of fatigue or sedation, shared with alpha-2 agonists but not stimulants, can
be unacceptable. (f) ATX may pose more gastrointestinal side effects than ADHD
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alternatives. (g) The risk of reversible liver toxicity exists, although it is rare. (h) ATX may
pose sensitivity to metabolic aberrations or enzyme induction or suppression by other drugs.
(i) Whereas ATX probably is responsible for less growth inhibition than stimulants, it occurs
more frequently than with alpha-2 agonists. (j) In adults, ATX may cause dry mouth, urinary
retention, and sexual dysfunction. (k) ATX is irritating to skin and eyes if capsules are
opened.

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Aman et al. Page 6

2. Review Method
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We used PsychInfo, PubMed, and Google Scholar to search for the following terms in
combination with atomoxetine and Strattera: “mental retardation,” “intellectual disability,”
“developmental disability,” “autism spectrum disorder,” “autistic disorder,” “autism,”
“pervasive developmental disorder,” “PDD,” and “Asperger's disorder.” These searches
turned up numerous papers, but the majority simply referred in passing to children with
some form of DD and treatment of ADHD symptoms. Ultimately, our search turned up 11
relevant papers. Data from these articles were extracted by the authors and checked by the
first author for accuracy.

The findings were analyzed by subjects, design, and results. Under “Subjects,” we reported
the number of participants, clinical condition or disorder, functional level (IQ), and gender
breakdown. Within “Design,” we reported type of design (case report, open-label [OL],
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crossover, or parallel groups); duration of the trial; and whether the study used a randomized
controlled design. Finally, under “Results,” we reported types of outcome measure, baseline
(BL) and end-point (EP) scores for standardized scales, effect sizes (ES), and adverse events
(AEs).

Most studies used standardized scales to assess behavior problems (including subscales
intended to measure ADHD); periodically studies also reported measures of ASD
symptoms, adaptive behavior, and cognitive functioning. The most commonly used scales
were the Aberrant Behavior Checklist (ABC; Aman, Singh, Stewart, & Field, 1985), the
ADHD Rating Scale (see Aman & Pearson, 1999), variations of Conners’ Parent and
Conners’ Teacher Rating scales (Aman & Pearson, 1999), and the Swanson, Nolan, and
Pelham SNAP) Rating Scale (https://www.omh.ny.gov/omhweb/ebt/resources/
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snap_instructions.html). The ABC was developed for assessing treatment effects and has
five subscales, as follows: (a) Irritability (15 items), (b) Social Withdrawal (16 items), (c)
Stereotypic Behavior (7 items), (d) Hyperactivity/Noncompliance (16 items), and
Inappropriate Speech (4 items). The ADHD Rating Scale was based on the 18 DSM-IV
symptoms for ADHD, and can be completed by parents, teachers, or professionals. The
Conners’ Scales come in numerous versions for completion by parents or teachers, and often
include some mix of the following subscales, with variable numbers of items: (a)
Oppositional, (b) Cognitive Problems, (c) Hyperactivity, (d) Anxious-Shy, (e)
Perfectionism, (f) Social Problems), (g) ADHD Index, (h) Conners’ Global Index, and
DSM-IV Symptoms (Aman & Pearson, 1999). Earlier versions of the Conners’ Scales also
included a Conduct Problem and an Inattention subscale. Finally, the SNAP is based on
DSM symptoms and most frequently involves parent or teacher ratings of DSM symptoms
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relevant to ADHD (ADHD Inattention [9 items]; ADHD Hyperactive/Impulsive [9 items]);


and oppositional defiant disorder (8 items).

3. Results
All 11 studies of ATX effects in children with DD are summarized in detail in Table 1. The
studies are arranged chronologically and are referenced by numeral (1-11) here. Only two
were randomized clinical trials (RCT) with placebo controls; seven were OL prospective,

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Aman et al. Page 7

one was an OL retrospective study, and one was a case report. In general, we reference the
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two RCTs (#2 & 10) in bold font, whereas the remainder are in regular font. In this narrative
summary, we focus mainly on primary outcome variables and commonly used outcomes.
When applicable, a “T” is used to signify that a rating scale was completed by a teacher or
“D” for doctor (as opposed to the default, parent-completed reports, which were most
common).

3.1. ADHD, Disruptive Behavior, and Adverse Events


The following scales were used multiple times across studies: various versions of Conners’
Rating Scale (#2, 4, 6, 9, 10), the Aberrant Behavior Checklist (ABC; #2, 3, 4, 7), and the
two DSMIV-derived scales (the ADHD Rating Scale and the SNAP scale; #2, 4, 6, 9, 10,
11D). The following general findings were supported with these scales. All Conners’-
derived Hyperactivity subscales (1, 4, 6, 6T, 10) showed a significant reduction in scores
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with ATX. Likewise, the Conners’ Inattention subscale scores were reduced in every
instance they were assessed (#1, 6, 6T, 9, 9T). The Conners’ ADHD Index scores declined
each time they were employed as outcomes (#4, 10). Conners’ Conduct or Oppositional
subscales were sensitive to ATX treatment several times (#1, 6, 6T, 10), but not always (#4).
Conners’ Learning and Cognitive Problems were rated improved with ATX in three studies
(#2, 4, 10).

With the ABC, the outcomes were less optimistic. The Hyperactivity/Noncompliance
subscale scores improved in two studies (#2, 3, 3T) but failed to improve in two others (#4,
7). Irritability scores improved in one instance (#3) but were unchanged in the remainder
(#2, 3T, 4, 7). Social Withdrawal subscale scores improved in two instances (#2, 3) but not
in three others (#3T, 4, 7). Stereotypic Behavior and Inappropriate Speech subscale scores
generally did not change (#2, 3T, 4, 7) except for one set of comparisons (#3).
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In terms of the DSM scales, the SNAP and ADHD Rating Scales provided positive, though
not uniform, results. First, the Inattention subscales declined with ATX in all comparisons
(#2, 4, 6, 6T, 9, 9T, 10D). The Hyperactive/Impulsive subscale scores declined in all but one
comparison (#2, 6, 6T, 9, 10D; not 9T). In the only study to report SNAP Oppositional
Behavior, it declined with ATX (#2). In the largest study done to date, the Clinical Global
Impressions-Improvement (CGI-I) subscale did not distinguish statistically between ATX
and placebo treatment [#10; Π2 (2) = 5.37; with Yates’ correction: p = 0.068]. In the open-
label studies, the rates of clinical response (CGI-I = 1 or 2) were as follows: 42% (study #7),
47% (#8), 49% (#6), 50% (#9), 60% (#1), and 75% (#3). In the only study (#8) to evaluate
the possible effect of IQ on CGI response (IQ ≥85 vs. <85), 77% of high-IQ subjects were
responders as compared with 21% of low-IQ subjects (p < 0.001).
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In the only study to include an extension phase (11D; 20-week ATX extension for both
subjects initially assigned to PBO or ATX), additional improvements were seen in children
initially assigned to ATX on ADHD-RS for the Inattention subscale (p= .02) but not the
Hyperactivity/Impulsivity subscale (p= .06). Although not reported separately, changes for
subjects originally assigned to PBO were almost certainly significant when they were treated

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openly with ATX, as the change scores were substantially larger than for the ATX acute trial
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to ATX extension.

We computed effect sizes (ES, Cohen's d) for the primary outcomes and priority secondary
variables, and these appear shaded in gray in Table 1. The ESs were generally large, ranging
from 0.29 to 2.30, with a median of 1.05.

3.2. Other Scales and Cognitive Performance


Subjects were assessed using additional rating scales. No effects of ATX were found on the
Repetitive Behavior Scale—Revised (#2). An open-label study found no ATX effect on the
Vineland Adaptive Behavior Scales (#3). One RCT (#2) found no ATX effect on the
following cognitive measures: (a) continuous performance task (measuring sustained
attention), (b) the delayed match-to-sample task (memory), or (c) the analogue classroom
task (motivation & sustained attention). Likewise, an open-label study (3) found no ATX
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effect on the continuous performance task. Thus, unlike the case with stimulants (Aman,
1980), there is no evidence that ATX significantly enhances cognitive function in children
with developmental disabilities.

3.3 Adverse Events (AEs)


We made an effort to document the most commonly occurring AEs in Table 2. Study 11 is
not included because its subjects overlapped with study 10. The number of subjects in each
study appears near the column headers. The figures in parentheses indicate the percentage of
subjects in that study to show the AE. The right-most column, with bolded numerals,
indicates the total number of participants across all studies to show that AE. The first
percentage in the right column is based on total sample only for cells where that adverse
event was reported; the second percentage is based on all 241 subjects across all studies and
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assumes that investigators screened for that adverse event (unlikely to be true) in all studies.
We regard the first percentage as likely to be more accurate, perhaps a bit on the high side.

The most commonly occurring AEs were decreased appetite (n=66; 29.1/27.4%) and nausea
(n=44, 29.5/18.3%). Irritability (n=39; 30.0/16.2%) and sedation/sleepiness (n=29;
19.0/12.1%) were also prominent. Other AEs included fatigue, sleep difficulty, mood
swings, gastrointestinal discomfort, and vomiting. It is important to be aware that some of
these AEs are common ailments of childhood. For instance, 10% of subjects in one placebo
group (#10) also experienced vomiting; and irritability was reported for 81% of subjects
while receiving placebo in another study (#2). Suicidal ideation was not reported in these
articles, but the total number of study participants was small.
Author Manuscript

Several of the studies summarized in Table 1 referenced AEs that led to study
discontinuance. These more-serious AEs were as follows: (a) Study #1 (N=20), severe mood
swings (n=1); (b) Study #2 (N=16) aggressive rage (n=1); (c) Study #3 (N=16) lost one
subject because of irritability and another one because of irritability plus blunted affect plus
nausea; (d) in Study #4 (N=12), five subjects discontinued because of anxiety (n=1), nausea
(n=1), aggression (n=1), nausea/vomiting (n=1), and weight loss (n=1); (e) Study #6 lost 3
of 48 participants, all because of irritability; and (f) Study #10 (n=48 in ATX group) lost one

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
Aman et al. Page 9

participant because of fatigue. Study #5 was a case report of a 13-year-old boy with
Author Manuscript

intellectual disability and ADHD. When treated with ATX, titrated up to 60 mg/day, he
became psychotic, hearing voices and worrying about being followed; symptoms remitted
on withdrawal. Thus, of the reasons for discontinuance in the studies, mood swings were
cited in one case and some aspect of irritability in five more cases; the remaining seven
cases had various reasons given. If mood swings and irritability can be viewed as facets of
the same AE, then irritability/mood issues appear to warrant particular monitoring when
children with DD are being treated with ATX.

Finally, study #11 reported AEs after the first 8 weeks and later, after 12 or 20 additional
weeks of ATX treatment. It is noteworthy that three AEs showed evidence of significant
decline with time: (a) decreased appetite (p= .10), (b) fatigue (p= .04), and (c) nausea (p= .
003). Thus some of the most common AEs seem to remit with continued exposure to ATX.
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4. Discussion: State of the Research in the Developmental Disabilities


The clinical effects of ATX on ADHD were reportedly positive in all ten studies that were
reviewed, although the effects on co-occurring behavioral and cognitive problems were
much less consistent. This positive outcome for ADHD is very welcome, but we note that
the large majority of these investigations were not double blind, placebo controlled,
randomized clinical trials (RCTs). Thus the effects of publication bias and the extent of
placebo response are unknown for much of this work. Our computations suggested very
large ESs in these studies, with a median value of d=1.05. However, we are currently
investigating ATX in a large multi-site, placebo-controlled investigation of children with
ASD and ADHD symptoms. Based on clinical experience in this study, we believe these
existing ES values to be inflated, perhaps due in part to the use of uncontrolled designs in so
Author Manuscript

many previous studies.

Both RCTs used methodologically rigorous double-blind, placebo-controlled designs. One


RCT also included a comprehensive battery of outcome measures but was limited by a small
sample size (N = 16, Arnold et al., 2006). The other RCT recruited a much larger sample (N
= 102) and incorporated a long-term follow-up, but relied solely on parent and clinician
ratings as measures of outcome (Harfterkamp et al., 2012; Harfterkamp et al., 2013). Both
RCTs restricted enrollment to children with ASD. Thus, RCTs of ATX in other DD
populations are currently unavailable.

Clearly more RCTs with ATX in children with ASD and other DD are badly needed. Our
group is currently completing a RCT trial of ATX; this study has included 128 children and
may help to resolve some of the questions posed in this review. For instance, we have
Author Manuscript

gathered data on ATX effects on a number of cognitive measures, and the trial includes
parent management training (PMT) and a control condition. This will enable us to determine
if there are clinically synergistic effects from the combination of ATX and PMT.

The median response rate of the reviewed studies was about 50%, which is lower than rates
usually reported in TD children (Schwartz & Correll, in press). However, this somewhat
muted response rate is consistent with what has been reported with psychostimulants in
children with ASD (RUPP, 2005) and in children with intellectual disability (Aman, Buican,

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
Aman et al. Page 10

& Arnold, 2003). Indeed as in Mazzone et al.'s (2011) study of ATX, Aman et al. (2003)
Author Manuscript

found that lower IQ was associated with a poorer response rate to methylphenidate in
children with ID and ADHD. It suggests that response rates to noradrenergic and
dopaminergic ADHD medicines may be diminished in young people with IDD relative to
responses of TD children with ADHD.

Somnolence and fatigue were among the most common AEs found in these studies. This is a
double-edged sword in that it can be viewed as potentially harmful (interfering with learning
in children, many of whom have cognitive handicaps) but potentially helpful in children
with sleep onset insomnia (by timing dosing so that any somnolence enhances sleep). Mild
to moderate initial side effects typically diminish over time as witnessed in the
Harfterkaamp et al. (2013) study; however, careful side effect monitoring in this population
is warranted. Splitting the daily dose initially, starting lower than recommended in the
package insert, and escalating slowly may prevent or ameliorate side effects. As noted
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above, irritability and mood swings with ATX appear to be more common among children
with DD than in TD children (Schwartz & Correll, in press). This is an important
consideration for clinicians and families while choosing and monitoring treatment in
children with DD.

5. Summary and Conclusions


Our conclusions are as follows. First, ATX holds promise for reducing ADHD symptoms in
persons with DD, but only two RCTs have been published at the time of this writing.
Second, only one study has been completed in children with ID without ASD, and this was
only an open-label study. Clearly, studies are needed to determine the usefulness of ATX in
children with ID but without ASD. Third, even in children with ASD, the overall strength of
Author Manuscript

evidence is low. The evidence thus far suggests improvements in both inattentive and
hyperactive/impulsive behavior, as well as possible reductions in oppositional behavior with
ATX. Nevertheless, additional RCTs with ATX are needed. Fourth, we are aware of no
RCTs, either within DD or among TD children, to show enhancement (or worsening) of
cognitive functioning with ATX treatment. This is an area that needs further study. Given
that many trials of psychostimulants have shown enhancement of cognitive functioning,
both in TD children and those with DDs, this could be an important qualitative difference
between the two treatments. Fifth, irritability appears to be a common AE that accompanies
ATX treatment in DD (as it does with stimulants, although perhaps not as severely (RUPP,
2005). Both future researchers and clinicians should attend to cost-benefit analyses that take
this possible AE into account.
Author Manuscript

Acknowledgements
This work was supported by grants from the National Institute of Mental Health to Ohio State University
(5R01MH079080), University of Pittsburgh (5R01MH079082-05), and University of Rochester (5R01MH083247)

References
Aman MG. Psychotropic drugs and learning problems - A selective review. Journal of Learning
Disabilities. 1980; 13:87–97. [PubMed: 7391681]

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
Aman et al. Page 11

Aman MG, Buican B, Arnold LE. Methylphenidate treatment in children with low IQ and ADHD:
Analysis of three aggregated studies. Journal of Child and Adolescent Psychopharmacology. 2003;
Author Manuscript

13:27–38.
Aman MG, Farmer CA, Hollway J, Arnold LE. Treatment of inattention, overactivity, and
impulsiveness in autism spectrum disorders. Child and adolescent psychiatric clinics of North
America. 2008; 17:713–738. [PubMed: 18775366]
Aman, MG.; Pearson, DA. Monitoring and measuring drug effects. II. Behavioral, emotional, and
cognitive effects.. In: Werry, JS.; Aman, MG., editors. Practitioner's guide to psychoactive drugs for
children and adolescents. 2nd ed.. Plenum Press; New York: 1999. p. 99-164.(in press)
Aman MG, Singh NN, Stewart AW, Field CJ. The Aberrant Behavior Checklist: A behavior rating
scale for the assessment of treatment effects. American Journal of Mental Deficiency. 1985;
89:485–491. [PubMed: 3993694]
Arnold LE, Aman MG, Cook AM, Witwer AN, Hall KL, Thompson S, Ramadan Y. Atomoxetine for
hyperactivity in autism spectrum disorders: Placebo-controlled crossover pilot trial. Journal of the
American Academy of Child & Adolescent. 2006; 45:1196–1205.
Bangs ME, Tauscher-Wisniewski S, Polzer J, Zhang S, Acharya N, Desaiah D, Trzepacz PT, Allen AJ.
Author Manuscript

Meta-analysis of suicide-related behavior events in patients treated with atomoxetine. Journal of the
American Academy of Child & Adolescent Psychiatry. 2008; 47:209–218. [PubMed: 18176331]
Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin
SM, Gehlert DR, Perry KW. Atomoxetine increases extracellular levels of norepinephrine and
dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/
hyperactivity disorder. Neuropsychopharmacology. 2002; 27:699–711. [PubMed: 12431845]
Charnsil C. Efficacy of atomoxetine in children with severe autistic disorders and symptoms of
ADHD: An open-label study. Journal of Attention Disorders. 2011; 15:684–689. [PubMed:
20686100]
Cheng JY, Chen RY, Ko JS, Ng EM. Efficacy and safety of atomoxetine for attention-deficit/
hyperactivity disorder in children and adolescents—meta-analysis and meta-regression analysis.
Psychopharmacology. 2007; 194:197–209. [PubMed: 17572882]
Tang C, Chou W, Cheng ATA. Atomoxetine Hydrochloride-Associated Transient Psychosis in an
Adolescent with Attention-Deficit/Hyperactivity Disorder and Mild Mental Retardation. Journal of
Child and Adolescent Psychopharmacology. 2009; 19:319–320. [PubMed: 19519271]
Author Manuscript

Dell'Agnello G, Zuddas A, Masi G, Curatolo P, Besana D, Rossi A. Use of atomoxetine in patients


with attention-deficit hyperactivity disorder and co-morbid conditions. CNS Drugs. 2009; 23:739–
753. [PubMed: 19689165]
Emerson E. Prevalence of psychiatric disorders in children and adolescents with and without
intellectual disability. Journal of Intellectual Disability Research. 2003; 47:51–58. [PubMed:
12558695]
Fernández-Jaén A, Fernández-Mayoralas DM, Pérez BC, Muñoz - Jareño N, Campos-Diáz M.
Atomoxetine for attention deficit hyperactivity disorder in mental retardation. Pediatric Neurology.
2010; 43:341–347. [PubMed: 20933178]
Gabriel A, Violato C. Adjunctive atomoxetine to SSRIs or SNRIs in the treatment of adult ADHD
patients with comorbid partially responsive generalized anxiety (GA): an open-label study.
Attention Deficit Hyperactivity Disorders. 2011; 3:319–326. [PubMed: 21833565]
Garnock-Jones K, Keating G. Atomoxetine: A review of its use in attention-deficit hyperactivity
disorder in children and adolescents. Paediatric Drugs. 2009; 11:203–226. [PubMed: 19445548]
Author Manuscript

Greenhill LL, Newcorn JH, Gao H, Feldman PD. Effect of two different methods of initiating
atomoxetine on the adverse event profile of atomoxetine. Journal of the American Academy of
Child & Adolescent Psychiatry. 2007; 46:566–572. [PubMed: 17450047]
Hammerness P, McCarthy K, Mancuso E, Gendron C, Geller D. Atomoxetine for the treatment of
attention-deficit/hyperactivity disorder in children and adolescents: a review. Neuropsychiatric
disease and treatment. 2009; 5:215. [PubMed: 19557116]
Handen BL, Gilchrist R. Practitioner review: psychopharmacology in children and adolescents with
mental retardation. Journal of Child Psychology and Psychiatry. 2006; 47:871–882. [PubMed:
16930381]

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
Aman et al. Page 12

Harfterkamp M, van de Loo-Neus G, Minderaa RB, van der Gaag R-J, Escobar R, Schacht A,
Pamulapati S, Buitelaar JK, Hoekstra PJ. A Randomized double-blind study of atomoxetine versus
Author Manuscript

placebo for attention-deficit/hyperactivity disorder symptoms in children with autism spectrum


disorder. Journal of the American Academy of Child and Adolescent Psychiatry. 2012; 5:733–741.
[PubMed: 22721596]
Harfterkamp M, Buitelaar JK, Minderaa RB, van de Loo-Neus G, van der Gaag R-J, Hoekstra PJ.
Long-term treatment with atomoxetine for attention-deficit/hyperactivity disorder symptoms in
children and adolescents with autism spectrum disorder: An open-label extension study. Journal of
child and Adolescent Psychopharmacology. 2013; 23:194–199. [PubMed: 23578015]
Hollway JA, Aman MG. Sleep correlates of pervasive developmental disorders: A review of the
literature. Research in Developmental Disabilities. 2011; 32:1399–1421. [PubMed: 21570809]
Jou RJ, Handen BL, Hardan AY. Retrospective assessment of atomoxetine in children and adolescents
with pervasive developmental disorders. Journal of child and adolescent psychopharmacology.
2005; 15:325–330. [PubMed: 15910217]
King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, Golder S, Taylor E,
Drummond M, Riemsma R. A systematic review and economic model of the effectiveness and
Author Manuscript

cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of


attention deficit hyperactivity disorder in children and adolescents. International Health
Technology Assessment. 2006; 10:iii–iv. xiii–146. Review.
Kratochvil C, Milton D, Vaughan B, Greenhill L. Acute atomoxetine treatment of younger and older
children with ADHD: a meta-analysis of tolerability and efficacy. Child and Adolescent
Psychiatry and Mental Health. 2008; 2:25. [PubMed: 18793405]
Kratochvil CJ, Wilens TE, Greenhill LL, Gao H, Baker KD, Feldman PD, Gelowitz DL. Effects of
long-term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder.
Journal of the American Academy of Child & Adolescent Psychiatry. 2006; 45:919–927.
[PubMed: 16865034]
Mazzone L, Reale L, Mannino V, Cocuzza M, Vitiello B. Lower IQ is associated with decreased
clinical response to Atomoxetine in children and adolescents with Attention-Deficit Hyperactivity
Disorder. CNS Drugs. 2011; 25:503–509. [PubMed: 21649450]
Posey DJ, Wiegand RE, Wilkerson J, Maynard M, Stigler KA, McDougle CJ. Open-label Atomoxetine
for Attention-Deficit/Hyperactivity Disorder symptoms associated with high-functioning pervasive
Author Manuscript

developmental disorders. Journal of Child and Adolescent Psychopharmacology. 2006; 16:599–


610. [PubMed: 17069548]
Ravindran LN, Kim DS, Letamendi AM, Stein MB. Adjunctive treatment in adults to SSRI: A
randomized controlled trial of atomoxetine in generalized social anxiety disorder. Journal of
Clinical Psychopharmacology. 2009; 29:561–564. [PubMed: 19910721]
Research Units on Pediatric Psychopharmacology Autism Network. Aman MG, Arnold LE, Ramadan
Y, Witwer A, Lindsey R, McDougle CJ, Posey D, Swiezy N, Kohn A, McCracken JT, Shah B,
Cronin P, McGough J, Lee L, Scahill L, Martin A, Koenig K, Carroll D, Young C, Lancor A,
Tierney E, Ghuman J, Gonzalez NM, Grados M. A randomized, double-blind, placebo-controlled,
crossover trial of methylphenidate in children with hyperactivity associated with pervasive
developmental disorders. Archives of General Psychiatry. 2005; 62:1266–1274. [PubMed:
16275814]
Sauer J, Ring B, Witcher J. Clinical pharmacokinetics of atomoxetine. Clinical Pharmacokinetics.
2005; 44:571–590. [PubMed: 15910008]
Sauer J, Long A, Ring B, Gillespie J, Sanburn N, DeSante N, Petullo D, VandenBraden M, Jensen C,
Author Manuscript

Wrighton S, Smith B, Read H, Witcher J. Atomoxetine hydrochloride: Clinical drug-drug


interaction, prediction and outcome. Journal of Pharmacology and Experimental Therapeutics.
2004; 302:410–418. [PubMed: 14610241]
Sauer J, Ponsler G, Mattiuz E, Long A, Witcher J, Thomasson H, Desante K. Disposition and
metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and
metabolism. Drug Metabolism & Disposition. 2003; 31:98–107. [PubMed: 12485958]
Strømme P, Diseth TH. Prevalence of psychiatric diagnoses in children with mental retardation: data
from a population-based study. Developmental Medicine & Child Neurology. 2000; 42:266–270.
[PubMed: 10795566]

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
Aman et al. Page 13

Swanson CJ, Perry KW, Koch-Krueger S, Katner J, Svensson KA, Bymaster FP. Effect of the
attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of
Author Manuscript

norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology. 2006;
50:755–760. [PubMed: 16427661]
Schwartz S, Correll CU. Efficacy and safety of atomoxetine in children and adolescents with attention-
deficit/hyperactivity disorder: Results from a comprehensive meta-analysis and metaregression.
Journal of the American Academy of Child and Adolescent Psychiatry. 2014; 53:174–186.
[PubMed: 24472252]
Troost PW, Steenhuis MP, Tuynman-Qua HG, Kalverdijk LJ, Buitelaar JK, Minderaa RB, Hoekstra
PJ. Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive
developmental disorders: A pilot study. Journal of Child and Adolescent Psychopharmacology.
2006; 16:611–619. [PubMed: 17069549]
Wernicke JF, Faries D, Girod D, Brown JW, Gao H, Kelsey D, Quintana H, Lipetz R, Michelson D,
Heiligenstein J. Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug
Safety. 2003; 26:729–740. [PubMed: 12862507]
Witcher J, Long A, Smith B, Sauer J, Heilgenstein J, Wilens T, Spencer T, Biederman J. Atomoxetine
Author Manuscript

pharmacokinetics in Children and adolescents with Attention Deficit Hyperactivity Disorder.


Journal of Child and Adolescent Psychopharmacology. 2003; 13:53–63. [PubMed: 12804126]
Wilens TE, Kratochvil C, Newcorn JH, Gao H. Do children and adolescents with ADHD respond
differently to atomoxetine?. Journal of the American Academy of Child & Adolescent Psychiatry.
2006; 45:149–157. [PubMed: 16429085]
Young JL, Sarkis E, Qiao M, Wietecha L. Once-daily treatment with atomoxetine in adults with
attention-deficit/hyperactivity disorder: A 24-week, randomized, double-blind, placebo-
controlledtrial. Clinical Neuropharmacology. 2011; 34:51–60. [PubMed: 21406998]
Zeiner P, Gjevik E, Weidle B. Response to atomoxetine in boys with high-functioning autism
spectrum disorders and attention deficit/hyperactivity disorder. Acta Pediatrica. 2011; 100:1258–
1261.
Author Manuscript
Author Manuscript

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Highlights
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• Ten published trials and one case study of atomoxetine in developmental


disabilities

• Only two controlled clinical trials; and only one non-acute extension

• Individuals with intellectual disability especially neglected in studies

• Improved attention, impulsivity, overactivity, oppositional behavior often


reported

• Common adverse events include anorexia, nausea, and irritability/mood


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Table 1

Summary of Studies of Atomoxetine in Participants with Developmental Disabilities

Authors Subjects Design Results


Aman et al.

1. Jou et al., 2005 20 patients, including 16 OL, case series. Retrospective End-point (EP) dose was 43.3 mg on average (SD = 18.1 mg).
M and 4 F (mean age = case review. a) 12 subjects (60%) judged to be responders, as defined by a score of 1 or 2 on the CGI-I.
11.5 years; SD = 3.5 Review of outpatient clinic b)One patient discontinued ATX because of severe mood swings.
years). 16 subjects (80%) registry for individuals with Children's Psychiatric Rating Scale (CPRS):
with AD, 2 (10%) with PDDs. c)Conduct: BL= 10.5; EP= 8.1 (p = 0.01).
ASP, and 2 (10%) with ATX initiated at 18 mg/day for 7 d)Hyperactivity: BL= 17.1; EP= 13.0 (p = 0.001); ES=0.89.
PDDNOS. 10 subjects days. ATX then titrated up to e)Inattention: BL= 7.5; EP= 5.8 (p = 0.01)
(50%) had a diagnosis of target dose of 1.2 mg/kg/day. f)Learning: (BL= 7.2 ; EP= 5.6 (p = 0.01).
intellectual disability If no acceptable clinical g)Psychosomatic: BL= 0.55; EP= 0.20 (p = 0.05)*
(ID), 4 (20%) with mild response, dose was increased to h)Anxiety: BL= 3.7; EP= 3.2 (p = 0.09)
ID, 4 (20%) with a maximum of 1.4 mg/kg/day as AEs:
moderate ID, and 2 tolerated. Subjects seen on Constipation (n=6), decreased appetite (n=6), ear ringing (n=6), mood swings (n=6), and sedation (n=6)were
(10%) with severe ID. average of once per month; reported.
Most patients (80%) phone calls were conducted on One patient who discontinued ATX because of severe mood swings.
were taking at least 1 weekly basis during titration Mean weight change was 0.36 ± 2.41 kg (range, −3.18 to 9.09 kg); 5 subjects experienced weight loss, 7 weight
concomitant medication. period. gain, and 8 no change.
Duration mean= 19.5 weeks (SD
= 10.5 weeks; Range, 1-36
weeks).
Treatment response assessed
using Improvement item of
Clinical Global Impressions
scale (CGI-I) based on the
Conners’ Parent Rating Scale
(CPRS) completed by primary
caretakers and other clinical
information in the registry.

2. Arnold et al, 16 subjects (12M, 4F) Double-blind, PBO-controlled, Aberrant Behavior Checklist (ABC):
2006 age 5-15 (mean 9.3 yr), randomized-order crossover, 6 a)Hyperactivity (primary): ATX, BL=24.69, EP=19.31; PBO, BL=22.50, EP=22.37, p=0.04, ES=0.74
with ASD (7 AD, 8 weeks each condition, 1-week b)Irritability: ATX BL=16.00, EP=13.06; PBO BL=14.18, EP=14.13, p=0.12, ES=0.61
PDDNOS) and DSM-IV washout between. Dose 20-100 c)Social Withdrawal: ATX BL=8.69, EP=6.5; PBO BL=6.62, EP=7.43, p=0.01, ES=1.18
ADHD syndrome. mg/day, 1.0-1.4 mg/kg/day. d)Stereotypic Behavior: ATX BL=7.37, EP=4.69; PBO BL=6.19, EP=6.63, p=0.08, ES=0.87
Diagnosed by DSM e)Inappropriate Speech: ATX BL=5.75, EP=4.87; PBO BL=4.68, EP=5.43, p=0.28, ES=0.52
criteria and ADI-R. ABC DSM-IV (SNAP):

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
Hyperactivity subscale f)Inattentive: ATX BL=16.06, EP=11.20; PBO BL=14.81, EP=13.63, p=0.053, ES=0.89
score 25.0±12.07. g)Hyperactive-Impulsive: ATX BL=17.31, EP=10.40; PBO BL=14.88, EP=14.50, p=0.005, ES=1.27
ADHD symptom mean h)Oppositional defiant: ATX BL=8.81, EP=6.07; PBO BL=8.83, EP=7.25, p=0.59, ES=0.20
1.91±0.54. 6 with Repetitive Behavior Scale–R (RBS–R):
concomitant meds, i) Stereotypy: ATX BL=8.56, EP=5.37; PBO BL=7.00, EP=6.56, p=0.11, ES=0.19
mostly antipsychotics j) Self-injury: ATX BL=1.25, EP=1.88 PBO BL=2.13, EP=2.38, p=0.29, ES=0.65
k) Compulsions: ATX BL=4.25, EP=3.19; PBO BL=3.93, EP=4.13, p=0.07, ES=1.10
l) Rituals: ATX BL=10.50, EP=7.88; PBO BL=9.43, EP=9.31, p=0.13, ES=0.23
m) Restrictive ATX BL=4.06, EP=4.25; PBO BL=3.81, EP=4.13, p=0.75, ES=0.04
n) Total score: ATX BL=53.12, EP=43.50; PBO BL=49.06, EP=45.00, p=0.57, ES=0.09
Responders (CGI-I of 1-2, plus 25% improv't on ABC-Hyperactivity): ATX, 57% vs. placebo, 25%.
Mean EP ATX dose= 44.2 mg/day.
AEs:
Heart Rate: ATX BL=88.5, EP=92.4; PBO BL=92.4, EP=84.1, p=0.005, ES=0.83
AEs higher for ATX than PBO:
Page 15
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Authors Subjects Design Results


Nausea/vomiting/upset stomach (100% vs. 31%; p= .006);
Fatigue (75% vs. 44%; p= .004)
Racing heart (25% vs. 0%; p= .048)
Appetite suppression (75% vs. 50%)
Irritability (88% vs. 81%)
Aman et al.

One dropout on ATX; hospitalized for aggressive rage.


Cognition: No effects on (a) Continuous Performance Task, (b) Match-To-Sample Task, or (c) Analogue
Classroom Task.

3. Posey et al., 17 enrolled, 16 analyzed; OL, uncontrolled; structured a)13 subjects completed 8 weeks, 12 (75%) considered responders.
2006 ages 6-14 years titration in first 3 wks. of 8-week b)Weight decreased mean of 0.8 kg (p = 0.0006)
(mean=7.7±2.2); 7 AD, 7 trial (0.5 mg/kg/day-0.8 c)CGI-Severity (CGI-S)
ASP, 2 PDDNOS; 3 F, mg/kg/day to 1.2 mg/kg/day). If BL= 5.1; EP= 3.9 (p = 0.0007)
13 M; non-verbal IQ CGI-Improvement in week 4 SNAP-IV Total
70-121 (M=93.9±18); no <much improved, then dose to d)Teachers BL= 29.6; EP= 12.8 (p <0.0001), ES=1.4
concomitant 1.4 mg/kg/day; flexibility to e)Parents BL= 44.4; EP= 22.6 (p <0.0001), ES=1.9
psychotropics during adjust dose down to decrease ABC
trial (2-4 weeks free adverse effects (AEs). Teachers
prior to baseline); no Outcomes: CGI, SNAP-IV & f)Irritability: BL=8.8; EP= 2.4 (p=0.01, ns)
medical conditions & no ABC 2-weekly; SRS, VABS, g)Social Withdrawal: BL=10.3; EP= 5.3 (p=0.05, ns), ES=0.8
comorbid psychiatric ADOS pre/post; CPT baseline, 4 h)Stereotypic Behavior: BL= 6.5; EP= 4.3 (p=0.03, ns), ES=0.4
disorders; ADI-R- & & 8. h)Hyperactivity: BL= 18.2; EP= 8.4 (p=0.004), ES=1.0
ADOS-confirmed i)Inappropriate Speech: BL= 8.8; EP= 2.4 (p=0.01, ns), ES=0.9
diagnosis. Parents
j) Irritability: BL= 14.3; EP= 8.5 (p=0.03, ns), ES=0.7
k) Social Withdrawal: BL= 13.0; EP= 8.6 (p=0.003), ES=0.8
l) Stereotypy: BL= 5.6; EP= 2.4 (p <0.0001), ES=1.1
m) Hyperactivity: BL= 28.4; EP= 14.2 (p <0.0001), ES=1.9
n) Inappropriate Speech: BL= 4.1; EP= 1.8 (p <0.0001), ES=1.0
SRS:
0) BL= 110.2; EP= 92.7 (p=0.005, ns), ES=0.9
VABS:
p) Communication: BL= 67.7; EP= 66.4 (p=0.71, ns)
q) Daily Living Skills: BL= 46.8; EP= 43.3 (p=0.70, ns)
r) Motor Development: BL= 62.8; EP= 59.5 (p=0.76, ns)
s) Adaptive Behavior Composite: BL= 54.4; EP= 5.3 (p=0.94, ns)
t) Maladaptive Part 1: BL= 21.9; EP= 15.2 (p=0.0003), ES=1.0
u) Maladaptive Part 2: BL= 8.1; EP= 4.8 (p=0.003), ES=1.4
AEs:
1 subject withdrew (week 6) due to increased irritability, 1 after experiencing irritability, blunted affect, and

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
nausea at lowest dose.
No significant differences from BL to EP on CPT or ADOS raw scores.

4. Troost et al., 12 children, ages 6-17 OL (10 weeks); semi-structured Seven study completers, 10 with ≥ 6 weeks of participation.
2006 years (M=10.22, titration, with target dose of 1.2 a)Primary: ADHD Rating Scale–Parent Rating (investigator completed): BL= 40.33; EP= 22.42; ES=2.3
SD=2.82); with mg/kg/day. Single daily dose in Conners’ Parent Rating Scale–Revised:
investigator-assigned the morning or twice-daily b)Oppositional: BL= 9.17; EP= 8.17 N.S.
diagnosis of ASD and divided dose. c)Cognitive Problems: BL= 12.42; EP= 9.33 (p= 0.05), ES= 0.66
high levels of parent- d)Hyperactivity: BL= 9.83; EP= 6.67 (p= 0.05), ES= 0.65
rated ADHD symptoms; e)ADHD Index: BL= 24.25; EP= 18.67 (p= 0.05), ES= 0.63
7 with autistic disorder, 4 Aberrant Behavior Checklist
with PDD-NOS, 1 with f)Irritability: BL= 15.83; EP= 14.50 NS
Asperger's Disorder; 4 g)Social Withdrawal: BL= 8.92; EP= 7.17 NS
with “average IQ,” 8 h)Stereotypic Behavior: : BL= 3.42; EP= 2.58 NS
with “borderline IQ” i)Hyperactivity/Noncomp. : BL= 23.58; EP= 18.67 (p= 0.07), ES= 0.44
Page 16
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Authors Subjects Design Results


j) Inappropriate Speech: BL= 3.33; EP= 3.75 NS
AEs: Five of the 12 subjects discontinued due to AEs: nausea (n=1), anxiety (n=1), aggression/agitation (n=1),
nausea/vomiting (n=1), and loss of appetite/weight loss (3.3 kg) (n=1). Most common AEs were anorexia (n =
10), irritability (n = 9), sleeping problems (n = 7).
Aman et al.

5. Tang et al., 13-year-old boy, with N/A: Case report. AEs: Patient became suspicious, complained of being followed by strangers, heard voices talking about him.
2009 ADHD Inattentive type; Patient was initially treated with After discontinuance of ATX, all psychotic symptoms remitted.
Wechsler Intelligence OROS methylphenidate, which
Scale for Children FS was discontinued because of
IQ= 66. No substance severe headache.
abuse. Patient was slowly titrated up to
60 mg ATX over 4 weeks.

6. Fernández – 48 youth (32 boys, 16 16-week, OL, prospective study. a) CGI-S: Mean scores statistically significant between BL and EP (BL = 5.31; EP= 4.13 (p < 0.001); ES=1.4
Jaén et al., 2010 girls), mean age = 8.8 Approximate dose of 0.4 b) CGI-I: Of the 45 Ss who finished 16-week treatment period, 22 (49%) much improved or very much improved;
years (range = 5 – 19 mg/kg/day during the Week 1, 14 (31%) minimally improved; no change in 7 (16%); 1 (2%) minimally worse; 1 (2%) much worse.
years). All subjects had 0.8 mg/kg/day during Week 2, ADHD-RS-IV
ID (IQ < 62) and ADHD and 1.2 mg/kg/day at 3rd week Parent ratings
(DSM-IV-TR criteria). 4 (mean EP dose = 1.22; S.D. = c)Inattention: BL= 19.50; EP= 13.4 (p <0.001)
subjects excluded due to 0.19 max. dose of 60 mg/day), d)Hyperactivity-Impulsiveness: BL= 16.72; EP= 11.67 (p <0.001); ES=1.3
nonadherence with single dose taken at breakfast. e)Total: BL= 36.22; EP= 25.07 (p <0.001)
protocol (2 because of Assessed at BL and at 16 weeks Teacher ratings
missed appointments; 2 on CGI-S, ADHD-RS-IV f)Inattention: BL= 16.21; EP= 11.04 (<0.001)
because they failed to (Parents & Teachers); Conners’ g)Hyperactivity-Impulsiveness: BL= 12.95; EP= 8.52 (p <0.001)
“follow the methodology Rating scale (short version; h)Total: BL= 29.17; EP= 19.56 (p <0.001).
for monitoring treatment Parents & Teachers), at Week 16 Conners’ Rating Scale
efficacy”). on CGI-I. Parent ratings
i)Inattention: BL= 11.02; EP= 7.94 (p <0.001)
j) Hyperactivity: BL= 9.52; EP= 6.63 (p <0.001); ES= 1.1
k) Conduct Problem: BL= 11.75; EP= 8.88 (p<0.001);
l) Total : BL= 32.30; EP= 23.47 (p <0.001)
Teacher ratings
m) Inattention: BL= 10.25; EP= 6.95 (p <0.001)
n) Hyperactivity: BL= 8.15; EP= 5.50 (p 0.001)
o) Behavior Issues:† BL= 9.45; EP= 6.05 (p<0.001)
p) Total: BL= 27.85; EP= 18.50 (p <0.001)
q) No association of age, sex, history of neuroleptic use, or methylphenidate use with ATX response.
AEs: 15/48 (31%) presented with AEs. three of 48 (6%) were unable to complete titration due to excessive
irritability; 12 of 48 (25%) exhibited one or more of the following: sleepiness (n=6, 12%), irritability (n=4, 8%),
GI discomfort (n=3, 7%), anorexia (n=1, 2%).

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
7. Charnsil, 2011 12 children, ages 7-17 OL: dose titration to 1.2 mg/kg. Average daily dose= 0.98 mg/kg/day (0.8-1.2 mg//kg/day). Three S's could only tolerate 0.8 mg/kg/day. .Three
years (M=10.67, (given in morning, starting at S's withdrew due to adverse effects (abdominal discomfort, irritable mood) during the first 2 weeks. Nine S's
SD=2.96); with 0.25 mg/kg/day and increased completed the study.
diagnosis of ASD based every 4-5 days by .3-.4 a)CGI-I by study nurse: Much/Very much improved, n=5; 3 Mimimally improved, n=3; No change, n=1.
on investigator- mg/kg/day as tolerated. (However, authors “concluded that atomoxetine was inefficient in reducing attention deficit in hyperactive
completed CARS and 10-week trial and 1-month symptoms” in these subjects due to lack of statistically significant improvement on the ABC-I and ABC-H
DSM-IV-TR criteria. follow-up safety check. subscales..
Sample characterized as Measures; ABC by parent at ABC Parent ratings:
having severe autistic baseline, Week 6 and Week 10. b)Irritability BL=27.11; EP=24.33 (p= .33), ES= .095
disorder. ADHD based CGI-I by nurse at Week 10. c)Social Withdrawal BL=23.44; EP=24.56 (p= .82), ES= .044
upon parent completed Safety measures of weekly vitals d)Stereotypic Behavior BL=11.78; EP=13.11 (p= .76), ES= .097
ABC, but no minimum and weight. Definition of e)Hyperactivity BL=33.89; EP=31.78 (p= .34), ES= .29
cutoff reported. response: 25% decrease on f)Inappropriate Speech BL=3.11; EP=2.78 (p= .22), ES= .032
ABC-Hyperactivity subscale and AEs:
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Authors Subjects Design Results


CGI-I of 1 or 2. Eight of 12
11 subjects had AEs: decreased appetite (n=5), insomnia (n=3), moodiness (n=3); irritability (n=2); abdominal
subjects taking risperidone
discomfort (n=1); diarrhea (n=1).
plus fluoxetine (n=1), valpr
ate (n=2) or diphenhydramine
(n=1)] prior to and during t
Aman et al.

e study.

8. Mazzone et al., 55 youth (53 male; 2 OL, retrospective case review, of a)CGI-I was correlated with full IQ (r= −0.68, p < 0.01), Verbal IQ (r = −0.61, p < 0.01), and Performance IQ (r
2011 female), ages 5-15 years variable duration, using medical = −0.69, p < 0.01).
(mean = 9.9; SD = 2.4) records for all child/adolescent b)CGI-I of 1 or 2 more likely in IQ≥85 group (20 of 26 subjects; 76.9%) than in IQ < 85 group (6 of 29 subjects;
with ADHD symptoms. patients given ATX over 3½- 20.7%), Fisher's exact test p < 0.001).
53 (96%) were year period. ATX initiated at 0.5 c)Smaller response rate in ID (IQ < 70): only 1 in 17 responders; χ2 = 14.59; p < 0.01) compared to subjects with
Combined Type, 2 (4%) mg/kg/day, and increased based IQ >70.
were Hyperactive/ on response. Treatment duration d)No difference between IQ subgroups in mean duration of treatment or dose.
Impulsive Type based on was 1-168 weeks (mean = 57.3 e)AEs: loss of appetite (n=13); abdominal pain (n=12); nausea (n=7); weight loss (n=4); vomiting (n=3);
DSM-IV-TR and ≥ 6 weeks; SD = 39.45). Treatment sleepiness (n=2); paraesthesia (n=1); and myadrasis (n=1).
inattention and/or outcome based on CGI– f)Discontinuance: 20 subjects stopped treatment due to no response or reservations about medication.
hyperactivity/impulsivity Improvement (CGI-I) and CGI–
items rated “pretty Severity (CGI-S). Final dose
much” on SNAP-IV. IQ ranged from 0.32 to 1.76
ranged from 43-117 mg/kg/day (mean= 1.28; SD =
(mean = 80.6, SD = 18.6) 0.39).
(17 had ID). 49% of
subjects had ODD. No
comorbid ASD, anxiety
or mood disorder. No
prior history of
medication

9. Zeiner, Gjevik, 14 subjects, ages 7-17 OL; intent-to-treat (ITT) design; Clinician-completed AD/HD-RS
& Weidle (2011) years (M=11.6 ± 3.5); titration started at 0.5 mg/kg/day a)Inattention: BL= 21.00; EP= 14.79 (p = 0.003); ES=1.1
with ASD and ADHD with upper limit of 1.4 mg/kg/ b)Hyp/Imp: BL= 16.43; EP= 10.36 (p = 0.001).
symptoms; 2 had AD, 8 day; 10-week trial; assessments Teacher-completed AD/HD-RS
had ASP; 4 PDDNOS; every 14 days; statistical c)Inattention: BL= 16.00; EP= 12.80 (p = 0.012)
diagnosed with DSM-IV analyses= Wilcoxon Signed d)Hyp/Imp: BL=10.46; EP= 6.90 (N.S.).
criteria alone. Ranks test Response rate
e)Seven of 14 participants (50%) classified as clinical responders
AEs
f)Significant increase in heart rate from BL to EP 77.6±6.5 to 84.7± 7.3, p=0.03; nausea (n=5); headache (n=5);
stomach ache (n=3); irritability (n=3); drowsiness (n=3); dizziness (n=2); compulsive behavior (n-1)

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
10. Harfter-kamp 102 enrolled, 97 Double-blind, PBO-controlled ADHD-RS (LOCF ANOVA)**
et al., 2012 analyzed; ages design, structured titration in a)Total score: ATX, BL=40.7, EP=31.2; PBO, BL=38.6, EP=38.3 (p<.001); ES=.93
6-17(ATX-mean=9.9, first 3 wks. of 8-week trial (0.5 b)Inattention: ATX, BL=20.7, EP=17.0; PBO, BL=20.6, EP=19.9 (p=.002)
SD=2.7, range=6-16; mg/kg/day to 0.8 mg/kg/day to c)Hyperactivity/impulsivity: ATX, BL=20.0, EP=14.2; PBO, BL=17.9, EP=18.4 (p=.001); ES=1.0
PBO-mean=10.0, 1.2 mg/kg/day), ITT design. CTRS-R:S Scores (LOCF ANCOVA)
SD=2.9, range=6-17); 58 a)Oppositional: ATX, BL=4.1, EP=3.2; PBO, BL=3.6, EP=3.7 (p=.37)
AD, 5 ASP, 32
PDDNOS, 2 No ASD; b)Hyperactivity: †† ATX-BL=8.8, EP=6.8; PBO-BL=8.2, EP=8.8 (p=.024)
83 M, 14 F; IQ 61-138; c)Cognitive/Attention: ATX, BL=6.8, EP=5.1; PBO, BL=4.8, EP=5.8 (p=.18)
diagnoses confirmed d)ADHD: ATX, BL=18.5, EP=15.1; PBO, BL=18.1, EP=17.8 (p=.077)
through clinical CGI
assessment and ADI-R; Much/Very much improved: ATX: n=9, PBO: n=4; Minimally improved: ATX: n=12, PBO, n=6; No change/
IQ≥60, comorbidity was Worse: ATX: n=22, PBO: n=36
allowed except for AEs (Sig. differences listed first) ATX and PBO, respectively:
psychosis or bipolar, no Nausea: 14 vs. 4, p=.009
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Authors Subjects Design Results


other psychoactive Decreased appetite: 13 vs. 3, p=.006
medications allowed Early morning awakening: 5 vs. 0, p=.027
Headache: 12 vs. 9, p=.47
Fatigue: 11 vs. 4, p=.053
AEs higher for ATX than PBO, respectively:
Aman et al.

Upper abdominal pain: 9 vs. 3, p=.55


Abdominal pain: 4 vs. 3, p=.72
Dizziness: 3 vs. 1, p=.36
Influenza: 3 vs. 0, p=.12
Myalgia: 3 vs. 0, p=.12
11. Harfter-kamp 88 subjects, 6-17 years 20-week, open-label, ITT ADHD-RS (paired sample t-tests); subjects originally assigned to ATX:
et al., 2013 of age (mean= 10.0); 51 extension, without breaking the a)Total score: ATX, Wk 8=32.4, EP=24.9; (p<.02)
AD, 5 ASP, 30 double blind from the previous b)Inattention: ATX, Wk 8=16.9, EP=13.0; (p<.01)
PDDNOS, 2 No ASD; trial. Subjects were previously in c)Hyperactivity/impulsivity: ATX, Wk 8=15.5, EP=11.8; (p<.06)
76 M, 12 F; IQ 61-138 an 8-week, controlled trial of Subjects originally assigned to PBO: Results not presented, although almost certainly statistically significant
(mean= 93.1); diagnoses ATX. 46 subjects previously reduction in ADHD scores.
confirmed through received PBO, and 37 previously Subjects originally assigned to both PBO and ATX: All comparisons were significant for both subscales and for
clinical assessment and received ATX (see Harfterkamp Total score.
ADI-R; IQ≥60, et al., 2012). Titration was AEs, reported from wk 8 of ATX and from EP (Wk 12 or 20 of ATX treatment) (N=88):
comorbidity was allowed structured in first 3 wks. of 20-
except for psychosis or week trial (0.5 mg/kg/day [wk 1] AE First 8 Wks After 12/20 Wks P level
bipolar, no other to 0.8 mg/kg/day [wk 2] to 1.2
psychoactive mg/kg/day [wk 3 and abdominal pain 6 2 N.S.
medications allowed. thereafter]). Subjects started on
PBO in the blinded trial received abdom. pain upper 11 7 N.S.
a total of 20 weeks of ATX
treatment; subjects assigned to decreased appetite 16 8 <.10
ATX in blinded trial received a early awakening 5 1 N.S.
total of 28 weeks ATX
treatment. fatigue 16 6 =.04

headache 18 13 N.S.

influenza 5 2 N.S.

initial insomnia 6 6 N.S.

nausea 12 1 .003

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
vomiting 6 5 N.S.

Abbreviations: ABC= Aberrant Behavior Checklist, AD= autistic disorder, ADOS= Autism Diagnostic Observation Schedule, AEs= adverse events ASP= Asperger's disorder, BL= baseline, bpm = beats
per minute, CGI= Clinical Global Impressions scale, CPRS= Conners’ Parent Rating Scale, CPT= Continuous Performance Task, EP= end-point, F= female(s), ES= Cohen's d (effect size), ID= Intellectual
disability, ITT= intent-to-treat, M= male(s), NS= non-significant/not significant, OL= open label, PDD= pervasive developmental disorder, PBO= placebo, PDDNOS= pervasive developmental disorder not
otherwise specified, RBS-R= Repetitive Behavior Scale-Revised,
*
Alpha set at .01 to minimize Type I Error; actual p value = .05, nominally significant.
**
Results using LS Means, from mixed models for repeated measures (MMRM) not summarized, to enable consistent reporting of results; MMRM not reported in original paper for CTRS-R:S.

There is apparently no “Behavior Issues” subscale in the English or Spanish versions of the Conners’ scales, so it is unknown which items comprised this subscale. Also, although the researchers used a
Spanish version, it is unclear what edition of Conners’ scales was used for the teachers ratings.
Page 19
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
††
This appears to be the 7-item subscale on Conners’ Teacher Rating Scale—Short version. If scored in the usual way (0-3 convention), scores between 8-9 at baseline would be relatively low for
symptoms of ADHD.
Aman et al.

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
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Table 2

Summary of Adverse Events Reported Across All Studies.

Percentages (%) and Totals Showing Adverse Events Across Studies Percent of Study Sample Showing AE
Aman et al.

Study: 1 2 4 6 7 8 9 10 Total Subjects Across Studies

Adverse Event Sample Size: 20 16 16 12 48 12 55 14 48


Decreased Appetite (30) (75) (44) (83) (2) (42) (24) – (27) 66 (29.1, 27.4%)

Nausea – (100) (13) – – – (13) (36) (29) 44 (29.5, 18.3%)

Irritability – (88) (57) (75) (8) (17) – (21) – 39 (30.0, 16.2%)


Sedation/Sleepiness (30) – (81) – (12) – (4) (21) – 29 (19.0, 12.0%)

Fatigue – (75) – – – – – – (23) 23 (35.9, 9.5%)

Sleep problems – – (19) (58) – (25) – – (10) 18(20.5, 7.5%)

Mood swings (30) – (31) – – (25) – – – 14 (23.0, 5.8%)

GI discomfort – – (19) – (7) (8) – (21) (8) 14 (10.1, 5.8%)


Vomiting – – (19) – – – (5) – (15) 13 (10.9, 5.4%)

Note. First percentage in right column is based on total sample for cells where adverse event is reported; second percentage is based on all 241 subjects across all studies and assumes that investigators
screened for that adverse event in all studies. Whereas neither percentage may be correct, we regard the first as more accurate, albeit possibly high.

Res Dev Disabil. Author manuscript; available in PMC 2015 August 11.
Page 21
Allely BMC Psychiatry 2014, 14:133
http://www.biomedcentral.com/1471-244X/14/133

RESEARCH ARTICLE Open Access

The association of ADHD symptoms to self-harm


behaviours: a systematic PRISMA review
Clare S Allely

Abstract
Background: Self-harm is a major public health issue in young people worldwide and there are many challenges
to its management and prevention. Numerous studies have indicated that ADHD is associated with completed
suicides and other suicidal behaviours (i.e., suicidal attempt and ideation). However, significantly less is known about
the association between ADHD and self-harm.
Method: This is the first review of the association between ADHD and self-harm. A systematic PRISMA review was
conducted. Two internet-based bibliographic databases (Medline and CINAHL) were searched to access studies
which examined to any degree the association between, specifically, ADHD and self-harm.
Results: Only 15 studies were identified which investigated the association between ADHD and self-harm and
found evidence to support that ADHD is a potential risk factor for self-harm.
Conclusion: This association raises the need for more awareness of self-harm in individuals with symptoms of ADHD.
Keywords: ADHD: Attention-Deficit/Hyperactivity Disorder, Self-harm, Self-injurious behaviour, Deliberate self-harm,
Suicide-related events

Background admission. Although international variation exists, find-


ADHD and self-harm ings from numerous community-based studies indicate
Attention-deficit/hyperactivity disorder (ADHD), as de- that approximately 10% of adolescents report having
fined by DSM-IV [1], is a syndrome that is first manifested self-harmed [8-12]. Self-harm refers to intentional self-
in childhood by variable combinations of inattention, poisoning or self- injury, irrespective of type of motive
hyperactivity and impulsivity. The prevalence of ADHD in or the extent of suicidal intent [13,14].
childhood is estimated to be approximately 5-7% [2] and
ADHD symptoms tend to persist into adulthood [3,4].
ADHD is a mediator of poor outcome such as low self- Association between ADHD and suicide
esteem and poor academic and vocation outcomes [5,6] Previous studies have shown a connection between
and one of the major public health problems in modern ADHD and attempted and completed suicide in male
societies [7]. adolescents and young adults [15-21], suicidal behaviour
Nomenclature used to describe acts of self-harm with- [22] and suicide ideation in female adolescents [23]. A
out fatal consequences varies considerably. For this re- longitudinal study found that early childhood ADHD is
view the terms deliberate self-harm (DSH), self-harm, a risk factor for suicidal behaviour between the ages of 9
self-mutilation, self-injury and self-injurious behaviour and 18 [24]. In a clinic- referred sample of female ado-
(SIB) are used interchangeably depending on the use ap- lescents, Biederman and colleagues found that girls with
plied in the paper discussed. DSH and SIB represent a comorbid ADHD and major depression had more sui-
significant health problem in the UK and are amongst cidal ideation compared with those with only major de-
the most common reasons for emergency hospital pression [25]. Among delinquent juvenile offenders,
suicidality relating to depression, ADHD and social pho-
bia were only found among males [26].
Correspondence: clare.allely@glasgow.ac.uk
Institute of Health and Wellbeing, University of Glasgow, RHSC Yorkhill,
A previous systematic review [27] showed an associ-
Glasgow 8SJ G3, Scotland ation between ADHD and suicide. Impey [21] conducted
© 2014 Allely; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited.
Allely BMC Psychiatry 2014, 14:133 Page 2 of 13
http://www.biomedcentral.com/1471-244X/14/133

a review of the relationship between ADHD and suicid- authors [37], further research is required to establish
ality and found that ADHD symptoms occur more fre- whether there are associations between suicide-related be-
quently in suicidal populations and may be a reason for haviours and specific ADHD treatment medications.
completed suicide. In sum, these reviews of the literature
showed that there is a positive relationship between Present review
ADHD and risk to self. There is a need for greater understanding of the factors
which contribute to self-harm. Identification of effective
Self-harm predicts suicide prevention initiatives and subsequent treatment strat-
Further research is necessary to develop a mean of pre- egies aimed at young people and those at particular high
venting adolescents from repeating self-harm, since sev- risk is clinically imperative. There is an urgent need to
eral studies have shown that around 10–15% of children identify those populations at risk and to intervene pro-
who self-harm are likely to repeat such episodes within a actively [38]. The purpose of this systematic PRISMA re-
year [28,29], sometimes also proceeding to suicide. In- view is to investigate the relationship between ADHD
deed, numerous studies have indicated that self-harm and self-harm, in order to see if self-harm can be consid-
predicts suicide (i.e., [30]) Suicide risk among self-harm ered to be a risk factor. As discussed above this is par-
patients is hundreds of times higher than in the general ticularly important given the increased rates of self-harm
population [27]. and the greater risk of these individuals to go on to at-
tempt and/or complete suicide. This is the first review
Associations of suicide related events and ADHD to explore the peer-reviewed literature which has investi-
medications gated this relationship.
Although the focus of this systematic review is on
ADHD and the outcomes, it is important to include a Method
brief discussion of the crossover with medication and Internet-based bibliographic databases (Medline and
what is currently known. With the treatment of ADHD CINAHL) were searched to access studies which exam-
it is thus important to establish any associations between ined to any degree the association between, specifically,
pharmacological treatments (such as atomoxetine and ADHD and self-harm rather than the association be-
methylphenidate) and suicide-related events. Atomoxe- tween ADHD and completed suicide, suicide attempts
tine (Strattera®) is a selective norepinephrine (noradren- and suicide ideation. The search criteria identified below
aline) reuptake inhibitor. It is not a stimulant, and is were entered in a number of other databases including
indicated for use in patients with ADHD [31]. Methyl- PsycINFO. However, the Medline was chosen as the pri-
phenidate is a central nervous system (CNS) stimulant mary database because it returned more relevant articles.
used to treat ADHD. From the European Union (EU) CINAHL was also used because it is the definitive re-
Supplementary protection certificates (SPCs) for methyl- search tool for nursing and allied health professionals.
phenidate, it is important to highlight that suicidal ten- The process of eliminating non-relevant papers can be
dencies have been found to be a contraindication for seen in the flowchart (following PRISMA guidelines
this medication [32,33]. The US Food and Drug Admin- [39], see Figure 1) below. Duplicates were excluded prior
istration and Health Canada also warned of increased to the retrieval of references. Searches on the two data-
rates of suicidal ideation among children taking atomox- bases were originally conducted on 9th May 2013. The
etine in placebo-controlled trials [34]. Based on fourteen following search criteria were entered into the two data-
identified trials in paediatric patients, Bangs and col- bases: [self-harm OR “self harm” OR self-injury OR “self
leagues (2008) [35] found that, despite being uncom- injury” OR self-poisoning OR “self poisoning” OR self-
mon, suicidal ideation was significantly more frequent in injurious OR “self injurious” OR self-mutilation OR “self
paediatric ADHD patients treated with atomoxetine mutilation”] AND [ADHD or “Attention-deficit/hyper-
compared to those treated with placebo [35]. One study activity disorder” or “attention-deficit hyperactivity dis-
found no evidence which suggested an increase in the order”]. Medline returned a total of 59 abstracts and
risk of sudden death associated with stimulants or ato- CINAHL returned a total of 27. Combining the two
moxetine. However, there was an increased risk of sui- search findings (total 86), nine were removed because
cide with the treatment [36]. they were duplicates. In addition to these database
However, a recent meta-analysis, the first focusing on searches, numerous permutations of ADHD and self-
five studies comparing suicide-related events in compara- harm were entered into Google Scholar and thoroughly
tive randomised double-blind atomoxetine and methyl- searched for any additional articles not found in the
phenidate clinical trials, found no significant evidence of a database searches, for instance, [ADHD AND self harm];
difference in risk between the two treatments [37]. Given [attention-deficit/hyperactivity disorder]; [ADHD AND
the limitations of meta-analyses, acknowledged by the self injury]. These searches only returned four additional
Allely BMC Psychiatry 2014, 14:133 Page 3 of 13
http://www.biomedcentral.com/1471-244X/14/133

Identification

Number of additional
Number of references references identified
identified through through other sources –
database search – 86 17

Number of duplicates Number of references excluded – 4 involved a


removed through reading sample of individuals with Autistic Spectrum
Screening titles of abstracts – 9 Disorders; 21 Tourette’s Syndrome; 1 effects
of cerebral malaria; 3 individuals with
developmental disabilities; 1 individuals with
epilepsy; 1 individuals with mental
retardation; 1 with Smith-Lemli-Opitz
Number of abstracts syndrome; 1 with Myotonic Dystrophy; 2
screened – 94 with Down Syndrome; 1 bulimia nervosa; 1
with intellectual disabilities;
1 with post-traumatic stress disorder; 1 with
Smith-Magenis Syndrome and 40 were not
relevant to the focus of the present review.

Number of full text Number of full text articles excluded -


Eligibility 0
articles assessed for
eligibility - 15

Number of papers Number of papers


Included eligible – 15 unobtainable – 0

Number of studies
included in the
qualitative synthesis – 15

Figure 1 Flow of information through systematic review.

relevant articles. Numerous references contained in the developmental disabilities; epilepsy; mental
papers found to be relevant from the database searches retardation; Smith-Lemli-Opitz syndrome; Myotonic
were also explored for inclusion in this review. Dystrophy; Down Syndrome; bulimia nervosa;
Abstracts for each reference were obtained and screened intellectual disabilities; post-traumatic stress disorder
using the following criteria: and Smith-Magenis Syndrome).

Inclusion criteria: Screening:


1. Human study population In the first stage, papers were rejected which:
2. Investigated the association between ADHD and  investigated completed suicide, suicide attempts or
self-harm. suicide ideation as this review is specifically interested
Exclusion criteria: in the association between ADHD and self-harm as
1. Paper not published in English even less is known about this association.
2. Dissertations  were not published in the English language
3. Book reviews For the next stage papers were rejected which:
4. Studies which investigated a sample that comprised  were not studies that involved a sample of
of individuals with a disorder other than ADHD (for individuals with ADHD (for instance, numerous
instance, individuals with: Autistic Spectrum studies involved samples of individuals with
Disorders; Tourette’s Syndrome; cerebral malaria; Tourette’s syndrome).
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In addition, review papers and book chapters which The idea that ADHD may act as a risk factor for sui-
were clearly reviews were excluded and if relevant are cidal ideation and DSH was also investigated in a study
referred to in the introduction. Full documents were ob- based on adolescents from a general population sample
tained for the remaining records. [48] derived from a population-based Northern Finland
Birth Cohort 1986 (n = 9432). Based on the Schedule for
Affective Disorders and Schizophrenia for School-Age
Results
Children, Present and Lifetime Version (Kiddie-SADS-
Fifteen studies were found that explored or included an
PL, [56]) interview performed in a subpopulation (n =
exploration of the association between ADHD and self-
457), associations between suicidal behaviour and DSH
harm (one of which was a case study). Table 1 lists the
and the diagnosis of ADHD were studied. Information
studies that were found to be relevant and details some
was also obtained from national registers about deaths
of the main points for each. In this section, the fifteen
related to suicide. Compared with adolescents without
studies are split into two sections. The first section in-
ADHD (n = 169), those with ADHD (n = 104) had more
cludes studies where the sample involved a study popu-
suicidal ideation (57% versus 28%, p < 0.001) and DSH
lation with ADHD and measures of self-harm behaviour
(69% versus 32%, p < 0.001). The effect of ADHD on sui-
were then conducted. The second section includes the
cidal ideation remained strong (OR = 6.1) after control-
studies which examined a population who were hospita-
ling for several other predictors.
lised due to injury and measures of ADHD were then
The effect of ADHD on substance-use disorder (SUD)
conducted. This was done given the possibility that dif-
as well as other behaviours such as SIB, suicide attempts
ferent results may be obtained depending on this. Under
and criminality is unclear which prompted the next
each of these headings, studies are divided depending on
study by Semiz, Basoglu, Oner et al. [52]. A total of 105
whether the samples involved children and/or adoles-
adult male offenders with Structured Clinical Interview
cents under the age of 18 years and adults (those above
for Axis II Disorders (SCID-II)-based DSM-III-R anti-
18 years of age).
social personality disorder (APD) were studied in terms
of: (i) psychopathy scores on the Hare Psychopathy
Studies with a population with ADHD and measures of Checklist-Revised (PCL-R) [57]; (ii) ADHD(c) diagnostic
self-harm behaviour were then conducted comorbidity on clinically administered DSM-IV ques-
Children and adolescent samples tionnaire; and (iii) ADHD(d) dimensional symptoms by
Deane and Young [41] investigated, using Interpretative means of Wender Utah Rating Scale (WURS) [58] and
Phenomenological Analysis of interviews, the experience Conners Adult ADHD Rating Scale (CAARS [59]), dur-
of eight adolescent girls. Four of whom had a history of ing a 12 month study period (May 2005-May 2006).
ADHD symptoms and conduct disorder problems Most importantly, for the focus of this review, was the
(ADHD/CP), four did not. However, they report two finding that the number of ADHD(d) symptom criteria
cases where there was a presentation of both ADHD endorsed correlated significantly with frequency of SIB
and self-harm or attempted suicide. (r = 0.32, p = 0.002). WURS total score was significantly
Hinshaw et al. [47] conducted a 10-year prospective correlated with frequency of SIB (r = 0.38, p < 0.001),
follow-up of a female childhood-ascertained (6–12 years) number of suicide attempts (r = 0.28, p = 0.011) and
ADHD (n = 140) plus a matched comparison group (n = negatively correlated with age at onset of SIB (r = − 0.23,
88). Ten-year outcomes (age range 17–24 years). p = 0.023). CAARS total score was significantly corre-
Hinshaw et al. [47] assessed variety and frequency of lated with frequency of SIB (r = 0.34, p < 0.001) and
nonsuicidal self-injury (NSSI) using a modification of number of suicide attempts (r = 0.32, p = 0.007).
Claes, Vandereycken, and Vertommen’s [54] Self-Injury Wehmeier, Schacht, Lehmann, Dittmann, Silva and
Questionnaire (SIQ). Suicide behaviours were investi- March [53] were interested in measuring changes in
gated using the Barkley Suicide Questionnaire [55]. The items on the Pediatric Adverse Event Rating Scale
family-completed Family Information Profile (FIP) enquired (PAERS) that relate to emotional well-being of children
about suicide attempts. For suicide attempts, individuals and adolescents with ADHD during treatment with ato-
with ADHD-combined had a higher rate (22%) compared moxetine. Patients aged 6–17 years with ADHD were
to individuals with ADHD-inattentive (8%) or the compar- treated with atomoxetine (target dose 1.2 mg/kg/day).
isons (6%), who did not differ significantly. Interestingly, The PAERS was used to assess the tolerability of ato-
self-injury was significantly more likely (OR = 4.4) in the moxetine in children and adolescents (n = 421). The ten
ADHD-combined group (51%) compared to the com- items that reflect emotional well-being were grouped in
parison group (19%). Self-harm was also more likely in five dimensions: depressed mood, self-harm, irritability/
the ADHD-combined group compared to the ADHD- agitation, drowsiness, and euphoria. The scores of these
inattentive group (29%; OR = 2.5). dimensions decreased over time. Only the dimension of
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Allely BMC Psychiatry 2014, 14:133
Table 1 Lists the studies that were found which explored to any degree the association between ADHD and self-harm and details some of the main points
from each (nature of sample; the aim of the study and the main findings)
Author Samples Aim of the study Findings
Ben-Yehuda et al. 232 ED referrals; 37 (15.9%) children and 195 To investigate the hypothesis that suicidal behaviour in Findings revealed a diagnostic difference between suicidal children
2012 [40] (84.1%) adolescents. children stems from a different diagnosis other than and suicidal adolescents. An act of DSH or ideation was the
suicidal behaviour in adolescents. presenting symptom of 232 ED referrals; this figure comprised
Children group – under 12 years old.
37 (15.9%) children and 195 (84.1%) adolescents. For children, the
Adolescent group between 12-18 years. prevalent diagnoses were ADHD (43.2%), conduct disorders (21.6%),
and adjustment disorders (16.2%). For adolescents, the prevalent
diagnoses were adjustment disorders (28.7%) and conduct
disorders (17.9%) (p < 0.001).
Deane and Young 8 female participants - 4 from the comorbid group To investigate the experience of girls growing up with
2 cases where there was a presentation of both ADHD and
(2012) [41] (ADHD/CP; Astrid, Anna, Abigail, and Alison) and cognitive and social disorders. self-harm or attempted suicide - Anna and Abigail had attempted
four from the control group. (All between 14 & suicide and Alison had engaged in extensive self-harm. The
The association between ADHD and self-harm was not
16 years of age at the time of the interviews). authors found that Alison was able to make a clear link between
the focus of this paper.
her feelings of emotional isolation, behavioural problems and
self-harming behaviour.
DiScala et al. 2 groups To investigate the differences between hospital Compared with the NO children, the children with ADHD were
(1998) [42] admitted injuries to children with pre-injury ADHD and more likely to inflict injury to themselves (1.3% versus 0.1%).
1) all cases of paediatric trauma that had a
injuries to those with no pre-injury conditions (NO).
pre-injury diagnosis of attention deficit or They were more likely to sustain injuries to multiple body
hyperactive disorder or both ADHD regions (57.1% versus 43%), to sustain head injuries
(53% versus 41%), and to be severely injured as measured by the
2) all cases of paediatric trauma with no pre-injury Injury Severity Score (12.5% versus 5.4%) and the Glasgow
condition (NO). Coma Scale (7.5% versus 3.4%).
ADHD patients (n = 240) to NO patients
(n = 21 902), 5 through 14 years of age.
Dowson et al. 59 adult patients (mean age: 30.6 years, range To investigate the associations between questionnaire Patients who reported a past history of ‘self-harm' (N = 33) had a
(2007) [43] 9.8 years) with a DSM-IV diagnosis of ADHD. assessments of behavioural features of adults with significantly worse mean performance on both measures of SWM
ADHD and an aspect of neurocognitive performance (p = 0.004, 0.003).
which has been reported to be impaired in adults
with ADHD.
Dowson et al. 73 male adults with DSM-IV ADHD (aged To investigate the associations between impulsive Adult ADHD-related impulsivity and hyperactivity predicted
(2010) [44] 18-65 years) and their informants. Impulsive aggression and ADHD. temper outbursts ⁄hitting people ⁄throwing, while self-reported
externally directed aggression was endorsed in adult ADHD-related inattention predicted threats ⁄actual self-harm.
29 of the 73 subjects and impulsive
autoaggression in 34 subjects. Impulsive externally directed aggression was endorsed in 29 of
the 73 participants and impulsive autoaggression in 34 participants.
Fulwiler et al. Inmates were classified as self-mutilators if they To test the hypothesis that prisoners who injured A logistic regression analysis incorporating childhood hyperactivity
(1997) [45] had inflicted objectively verifiable bodily injury themselves without intending to die would differ and affective disorder as covariates found that self-mutilators
without either the intent or wish to die (n = 16). clinically from prisoners who had attempted suicide. were 28 times more likely to report childhood hyperactivity.
Suicide attempters were de- fined as patients
whose intention was to die (n = 15). The early onset of psychiatric symptoms in self-mutilators was
Self-mutilators -mean age 30 years (SD = 7.2). also reflected in the fact that 75 percent (12/16) reported being
diagnosed hyperactive as children, compared with only one of
Suicide attempters – mean age 34 years
the attempters.
(SD =7.3).

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Allely BMC Psychiatry 2014, 14:133
Table 1 Lists the studies that were found which explored to any degree the association between ADHD and self-harm and details some of the main points
from each (nature of sample; the aim of the study and the main findings) (Continued)
Goodman et al. AS group - age 8.38 (1.97) years (n = 24). This study investigated mother and child’s aggression AS children were significantly more aggressive and suicidal, five
(2008) [46] as well as child correlates of suicidal behaviour in two times more likely to engage in serious assaultive behaviour, and
AO group - 8.74 (1.82) years (n = 19). groups—assaultive/suicidal (AS) and assaultive-only almost six times more likely to be diagnosed with ADHD than
(AO) —prepubertal psychiatric inpatients. their AO counterparts. Suicidal behaviour treated as a 5- point
dimensional scale in the total sample was associated with child’s
aggression, the presence of ADHD, maternal depression, and
maternal state anger, but not with child’s depression. Child’s
aggression mediated the relation between the presence of
ADHD and suicidal behaviour in the total sample.
Hinshaw et al. Childhood-ascertained (6-12 years) girls with To investigate the 10-year outcomes in girls diagnosed Self-injury was found to be significantly more likely (OR = 4.4) in
(2012) [47] ADHD (ADHD; n = 140: combined type [ADHD-C] with ADHD in childhood – outcomes investigated the ADHD-C group (51%) than the comparison group (19%).
n = 93; inattentive type [ADHD-I] n = 47) plus a were symptoms (ADHD, externalising, internalising),
matched comparison group (n = 88). 10 year substance use, eating pathology, self-perceptions, Self-injury was also found to be more likely in the ADHD-C
group compared to the ADHD-I group (29%; OR = 2.5).
outcomes (age range 17-24 years; retention functional impairment (global, academic, service
rate = 95%). utilisation), self-harm (suicide attempts, self-injury), These findings show that self-harmful behaviour predominated
and driving behaviour. in the participants originally diagnosed with ADHD-C.
Hurtig et al. Sample derived from a population-based To investigate the effect of ADHD on suicidal or Compared with adolescents without ADHD, those with ADHD
(2012) [48] Northern Finland Birth Cohort 1986 (n = 9432). self-harm behaviour in adolescents from a general had more suicidal ideation (57% versus 28%, p < 0.001) and
Based on the Schedule for Affective Disorders and population sample. DSH (69% versus 32%, p < 0.001).
Schizophrenia for School-Age Children, Present
and Lifetime Version (Kiddie-SADS-PL) interview
performed in a subpopulation (n = 457).
Compared adolescents without ADHD (n = 169)
and those with ADHD (n = 104).
Izutsu et al. 239 boys (mean age = 14.16 years, SD = 0.67) & To investigate the status of DSH among junior Overall, 8.00% and 27.70% of males and 9.30% and 12.20% of
(2006) [49] 238 girls (14.22, 0.68) from a junior high-school high-school students, and investigate the relationship females reported self-cutting and self-hitting, respectively.
in Kanagawa, Japan between DSH and substance use and childhood
With respect to the association between DSH and childhood
hyperactivity.
hyperactivity, comparisons of WURS scores between those
with and without experience of problematic behaviours
revealed that with all problematic behaviours in both
genders, scores of those with experience were significantly
higher than those without (p < 0.01 except for self-cutting
in females, p < 0.05).
Lam (2002) [17] 158 with ADD and 46,962 non-ADD individuals To investigate the following: What patient Significant association between different causes of injuries,
between the ages of 16 and 19 years admitted characteristics are associated with the diagnosis of in particular self-inflicted injuries and diagnosis of ADD
to hospitals due to accidental or self-inflicted ADD upon admission to the hospital? What types of were found.
injuries in New South Wales, Australia injury are associated with the diagnosis of ADD among
during 1996 to 2000. hospitalised young patients? What is the relationship
between the diagnosis of ADD and the outcome of
hospitalisation due to injury?
Lam (2005) [50] Children and adolescents between the ages of To investigate the associations between intra-and There were significant associations between suicide and
5 and 15 years admitted to hospital owing to interpersonal violence and related injuries and the self-harm, injuries owing to assault, and diagnosis of ADD.
injuries in 2000. 111 individuals with ADD and diagnosis of ADD among children and young The odds for self-inflicted injuries were about 8.5 for

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18,618 with no ADD. adolescents. children diagnosed with ADHD as compared with those without.
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Table 1 Lists the studies that were found which explored to any degree the association between ADHD and self-harm and details some of the main points
from each (nature of sample; the aim of the study and the main findings) (Continued)
Lynch et al. 12-15 year olds (selected from 8 secondary To investigate the prevalence rates of psychiatric Investigation of the association between ADHD and self-harm
(2006) [51] schools). disorders, suicidal ideation and intent, and parasuicide behaviours were not investigated in this paper.
in a population of Irish adolescents in a defined
geographical area.
Investigation of the association between ADHD and In the ‘at-risk’ group, six (5.9%) had a diagnosis of ADHD and
self-harm behaviours were not investigated in only three (3.2%) had a diagnosis of ADHD in the ‘not at-risk’
this paper. group. The estimated prevalence in the entire population
(based on a weighted analysis) was 3.7% (95% CI = 0.7-6.7).
Semiz et al. 105 adult male offenders with Structured Clinical Two-fold: 92 per cent of the participants (n = 97) reported SIB. These
(2008) [52] Interview for Axis II Disorders (SCID-II)-based included: self-cutting (82%), hitting (51%), burning (37%),
(1) to define the relationship between DSM-III-R APD
DSM-III-R APD. (Age 20–36 years, and biting (14%). Sixty-five per cent (n = 68) of the subjects
and PCL-R-based psychopathy scores with comorbid
mean ± SD = 22.7 ± 2.9 years). had received medical treatment for SIB, indicating the serious
diagnosis of ADHD (ADHDc) and dimensional ADHD and persistent nature of these self-inflicted wounds.
symptoms (ADHDd) in a group of male offenders.
(2) To examine the relationship of ADHD measures Number of ADHDd symptom criteria endorsed was significantly
within the study population with SUD, SIB, and record correlated with frequency of SIB (r = 0.32, p = 0.002). WURS total
of suicide attempts and criminal behaviours. score was significantly correlated with frequency of SIB (r = 0.38,
p < 0.001), number of suicide attempts (r = 0.28, p = 0.011),
number of criminal behaviours (r = 0.26, p = 0.016), PCL-R total
(r = 0.28, p = 0.016) and Factor 2 scores (r = 0.36, p = 0.002), and
negatively correlated with age at onset of SIB (r = – 0.23,
p = 0.023). CAARS total score was significantly correlated
with frequency of SIB (r = 0.34, p < 0.001) and number of
suicide attempts (r = 0.32, p = 0.007).
Wehmeier et al. Patients aged 6-17 years with ADHD treated with To measure changes in items on the PAERS that relate 421 ADHD patients were treated with atomoxetine - The ten
(2008) [53] atomoxetine (target dose 1.2 mg/kg/day). 355 to emotional well-being of children and adolescents items that reflect emotional well-being were grouped in five
patients completed the 8-week treatment course with ADHD during treatment with atomoxetine for dimensions: depressed mood, self-harm, irritability/agitation,
& 260 patients completed the 24-week up to 24 weeks from the perspective of the patient, drowsiness, and euphoria. The scores of these dimensions
treatment course. the parent, and the physician. decreased over time, both from a patient as well as from a
parent and physician perspective.
Only the dimension self-harm was extremely low at baseline
and stayed low over time.
Key
ADHD-C: Attention-Deficit/Hyperactivity Disorder - combined type.
ADHD-I: Attention-Deficit/Hyperactivity Disorder - inattentive type.
ADHDd: ADHD(d) dimensional symptoms by means of Wender Utah Rating Scale (WURS) and Conners Adult ADHD Rating Scale (CAARS) during a 12 month study period (May 2005-May 2006).
ADD: Attention Deficit Disorder.
APD: Antisocial Personality Disorder.
AS: Assaultive/Suicidal.
AO: Assaultive-Only.
CAARS: Conners Adult ADHD Rating Scale.
DSH: Deliberate Self-Harm.
ED: Emergency Department.
NO children: Injuries to children admitted to hospital with no preinjury conditions (NO).

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PAERS: Pediatric Adverse Event Rating Scale.
SIB: Self-Injurious Behaviour.
SWM: Spatial Working Memory.
WURS: Wender Utah Rating Scale.
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self-harm was extremely low at baseline and stayed low two groups, assaultive/suicidal (AS) and assaultive-only
over time. (AO). Mother and child aggression and child correlates
of suicidal behaviour in the two groups was investigated.
Adult samples ADHD, child’s aggression, and maternal depression and
Dowson, Blackwell, Turner, Harvey, Malhotra, Robbins state anger accounted for 33% of the variance in
and Sahakian [43] examined the associations between suicidal-scale scores. Aggression mediated the relation
questionnaire ratings and performance on a computer- between ADHD and suicidal behaviour. AS children
administered task of spatial working memory (SWM). were significantly more aggressive and suicidal, five
Fifty-nine adult patients (mean age: 30.6 years) with a times more likely to engage in serious assaultive behav-
DSM-IV diagnosis of ADHD, and their informants, were iour, and almost six times more likely to be diagnosed
asked to complete questionnaires relating to aspects of with ADHD than their AO counterparts.
severity of ADHD. The findings of interest to this par- Izutsu, Shimotsu, Matsumoto, Okada, Kikuchi, Kojimoto
ticular review were that patients who reported a past et al. [49] explored the status of DSH among 239 junior
history of ‘self-harm’ (n = 33) had a significantly worse high-school boys (mean age = 14.16 years, SD = 0.67) and
mean performance on both measures of SWM (p = 0.004, 238 girls (14.22, 0.68) and investigated the relationship be-
0.003). tween DSH and substance use and childhood hyperactiv-
In a more recent study by the same research group, ity. A self-reporting questionnaire consisting of original
Dowson and Blackwell [44] investigated impulsive ag- questions on self-cutting, self-hitting, and tobacco and al-
gression in 73 adults with DSM-IV ADHD adults (mean cohol were used in addition to the Wender Utah Rating
age of 29). Using questionnaires, they looked at both ex- Scale (WURS) for assessing childhood hyperactivity. With
ternally directed aggression and autoaggression. Impul- respect to the association between DSH and childhood
sive autoaggression was identified if one or both of the hyperactivity, comparisons of WURS scores between those
following Structured Clinical Interview for DSM-IV Per- with and without experience of problematic behaviours
sonality Disorder (SCID II) questions for BPD criterion revealed that with all problematic behaviours in both gen-
5 were endorsed: “Have you tried to hurt or kill yourself ders, scores of those with experience were significantly
or threatened to do so?”, “Have you ever cut, burned, or higher than those without (p < 0.01 except for self-cutting
scratched yourself on purpose” [60,61]. Impulsive ag- in females, p < 0.05).
gression was assessed by ratings of two criteria for bor- Lam [17] found a four-fold higher likelihood of having
derline personality disorder (BPD), involving hot temper a diagnosis of ADD for children and adolescents hospi-
and/or self-harm. Adult ADHD-related impulsivity and talised for suicide attempts and self-harm based on a
hyperactivity was found to predict temper outbursts/hit- population-based epidemiological design which analysed
ting people ⁄throwing, while self-reported adult ADHD- data routinely collected on patients hospitalised due to
related inattention predicted threats/actual self-harm. injuries.
Lam [50] investigated the associations between intra-
Studies which examined a population who were and interpersonal violence and related injuries and the
hospitalised due to injury (or identified by records/self- diagnosis of attention deficit disorder (ADD) among
assessment) and measures of adhd were then conducted children and young adolescents. This was a population-
Children and adolescents samples based epidemiological study that analysed data routinely
Ben-Yehuda, Aviram, Govezensky, Nitzan, Levkovitz and collected on hospitalised patients owing to injuries. Chil-
Bloch [40] found an act of DSH or ideation was the pre- dren and adolescents (between 5–15 years) were identi-
senting symptom of 232 emergency department referrals fied from the ISC data bank by the selection criteria of
out of 905: comprising of 37 (15.9%) children (under having a diagnosis of external causes of injury and poi-
12 years) and 195 (84.1%) adolescents (12–18 years). soning according to the International Classification of
DiScala et al. [42] investigated the differences between Diseases 9th Revision-Clinical Modification (ICD-9-CM)
hospital admitted injuries to children (5–14 years) with [62]. Patients with comorbidity of ADD were further
preinjury ADHD (n = 240) and injuries to those with no identified from this data set by the ICD-9-CM. The like-
preinjury conditions (NO) (n = 21,902). Findings showed lihood of being diagnosed with ADD was about four
that, compared with the NO children, the children with times higher (OR = 3.76, 95% CI = 1.73-8.15) for children
ADHD were more likely to inflict injury to themselves and adolescents hospitalisations owing to suicide and
(1.3% versus 0.1%). self-harm. Patients who were admitted to hospitals
Goodman, Gerstadt, Pfeffer, Stroh and Valdez [46] ex- owing to suicide/self-harm were six times (OR = 6.27,
amined forty-three psychiatrically hospitalised prepuber- 95% CI = 2.76-14.26) and three times (OR = 3.05, 95%
tal children regarding their assaultive and suicidal CI = 1.31-7.06) more likely to be diagnosed with ADD,
behaviours and they were subsequently classified into respectively, as compared with other causes of injury.
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The odds for self-inflicted injuries were about 8.5 for instance, ADHD diagnosed at school age increases the
children diagnosed with ADHD compared to individuals risk for antisocial development, drug misuse, patho-
without ADHD. logical aggression, and social and academic exclusion by
Lynch, Mills, Daly and Fitzpatrick [51] investigated the a factor of five to ten compared to the general popula-
prevalence rates of psychiatric disorders, suicidal idea- tion [69-71].
tion and intent and parasuicide in a population of Irish It is also important to highlight the gender in the stud-
adolescents aged 12–15 years. 19.4% of the 723 screened ies identified by this review given the gender differences
were identified as being ‘at risk’ and this ‘at risk’ group seen in individuals with ADHD [72]. The existing litera-
were interviewed along with a comparison sample ture shows that although the gender difference in child-
matched for gender, school and school year. In the ‘at- hood is quite large, in adult samples this difference
risk’ group, six (5.9%) had a diagnosis of ADHD and only diminishes or disappears. Studies investigating gender
three (3.2%) had a diagnosis of ADHD in the ‘not at-risk’ differences, indicates that girls may consistently be
group. The estimated prevalence in the entire population under-identified and under-diagnosed and it is suggested
(based on a weighted analysis) was 3.7% (95% CI = 0.7-6.7). that differences in the expression of ADHD between the
genders might be one explanation for this [73-76]. Fe-
Adults samples males with ADHD are reported to have less hyperactive/
Fulwiler, Forbes, Santangelo and Folstein [45] tested the impulsive symptoms and more inattentive symptoms
hypothesis that prisoners who injured themselves with- compared to males with ADHD [73,77,78]. Diagnosis of
out intending to die would differ clinically from pris- the inattentive subtype also appears to be more common
oners who had attempted suicide. Fifteen patients in females with ADHD [79]. Boys with ADHD appear to
reported that they had attempted to take their own lives, exhibit more externalising disorders compared to boys
while 16 reported other reasons for harming themselves. without ADHD. Females, on the other hand, tend to ex-
The findings most relevant to the focus of this review hibit more internalising disorders compared to girls
was that of self-mutilation with a history of childhood without ADHD [73,74,78,80] and to their male counter-
hyperactivity (12/16 versus 1/15 suicide attempters). Five parts [80].
remembered being treated with Ritalin and several Looking at the gender in the group of interest across
reported that illicit stimulant drugs (cocaine. amphet- all fifteen studies it is clear that there are much higher
amines) had a calming effect and helped them concen- numbers of males than females. This can be seen more
trate. Self-mutilators were 28 times more likely to report clearly in Table 2. Studies which include greater levels of
childhood hyperactivity, and suicide attempters were 21 females are required. The small number of females in a
times more likely to be diagnosed with major affective large proportion of studies is limiting the power and the
disorder. ability to find any significant association between ADHD
and self-harming behaviours.
Discussion The majority of the studies used samples of children
This review identified 15 studies which investigated the (below the age of 18 years). Only three studies used a
association between ADHD and self-harm (one of which sample of adults (older than 18 years) [43-45], of which
was a case study design). All of these studies indicate an two were by the same research group [43,44]. Given
association between ADHD and self-harm which suggests what has just been described about the potential effect
that ADHD may be a potential risk factor for self-harm. of age on ADHD symptoms, more studies are required
It is important to consider the age of the individuals which use samples to include older people in order to
with ADHD in the studies which have been identified by elucidate the effect of ADHD over the course of their
this review (which investigated the association between lifetime.
ADHD and self-harming behaviours) given the literature From the 15 identified studies in this review, seven
which suggests that ADHD symptoms can sometimes were studies using a population with ADHD and mea-
change with age. Although ADHD symptoms frequently sures of self-harming behaviour were then conducted
persist over time [63], maturation has been found to [41,43,44,47,48,52,53]. The remaining studies investi-
have a significant positive effect on ADHD symptoms in gated a population who were hospitalised due to injury
many children [64]. These findings have resulted in the (or identified by records/self-assessment) and measures
hypothesis that ADHD is associated with a delay as op- of ADHD were then conducted [17,40,42,45,46,49-51].
posed to an abnormal brain development [65,66]. How- Three of the 15 studies discussed in this systematic
ever, few studies have examined the persistence of review were identified as the most relevant and meth-
ADHD from childhood to adulthood [67,68]. This lack odologically reliable [42,47,48]. DiScala et al. [42] investi-
of rigorous research is surprising, given the significant gated the differences between hospital admitted injuries
impact that ADHD frequently has on the individual. For to children with pre-injury ADHD and injuries to those
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Table 2 The number of males and females in each group of interest across all 15 studies identified in this review
Study Male Female
Ben-Yehuda et al. [40] Does not specify for the DSH individuals. Does not specify for the DSH individuals.
Of the 39 suicidal children, 25 were males (64%). Of the 39 suicidal children, 14 were females (36%).
Of the 227 suicidal adolescents, 58 (26%) were males. Of the 227 suicidal adolescents, 169 (74%) were females.
Deane and Young (2012) [41] No males (n = 0) ADHD (n = 4)
DiScala et al. (1998) [42] ADHD (n = 211) ADHD (n = 28)
Dowson et al. (2007) [43] ADHD (n = 43) ADHD (n = 16)
Dowson et al. (2010) [44] ADHD (n = 73) No females (n = 0)
Fulwiler et al. [45] Self-mutilators (n = 15) Self-mutilators (n = 1)
Suicide-attempters (n = 11) Suicide-attempters (n = 4)
Goodman et al. [46] Assaultive/suicidal (83.3% of 24). Assaultive/suicidal (16.7% of 24)
Assaultive-only (89.5% of 19) Assaultive-only (10.5% of 19)
Hinshaw et al. [47] No males (n = 0) ADHD (n = 140)
Hurtig et al. (2012) [48] ADHD and DSH (n = 15) ADHD and DSH (n = 30)
Suicidal Acts & ADHD (n = 4) Suicidal Acts & ADHD (n = 4)
Izutsu et al. (2006) [49] DSH (n = 239) DSH (n = 238)
Lam (2002) [17] ADD and ED admission for injury (n = 125). * States that ADD and ED admission for injury (n = 33). See male
of the types of injuries they looked at, there were column for more detail.
59 cases of suicide/self-harm but does not specify the
gender of this group of injuries.
Lam (2005) [50] ADD (n = 97) ADD (n = 33)
Lynch et al. (2006) [51] ‘At-risk’ of psychiatric disorder (n = 67) ‘At-risk’ of psychiatric disorder (n = 73)
Semiz et al. (2008) [52] ADHD (n = 68.25) (65% of 105) No females (n = 0)
Wehmeier et al. (2008) [53] ADHD (n = 338) (80.3%) ADHD (n = 83) c19.7%)

with no pre-injury conditions (NO). Compared with the investigated the increased rates of suicide in individuals
NO children, the children with ADHD were more likely with ADHD. For instance, Barbaresi, Colligan, Weaver,
to inflict injury upon themselves (1.3% versus 0.1%). The Voigt, Killian and Katusic (2013) [81] investigated long-
importance of early identification of individuals at term outcomes of ADHD in a population-based sample
greater risk of self-harm is further validated by the find- of childhood ADHD cases (n = 367) and controls, who
ings of Hinshaw et al. [47] which showed that girls with were all prospectively assessed as adults. Importantly,
childhood ADHD maintain marked impairment by early findings revealed that childhood ADHD is a chronic
adulthood (including higher rates of suicide attempts health problem, with significant risk for mortality, per-
and self-injury). Hinshaw et al. [43] found that girls with sistence of ADHD, and long-term morbidity in adult-
childhood-diagnosed ADHD continued to display higher hood. The cause-specific mortality for suicide only was
rates of ADHD and comorbid symptoms and exhibited significantly higher among ADHD cases (standardised
higher rates of suicide attempts and self-injury compared mortality ratios, SMR, 4.83; 95% CI, 1.14–20.46; P = .032)
with the comparison sample. Self-harm behaviour pre- compared to non-ADHD controls from the same birth
dominated in the participants originally diagnosed with cohort [81].
ADHD-combined. Hinshaw et al. [47] indicated that in-
dividuals with the ADHD combined type are at even Limitations
greater risk of self-harm behaviours which merits further The conclusions that can be made regarding the
attention. Lastly, Hurtig et al. [48] investigated the effect strength of association between ADHD and self-harm
of ADHD on suicidal or self-harm behaviour in adoles- are limited due to the relatively small amount of studies
cents from a general population sample and found that, that have been conducted to date. In addition, the ma-
compared with adolescents without ADHD, those with jority of these studies use small populations and some
ADHD had more suicidal ideation (57% versus 28%) and do not contain (or report on) control group findings.
DSH (69% versus 32%)”. Publication bias is likely to be present as studies report-
The importance of further research into the associ- ing no correlation are unlikely to be published [21]. Dif-
ation between ADHD and self-harm is further high- fering methodologies and differing measurement tools
lighted by the studies (outwith this review) which have used across all the studies are a further complication
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[32]. For instance, in one of the studies found in this re- including the younger population which may introduce
view, childhood hyperactivity was inferred only by self- new ways of further reducing the youth suicide and self-
report (as opposed to potentially more robust reports harm rate [32]. This review also indicates that there
such as clinical assessments and/or parental reports) needs to be a revision of the standardised ADHD rating
which the authors acknowledge in their paper [49]. scales since they generally do not enquire about self-
Another limitation is the fact that data for the studies harm and risk to self and others. This review clearly em-
were collected retrospectively and then analysed for sui- phasises the need for inclusion of these aspects during
cidal related events which exposes the studies to a de- routine assessment (either in questionnaires, clinical as-
gree of confounding bias, particularly in the studies sessment or both). Effective screening requires an integra-
where, for example, the Columbia Classification Algo- tion of all the currently known predictors of self-harm
rithm for Suicide Assessment (C-CASA) (the standar- (and this review strongly highlights the need for symp-
dised suicidal rating system) and the Computerized toms of ADHD to be one of them) and further research to
Suicide Risk Scale (CSRS) have not been delivered. Map- identify any others. One study discussed in this review also
ping any event to a specific code is possible, however, supports the idea that there needs to be distinctive screen-
the potential for error is greater than if the scales were ing procedures for each of these sub-types [46].
used prospectively. The use of these scales are often
mandatory in trials. Additionally, the ability to separate Conclusions
self-harm as an entity from a suicide attempt is not al- Despite the contribution to our knowledge of self-harm
ways easy which is a potential confounding bias. In par- behaviours to date, we remain unclear as to exactly why
ticular, Silverman, Berman, Sanddal, O’Carroll and Joiner individuals engage in these behaviours and, even more
(2007) [82] emphasised the potential complication with importantly, we do not have in place effective methods
trying to separate self-harm and suicide attempt into of accurately predicting or reducing these behaviours as
two independent categories by highlighting that self- a consequence. Therefore, it is vitally important that risk
injurious intent and suicidal intent can be present factors for self-harm (such as symptoms of ADHD) are
simultaneously in an individual [82]. SIB and suicidal be- recognised and identified to produce more reliable risk
haviours exists along the same continuum, with SIB level indicators.
representing a lesser form [83,84]. Research has also
Competing interests
found that 28% to 41% of individuals who engage in SIB
The author declares that she has no competing interests.
report suicidal thoughts at the time they were engaged
in self-injury [85]. Received: 7 August 2013 Accepted: 3 April 2014
Published: 7 May 2014
Lastly, the influence of comorbidity is difficult to dis-
entangle from the main findings, particularly for sub- References
stance misuse and delinquency, prompting the need for 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental
further research using younger populations and those Disorders. 4th edition. Washington, DC: American Psychiatric Association; 1994.
2. Ullebø AK, Posserud MB, Heiervang E, Obel C, Gillberg C: Prevalence of the
without co-morbidity [21]. ADHD phenotype in 7- to 9-year-old children: effects of informant,
gender and non-participation. Soc Psychiatry Psychiatr Epidemiol 2012,
Future directions and clinical implications 47:763–769.
3. Lundervold AJ, Adolfsdottir S, Halleland H, Halmoy A, Plessen KJ, Haavik J:
One study has shown some understanding of this rela- Attention network test in adults with ADHD-the impact of affective
tionship in their treatment strategies. Carminati, Deriaz fluctuations. Behav Brain Funct 2011, 7:27.
and Bertschy [86] had good experiences with venlafaxine 4. Sorensen L, Plessen KJ, Nicholas J, Lundervold AJ: Is behavioral regulation
in children with ADHD aggravated by comorbid anxiety disorder? J Atten
in the treatment of SIB and ADHD-like symptoms in pa- Disord 2011, 15:56–66.
tients with pervasive developmental disorders. This re- 5. Babinski DE, Pelham WE, Molina BSG, Gnagy EM, Wasch-busch DA, Yu J,
view highlights the need for clinicians to recognise the MacLean MG, Wymbs BT, Sibley MH, Biswas A, Robb JA, Karch KM: Late
adolescent and young adult outcomes of girls diagnosed with ADHD in
ADHD population as being at increased risk of self- childhood: an exploratory investigation. J Atten Disord 2011, 15:204–214.
harm. Children with ADHD pose particular problems of 6. Biederman J, Petty CR, Yvonne Woodworth K, Lomedico A, Hyder LL,
engagement with child mental health services which is Faraone SV: Adult outcome of attention-deficit/hyperactivity disorder: a
controlled 16-year follow-up study. J Clin Psychiatry 2012, 7:941–950.
another issue that needs to be addressed (a review of this 7. Barkley RA: Global issues related to the impact of untreated attention-
is outside the scope of this review). Also, as the review deficit/hyperactivity disorder from childhood to young adulthood.
by James [32] highlights, there is a need for clinicians to Postgrad Med 2008, 120:48–59.
8. De Leo D, Heller TS: Who are the kids who self-harm? An Australian self-
also recognise that the ADHD population is at increased report school survey. Med J Aust 2004, 181:140–144.
risk of suicide attempt and completed suicide. The clin- 9. Madge N, Hewitt A, Hawton K, Wilde EJD, Corcoran P, Fekete S,
ical implications of the main findings from the present van Heeringen K, De Leo D, Ystgaard M: Deliberate self-harm within an
international community sample of young people: comparative findings
review is that clinicians need to routinely screen for from the Child and Adolescent Self-harm in Europe (CASE) Study. J Child
suicide attempts and self-harm in ADHD subjects, Psychol Psychiatry 2008, 49:667–677.
Allely BMC Psychiatry 2014, 14:133 Page 12 of 13
http://www.biomedcentral.com/1471-244X/14/133

10. Hawton K, Rodham K, Evans E, Weatherall R: Deliberate self-harm in 33. Datapharm Communications Limited Electronic Medicines Compendium:
adolescents: self report survey in schools in England. Br J Psychiatry 2002, Concerta. http://www.medicines.org.uk/EMC/medicine/8382/SPC/Concerta
325:1207–1211. +XL+18+mg+−+36+mg+prolonged+release+tablets/.
11. Hargus E, Hawton K, Rodham K: Distinguishing between subgroups of 34. Wooltorton E: Suicidal ideation among children taking atomoxetine
adolescents who self-harm. Suicide Life Threat Behav 2009, 39:518–537. (Strattera). Can Med Assoc J 2005, 173:1447–1447.
12. Moran P, Coffey C, Romaniuk H, Olsson C, Borschmann R, Carlin JB, Patton 35. Bangs ME, Tauscher-Wisniewski S, Polzer J, Zhang S, Acharya N, Desaiah D,
GC: The natural history of self-harm from adolescence to young Trzepacz PT, Allen AJ: Meta-analysis of suicide-related behavior events in
adulthood: a population-based cohort study. Lancet 2012, 379:236–243. patients treated with atomoxetine. J Am Acad Child Adolesc Psychiatry
13. National Collaborating Centre for Mental Health: Self-Harm: Longer Term 2008, 47:209–218.
Management. NICE Clinical Guideline 133. London: National Institute for 36. McCarthy S, Cranswick N, Potts L, Taylor E, Wong IC: Mortality associated
Clinical Excellence; 2011. with attention-deficit hyperactivity disorder (ADHD) drug treatment.
14. Hawton K, Hall S, Simkin S, Bale L, Bond A, Codd S, Stewart A: Deliberate Drug Saf 2009, 32:1089–1096.
self-harm in adolescents: a study of characteristics and trends in Oxford, 37. Bushe CJ, Savill NC: Suicide related events and attention deficit
1990–2000. J Child Psychol Psychiatry 2003, 44:1191–1198. hyperactivity disorder treatments in children and adolescents: a meta-
15. Miller M, Chiles J, Barnes V: Suicide attempters within a delinquent analysis of atomoxetine and methylphenidate comparator clinical trials.
population. J Consult Clin Psychol 1982, 50:491–498. Child Adolesc Psychiatry Ment Health 2013, 7:19–19.
16. Gould MS, King R, Greenwald S, Fisher P, Schwab-Stone M, Kramer R, Flisher AJ, 38. James A: Completed suicide, ideation and attempts in attention deficit
Goodman S, Canino G, Shaffer D: Psychopathology associated with suicidal hyperactivity disorder. Acta Psychiatr Scand 2012, 125:91–92. An editorial
ideation and attempts among children and adolescents. J Am Acad Child comment to M. Impey “Completed suicide, ideation and attempt in
Adolesc Psychiatry 1998, 37:915–923. Attention Deficit Hyperactivity Disorder”.
17. Lam L: Attention deficit disorder and hospitalization due to injury 39. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Götzsche PC, Ioannidis JPA,
among older adolescents in New South Wales, Australia. J Atten Disord Clarke M, Devereaux PJ, Kleijnen J, Moher D: The PRISMA statement for
2002, 6:277–282. reporting systematic reviews and meta-analyses of studies that evaluate
18. Murphy KR, Barkley RA, Bush T: Young adults with attention deficit healthcare interventions: explanation and elaboration. Br J Psychiatry
hyperactivity disorder: subtype differences in comorbidity, educational 2009, 6:b2700.
and clinical history. J Nerv Ment Dis 2002, 190:147–157. 40. Ben-Yehuda A, Aviram S, Govezensky J, Nitzan U, Levkovitz Y, Bloch Y:
19. Kelly TM, Cornelius JR, Clark DB: Psychiatric disorders and attempted Suicidal behavior in minors–diagnostic differences between children and
suicide among adolescents with substance use disorders. Drug Alcohol adolescents. J Dev Behav Pediatr 2012, 33:542–547.
Depend 2004, 73:87–97. 41. Deane H, Young S: Navigating adolescence: an epidemiological follow-up
20. James A, Lai FH, Dahl C: Attention deficit hyperactivity disorder and of adaptive functioning in girls with childhood ADHD symptoms and
suicide: a review of possible associations. Acta Psychiatr Scand 2004, conduct disorder. J Atten Disord 2014, 18:44–51.
110:408–415. 42. DiScala C, Lescohier I, Barthel M, Li G: Injuries to children with attention
21. Impey M: Completed suicide, ideation and attempts in Attention Deficit deficit hyperactivity disorder. Pediatrics 1998, 102:1415–1421.
Hyperactivity Disorder. Acta Psychiatr Scand 2011, 125:93–102. 43. Dowson JH, Blackwell AD, Turner DC, Harvey E, Malhotra T, Robbins TW,
22. Manor I, Gutnik I, Ben-Dor DH, Apter A, Sever J, Tyano S, Weizman A, Sahakian BJ: Questionnaire ratings of attention-deficit/hyperactivity
Zalsman G: Possible association between attention deficit hyperactivity disorder (ADHD) in adults are associated with spatial working memory.
disorder and attempted suicide in adolescents—a pilot study. Eur Psychiatry Eur Psychiatry 2007, 22:256–263.
2010, 25:146–150. 44. Dowson JH, Blackwell AD: Impulsive aggression in adults with attention‐
23. Cho SC, Kim JW, Choi HJ, Kim BN, Shin MS, Lee JH, Kim EH: Associations deficit/hyperactivity disorder. Acta Psychiatr Scand 2010, 121:103–110.
between symptoms of attention deficit hyperactivity disorder, 45. Fulwiler C, Forbes C, Santangelo SL, Folstein M: Self-mutilation and suicide
depression, and suicide in Korean female adolescents. Depress Anxiety attempt: distinguishing features in prisoners. J Am Acad Psychiatry Law
2008, 25:E142–E146. 1997, 25:69–77.
24. Chronis-Tuscano A, Molina BSG, Pelham WE, Applegate B, Dahlke A, 46. Goodman G, Gerstadt C, Pfeffer CR, Stroh M, Valdez A: ADHD and
Overmeyer M, Lahey BB: Very early predictors of adolescent depression aggression as correlates of suicidal behavior in assaultive prepubertal
and suicide attempts in children with attention-deficit/hyperactivity psychiatric inpatients. Suicide Life Threat Behav 2008, 38:46–59.
disorder. Arch Gen Psychiatry 2010, 67:1044–1051. 47. Hinshaw SP, Owens EB, Zalecki C, Huggins SP, Montenegro-Nevado AJ,
25. Biederman J, Ball SW, Monuteaux MC, Mick E, Spencer TJ, McCreary M, Cote M, Schrodek E, Swanson EN: Prospective follow-up of girls with attention-
Faraone SV: New insights into the comorbidity between ADHD and major deficit/hyperactivity disorder into early adulthood: continuing impairment
depression in adolescent and young adult females. J Am Acad Child Adolesc includes elevated risk for suicide attempts and self-injury. J Consult Clin
Psychiatry 2008, 47:426–434. Psychol 2012, 80:1041–1051.
26. Plattner B, The SS, Kraemer HC, Williams RP, Bauer SM, Kindler J, Feucht M, 48. Hurtig T, Taanila A, Moilanen I, Nordström T, Ebeling H: Suicidal and self-
Friedrich MH, Steiner H: Suicidality, psychopathology, and gender in harm behaviour associated with adolescent attention deficit hyperactivity
incarcerated adolescents in Austria. J Clin Psychiatry 2007, disorder-A study in the Northern Finland Birth Cohort 1986. Nord J Psychiat
68:1593–1600. 2012, 66:320–328.
27. Owens D, Horrocks J, House A: Fatal and non-fatal repetition of self-harm: 49. Izutsu T, Shimotsu S, Matsumoto T, Okada T, Kikuchi A, Kojimoto M, Noguchi H,
systematic review. Brit J Psychiat 2002, 181:193–199. Yoshikawa K: Deliberate self-harm and childhood hyperactivity in junior
28. Hawton K, Fagg J, Simkin S: Deliberate self-poisoning and self injury in high school students. Eur Child Adolesc Psychiatry 2006, 15:172–176.
children and adolescents under 16 years of age in Oxford, 1976–1993. 50. Lam LT: Attention deficit disorder and hospitalization owing to intra-and
Br J Psychiatry 1996, 169:202–208. interpersonal violence among children and young adolescents. J Adolesc
29. Spirito A, Plummer B, Gispert M, Levy S, Kurkjian J, Lewander W, Hagberg S, Health 2005, 36:19–24.
Devost L: Adolescent suicide attempts: outcomes at follow-up. Am J 51. Lynch F, Mills C, Daly I, Fitzpatrick C: Challenging times: prevalence of
Orthopsychiatry 1992, 62:464–468. psychiatric disorders and suicidal behaviours in Irish adolescents.
30. Cooper J, Kapur N, Webb R, Lawlor M, Guthrie E, Mackway-Jones K, Louis J Adolescence 2006, 29:555–573.
Appleby L: Suicide after deliberate self-harm: a 4-Year Cohort Study. Am J 52. Semiz UB, Basoglu C, Oner O, Munir KM, Ates A, Algul A, Ebrinc S, Cetin M:
Psychiatry 2005, 162:297–303. Effects of diagnostic comorbidity and dimensional symptoms of
31. Garnock-Jones KP, Keating GM: Atomoxetine. Pediatr Drugs 2009, attention-deficit-hyperactivity disorder in men with antisocial personality
11:203–226. disorder. Australas Psychiatry 2008, 42:405–413.
32. Datapharm Communications Limited Electronic Medicines Compendium: 53. Wehmeier PM, Schacht A, Lehmann M, Dittmann RW, Silva SG, March JS:
Strattera. http://www.medicines.org.uk/EMC/medicine/14482/SPC/Strattera+ Emotional well-being in children and adolescents treated with
+10mg%2c+18mg%2c+25mg%2c+40mg%2c+60mg+or+80mg+hard atomoxetine for attention-deficit/hyperactivity disorder: findings from a
+capsules. patient, parent and physician perspective using items from the pediatric
Allely BMC Psychiatry 2014, 14:133 Page 13 of 13
http://www.biomedcentral.com/1471-244X/14/133

adverse event rating scale (PAERS). J Am Acad Child Adolesc Psychiatry disorder: findings in nonreferred subjects. Am J Psychiatry 2005,
2008, 2:11. 162:1083–1089.
54. Claes L, Vandereycken W, Vertommen H: Self-injurious behavior in eating- 78. Gershon J: A meta-analytic review of gender differences in ADHD. J Atten
disordered patients. Eat Behav 2001, 2:263–272. Disord 2002, 5:143–154.
55. Barkley RA: Attention-Deficit Hyperactivity Disorder. New York, NY: Guilford 79. Hinshaw SP, Owens EB, Sami N, Fargeon S: Prospective follow-up of girls
Press; 2006. with attention-deficit/hyperactivity disorder into adolescence: evidence
56. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, for continuing cross-domain impairment. J Consult Clin Psychol 2006,
Ryan N: Schedule for Affective Disorders and Schizophrenia for School- 74:489–499.
Age Children— P resent and Lifetime Version (K-SADS-PL): Initial reliability 80. Rucklidge JJ, Tannock R: Psychiatric, psychosocial, and cognitive
and validity data. J Am Acad Child Adolesc Psychiatry 1997, 36:980–988. functioning of female adolescents with ADHD. J Am Acad Child Adolesc
57. Hare RD: Manual for the Revised Psychopathy Checklist. 2nd edition. Toronto, Psychiatry 2001, 40:530–540.
ON, Canada: Multi-Health Systems; 2003. 81. Barbaresi WJ, Colligan RC, Weaver AL, Voigt RG, Killian JM, Katusic SK:
58. Ward MF, Wender PH, Reimherr FW: The Wender Utah rating scale: an aid Mortality, ADHD, and psychosocial adversity in adults with childhood
in the retrospective diagnosis of childhood attention deficit ADHD: a prospective study. Pediatrics 2013, 131:637–644.
hyperactivity disorder. Am J Psychiatry 1993, 150:885–890. 82. Silverman MM, Berman AL, Sanddal ND, O’Carroll PW, Joiner TE: Rebuilding
59. Conners CK, Erhart D, Sparrow E: Conners’ Adult ADHD Rating Scales, the tower of babel: a revised nomenclature for the study of suicide and
technical manual. New York, NY: Multi-Health Systems; 1999. suicidal behaviors Part 2: suicide-related ideations, communications, and
60. First MB, Gibbon M, Spitzer RL, Williams JBW, Benjamin LS: Structured Clinical behaviors. Suicide Life Threat Behav 2007, 37:264–277.
Interview for DSM-IV Axis II Personality Disorder. Washington, DC: American 83. Linehan MM: Behavioral Treatments of Suicidal Behaviors: Definitional
Psychiatric Press; 1997. Obfuscation and Treatment Outcomes. In Review of Suicidology. Edited by
61. First MB, Gibbon M, Spitzer RL, Williams JBW, Benjamin LS: SCID-II Personality Maris RW, Cannetto SS, McIntosh JL, Siverman MM. New York: Guilford
Questionnaire. Washington, DC: American Psychiatric Press; 1997. Press; 2000:84–111.
62. HCIA International Classification of Diseases: 9th Revision Clinical Modification 84. Stanley B, Winchel R, Molcho A, Simeon D, Stanley M: Suicide and the self-
(ICD-9-CM). Baltimore, MD: HCIA Inc; 1993. harm continuum: phenomenological and biochemical evidence. Int Rev
63. Greydanus DE, Pratt HD, Patel DR: Attention deficit hyperactivity disorder Psychiatry 1992, 4:149–155.
across the lifespan: the child, adolescent, and adult. Dis Mon 2007, 85. Favazza AR: Bodies Under Siege: Self-Mutilation and Body Modification in
53:70–131. Culture and Psychiatry. 2nd edition. Baltimore: John Hopkins University Press;
64. Faraone SV, Biederman J, Spencer T, Wilens T, Seidman LJ, Mick E, Doyle AE: 1996.
Attention-deficit/hyperactivity disorder in adults: an overview. Biol 86. Carminati GG, Deriaz N, Bertschy G: Low-dose venlafaxine in three
Psychiatry 2000, 48:9–20. adolescents and young adults with autistic disorder improves self-
65. Steffensson B, Larsson JO, Fried I, El-Sayed E, Rydelius PA, Lichtenstein P: injurious behavior and attention deficit/hyperactivity disorders (ADHD)-
Genetic disposition for global maturity: an explanation for genetic like symptoms. Prog Neuropsychopharmacol Biol Psychiatry 2006,
effects on parental report on ADHD. Int J Behav Dev 1999, 23:357–374. 30:312–315.
66. El-Sayed E: Brain Maturation, Cognitive Tasks and Quantitative
Electroencephalography: A Study in Children With Attention Deficit Hyperactive doi:10.1186/1471-244X-14-133
Disorder. Stockholm: Ph.D. thesis, Karolinska Institutet; 2002. Cite this article as: Allely: The association of ADHD symptoms to
67. Lara C, Fayyad J, de Graaf R, Kessler RC, Aguilar-Gaxiola S, Angermeyer M, self-harm behaviours: a systematic PRISMA review. BMC Psychiatry
2014 14:133.
Demytteneare K, de Girolamo G, Haro JM, Jin R, Karam EG, Lépine JP, Mora
ME, Ormel J, Posada-Villa J, Sampson N: Childhood predictors of adult
attention-deficit/hyperactivity disorder: results from the World Health
Organization World Mental Health Survey Initiative. Biol Psychiatry 2009,
65:46–54.
68. Kessler RC, Adler LA, Barkley R, Biederman J, Conners CK, Faraone SV:
Patterns and predictors of attention-deficit/hyperactivity disorder persistence
into adulthood: results from the national comorbidity survey replication. Biol
Psychiatry 2005, 57:1442–1451.
69. Rasmussen P, Gillberg C: Natural outcome of ADHD with developmental
coordination disorder at age 22 years: a controlled, longitudinal,
community-based study. J Am Acad Child Adolesc Psychiatry 2000,
39:1424–1431.
70. Lichtenstein P, Halldner L, Zetterqvist J, Sjölander A, Serlachius E, Fazel S,
Långström N, Larsson H: Medication for attention deficit-hyperactivity
disorder and criminality. N Engl J Med 2012, 367:2006–2014.
71. Brook JS, Brook DW, Zhang C, Seltzer N, Finch SJ: Adolescent ADHD and
adult physical and mental health, work performance, and financial
stress. Pediatrics 2013, 131:5–13.
72. Skogli EW, Teicher MH, Andersen PN, Hovik KT, Øie M: ADHD in girls and
boys–gender differences in co-existing symptoms and executive Submit your next manuscript to BioMed Central
function measures. BMC Psychiatry 2013, 13:298. and take full advantage of:
73. Gaub M, Carlson CL: Gender differences in ADHD: a meta-analysis and
critical review. J Am Acad Child Adolesc Psychiatry 1997, 36:1036–1045.
• Convenient online submission
74. Quinn PO: Attention-deficit/hyperactivity disorder and its comorbidities in
women and girls: an evolving picture. Curr Psychiatry Rep 2008, 10:419–423. • Thorough peer review
75. Biederman J, Mick E, Faraone SV, Braaten E, Doyle A, Spencer T, Wilens TE, • No space constraints or color figure charges
Frazier E, Johnson MA: Influence of gender on attention deficit
hyperactivity disorder in children referred to a psychiatric clinic. Am J • Immediate publication on acceptance
Psychiatry 2002, 159:36–42. • Inclusion in PubMed, CAS, Scopus and Google Scholar
76. Sciutto MJ, Eisenberg M: Evaluating the evidence for and against the • Research which is freely available for redistribution
overdiagnosis of ADHD. J Atten Disord 2007, 11:106–113.
77. Biederman J, Kwon A, Aleardi M, Chouinard VA, Marino T, Cole H, Mick E,
Faraone SV: Absence of gender effects on attention deficit hyperactivity Submit your manuscript at
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research-article2016
TPP0010.1177/2045125316647686Therapeutic Advances in PsychopharmacologySL Hutchison, JK Ghuman

Therapeutic Advances in Psychopharmacology Review

Efficacy of atomoxetine in the treatment


Ther Adv Psychopharmacol

2016, Vol. 6(5) 317­–334

of attention-deficit hyperactivity disorder DOI: 10.1177/


2045125316647686

in patients with common comorbidities in


© The Author(s), 2016.
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children, adolescents and adults: a review


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Shari L. Hutchison, Jaswinder K. Ghuman, Harinder S. Ghuman, Irina Karpov


and James M. Schuster

Abstract:  Attention-deficit hyperactivity disorder (ADHD) is one of the most commonly


diagnosed mental health disorders and is associated with higher incidence of comorbid
oppositional or conduct, mood, anxiety, pervasive developmental, and substance-use
disorders. Comorbid mental health conditions may alter the presence of symptoms and
treatment of ADHD. Atomoxetine (ATX), a nonstimulant medication for the treatment of
ADHD, may be prescribed for individuals with ADHD and comorbid conditions despite some
risk for certain undesirable side effects and lower effectiveness for the treatment of ADHD
than stimulants. In this paper, we review studies utilizing randomized, placebo-controlled
trials (RCTs) as well as within-subject designs to determine the effectiveness of ATX in the
treatment of children and adults with ADHD and comorbid conditions. The current review uses
an expanded methodology beyond systematic review of randomized controlled trials in order
to improve generalizability of results to real-world practice. A total of 24 articles published
from 2007 to 2015 were reviewed, including 14 RCTs: n = 1348 ATX, and n = 832 placebo.
The majority of studies show that ATX is effective in the treatment of ADHD symptoms for
individuals with ADHD and comorbid disorders. Cohen’s d effect sizes (ES) for improvement
in ADHD symptoms and behaviors range from 0.47 to 2.21. The effectiveness of ATX to
improve symptoms specific to comorbidity varied by type but appeared to be most effective
for diminishing the presence of symptoms for those with comorbid anxiety, ES range of 0.40
to 1.51, and oppositional defiant disorder, ES range of 0.52 to 1.10. There are mixed or limited
results for individuals with ADHD and comorbid substance-use disorders, autism spectrum
disorders, dyslexia or reading disorder, depression, bipolar disorder, and Tourette syndrome.
Results from this review suggest that ATX is effective in the treatment of some youth and
adults with ADHD and comorbid disorders, and may be a treatment option in these patients.

Correspondence to:
Keywords:  ADHD, adults, atomoxetine, attention deficit, attention deficit with hyperactivity, Shari L. Hutchison, MS
children and youth, comorbidity, psychopharmacology, review Community Care
Behavioral Health, UPMC
Insurance Services
Division, 339 Sixth Avenue,
Suite 1300, Pittsburgh, PA
Introduction underdiagnosing [Štuhec et al. 2015c]. ADHD is a 15222, USA
hutchisons@ccbh.com
Attention-deficit hyperactivity disorder (ADHD) neuropsychiatric disorder diagnosed by the pres-
Jaswinder K. Ghuman, MD
is one of the most commonly diagnosed behavioral ence of inattention with or without hyperactivity Irina Karpov, MS
health disorders with a lifetime prevalence rate of and impulsivity for at least 6 months with func- James M. Schuster, MD,
MBA
8.1% [Kessler et  al. 2005b], although rates vary tional impairment in at least two settings, for Community Care
from 13% of men to 5% of women [Holland and example, school, home, or community, as defined Behavioral Health, UPMC
Insurance Services
Riley, 2014]. Current rates of ADHD are 5.5– by the Diagnostic and Statistical Manual of Mental Division, Pittsburgh, PA,
9.3% in children [US CDC, 2010] and 4% in Disorders, 5th edition [APA, 2013]. Thus, infor- USA
Harinder S. Ghuman
adults [Kessler et al. 2006]. Prevalence of ADHD mation about a child’s behavior, collected from Allegheny Behavioral
is lower in some countries, possibly due to direct caregivers as well as from sources outside Health, Sewickley, PA, USA

http://tpp.sagepub.com 317
Therapeutic Advances in Psychopharmacology 6(5)

the home is valuable in aiding diagnosis and moni- ATX observed in the population, concomitant
toring response to treatment [Shier et al. 2013]. with lower rates of stimulants may indicate inap-
propriate monotherapy prescribing [Garbe et  al.
ADHD is associated with disruptive, mood, anxi- 2012; Štuhec et  al. 2015a] since the majority of
ety, eating, and substance-abuse disorders [Shier youth are adequately treated by stimulants. For
et al. 2013]. Greater severity in the manifestation example, in an observational study of over seven
of symptoms associated with ADHD has been million youth in Germany, only 2% of those pre-
observed for individuals with ADHD and comor- scribed a stimulant medication switched to ATX
bid mental health, substance use, and other devel- within the 2-year study period [Garbe et al. 2012].
opmental disorders [Biederman et  al. 2007; In another study, only 43% of stimulant nonre-
Kuhne et  al. 1997]. The most common comor- sponders improved with ATX [Newcorn et  al.
bidity with ADHD is oppositional defiant disor- 2008].
der (ODD) with or without comorbid conduct
disorder, occurring in 30–67% of youth with ATX may be prescribed in lieu of stimulants for
ADHD [Steinhausen et al. 2006]. Other comor- individuals with ADHD and comorbidity because
bidity has been well documented. Rates for stimulants may increase symptoms, intensified by
comorbid autism spectrum disorder are 20–50% comorbid conditions including tics, mania, and
[Rommelse et  al. 2010]; major depressive disor- suicidal ideation [Garnock-Jones and Keating,
der (MDD), 9–38%, bipolar disorder, 10–11%, 2009; Gerhard et  al. 2010; Reichart and Nolan,
anxiety/social anxiety disorder, 20–40%, and sub- 2004]. ATX is also commonly believed to have
stance-use disorder (SUD), 15–30% [Anderson little potential for abuse [Heil et  al. 2002].
et al. 1987; Chang et al. 2009; Kessler et al. 2006; Nonstimulant medications are less efficacious for
Kunwar et al. 2007]. the treatment of ADHD; Cohen’s d effect size
(ES) for ATX is 0.6–0.7 [Faraone, 2009; Štuhec
Stimulants are considered first-line pharmacologi- et al. 2015b; Wigal, 2009] compared with imme-
cal agents for the treatment of ADHD as approved diate-release stimulants, 0.8–0.99, and long-
by the US Food and Drug Administration. The acting with or without osmotic-release oral-
most common side effects of stimulants include delivery stimulants, 0.8–0.95 [Faraone, 2009;
decreased appetite, insomnia, stomach ache, and Štuhec et al. 2015b]. Another long-acting stimu-
headache [Handen et al. 2000]. Stimulant medi- lant, lisdexamfetamine, was found to have ESs
cation for treatment of ADHD is associated with ranging 1.28–1.58 [Faraone, 2009; Štuhec et al.
several undesirable effects, including increased 2015b]. ESs display a similar pattern in adults as
risk of growth retardation in weight and height in published in several reviews or meta-analyses:
children, tics, increases in blood pressure, and 0.33–0.40 for ATX [Cunill et  al. 2013]; 0.57–
abuse or misuse [Cortese et al. 2013; Katragadda 0.72 for immediate-release or noncontinuous
and Schubiner, 2007; Spencer et  al. 2008]. stimulants [Castells et  al. 2011; Epstein et  al.
Nonstimulant medication, such as atomoxetine 2014]; and 0.85–1.14 for lisdexamfetamine
(ATX) is a selective presynaptic norepinephrine [Maneeton et  al. 2014]. Thus, a diminished
reuptake inhibitor approved by the US Food and impact on ADHD symptoms may be expected for
Drug Administration for the treatment of ADHD individuals receiving nonstimulant versus stimu-
in children and adults. ATX is the most com- lant medication therapy. Commonly reported
monly prescribed nonstimulant medication for the side effects of ATX include nausea, decreased
treatment of ADHD and prescribing rates for appetite, insomnia, dry mouth, irritability, dizzi-
ATX have significantly increased in some coun- ness, and dyspepsia [Durrell et  al. 2013]. ATX
tries over the past decade [Dalsgaard et al. 2013]. may be associated with increased risk of suicide
ATX is recommended as monotherapy for the behavior in youth [Bangs et al. 2005] and cardio-
treatment of ADHD for youth who do not respond vascular adverse effects [Cortese et  al. 2013;
well to stimulants [Pliszka et al. 2006; Shier et al. Peterson et  al. 2008; Štuhec and Švab, 2013].
2013], followed by buproprion, clonidine, or Warnings from the manufacturer of Strattera TM
guanfacine [American Academy of Pediatrics, (ATX) [Eli Lilly, 2015] include suicidal ideation,
2011; Pliszka et al. 2006]. The British Association liver injury, severe cardiac events, and worsening
of Psychopharmacology recommends a similar of blood pressure and heart rate. Nevertheless,
prescribing practice for adults [Bolea-Alamañac nonstimulant medication may be a first-line treat-
et  al. 2014]. Since pharmacotherapy algorithms ment for individuals with comorbidity [Hah and
dictate starting with stimulants first, high rates of Chang, 2005; Shier et al. 2013].

318 http://tpp.sagepub.com
SL Hutchison, JK Ghuman et al.

Due to the high prevalence of ADHD and ADHD Finally, the table of contents for the last 5 years of
with comorbid conditions, and the increasing rate the two journals with the most articles referenced
of ATX in treatment, a review of published litera- were scanned for relevant articles. Information
ture on the efficacy of ATX in youth and adults was abstracted from each article around publica-
with ADHD and comorbid conditions is war- tion, sample characteristics, dosage, comorbidity,
ranted. The current investigation reviews the efficacy measures and results. ES was calculated
effectiveness of ATX in youth and adults with where possible by computing the standardized
ADHD and comorbid conditions. Effectiveness is mean difference as the difference between ATX
determined by impact of treatment to decrease and placebo (PBO) or difference between final
symptoms of both ADHD and the comorbid con- assessment and baseline for within-subject
dition. This review builds on previous work by designs divided by the pooled standard deviation.
Dell’Agnello and colleagues [Dell’Agnello et  al. Because studies including research designs in
2009b] by reviewing studies utilizing within- addition to RCT were included, all studies were
subject designs in addition to randomized con- assessed for quality and given a score based on a
trolled trials (RCTs), many of which are industry 5-point system, including a point for each factor:
sponsored. A review and search strategy more use of a double-blind RCT design; all diagnoses
inclusive of various study designs may help in determined through the Diagnostic and Statistical
generalizability of results to real-world practice. Manual for Mental Health Disorders or
We also make recent the current knowledge of International Classification of Diseases; specifica-
this area over the 9 years that ATX has been in tion of an intent-to-treat analysis, or last-
practice, since the publication of any previous observation-carried-forward analysis; reporting of
review of the efficacy of ATX in individuals with ES or data reported so that ES can be computed;
ADHD and common comorbidities. adequate description of sample characteristics
and measures to support replication. Thus, stud-
ies that may introduce bias by not utilizing a
Methods blinded, RCT design, excluded participants from
An a priori search strategy was developed to iden- final assessment, omitted raw outcome values,
tify all studies on the efficacy of ATX in youth permitted adjunctive medication treatment, or
and adults with ADHD and comorbid conditions. did not specify how diagnoses were determined or
An online search was conducted in early October adequately described participants were included
2015 using OVID and PsycINFO from the in the review but received lower quality scores.
University of Pittsburgh Health Services Library These studies are provided as additional, albeit
System. Search terms included the MeSH sub- limited, evidence for effectiveness. Quality scores
heading, attention deficit with hyperactivity, in range from 0 to 5.
addition to search terms, attention deficit and
ADHD and all variations of these search terms.
This resulted in 27,973 unduplicated studies. Results
Search terms for medication included ATX or Studies were eliminated because they did not
StratteraTM (which yielded no additional studies include ATX, did not include ADHD, did not
than ATX alone). This resulted in 1179 studies. include a comorbid condition, were animal stud-
Combination of ADHD terms with ATX yielded ies, or were studies of prescribing practice and not
924 studies. Studies were not eliminated based of efficacy, for example, method of action, poten-
on design; therefore, no search term was added to tial for abuse, or cost. In addition, studies with
specify certain research designs, such as RCTs. pregnancy as the comorbid condition were
Studies were limited to English language, human excluded. A total of 477 studies were eliminated
or humans, and publication years 2007–2015. by title or abstract. The full text of 89 articles was
Duplicates were removed. The resulting search reviewed and 65 articles were eliminated; 40
yielded 566 studies. studies were excluded for the reasons above, 22
were review articles, and three studies were dupli-
Titles with or without abstracts were reviewed for cates. In the final review, 24 articles were included.
relevance and eliminated. Full text for remaining Of these, 14 studies were RCTs utilizing ATX
articles were reviewed for final inclusion. Review versus PBO and 10 studies utilized a within-
articles were scanned for relevant publications. subject design. Nine within-subject studies were
Any referenced article in an included study that prospective, utilizing a pretreatment initiation
appeared to be relevant to the topic was reviewed. phase as baseline, and one study was retrospective,

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Therapeutic Advances in Psychopharmacology 6(5)

in which the baseline period was derived from a studies. Quality scores ranged 2–5; 58% of the
previous treatment episode for individuals studies had a 4 or 5 quality score. Review of treat-
included in the sample. Further details on the ment efficacy in individuals with ADHD with
design of each study are outlined below. comorbidity.

Resulting studies include comorbidities in the fol-


lowing areas: SUD [Wilens et  al. 2008; Benegal Autism spectrum disorders
et al. 2013; Thurstone et al. 2010], anxiety disor- Seven studies investigated efficacy of ATX in
ders [Geller et al. 2007; Adler et al. 2009; Gabriel autism, autism spectrum disorder (ASD), with or
and Violato, 2011], autism spectrum disorders without pervasive developmental disorder (PDD),
[Gabriel and Violoto, 2011; Harfterkamp et  al. n = 266 ATX, and n = 130 PBO. Three studies
2012, 2013, 2014; Zeiner et  al. 2011; Charnsil, were RCTs and four studies utilized within-
2011; Fernández-Jaén et al. 2011; Handen et al. subject designs. Quality scores ranged 2–5, with
2015]; oppositional defiant disorder [Holzer et al. two studies having a quality score of 4 or 5.
2013; Bangs et al. 2008; Dell’Agnello et al. 2009; Patient characteristics and severity varied across
Dittmann et al. 2011], major depressive disorder these studies from ‘severe autistic disorder’
[Bangs et al. 2007], bipolar disorder [Chang et al. [Charnsil, 2011] to inclusion of youth with
2009], dyslexia or reading disorder [Shaywitz autism, Asperger’s disorder, and PDD not other-
et  al. 2014; Wietecha et  al. 2013; deJong et  al. wise specified [Fernández-Jaén et al. 2011]. Four
2009], and Tourette syndrome [Gilbert et  al. of the seven studies investigated efficacy or effec-
2007; Spencer et al. 2008]. A summary of studies tiveness of ATX on ADHD symptoms using the
is listed in Table 1, including study design, sam- ADHD rating scale, Parent report-Investigator-
ple size, comorbidity, average age, % of sample scored version (ADHDRS-IV) [DuPaul et  al.
that was male, starting ATX dose and maximum 1998]. The ADHDRS-IV is an 18-item rating
ATX dose, trial duration, outcome measure to scale that measures the severity of inattentive and
assess ADHD symptoms, outcome measure to hyperactive–impulsive symptoms as established
assess symptoms of the comorbid condition, ESs, by the Diagnostic and Statistical Manual of
and quality score. Total sample sizes across Mental Disorders, fourth edition [DSM-IV; APA
comorbid conditions were 1348 ATX and 832 1994]. Respondents are asked to rate the occur-
PBO. The majority of studies, 20 of 24, were in rence of specific behaviors of the child over the
children or adolescents. The smallest study past 6 months on a scale from 0 = never, to 3 =
included 14 individuals and the largest study very often. Average baseline scores for these stud-
included 171 individuals receiving ATX. Male ies ranged from 40.7 (SD = 7.5) to 35.3 (6.5).
sex is associated with higher prevalence of ADHD Harfterkamp and colleagues, performing the only
[Biederman and Faraone, 2005] and thus, the double-blind RCT utilizing the ADHDRS-IV to
participant samples included in all but one study investigate the efficacy of ATX for ADHD symp-
are predominantly male. The proportion of male toms, found a significantly greater reduction in
participants in the reviewed studies ranged 30– ADHDRS-IV score for ATX (n = 48) versus PBO
100%. ATX trial length varied from 4 to 20 (n = 49) over 8 weeks [Harfterkamp et al. 2012].
weeks. Fourteen studies were conducted in the Change score in the ATX group was −8.2 (8.8)
US and Canada, one in India, one in Thailand, and for PBO −1.2 (7.3), ES = 0.87. Three stud-
one in Germany, one in Norway, one in Italy, one ies utilizing an open-label, prospective, within-
in Spain, and four in the Netherlands. Unless subject design, found a significant improvement
indicated, the majority of studies excluded par- in ADHDRS-IV score over 10–20 weeks of treat-
ticipants with psychosis, SUD, major depressive ment [Harfterkamp et al. 2013, Zeiner et al. 2011,
disorder, schizophrenia, bipolar disorder or any Fernández-Jaén et  al. 2011]. Zeiner and col-
other behavioral health condition that could not leagues report change in ADHDRS-IV parent-
permit a medication-free, or clean period prior to reported total score from baseline value of 37.43
study participation, or those having a condition (9.17) to post-trial value of 25.14 (9.43), ES =
requiring ongoing treatment that may confound 1.32. Teacher-reported ADHDRS-IV values also
results. Other comorbid behavioral health condi- showed significant improvement, from 26.46
tions not listed above were generally not used as (14.18) to 19.70 (10.53), ES = 0.54 [Zeiner et al.
exclusion criteria while physical health conditions 2011]. Similar results are reported by Fernández-
such as cardiovascular and seizure disorders were Jaén and colleagues [Fernández-Jaén et al. 2011].
used as exclusion criteria in the majority of the In this study, teacher-completed ADHDRS-IV

320 http://tpp.sagepub.com
Table 1.  Study characteristics and effect sizes.

Study Design; Comorbidity Patient ATX dose; ADHD measure Effect size Comorbid Effect size Quality
n (ATX) age; % trial length (weeks) condition score
n (PBO) male measure
Charnsil WS ASD 10 yrs; 0.25–1.2 mg/kg per day; None ABC 2
[2011] n = 12 66.7% 10 weeks ns
Fernández- WS ASD 8 yrs; 0.4–1.2 mg/kg per day; ADHDRS-IV CGI-S 1.18* 3
Jaén et al. n = 24 58.0% 16 weeks Parent 1.27*
[2011] Teacher 0.73*
Handen et al. RCT ASD 8 yrs; 0.3–1.8 mg/kg per day; SNAP-ADHD 0.80 ABC ns 5
[2015] Parallel 85.2% 10 weeks
n = 32
n = 32
Harfterkamp RCT ASD 10 yrs; 1.2 mg/kg per day; ADHDRS-IV 0.87* None 3
et al. [2012] n = 48 87.6% 8 weeks
n = 49
Harfterkamp WS ASD 10 yrs; 1.2 mg/kg per day; ADHDRS-IV 1.54* None 3
et al. [2013] n = 88 86.4% 20 weeks
Harfterkamp RCT ASD 10 yrs; 1.2 mg/kg per day; None ABC 0.50* 4
et al. [2014] n = 48 85.6% 8 weeks CSBQ 0.40*
n + 49
Zeiner et al. WS ASD 11 yrs; 0.5–1.4 mg/kg per day; ADHDRS-IV None 3
[2011] n = 14 100% 10 weeks Parent 1.32*
Teacher 0.54*
Bangs et al. RCT ODD 9 yrs; 0.8–1.2 mg/kg per day; SNAP-IV SNAP-IV-ODD ns 5
[2008] n = 156 93.4% 8 weeks combined 0.52*
n = 70 inattentive ; 0.52*
hyper/impul 0.44*
Dell’Agnello RCT ODD 9 yrs; 0.5–1.4 mg/kg per day; SNAP-IV ADHD 0.91* SNAP-IV-ODD 0.52* 5
et al. [2009] n = 105 92.9% 8 weeks
n = 32
Dittmann RCT ODD 11 yrs; 1.2 mg/kg per day; SNAP-IV ADHD 0.72 SNAP-IV-ODD 0.69 5
et al. [2011] n = 121 84.4% 9 weeks
n = 59
Holzer et al. WS ODD 13 yrs; ATX: 0.46–1.8 mg/kg per ADHDRS-IV 1.81* MOAS 1.10* 3
[2013] n = 11 90.9% day + OLZ: 0.02–0.09
mg/kg per day;
10 weeks
Adler et al. RCT Anxiety 38.0 yrs; 40–100 mg per day; CAARS 0.47 LSAS 0.40 5
[2009] n = 171 53.6% 14 weeks
n = 158
Gabriel WS Anxiety 38 yrs; 80 mg per day; CGI-S 1.43* HAM-A 1.51* 4
andViolato, n = 29 30% 12 weeks ASRS 1.28*
[2011]

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SL Hutchison, JK Ghuman et al.

(Continued)
Table 1. (Continued)

Study Design; Comorbidity Patient ATX dose; ADHD measure Effect size Comorbid Effect size Quality
n (ATX) age; % trial length (weeks) condition score
n (PBO) male measure
Geller et al. RCT Anxiety 12 yrs; 0.8–1.8 mg/kg per day; ADHDRS-IV 1.0 PARS 0.50 4
[2007] n = 87 62.5% 12 weeks
n = 89
Bangs et al. RCT MDD 14 yrs; 1.2–1.8 mg/kg per day; ADHDRS-IV 0.84 CDRS-R ns 5
[2007] n = 72 73.2% 9 weeks
n = 70
Chang et al. WS Bipolar 11 yrs; 0.5–1.2 mg/kg per day; ADHDRS-IV 2.18 YMRS ns 3
[2009] n = 12 58.3% 8 weeks CDRS-R ns
Benegal WS SUD 27 yrs; Up to 50 mg per day + ASRS 2.21* Maximum 2.09* 2
et al. [2013] retrospective 100% TAU; abstinent
n = 18 7–52 weeks, (days)
average = 17 weeks
Thurstone RCT SUD 16 yrs; 0.5–1.5 mg/kg per day; ADHD checklist ns No. days using ns 5
et al. [2010] n = 35 78.6% older or heavier = substance in
Therapeutic Advances in Psychopharmacology 6(5)

n = 35 50–100 mg per day; past 28


12 weeks
Wilens et al. RCT SUD 34 yrs; 25–100 mg per day; AISRS 0.48 Drinks per day ns 4
[2008] n = 72 (alcohol) 85.0% 12 weeks
n = 75
Gilbert et al. WS Tourette 12 yrs; 0.8–1.5 mg/kg per day; ADHDRS-IV 1.17* SICI n.s. 3
[2007] n = 14 Syndrome Unknown 4 weeks
Spencer RCT Tourette 11 yrs; 0.5–1.5 mg/kg per day; ADHDRS-IV 0.57 YGTSS 0.40 4
et al. [2008] n = 61 syndrome 87.2% 18 weeks
n = 56
Shaywitz WS Dyslexia 12 yrs; 1.0–1.4 mg/kg per day; ADHDRS-IV 1.79 K-TEA 4
et al. [2014] parallel 66.7% 16 weeks Decoding 0.50,
n = 36 comprehensive 0.62,
composite 0.61
Wietecha RCT Dyslexia 12 yrs; 0.5–1.4 mg/kg per day; ADHDRS-IV 0.53 K-SCT-Teacher 0.77 5
et al. [2013] n = 62 62.0% 16 weeks
n = 58
De Jong RCT Reading 9 yrs; 0.6–1.2 mg/kg per day; ADHDRS-IV 1.08* Lexical ns 3
et al. [2009] crossover disorder unknown 16 weeks decision task
n = 20
*Cohen’s d effect size computed using published data.
ABC, Aberrant Behavioral Checklist; ADHDRS-IV, Parent report-Investigator-scored ADHD Rating Scale; ASRS, ADHD Self-Report Scale; AISRS, ADHD Investigator Symptom Rating
Scale; CAARS, Conners’ Adult ADHD Rating Scale; CDRS-R, Children’s Depression Rating Scale; CGI-S Clinical Global Impressions, Severity Scale; CGI-I, Clinical Global Impressions,
Improvement Scale; CSBQ, Children’s Social Behavior Questionnaire; HAM-A, Hamilton Anxiety Scale; K-TEA, Kaufman Test of Educational Achievement; K-SCT, Kiddie-Sluggish Cogni-
tive Tempo; LSAS, Liebowitz Social Anxiety Scale; MOAS, Modified Overt Aggression Scale; SICI, Short interval cortical inhibition; SNAP-IV, Swanson, Nolan, and Pelham Rating Scale;
YMRS, Young Mania Rating Scale; YGTSS, Yale Global Tic Severity Scale; ASD, Autism Spectrum Disorder; ODD, Oppositional Defiant Disorder; PARS, Pediatric Anxiety Rating Scale;
MDD, major depressive disorder; SUD, substance use disorder; ns, not significant; ATX, atomoxetine; OLZ, olanzapine, TAU, treatment as usual; RCT, randomized controlled trial; WS,
within subject.

322 http://tpp.sagepub.com
SL Hutchison, JK Ghuman et al.

values were slightly lower than parent-reported for the hyperactivity subscale for ATX versus PBO
values, while change scores over the 16 weeks of over 10 weeks, but no difference was observed for
study were similar, 35.31 (6.51) to 25.68 (8.47) ATX and PBO conditions for all other ABC sub-
and 30.76 (11.54) to 22.46 (11.22) for parent- scales in the absence of adjuvant parent training.
and teacher-completed ADHDRS-IV at pre and Finally, in an open-label prospective trial, Charnsil
postassessment, respectively. ESs for parent- found that ABC scores rated by parents did not
completed ADHDRS-IV scores were 1.27 and show significant improvement over 10 weeks in
0.73 for teacher-completed ADHDRS-IV scores. youth with ADHD and comorbid ASD [Charnsil,
Two participants in this study continued stimu- 2011]. In Harfterkamp’s RCT, a second behavio-
lant therapy and 13 (54%) continued to take a ral assessment, the Children’s Social Behavior
neuroleptic; thus, the ability to determine ATX Questionnaire (CSBQ), that measures parent-
effectiveness in this study is diminished. reported ratings of social, communication, and
Harfterkamp and colleagues report significant behaviors specific to autism [Hartman et al. 2006],
change in ADHDRS-IV scores over 20 to 28 showed no difference between ATX versus PBO
weeks of treatment from a baseline score of 40.3 [Harfterkamp et al. 2014]. Mixed results were also
(7.1) to 24.9 (12.2), ES = 1.54 [Harfterkamp found for the Clinical Global Impressions scale
et  al. 2013]. One RCT utilized the Swanson, (CGI) [Guy, 1976]. The CGI rates severity of
Nolan, and Pelham Rating Scale ADHD subscale symptoms and progress based on parent and clini-
(SNAP-IV) to determine efficacy of ATX on cian report on a scale ranging from 0 = normal,
ADHD symptoms and behaviors [Swanson, not at all, to 7 = extremely ill. In Charnsil’s study,
1992]. The SNAP-IV is a caregiver- or teacher- CGI-improvement subscale (CGI-I) improved for
completed assessment for monitoring inattention, some youth, but authors state that overall, scores
hyperactivity or impulsivity, and oppositional did not improve over time for the nine study par-
behavior. The SNAP-IV includes 20 items spe- ticipants [Charnsil, 2011]. CGI-severity subscale
cific to ADHD and 10 items specific to ODD. scores (CGI-S) in the study by Fernández-Jaén
Final scores are average ratings for all completed and colleagues showed significant improvement
items for the frequency of specific behaviors on a over 16 weeks for 23 participants, from baseline
scale from 0 = not at all, to 3 = very much. score of 5.37 (0.96) to post-treatment score of
Handen and colleagues, using a four-group par- 4.20 (1.02), ES = 1.18 [Fernández-Jaén et  al.
allel design, randomized youth to receive ATX or 2011]. This difference in findings among the stud-
PBO with and without adjuvant parent training. ies in the effectiveness of ATX to reduce symp-
Change in SNAP-IV ADHD subscale scores was toms associated with ASD may be due to outcome
significantly greater for ATX versus PBO, 2.18 and measure utilized, but may also be due to
(0.44) to 1.24 (0.56) and 2.20 (0.52) to 1.74 patient characteristics, mainly symptom severity.
(0.86), ES = 0.80. A nonsignificant difference in
change sores between ATX and PBO on the Of the seven studies investigating the efficacy of
teacher-reported SNAP-IV ADHD subscale was ATX in youth with ADHD and comorbid ASD,
reported in this study [Handen et al. 2015]. only four utilized a primary efficacy measure for
ASD functioning and behavior. Findings relating
Various measures were used to determine the effi- to changes in general levels of functioning and
cacy of ATX on functioning and behavior in youth behaviors in youth with ADHD and comorbid
with ADHD and comorbid ASD. Three studies ASD are mixed. Most common adverse events
used the Aberrant Behavioral Checklist (ABC) (AEs) reported by youth in the four studies that
[Aman et al. 1985]. The ABC is parent-reported also utilized global measures of functioning and
ratings on 58 items with subscales of irritability, behavior were somnolence, decreased appetite,
agitation and crying; lethargy and social with- nausea, irritability, and agitation. The findings
drawal; stereotypic behaviors; hyperactivity and from these studies suggest that while ATX may be
noncompliance; and inappropriate speech. In a associated with significantly improved behaviors
double-blind RCT, significantly greater improve- related to ADHD, the efficacy of ATX on global
ment was observed for ATX versus PBO over 8 measures of functioning and behaviors with or
weeks on ABC subscales of hyperactivity, inap- without behaviors specific to ASD is less robust.
propriate speech, and stereotypic behavior The positive results observed on several ABC sub-
[Harfterkamp et al. 2014]. Handen and colleagues scales in the RCT along with improved global
found mixed results [Handen et  al. 2015]. severity are worth noting and suggest that youth
Significantly greater improvement was observed with ADHD and ASD may benefit from ATX.

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Therapeutic Advances in Psychopharmacology 6(5)

Oppositional defiant disorder ADHD. Mixed results are reported. In the study
ODD is the most commonly reported comorbid by Dell’Agnello and colleagues, baseline
mental health condition for individuals with SNAP-IV ODD scores were 17.2 and 17.5 for
ADHD [Steinhausen et  al. 2006]. Although six ATX and PBO, respectively. Significantly greater
studies were found during the search strategy, improvement was observed for ATX than PBO
several of these studies were continuation of pre- over 8 weeks, −2.7 (4.1) versus −0.3 (2.6), ES =
viously published studies; thus, results are pre- 0.52 [Dell’Agnello et al. 2009a]. As reported by
sented for four studies, n = 393 ATX, and n = Dittmann and colleagues, least squares mean
161 PBO. All studies included youth only. Three treatment group difference with baseline scores of
of the four studies examining the efficacy of ATX 15.6 and 15.5, ATX and PBO, respectively, were
in youth with ADHD and comorbid ODD were −3.2, 95% CI, −5.0 to −1.5, ES = 0.69 [Dittmann
RCTs. In the fourth study, Holzer and colleagues et al. 2011]. In a study by Bangs and colleagues,
utilized an open-label, prospective, within-subject SNAP-IV ODD scores were similar at baseline,
design. Their study also included ATX + olan- 18.9, and improved equally for ATX and PBO,
zapine for all participants in its 10-week treat- with a change of −3.7 (5.3) and −2.9 (4.3),
ment protocol. While olanzapine dosage was kept respectively, (nonsignificant). Holzer and col-
stable, the additional medication is a caveat to the leagues, utilizing the clinician–interview com-
interpretation of the findings for ATX for this pleted Modified Overt Aggression Scale (MOAS)
study [Holzer et al. 2013]. Quality scores ranged [Yudofsky et  al. 1986], reported significant
3–5 with three of the four studies having the high- improvement in scores over time, 20.45 (6.0) to
est quality score. Three studies, all double-blind 12.64 (8.0), ES = 1.10 [Holzer et  al. 2013].
RCTs, utilized the SNAP-IV ADHD subscale as Scores on the MOAS reflect the number of diffi-
the primary efficacy measure for ADHD symp- cult behaviors in four domains of aggression;
toms and behaviors. In all three studies, signifi- items in the physical aggression domain are
cantly greater improvement was observed for weighted highest in the final score.
SNAP-IV ADHD subscale total scores for ATX
versus PBO. Dell’Agnello and colleagues found One study reported a high level of AEs. In the
significantly greater improvement in SNAP-IV study by Dittmann and colleagues, 70% of youth
ADHD scale scores for ATX versus PBO in 137 with fast titration of ATX (0.5 mg/kg/day for 7
randomized youth over 8 weeks [Dell’Agnello days to 1.2 mg/kg/day target dose) experienced
et al. 2009a]. Change scores for ATX versus PBO AEs versus 31% of youth in the PBO condition
were −8.9 (9.2) and −2.0 (4.7), respectively, ES [Dittmann et  al. 2011]. The most commonly
= 0.91. Also, Bangs and colleagues [Bangs et al. reported AEs in their study were fatigue, nausea,
2008; Hazell et al. 2009], observed similar results headache, vomiting, upper abdominal pain, and
over 8 weeks for 226 randomized youth aged anorexia. Based on the reported results of these
6–12 yrs for the SNAP-IV inattentive subscale studies, ATX is effective in youth with comorbid
and Hyperactivity/Impulsivity subscales. Mean ADHD and ODD. While mixed findings are
change scores on the inattentive subscale for ATX reported for the efficacy of ATX to improve symp-
and PBO were −5.0 (6.0) and −2.2 (4.8), respec- toms of ODD, the majority of studies suggest that
tively, and for the Hyperactivity/Impulsivity sub- ATX is effective in ODD treatment. ATX is mod-
scale, −4.6 (6.2) and −2.2 (4.5) respectively. ESs erately tolerated by individuals with ADHD and
in this study ranged from 0.52 to 0.44. Finally, comorbid ODD and this can be improved with
significantly greater improvement was observed slow titration of ATX to maximum dose.
in SNAP-IV ADHD total score for 181 youth
over 9 weeks, least squares mean treatment group
difference, −7.4, 95% CI, −11.0 to −3.8, ES = Anxiety disorders
0.72 [Dittmann et  al. 2011; Wehmeier et  al. Two RCTs investigated efficacy of ATX versus
2011]. Holzer and colleagues found a significant PBO in individuals with ADHD and comorbid
improvement in ADHDRS-IV score over 10 social anxiety disorder: one in adults [Adler et al.
weeks for 11 youth, 41.95 (3.69) to 26.0 (11.99), 2009] and one in youth [Geller et al. 2007]. An
ES = 1.81 [Holzer et al. 2013]. additional open-label, prospective, within-subject
study investigated ATX in adults with ADHD
All RCTs utilized the SNAP-IV ODD subscale to and comorbid generalized anxiety disorder
assess efficacy of ATX on symptoms and behav- [Gabriel and Violato, 2011]. In total, 287 sub-
iors specific to ODD in youth with comorbid jects were included in the ATX group and 247

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SL Hutchison, JK Ghuman et al.

subjects in the PBO group. All studies had a qual- often in ATX versus PBO conditions and included
ity score of 4 or 5. insomnia, nausea, dry mouth, and dizziness;
however, discontinuation during the study due to
In a study by Geller and colleagues, 87 youth ran- side effects did not differ between groups.
domized to up to 1.8 mg/kg per day of ATX for
12 weeks showed a significantly greater improve- In 27 adults with ADHD and comorbid general-
ment in ADHDRS-IV scores than 89 youth rand- ized anxiety disorder, significant improvement was
omized to PBO, with change values of −10.5 and found over 12 weeks for ADHD symptoms on both
−1.4 for ATX and PBO, respectively, ES = 1.0 the CGI-S and ADHD Self-Report Scale (ASRS),
[Geller et  al. 2007]. Scores on the Pediatric an 18-item symptom checklist rated from 0 = never
Anxiety Rating Scale (PARS) [Research Unit on to 4 = very often [Kessler et al. 2005a]. Significant
Pediatric Psychopharmacology, 2002], a clini- improvement was also found for reported severity
cian–interview-completed measure of severity on of anxiety symptoms including cognitive anxiety
seven items of separation anxiety, social phobia, and somatic anxiety, on the 14-item Hamilton
and generalized anxiety symptoms, also showed Anxiety Scale (HAM-A) [Hamilton, 1959; Gabriel
significantly greater improvement in the ATX and Violato, 2011]. CGI-S scores changed from
condition, change values of −5.5 and −3.2 for 4.2 (0.64) to 3.0 (1.0), ES = 1.43 and ASRS scores
ATX and PBO, respectively, ES = 0.5. changed from 47.9 (10.3) to 32.9 (13.0), ES =
Participants in their study met criteria for ADHD 1.28. Total HAM-A scores changed from 12.1
with any of the following comorbidities: separa- (4.2) to 6.7 (2.3), ES = 1.51; significant improve-
tion anxiety, generalized anxiety disorder, or ment was also observed for cognitive and somatic
social phobia. Their study had one of the highest anxiety subscales separately. Most common side
doses of ATX of the studies reviewed for youth. effects reported were dry mouth (40%), nausea
(26%), palpitation (15%), and light-headedness
In a 14-week, multisite, double-blind RCT of (15%). The percent male population for this study,
adults with ADHD and comorbid social anxiety 30%, was the lowest proportion of males for all
disorder, Adler and colleagues found significantly studies reviewed.
greater reduction on the Conners’ Adult ADHD
Rating Scale, Investigator-rated, screening ver- Interpretation of results for the three studies
sion (CAARS:Inv:SV) [Conners et  al. 1999] in investigating efficacy of ATX in individuals with
171 adults with ADHD and anxiety disorder ADHD and comorbid anxiety is limited. Only
receiving ATX versus 158 adults receiving PBO one study investigated ATX in youth; however,
[Adler et  al. 2009]. The CAARS is an 18-item with all studies, including two RCTs of higher
assessment of the occurrence of behaviors of quality indicating positive results, ATX appears
hyperactivity and inattention rated on a scale efficacious in the treatment of individuals with
from 0 = not at all, to 3 = very much. Scores ADHD and comorbid anxiety disorder. The pro-
reduced from 29.6 (10.4) to 20.9 (11.3) for the portion of females included in these studies was
ATX condition and 31.2 (9.4) to 25.6 (10.6) for higher than other studies reviewed at 38–70%
the PBO condition, ES = 0.47. Scores on the which may have impacted results.
Liebowitz Social Anxiety Scale (LSAS), a clini-
cian-rated measure on 24 activities of social inter-
action and performance situations rated on a MDD and bipolar disorder
severity scale ranging from 0 = none, to 4 = The majority of studies included in this review
severe, [Liebowitz, 1987] also showed signifi- excludes individuals with ADHD and comorbid
cantly greater improvement for ATX versus PBO, major depressive disorder, psychosis, and bipolar
85.3 (23.6) to 62.4 (29.7) versus 82.1 (21.3) to disorder. Studying these comorbid conditions
67.7 (26.9), ES = 0.40. The participants showing may be more complex because these individuals
high response on the LSAS during the pretrial are under current treatment with psychotropic
PBO period were excluded from the study. ESs medication that cannot be stopped to initiate a
indicate small improvement in both ADHD and clean period before investigating efficacy of ATX
anxiety symptoms. Change in CAARS total alone. Few recent studies have investigated effi-
ADHD symptoms scores and LSAS total scores cacy of ATX in youth or adults with these comor-
was significantly correlated indicating an associa- bid disorders. Two studies are included in this
tion between improved ADHD and anxiety review, n = 84 ATX, and n = 70 PBO. Quality
symptoms. AEs were reported significantly more scores are 3 and 5.

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Therapeutic Advances in Psychopharmacology 6(5)

One multisite, double-blind RCT investigated the ADHDRS-IV decreased significantly over 8
the efficacy of ATX in adolescents with ADHD weeks from 39.0 (7.7) to 22.1 (7.7), ES = 2.18
and MDD [Bangs et al. 2007]. In a sample of 142 [Chang et  al. 2009]. The reported presence of
youth, ages 12–18 years, 73.2% male, signifi- manic symptoms as measured by the 11-item
cantly improved scores on the ADHDRS-IV in clinician-completed, Young Mania Rating Scale
ATX versus PBO over 9 weeks were reported but (YMRS) [Young et al. 1978] did not change over
no difference in the Children’s Depression Rating time, 7.9 (4.7) to 7.4 (4.8), (nonsignificant); nor
Scale, Revised (CDRS-R) [Poznanski and was significant improvement found in CDRS-R
Mokros, 1999] between conditions was reported. scores, 25.9 (4.0) to 25.2 (5.6). In addition, the
The CDRS-R is a semistructured interview con- authors reported worsening of symptoms in two
sisting of 17 symptom areas rated on a 7-point youths. AEs reported by youth in the study were
scale used to diagnose and monitor depression tiredness, 25%, stomach ache, 25%, agitation,
symptoms. Youth were treated after a 1-week 16%, nausea, 8%, dizziness, 8%, anticholinergic
clean period with up to 1.8 mg/kg of ATX per reaction, 8% and suicidal ideation, 8%. A moder-
day, a slightly higher dose than used in other effi- ate ES indicating substantial change was observed
cacy studies. Youth initiating psychotherapy in for ADHD symptoms and behaviors over time;
the month prior were excluded. ADHDRS-IV however, no association was observed for ATX
scores were similar in ATX and PBO conditions and improved mania or depression. Based on the
at baseline; change scores on the ADHDRS-IV, limited, recent studies available, ATX appears to
which were significantly greater in the ATX versus be effective in improving ADHD-associated
PBO condition, were −13.3 (10.0) and −5.1 (9.9) symptoms and behaviors but not symptoms spe-
in the ATX and PBO groups, respectively, ES = cific to bipolar and MDD. Suicidal ideation was
0.84. Improved ADHDRS-IV scores for ATX reported by some youth receiving ATX, but in an
over PBO indicate efficacy of ATX for ADHD RCT, report of this AE did not differ between
symptoms in youth with ADHD and comorbid ATX and PBO.
MDD. Scores on the CDRS-R were required to
be at least 40 at randomization for inclusion crite-
ria; baseline scores were 53.4 (10.9) for ATX and SUD
52.0 (8.9) for PBO. Change scores on the Three studies investigated efficacy of ATX in
CDRS-R were −14.8 (13.3) and −12.8 (10.4), individuals with ADHD and comorbid SUD: two
for ATX and PBO groups, respectively (nonsig- in non-nicotine SUD and one specific to alcohol,
nificant). Despite the large ES in the change n = 125 ATX, and n = 110 PBO. Quality scores
observed between ATX and PBO for ADHD ranged 2–5 with two studies having quality scores
symptoms, it did not directly translate into a simi- of 4 or 5. Among studies in adults, one double-
lar finding for MDD. It is unclear why such a sub- blind RCT showed a significant improvement in
stantial decrease in depressive symptoms was ADHD symptoms in ATX over PBO during a
observed in the PBO condition. In this trial, sig- 12-week trial. Wilens and colleagues, in a study
nificantly more AEs were reported for ATX versus specific to alcohol, found baseline scores on the
PBO for nausea (22% versus 4%, respectively), ADHD Investigator Symptom Rating Scale
and decreased appetite (13% versus 0%, respec- (AISRS) [Spencer et al. 2010], an 18-item clini-
tively). Very few participants reported suicidal cian–interview measure of ADHD symptom
ideation and this did not differ between ATX and severity rated from 0 = none, to 3 = severe, were
PBO groups. Thus, ATX appears to be effica- similar between groups, 40.6 (7.8) for ATX and
cious in the treatment of ADHD symptoms in 40.1 (7.9) for PBO [Wilens et  al. 2008].
youth with ADHD and comorbid MDD, but evi- Significantly greater improvement was observed
dence is limited. for ATX versus PBO over time, −13.6 (11.4) and
−8.3 (11.4) respectively, ES = 0.48. In a within-
One study investigated ATX in the treatment of subject, retrospective naturalistic study, ASRS
youth with ADHD and comorbid bipolar disor- scores following an average of 17 weeks of ATX
der. In an open-label, prospective design, Chang treatment in 14 young males aged 18–24 years,
and colleagues followed 12 youth, 6–14 years old, were significantly lower than scores before treat-
with ADHD and comorbid bipolar disorder. ment initiation 29.32 (9.6) versus 52.68 (11.48),
Participants continued their current mood- respectively, ES = 2.21 [Benegal et al. 2013]. In
stabilizing medication with dose kept constant 3 a double-blind RCT of 70 adolescents, 13–19
weeks prior and during the study trial. Scores on years, nonsignificant results were observed for

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SL Hutchison, JK Ghuman et al.

improved symptoms, self-reported, on the Significant differences were also found for the
DSM-IV ADHD symptom checklist [APA, 1994] Inattention and Hyperactivity/Impulsivity sub-
for ATX over PBO as both groups improved sig- scales of the ADHDRS-IV in the expected direc-
nificantly, but equally, over time [Thurstone et al. tion, ES = 0.49 and 0.57 respectively. In an
2010]. Change over 12 weeks of treatment using open-label, prospective, within-subject design,
the ADHD checklist for ATX and PBO condi- Gilbert and colleagues monitored 14 youth with
tions was −18.19 versus −19.02, respectively, ADHD and Tourette syndrome over 1 month.
(nonsignificant). Scores on the ADHDRS-IV significantly
improved over time from 32.0 (8.0) to 22.0 (9.0),
When considering the association of ATX on ES = 1.17 [Gilbert et al. 2007].
substance-use behavior, only one study found a
significant association. Benegal and colleagues Two very different efficacy measures were used to
found significantly greater number of abstinent monitor response to ATX treatment on tics and
days during ATX treatment compared with the other symptoms of Tourette syndrome. Gilbert
same individuals during a previous treatment and colleagues used a physiological measure of
period without ATX, 229.11 (119.37) versus cortical functioning, short-interval cortical inhibi-
38.89 (48.21) days [Benegal et al. 2013]. Caveats tion (SICI) [Gilbert et  al. 2007], while Spencer
to interpretation of this finding, however, could and colleagues [Spencer et al. 2008] used the Yale
be the removal of dropouts from analyses (n = 4, Global Tic Severity Scale (YGTSS) [Leckman
out of 18 participants) and the large amount of et  al. 1989]. Significantly greater improvement
variability in reported abstinent days. Number of was observed in YGTSS scores for ATX versus
days using substances in the past month PBO, −5.1 (7.1) and −2.0 (−8.4), respectively,
[Thurstone et al. 2010] and drinks per day, pro- ES = 0.4. A nonsignificant change, −0.61, in cor-
portion of days drinking, number of drinks per tical inhibition was observed by Gilbert and col-
drinking day, or proportion of days using sub- leagues [Gilbert et  al. 2007]. Despite a high
stances other than alcohol [Wilens et al. 2008] did prevalence of ADHD among those with Tourette
not differ between ATX and PBO conditions. syndrome [Denckla, 2006], no other recent stud-
This null finding for Thurstone and colleagues ies have been conducted examining the efficacy of
may be due to adjuvant motivational and cogni- ATX in individuals with ADHD and comorbid
tive behavioral therapies [Thurstone et al. 2010]. Tourette syndrome and results remain equivocal.
In their study, significantly more reports of AEs
for ATX over PBO were observed for vomiting,
but significantly fewer reports were made for Dyslexia and reading disorder
muscle cramps and sadness. Based on these find- Three studies investigated the efficacy of ATX in
ings and the specific populations studied, the effi- youth with ADHD and comorbid reading disor-
cacy of ATX for reducing symptoms of ADHD is der or dyslexia, n = 118 ATX, and n = 58 PBO.
equivocal and ATX appears to have little impact Quality scores ranged 3–5; two studies had qual-
on substance-using behavior in adolescents and ity scores of 4 or 5. Two studies investigated effi-
adults with ADHD and comorbid SUD. cacy of ATX in youth with ADHD and comorbid
dyslexia: a double-blind RCT and an open-label,
parallel (two group), within-subject design.
Tourette syndrome Wietecha and colleagues randomized 159 youth
Two studies investigated the efficacy of ATX in with ADHD and dyslexia to ATX or PBO for 16
youth with ADHD and comorbid Tourette syn- weeks with an additional follow-up period to 32
drome, n = 75 ATX, and n = 56 PBO. Quality weeks. Baseline ratings on the ADHDRS-IV were
scores are 3 and 4. In a double-blind RCT by 37.22 and 37.57 for ATX and PBO, respectively.
Spencer and colleagues [Spencer et  al. 2008; Change scores on this measure indicated signifi-
Allen et  al. 2005], 116 youth, ages 7–17 years, cantly greater improvement for ATX versus PBO,
with ADHD and comorbid Tourette syndrome −18.87 and −12.98, respectively, ES = 0.53
were randomized to ATX (n = 6) or PBO (n = [Wietecha et  al. 2013]. In an open-label trial,
56) for 18 weeks. A significantly greater improve- Shaywitz and colleagues found significant
ment in ADHD symptoms on the ADHDRS-IV improvement in ADHDRS-IV scores for 35 youth
was observed for the ATX versus PBO conditions. with ADHD and comorbid dyslexia over 16
Change over time for those receiving ATX was weeks of treatment with ATX, from 36.0 (8.2) to
−10.4 (11.0) and for PBO −4.4 (9.9), ES = 0.57. 17.8 (12.3), ES = 1.79 [Shaywitz et al. 2014].

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Therapeutic Advances in Psychopharmacology 6(5)

Two different efficacy measures were used to found that the efficacy and effectiveness of ATX
determine impact of ATX on dyslexia in youth are not diminished by the presence of the majority
with ADHD and comorbid dyslexia. In the of comorbid disorders studied. ESs for observed
Wietecha and colleagues study, significantly improvements in ADHD symptoms in ATX ver-
greater improvement was observed for sluggish or sus PBO or in pre-post within-subject designs
apathetic behaviors as measured by the Kiddie- ranged from 0.47 to 2.21, indicating moderate-to-
Sluggish Cognitive Tempo (K-SCT) [Lee et  al. large ESs. Overall, the impact of ATX on ADHD
2013], with scores for ATX over PBO, −6.88 ver- symptoms and behaviors in individuals with
sus −1.64, ES = 0.77 [Wietecha et  al. 2013]. ADHD and comorbid disorders appears to be reli-
Similar results were found by Shaywitz and col- able and not influenced by specific outcome meas-
leagues on the standardized, Kaufman Test of ure utilized or age of the patient (child versus
Educational Achievement for youth in grades 1 adult).
through 12 (K-TEA) [Kaufman and Kaufman,
1998] with significant improvement observed on Results for the effectiveness of ATX to reduce or
three subscales, reading decoding, 80.2 (7.6) to improve symptoms and behaviors relating to
84.8 (10.6), ES = 0.50, reading comprehension, comorbid conditions are mixed. Results for the
81.6 (10.8) to 89.3 (13.8), ES = 0.62, and read- effectiveness of ATX on comorbid conditions are
ing composite, 80.3 (8.6) to 86.4 (11.4), ES = more robust for ODD and anxiety in both youth
0.61 [Shaywitz et al. 2014]. and adults. Results from two RCTs [Dell’Agnello
et al. 2009a; Dittmann et al. 2011] support posi-
In youth with ADHD and comorbid reading dis- tive findings for efficacy of ATX to improve
order as determined through community-based symptoms of ODD. The third RCT investigating
providers, significantly greater improvement was efficacy of ATX to improve ODD symptoms
observed in 36 youth with either ADHD or [Bangs et  al. 2008] did not find differences
ADHD with comorbid reading disorder receiving between ATX and PBO at endpoint, but did find
ATX compared with PBO on ADHDRS-IV differences in earlier assessments as well as differ-
Scores [de Jong et al. 2009]. In this double-blind ences on secondary outcome measures for ODD
crossover study, youth were randomized by order symptoms. Missing from studies on ATX in
of treatment: ATX–PBO or PBO–ATX. In the 20 youth with ADHD and ODD is a description of
youth with ADHD and comorbid reading disor- ODD subtype: irritable and defiant, or vindictive.
der, baseline score on the ADHDRS-IV was 39.0 These subtypes have been shown to be associated
(9.1) which decreased to 26.4 (13.7) following with suicidality, criminal behavior, and comorbid
ATX treatment and decreased slightly to 36.9 anxiety [Aebi et al. 2015] and it is likely that these
(11.1) following PBO, ES = 1.08. Performance traits within ODD may impact response to ATX
on a lexical decision task [Meyer and Schvaneveldt, and other medications. Thus, it is difficult to
1971], the primary efficacy measure for dyslexia, determine how the responses observed in the cur-
did not improve differentially between ATX and rent review may generalize to other youth with
PBO conditions, 1.9 (0.7) to 2.0 (0.7) and 1.9 ADHD and comorbid ODD. Results from two
(0.7) to 1.8 (0.6), (nonsignificant). RCTs [Adler et al. 2009; Geller et al. 2007] sup-
port efficacy of ATX on anxiety symptoms. The
ATX is efficacious in the treatment for youth with ranges in ES for change observed in symptoms
ADHD and comorbid dyslexia. This association and behaviors related to these comorbid condi-
may also be true for other comorbid learning dis- tions are 0.52 to 1.10 for ODD and 0.40 to 1.51
abilities. The association between ATX and for anxiety, indicating small-to-large ESs. ODD
improvements related to dyslexia including word and anxiety are commonly occurring comorbid
recognition, comprehension, and reading ability conditions with ADHD and effectiveness of ATX
is promising and warrants more attention and in the treatment of these conditions is promising.
research.
Studies failed to show efficacy of ATX for ASD,
depression, bipolar, Tourette syndrome, and dys-
Discussion lexia either because of equivocal findings or lim-
Evidence for the efficacy of ATX on ADHD ited high quality trials available for review. Results
symptoms is well established and as in previously for the effectiveness of ATX on ASD-associated
published reviews [Dell’Agnello et  al. 2009b; behaviors are mixed with one RCT reporting effi-
Garnock-Jones and Keating, 2009], this review cacy on ASD symptoms and behaviors and one

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SL Hutchison, JK Ghuman et al.

RCT reporting null findings. ATX may be effec- Withdrawal rates from studies due to AEs did not
tive in major depressive disorder and reading dis- vary between ATX and PBO in the majority of
order but few trials are available to confirm RCTs; however, many studies reviewed reported
judgement. More research is also needed on the that a higher proportion of individuals receiving
efficacy of ATX in the areas of ADHD with ATX versus PBO were more likely to experience
comorbid bipolar disorder and Tourette syn- nausea and decreased appetite. The current
drome. In a review by Cortese and colleagues, the review did not find increased report of suicidal
authors conclude that ATX may improve presen- behaviors for youth with ADHD and comorbid
tation of tics, while stimulants may worsen tics MDD receiving ATX versus PBO [Bangs et  al.
[Cortese et  al. 2013]. This finding is consistent 2007]. Only one youth (8%) with ADHD and
with outcomes presented in the current review as comorbid bipolar disorder reported suicidal
measured by the YGTSS in an RCT with over behaviors after receiving ATX [Chang et  al.
117 youth [Spencer et al. 2008]. 2009]. One study found a possible negative out-
come of decreased cortical functioning in chil-
Studies reviewed failed to show a reliable pattern dren with ADHD and comorbid Tourette
of efficacy for ATX on SUD behavior in young syndrome after receiving ATX [Gilbert et  al.
adults with ADHD and comorbid alcohol or non- 2007]. Aside from this physiological AE, the cur-
nicotinic substance use. These studies also failed rent review concurs with prior research showing
to show effectiveness for ATX in the treatment of similar reported AEs in individuals with ADHD
the ADHD symptoms. Wilens and colleagues and comorbid conditions to those in the general
have found a correlation between change in ADHD population [Dell’Agnello et  al. 2009a].
ADHD symptoms and drug cravings among More research is needed to address cortical func-
adults with ADHD and comorbid SUD [Wilens tioning in children and adults with ADHD and
et al. 2008, 2011]. More studies such as this may comorbid conditions.
improve our understanding of how pharmaco-
therapy may influence symptoms and substance- Data sources used in this review may have limita-
use behaviors for individuals with ADHD and tions. Inclusion of study designs other than RCTs
comorbid SUD. in this review was valuable in supporting the find-
ings and in describing the knowledge base of
There are several treatment-related factors that ATX in the treatment of ADHD with comorbid-
may contribute to reported efficacy. There is ity. While of lower methodological quality, these
reported evidence that maximum efficacy of ATX studies provide an assessment of the effectiveness
may not be reached until 10–12 weeks of treat- of ATX in environments similar to those environ-
ment with ATX [Savill et  al. 2015]. This phe- ments experienced by the general clinical com-
nomenon was not confirmed in our review, as munity in which individuals are prescribed
many trials reported positive findings in under 10 medication and monitored over time. The impact
weeks. More studies with longer treatment dura- of these studies on effectiveness of ATX to treat
tions are needed to determine the impact of long- ADHD and comorbid conditions was interpreted
term treatment with ATX on efficacy and AEs. conservatively. ESs reported in this review were
Also, several studies utilized a dosage above the provided for reference and not intended for com-
recommended maximum dosage specified by the bined analysis as different outcome assessments
manufacturer of 1.4 mg/kg per day in youth, while were utilized across studies. ESs may have been
not the case for the highest recommended dosage influenced by study design and reporting of out-
in adults of 100 mg per day. There does not comes. Faraone and colleagues found larger ESs
appear to be a strong relationship between dose for crossover versus parallel-design studies and for
and efficacy in the current review as large ESs studies reporting outcome values versus change
were found for both high and recommended scores [Faraone et al. 2006]. In the current review,
doses of ATX. Thus, this review supports the the largest ESs were observed in studies utilizing
practice that prescribing be dictated by individual within-subject designs, thus providing another
tolerability and medication response. reason to interpret results from lower quality
studies cautiously. Many studies included in this
Described above, ATX is often prescribed in lieu review had small sample sizes and may not have
of stimulants because the latter may increase had adequate power to discern differences
symptoms exacerbated by comorbid conditions between treatment groups. The majority of stud-
including tics, mania, and suicidal ideation. ies did not address or present results from power

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Therapeutic Advances in Psychopharmacology 6(5)

calculations. Finally, inclusion of studies utilizing disorder in children and adolescents. Pediatrics 128:
within-subject designs may have increased the 1007–1022.
risk of publication bias which may have influ- American Psychiatric Association: Diagnostic and
enced the findings of this review. Statistical Manual of Mental Disorders, 4th ed. (1994)
Washington, DC: American Psychiatric Association.
American Psychiatric Association: Diagnostic and
Conclusion Statistical Manual of Mental Disorders, 5th ed.: DSM-
Results from this review suggest that the efficacy 5. (2013) Washington, DC: American Psychiatric
and effectiveness of ATX to treat symptoms of Association.
ADHD are not diminished by the presence of
comorbid disorders. Moderate-to-large ESs Anderson, J., Williams, S., McGee, R. and Silva, P.
(1987) DSM-III disorders in preadolescent children:
(0.47–2.21) were reported for improvements in
Prevalence in a large sample from the general
ADHD symptoms. Efficacy of ATX in the treat- population. Arch Gen Psychiatry 44: 69–76.
ment of comorbid conditions showed mixed
results. Evidence did not support efficacy of ATX Bangs, M., Emslie, G., Spencer, T., Ramsey, J.,
for ASD, depression, bipolar, Tourette syndrome, Carlson, C., Bartky, E. et al. (2007) Efficacy and
dyslexia, and SUD, either because of equivocal safety of atomoxetine in adolescents with attention-
deficity/hyperactivity disorder and major depression. J
findings or limited high quality trials available for
Child Adolesc Psychopharmacol 17: 407–419.
review. Findings for ATX in the treatment of
comorbid anxiety and ODD were more robust. Bangs, M., Hazell, P., Danckaerts, M., Hoare, P.,
Moderate ESs in youth were reported for symp- Coghill, D., Wehmeier, P. et al. (2008) Atomoxetine
toms of ODD (0.52–1.10) and small-to-large ESs for the treatment of attention-deficit/hyperactivity
were reported for symptoms of anxiety (0.40– disorder and oppositional defiant disorder. Pediatrics
121: e314–e320.
1.51), suggesting that these youth may benefit
from ATX monotherapy treatment. Bangs, M., Tauscher-Wisniewski, S., Polzer,
J., Zhang, S., Acharya, N., Desaiah, D. et al.
Conflict of interest statement (2005) Meta-analysis of suicide-related events in
The authors declare that there is no conflict of atomoxetine-treated patients. Scientific Proceedings of
interest. the 52nd Annual Meeting of the American Academy of
Child and Adolescent Psychiatry, Toronto, ON.
Funding Benegal, V., Viswanath, B., Narayanaswamy, J., Jose,
This research received no specific grant from any S., Chakraborty, V., Sankar, D. et al. (2013) The
funding agency in the public, commercial, or not- efficacy of atomoxetine as adjunctive treatment for
for-profit sectors. co-morbid substance use disorders and externalizing
symptoms. Asian J Psychiatry 6: 544–547.
Biederman, J. and Faraone, S.V. (2005) Attention-
deficit hyperactivity disorder. Lancet 366: 237–48.
References Biederman, J., Spencer, T., Newcorn, J., Gao, H.,
Adler, L., Liebowitz, M., Kronenberger, W., Qiao,
Milton, D., Feldman, P. et al. (2007) Effect of
M., Rubin, R., Hollandbeck, M. et al. (2009)
comorbid symptoms of oppositional defiant disorder
Atomexetine treatment in adults with attention-deficit/
on responses to atomoxetine in children with ADHD:
hyperactivity disorder and comorbid social anxiety
a meta-analysis of controlled clinical trial data.
disorder. Depress Anxiety 26: 212–221.
Psychopharmacology 190: 31–41.
Aebi, M., Barra, S., Bessler, C., Steinhausen, H.,
Bolea-Alamañac, B., Nutt, D., Adamou, M.,
Walitza, S. and Plattner, B. (2015) Oppositional
Asherson, P., Bazire, S., Coghill, D. et al. (2014)
defiant disorder dimensions and subtypes among
Evidence-based guidelines for the pharmacological
detained male adolescent offenders. J Child Psychol
management of attention deficit hyperactivity
Psychiatry [Epub ahead of print].
disorder: update on recommendations from the
Aman, M., Singh, N., Stewart, A. and Field, C. British Association for Psychopharmacology. J
(1985) The aberrant behavior checklist: a behavior Psychopharmacol 28: 179–203.
rating scale for the assessment of treatment effects.
Castells, X., Ramos-Quiroga, J., Rigau, D., Bosch,
Am J Ment Deficiency 89: 485–491.
R., Nogueira, M., Vidals, X. et al. (2011) Efficacy
American Academy of Pediatrics (2011) ADHD: of methylphenidate for adults with attention-deficit
clinical practice guideline for the diagnosis, evaluation, hyperactivity disorder. A meta-regression analysis.
and treatment of attention-deficit/hyperactivity CNS Drugs 25: 157–169.

330 http://tpp.sagepub.com
SL Hutchison, JK Ghuman et al.

Chang, K., Nayar, D., Howe, M. and Rana, M. (2011) Atomoxetine versus placebo in children and
(2009) Atomoxetine as an adjunct therapy in the adolescents with attention-deficit/hyperactivity
treatment of co-morbid attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder:
disorder in children and adolescents with bipolar I or A double-blind, randomized, multicenter trial in
II disorder. J Child and Adolesc Psychopharmacol 19: Germany. J Child Adolesc Psychopharmacol 21: 97–110.
547–551.
DuPaul, G., Power, T., Anastopoulos, A. and Reid,
Charnsil, C. (2011) Efficacy of atomoxetine in R. (1998) ADHD rating scale-IV: checklists, norms, and
children with severe autistic disorders and symptoms clinical interpretation. New York, NY: The Guildford
of ADHD: an open-label study. J Atten Disord 15: Press.
684–689.
Epstein, T., Patsopoulos, N. and Weiser, M. (2014)
Conners, C., Erhardt, D. and Sparrow, E. (1999) Immediate-release methylphenidate for attention
Conners’ adult ADHD rating scales technical manual. deficit hyperactivity disorder (ADHD) in adults.
North Tonawanda, NY: Multi-Health Systems Inc. Cochrane Database Syst Rev 9: CD005041.

Cortese, S., Holtmann, M., Banaschewski, T., Faraone, S. (2009) Using meta-analysis to compare
Buitelaar, J., Coghill, D., Danckaerts, M. et al. (2013) the efficacy of medications for attention-deficit/
Practitioner review: current best practice in the hyperactivity disorder in youths. PandT 34: 678–694.
management of adverse events during treatment with
Faraone, S., Biederman, J., Spencer, T. and Aleardi,
ADHD medications in children and adolescents. J
M. (2006) Comparing the efficacy of medications for
Child Psychol Psychiatry 54: 227–246.
ADHD using meta-analysis. Med Gen Med 8: 4.
Cunill, R., Castells, X., Tobias, A. and Capella, Fernández-Jaén, A., Fernández-Mayoralas, D.,
D. (2013) Atomoxetine for attention deficit Calleja-Pérez, B., Muñoz-Jareño, N., del Rosario
hyperactivity disorder in the adulthood: a meta- Campos Díaz, M. and López-Arribas, S. (2011)
analysis and meta-regression. Pharmacoepidemiol Efficacy of atomoxetine for the treatment of ADHD
Drug Saf 22: 961–969. symptoms in patients with pervasive developmental
Dalsgaard, S., Nielsen, H. and Simonsen, M. (2013) disorders: a propspective, open-label study. J Atten
Five-fold increase in national prevalence rates of Disord 17: 497–505.
attention-deficit/hyperactivity disorder medications Gabriel, A. and Violato, C. (2011) Adjunctive
for children and adolescents with autism spectrum atomoxetine to SSRIs or SNRIs in the treatment
disorder, attention-deficit/hyperactivity disorder, and of adult ADHD patients with comorbid partially
other psychiatric disorders: a Danish register-based responsive generalized anxiety (GA): an open-label
study. J Child Adolesc Psychopharmacol 23: 432–439. study. ADHD Atten Def Hyp Disord 3: 319–326.
De Jong, C., van de Voorde, S., Roeyers, H., Garbe, E., Mikolaiczyk, R., Banaschewski, T.,
Raymaekers, R., Allen, A., Knijff, S. et al. (2009) Petermann, U., Peterman, F., Kraut, A. et al.
Differential effects of atomoxetine on executive (2012) Drug treatment patterns of attention-deficit/
functioning and lexical decision in attention-deficit/ hyperactivity disorder in children and adolescents
hyperactivity disorder and reading disorder. J Child in Germany: results from a large population-based
Adolesc Psychopharmacol 19: 699–707. cohort study. J Child Adolesc Psychopharm 22: 452–
Dell’Agnello, G., Maschietto, D., Bravaccio, C., 458.
Calamoneri, F., Masi, G., Curatolo, P. et al. (2009a) Garnock-Jones, K. and Keating, G. (2009)
Atomoxetine hydrochloride in the treatment of Atomoxetine. A review of its use in attention-deficit
children and adolescents with attention-deficit/ hyperactivity disorder in children and adolescents.
hyperactivity disorder and comorbid oppositional Pediatr Drugs 11: 203–226.
defiant disorder: a placebo-controlled Italian study.
Euro Neuropsychopharmacol 19: 822–834. Geller, D., Donnelly, C., Lopez, F., Rubin, R.,
Newcorn, J., Sutton, V. et al. (2007) Atomoxetine
Dell’Agnello, G., Zuddas, A., Masi, G., Curatolo, P., treatment for pediatric patients with attention-deficit/
Besana, D. and Rossi, A. (2009b) Use of atomoxetine hyperactivity disorder with comorbid anxiety disorder.
in patients with attention-deficit hyperactivity disorder J Am Acad Child Adolesc Psychiatry 46: 1119–1127.
and co-morbid conditions. CNS Drugs 23: 739–753.
Gerhard, T., Winterstein, A., Olfson, M., Huang,
Denckla, M. (2006) Attention deficit hyperactivity C., Saidi, A. and Crystal, S. (2010) Pre-existing
disorder: the childhood comorbidity that most cardiovascular conditions and pharmacological
influences the disability burden in Tourette syndrome. treatment of adult ADHD. Pharmacoepidemiology Drug
Adv Neurol 99: 17–21. Safety 19: 457–464.
Dittmann, R., Schacht, A., Helsbert, K., Schneider- Gilbert, D., Zhang, J., Lipps, T., Natarajan, N.,
Fresenius, C, Lehmann, M., Lehmkuhl, G. et al. Brandyberry, J., Wang, Z. et al. (2007) Atomoxetine

http://tpp.sagepub.com 331
Therapeutic Advances in Psychopharmacology 6(5)

treatment of ADHD in Tourette Syndrome: hyperacitivy disorder and comorbid oppositional


reduction in motor cortex inhibition correlates with defiant disorder. ADHD Atten Def Hyp Disord 1:
clinical improvement. Clin Neurophysiology 118: 201–210.
1835–1841.
Heil, S., Holmes, H., Bickel, W., Higgins, S.,
Guy, W. (Ed.) (1976) ECDEU assessment manual Badger, G., Laws, H. et al. (2002) Comparison of the
of psychopharmacology, revised. (NIMH Publication subjective, physiological, and psychomotor effects of
76-338) Rockville, MD: Department of Health, atomoxetine and methylphenidate in light drug users.
Education, and Welfare. Drug Alcohol Dependence 67: 149–156.

Hah, M. and Chang, K. (2005) Atomoxetine for the Holland, K. and Riley, E. (2014) ADHD by the
treatment of attention-deficit/hyperactivity disorder numbers: facts, statistics, and you. Healthline Networks
in children and adolescents with bipolar disorders. J Inc. http://www.healthline.com/health/adhd/facts-
Child Adolesc Psychopharmacol 996–1004. statistics-infographic#1 accessed 14 November 2015.

Hamilton, M. (1959) The assessment of anxiety states Holzer, B., Lopes, V. and Lehman, R. (2013)
by rating. Br J Med Psychol 32: 50–55. Combination use of atomoxetine hydrochloride
and olanzapine in the treatment of attention-deficit/
Handen, B., Aman, M., Arnold, L., Hyman, hyperactivity disorder with comorbid disruptive
S., Tumuluru, R., Lecavalier, L. et al. (2015) behavior disorder in children and adolescents 10–18
Atomoxetine, parent training, and their combination years of age. J Child Adoles Psychopharmacol 23:
in children with autism spectrum disorder and 415–418.
attention-deficit/hyperactivity disorder. J Am Acad
Child Adolesc Psychiatry 54: 905–915. Katragadda, S. and Schubiner, H. (2007) ADHD
in children, adolescents, and adults. Prim Care 34:
Handen, B.L., Johnson, C. and Lubetsky, M. (2000) 317–341.
Efficacy and safety of methylphenidate in children
with autistic disorder. J Autism Dev Disord 35: Kaufman, A. and Kaufman, N. (1998) Kaufman Test
245–255. of Educational Achievement (K-TEA) comprehensive
form manual. Circle Pines, MN: American Guidance
Harfterkamp, M., Buitelaar, J., Minderaa, R., van Service, Inc.
de Loo-Neus, G., van der Gaag, R. and Hoekstra,
P. (2013) Long-term treatment with atomoxetine Kessler, R., Adler, L., Ames, M., Demler, O.,
for attention-deficit/hyperactivity disorder symptoms Faraone, S., Hiripi, E. et al. (2005a) The World
in children and adolescents with autism spectrum Health Organization Adult ADHD Self-Report Scale
disorder: an open-label extension study. J Child (ASRS): a short screening scale for use in the general
Adolesc Psychopharmacol 23: 194–199. population. Psycho Med 35: 245–256.

Harfterkamp, M., Buitelaar, J., Minderaa, R., van Kessler, R., Berglund, P., Demler, O., Jin, R. and
de Loo-Neus, G., van der Gaag, R. and Hoekstra, J. Walters, E. (2005b) Lifetime prevalence and age-
(2014) Atomoxetine in autism spectrum disorder: no of-onset distributions of DSM-IV disorders in the
effects on social functioning; some beneficial effects National Comorbidity Survey Replication (NCS-R)
on stereotyped behaviors, inappropriate speech, and Arch Gen Psychiatry 62: 593–602.
fear of change. J Child Adolesc Psychopharmacol 24: Kessler, R., Adler, L., Barkley, R., Biederman, J.,
481–485. Conners, C., Demler, O. et al. (2006) The prevalence
and correlates of adult ADHD in the United States:
Harfterkamp, M., van de Loo-Neus, G., Minderaa,
results from the National Comorbidity Survey
R., van der Gaag, R., Escobar, R., Schacht, A.
Replication. Am J Psychiatry 163: 716–723.
et al. (2012) A randomized double-blind study of
atomoxetine versus placebo for attention-deficit/ Kuhne, M., Schachar, R. and Tannock, R. (1997)
hyperactivity disorder symptoms in children with Impact of comorbid oppositional or conduct problems
autism spectrum disorder. J Am Acad Child Adolesc on attention-deficit hyperactivity disorder. J Am Acad
Psychiatry 51: 733–741. Child Adolesc Psychiatry 36: 1715–1725.
Hartman, C., Luteijn, E., Serra, M. and Minderaa, R. Kunwar, A., Dewan, M. and Faraone, S. (2007)
(2006) Refinement of the Children’s Social Behavior Treating common psychiatric disorders associated
Questionnaire (CSBQ): an instrument that describes with attention-deficit/hyperactivity disorder. Expert
the diverse problems seen in milder forms of PDD. J Opin Pharmacother 8: 555–562.
Autism Dev Disord 36: 325–342.
Leckman, J., Riddle, M., Hardin, M., Ort, S., Swarz,
Hazell, P., Becker, K., Nikkanen, E., Trzepacz, P., K., Stevenson, J. et al. (1989) The Yale Global Tic
Tanaka, Y., Tabas, L. et al. (2009) Relationship Severity Scale: initial testing of a clinician-rated scale
between atomoxetine plasma concentration, treatment of tic severity. J Am Acad Child Adolesc Psychiatry 28:
response and tolerability in attention-deficit/ 566–573.

332 http://tpp.sagepub.com
SL Hutchison, JK Ghuman et al.

Lee, S., Burns, G., Snell, J. and McBurnett, K. attention-deficit/hyperactivity disorder and autism
(2013) Validity of the sluggish cognitive tempo spectrum disorder. Eur Child Adolesc Psychiatry 19:
symptom dimension in children: Sluggish cognitive 281–295.
tempo and ADHD-inattention as distinct symptom
Savill, N., Buitelaar, J., Anand, E., Day, K., Treuer,
dimensions. J Abnorm Child Psychol [Epub ahead of
T., Upadhyaya, H. et al. (2015) The efficacy of
print].
atomoxetine for the treatment of children and
Liebowitz, M. (1987) Social phobia. Mod Probl adolescents with attention-deficit/hyperactivity
Pharmacopsychiatry 22: 141–173. disorder: A comprehensive review of over a decade of
clinical research. CNS Drugs 29: 131–151.
Lilly USA, LLC. (2015) StratteraTM (atomoxetine)
[prescribing information]. Indianapolis, IN; (2015, Shaywitz, B., Williams, D., Fox, B. and Wietecha, L.
April). (2014) Reading outcomes of children and adolescents
with attention-deficit/hyperactivity disorder and
Maneeton, N., Maneeton, B., Suttajit, S., Reungyos,
dyslexia following atomoxetine treatment. J Child
J., Srisurapanont, M. and Martin, S. (2014)
Adolesc Psychopharmacol 24: 419–425.
Exploratory meta-analysis on lisdexamfetamine versus
placebo in adult ADHD. Drug Des Devel Ther 8: Shier, A., Reichenbacher, T., Ghuman, H. and
1685–1693. Ghuman, J. (2013) Pharmacological treatment of
attention deficit hyperactivity disorder in children
Meyer, D. and Schvaneveldt, R. (1971) Facilitation in
and adolescents: Clinical strategies. J Central Nervous
recognizing pairs of words: Evidence of a dependence
System Dis 5: 1–17.
between retrieval operations. J Exp Psychol 90:
227–234. Spencer, T.J., Adler, L.A., Qiao, M., Saylor,
K.E., Brown, T.E., Holdnack, J.A. et al. (2010)
Newcorn, J., Kratochvil, C., Allen, A., Casat, C.D.,
Validation of the adult ADHD investigator
Ruff, D.D., Moore, R.J. et al. (2008) Atomoxetine
symptom rating scale (AISRS) J Atten Disord 14:
and osmotically released methylphenidate for the
57–68.
treatment of attention deficit hyperactivity disorder:
Acute comparison and differential response. Am J Spencer, T., Sallee, F., Gilbert, D., Dunn, D.,
Psychiatry 165: 721–730. McCracker, J., Coffey, B. et al. (2008) Atomoxetine
Peterson, K., McDonagh, M. and Fu, R. (2008) treatment of ADHD in children with comorbid
Comparative benefits and harms of competing Tourette Syndrome. J Atten Disord 11: 470–481.
medications for adults with attention-deficit Steinhausen, H., Novik, T., Baldursson, G., Curatolo,
hyperactivity disorder: A systematic review and P., Lorenzo, M., Rodrigues-Pereira, R. et al. (2006)
indirect comparison meta-analysis. Psychopharm 197: Co-existing psychiatric problems in ADHD in the
1–11. ADORE cohort. Eur Child Adolesc Psychiatry 15:
Pliszka, S., Crismon, M., Hughes, C., Conners, 25–29.
C., Emslie, G., Jensen, P. et al. and The Texas Štuhec, M., Locatelli, I. and Švab, V. (2015a)
Consensus Conference Panel of Pharmacotherapy Trends in attention-deficit/hyperactivity disorder
of Childhood Attention-Deficit/Hyperactivity drug consumption in children and adolescents in
Disorder. (2006) The Texas Children’s Medication Slovenia from 2001 to 2012: A drug use study from
Algorithm Project: revision of the Algorithm for a national perpective. J Child Adolesc Physchopharm
Pharmacotherapy of Attention-Deficit/Hyperactivity 25: 254–259.
Disorder. J Am Acad Child Adolesc Psychiatry 45:
642–657. Štuhec, M., Munda, B., Švab, V. and Locatelli,
I. (2015b) Comparative efficacy and acceptability
Poznanski, E. and Mokros, H. (1999) Children’s of atomoxetine, lisdexamfetamine, bupropion and
Depression Rating Scale (CDRS-R) revised. Los methylphenidate in treatment of attention deficit
Angeles, CA: Western Psychological Services. hyperactivity disorder in children and adolescents: A
Reichart, C. and Nolan, W. (2004) Earlier onset of meta-analysis with focus on bupropion. J Affect Dis
bipolar disorder in children by antidepressants or 178: 149–159.
stimulants? An hypothesis. J Affect Disord 78: 81–84.
Štuhec, M. and Švab, V. (2013) Atomoxetine-induced
Research Unit on Pediatric Psychopharmacology life-threatening long QT syndrome. Ir J Med Sci 182:
(RUPP) Anxiety Study Group (2002) The Pediatric 535–537.
Anxiety Rating Scale (PARS): development and
Štuhec, M., Švab, V. and Locatelli, I. (2015c)
psychometric properties. J Am Acad Child Adolesc
Prevalence and incidence of attention-deficit/
Psychiatry 41: 1061–1069.
hyperactivity disorder in Slovenian children and
Rommelse, N., Franke, B., Geurts, H., Hartman, adolescents: A database study from a national
C. and Buitelaar, J. (2010) Shared heritability of perspective. Croat Med J 56: 159–165.

http://tpp.sagepub.com 333
Therapeutic Advances in Psychopharmacology 6(5)

Swanson, J. (1992) School-based assessment and Wigal, S. (2009) Efficacy and safety limitation
interventions for ADD. Irvine: KC Publishing. of attention-deficit hyperactivity disorder
pharmacotherapy in children and adults. CNS Drugs
Thurstone, C., Riggs, P., Salomonsen-Sautel, S. 23: 21–31.
and Mikulich-Gilbertson, S. (2010) Randomized,
controlled trial of atomoxetine for attention-deficit/ Wilens, T., Adler, L., Tanaka, Y., Xiao, F., D’Souza,
hyperactivity disorder in adolescents with substance D., Gutkin, S. et al. (2011) Correlates of alcohol
use disorder. J Am Acad Child Adolesc Psychiatry 49: use in adults with ADHD and comorbid alcohol
573–582. use disorders: Exploratory analysis of a placebo-
controlled trial of atomoxetine. Curr Med Res Opin
US Centers for Disease Control (CDC). (2010) 27: 2309–2320.
Increasing prevalence of parent reported attention-
deficit/hyperactivity disorder among children—United Wilens, T., Adler, L., Weiss, M., Michelson, D.,
States, 2003 and 2007. MMWR Morb Mortal Wkly Ramsey, J., Moore, R. et al. (2008) Atomoxetine
Rep. 59: 1439–1443. treatment of adults with ADHD and comorbid
alcohol use disorders. Drug Alcohol Dependence 96:
Wehmeier, P., Schacht, A., Dittmann, R., Helsberg, 145–154.
K., Schneider-Fresenius, C., Lehmann, M. et al.
(2011) Effect of atomoxetine on quality of life and Young, R., Biggs, J., Ziegler, V. and Meyer, D. (1978)
family burden: Results from a randomized, placebo- A rating scale for mania: reliability, validity and
controlled, double-blind study in children and sensitivity. Br J Psychiatry 133: 429–435.
adolescents with ADHD and comorbid oppositional Yudofsky, S., Silver, J., Jackson, W., Endicott, J. and
defiant or conduct disorder. Qual Life Res 20: 691–702. Williams, D. (1986) Overt aggression scale for the
objective rating of verbal and physical aggression. Am
Wietecha, L., Williams, D., Shaywitz, S., Shaywitz,
J Psychiatry 143: 35–39.
B., Hooper, S., Wigal, S. et al. (2013) Atomoxetine
improved attention in children and adolescents with Zeiner, P., Gjevik, E. and Weidle, B. (2011) Response
Visit SAGE journals online attention-deficit/hyperactivity disorder and dyslexia to atomoxetine in boys with high-functioning autism
http://tpp.sagepub.com in a 16 week, acute, randomized, double-blind trial. J spectrum disorders and attention deficit/hyperactivity
SAGE journals Child Adolesc Psychopharmacol 23: 605–613. disorder. Acta Pædiatrica 100: 1258–1261.

334 http://tpp.sagepub.com
ADHD Atten Def Hyp Disord (2015) 7:1–18
DOI 10.1007/s12402-014-0151-0

REVIEW ARTICLE

Associations of sleep disturbance with ADHD: implications


for treatment
Allan Hvolby

Received: 9 April 2014 / Accepted: 8 July 2014 / Published online: 17 August 2014
Ó The Author(s) 2014. This article is published with open access at Springerlink.com

Abstract Attention-deficit/hyperactivity disorder problems may cause or mimic ADHD; ADHD and sleep
(ADHD) is commonly associated with disordered or dis- problems may interact, with reciprocal causation and pos-
turbed sleep. The relationships of ADHD with sleep sible involvement of comorbidity; and ADHD and sleep
problems, psychiatric comorbidities and medications are problems may share a common underlying neurological
complex and multidirectional. Evidence from published etiology.
studies comparing sleep in individuals with ADHD with
typically developing controls is most concordant for asso- Keywords Sleep  ADHD  Stimulant  Amfetamine 
ciations of ADHD with: hypopnea/apnea and peripheral Methylphenidate  Atomoxetine
limb movements in sleep or nocturnal motricity in poly-
somnographic studies; increased sleep onset latency and
shorter sleep time in actigraphic studies; and bedtime Introduction
resistance, difficulty with morning awakenings, sleep onset
difficulties, sleep-disordered breathing, night awakenings Attention-deficit/hyperactivity disorder (ADHD) is a
and daytime sleepiness in subjective studies. ADHD is also common neurodevelopmental disorder that has been esti-
frequently coincident with sleep disorders (obstructive mated to affect approximately 5.3 % of children and ado-
sleep apnea, peripheral limb movement disorder, restless lescents worldwide (Polanczyk et al. 2007) and to persist
legs syndrome and circadian-rhythm sleep disorders). into adulthood in approximately two-thirds of patients
Psychostimulant medications are associated with disrupted (Spencer et al. 1998; Wender 1998). Inattention, hyperac-
or disturbed sleep, but also ‘paradoxically’ calm some tivity and impulsiveness are recognized as the symptoms of
patients with ADHD for sleep by alleviating their symp- ADHD according to the current diagnostic criteria [Diag-
toms. Long-acting formulations may have insufficient nostic and Statistical Manual of Mental Disorders (DSM),
duration of action, leading to symptom rebound at bedtime. Fifth Edition (American Psychiatric Association 2013;
Current guidelines recommend assessment of sleep dis- Casas et al. 2013) and International Classification of Dis-
turbance during evaluation of ADHD, and before initiation eases and Related Health Problems, 10th Revision (ICD-
of pharmacotherapy, with healthy sleep practices the first- 10) (World Health Organization 1992)] and are associated
line option for addressing sleep problems. This review aims with characteristic behavioral difficulties and impairments
to provide a comprehensive overview of the relationships of day-to-day functioning. Although diagnosis relies on
between ADHD and sleep, and presents a conceptual observations made while patients are awake, the prevalence
model of the modes of interaction: ADHD may cause sleep of sleep disturbances in individuals with ADHD is reported
problems as an intrinsic feature of the disorder; sleep to be in the range 25–55 % (Corkum et al. 1998; Hodgkins
et al. 2013; Owens 2005; Sung et al. 2008). In a recent
Australian study, 62 % of children with ADHD had mod-
A. Hvolby (&)
erate or severe sleep problems and 22 % took sleep med-
Department of Child and Adolescent Psychiatry, Psychiatry of
Southern Denmark, Gl. Vardevej 101, 6715 Esbjerg N, Denmark ications during the 1-week observation period (Efron et al.
e-mail: allan.hvolby@rsyd.dk 2014). Indeed, high nocturnal activity and disordered sleep

123
2 A. Hvolby

were defining characteristics of ‘hyperkinetic reaction in regions involved in attention, arousal and sleep regulation
childhood’ or ‘attention deficit disorder’ in earlier versions (Owens et al. 2013; Owens 2008). This review provides a
of the DSM (American Psychiatric Association 1980; broad but comprehensive overview of the relationships
Barkley 1990; Sadeh et al. 2006; Spruyt and Gozal 2011). between ADHD and sleep, with the aims of fostering
The association of sleep with ADHD is multifaceted and greater understanding of the sleep-related issues faced by
complex. Problems with sleep may be an intrinsic feature many individuals with ADHD and of informing the phar-
of ADHD, or may both exacerbate and be exacerbated by macological and non-pharmacological management of the
the symptoms of the disorder. Problems with sleep can, disorder. In support of these aims, this article presents a
however, also lead to the development of ADHD or conceptual model of the potential interactions of sleep with
ADHD-like symptoms, potentially resulting in misdiagno- ADHD which is intended as an aid in the interpretation of
sis (Cortese et al. 2006b; Owens 2008). The effects of evidence related to the interactions of sleep problems with
restricted, disordered or disturbed sleep can manifest as ADHD and with medications used to treat ADHD.
symptoms, behaviors or functional impairments that are
remarkably similar to those of ADHD (Beebe 2006; Gruber
2009; O’Brien 2009). The interrelationships are further Measuring sleep in patients with ADHD
complicated by the use of psychostimulant medications to
treat ADHD, which impair sleep in some patients (Spruyt Objective measures (polysomnography, actigraphy and the
and Gozal 2011) but paradoxically (Bradley 1937) improve multiple sleep latency test [MSLT]) and subjective mea-
sleep in others via a calming effect (Jerome 2001; Kins- sures (e.g., parent- or self-rated questionnaires and diaries)
bourne 1973; Kooij et al. 2001; Kratochvil et al. 2005). For are used to assess sleep in patients with ADHD.
these reasons, it has been recommended that primary sleep
disorders should be ruled out before initiating ADHD Polysomnography
medication (Cortese et al. 2013a; Lecendreux and Cortese
2007). Behavioral interventions targeted at improving sleep Polysomnography involves simultaneous and continuous
may benefit some patients (Cortese et al. 2013a) and should measurement of multiple physiological parameters, and is
form part of the multimodal ADHD management plan usually conducted in a sleep laboratory. A combination of
recommended for patients receiving pharmacotherapy electroencephalography, electrocardiography, electromy-
(Graham et al. 2011; Lecendreux and Cortese 2007; Wol- ography, electrooculography, pneumography and pulse
raich et al. 2011). oximetry is typical, sometimes together with audiovisual
Psychiatric comorbidities are common in children with recordings.
ADHD: up to 87 % of children with an ADHD diagnosis Polysomnography is considered the ‘gold standard’ for
have at least one comorbidity, and 20 % have three or more the objective measurement of sleep (Cortese et al. 2009;
comorbid conditions (Hodgkins et al. 2013; Rowland et al. Owens 2008), but is subject to a number of limitations.
2002; Spruyt and Gozal 2011). Psychiatric illnesses such as Children’s sleep patterns may be affected by the unfamiliar
bipolar disorder, autism, post-traumatic stress disorder and environment of the sleep laboratory or by the recording
obsessive compulsive disorder often occur coincidently apparatus (Beebe 2011; Bessey et al. 2013). At least some
with ADHD, and are also associated with sleep problems, polysomnographic parameters are subject to ‘first-night
which may both result from and exacerbate comorbid effects,’ whereby sleep characteristics on a single night
psychiatric symptoms (Ivanenko et al. 2004). Problems may differ from those recorded on subsequent nights (Katz
with sleep are likely to have adverse effects on health- et al. 2002; Kirov et al. 2012; Lorenzo and Barbanoj 2002;
related quality of life for children with ADHD and their Sadeh et al. 2006; Scholle et al. 2003).
families (Hvolby et al. 2008; Saxby and Morgan 1993) and Three published meta-analyses of polysomnographic
may also contribute to the development of comorbid anx- studies have investigated sleep in children with ADHD and
iety, depression or oppositional defiant disorder (Breslau typically developing controls (Cortese et al. 2006a, 2009;
et al. 1996; Hvolby et al. 2008; Mick et al. 2000). The Sadeh et al. 2006). In a meta-analysis of 11 studies, the only
interactions of comorbid disorders and associated medica- statistically significant polysomnographic finding was a
tions with ADHD and sleep disturbances are therefore higher incidence of periodic limb movements in sleep
important to consider when managing patients. (PLMS) in children with ADHD than in controls (Sadeh et al.
The complex, multidirectional interactions of sleep with 2006). A subsequent meta-analysis of studies in non-medi-
ADHD, medication and psychiatric comorbidities remain cated patients included 5 of these 11 studies and 4 additional
unclear despite extensive research. The reciprocal nature of polysomnographic studies (Cortese et al. 2009), and updated
the relationships between ADHD and sleep may reflect the a previous analysis by the same group (Cortese et al. 2006a).
functional and neuroanatomical overlap between brain Statistically significant polysomnographic findings were

123
Associations of sleep disturbance with ADHD 3

lower sleep efficiency, higher apnea–hypopnea index (AHI) movements which may not register on all polysomno-
and a larger number of sleep stage shifts per hour in children graphic indices of PLMS, yet these may be more likely
with ADHD than in controls (Cortese et al. 2009). Data on than highly periodic, stereotypical PLMS to be associated
limb movements could not be pooled in this meta-analysis, with arousal and sleep disturbance (Ferri et al. 2013).
but the authors noted that the included studies were consis- Polysomnographic studies are generally small (typically
tent in describing elevations in indices of PLMS or general 20–30 participants per arm), and there is a need for larger-
sleep movements in children with ADHD compared with scale, multicenter studies (Cortese et al. 2009; Sadeh et al.
controls (Cortese et al. 2006a, 2009). Since publication of 2006). Sleep parameters in children with ADHD are
these meta-analyses, four individual polysomnographic influenced by age, gender, comorbidities, ADHD diag-
studies in un-medicated children with ADHD versus controls nostic criteria and subtype, and the inclusion of an adap-
have each reported no statistically significant differences in tation night (to compensate for first-night effects), but these
any polysomnographic index, including PLMS, AHI and variables are not controlled in many studies (Sadeh et al.
sleep efficiency (Choi et al. 2010; Gruber et al. 2012a; Pri- 2006). In particular, the different diagnostic criteria used in
hodova et al. 2010, 2012), and one study has reported sta- different studies may be an important factor underlying the
tistically significant differences in almost all of the inconsistency of polysomnographic findings across studies
polysomnographic parameters assessed (Silvestri et al. (Gomes et al. 2013; Kirov and Brand 2014; Kirov et al.
2009). This study also indicated that children with hyper- 2004). Furthermore, children with ADHD often show
active symptoms had a higher mean PLMS index than those marked intra-individual variability and instability in sleep
with predominantly inattentive ADHD (Silvestri et al. 2009). parameters, rather than a consistent level of impairment
Polysomnographic data in adults with ADHD are scarce (Gruber and Sadeh 2004; Gruber et al. 2000; Hvolby et al.
(Yoon et al. 2012), with one study reporting no significant 2008; Lecendreux and Cortese 2007; Lecendreux et al.
differences (Philipsen et al. 2005) and one reporting signif- 2000; Moreau et al. 2013; Prihodova et al. 2010).
icant differences in four indices, compared with controls
(Sobanski et al. 2008). Actigraphy
Several studies have reported changes in rapid eye
movement (REM) sleep in children and adolescents with Actigraphy involves wearing a sensor, usually on the wrist,
ADHD (Golan et al. 2004; Gruber et al. 2009; Kirov et al. to measure motor activity. Current devices are small,
2004; O’Brien et al. 2003a, b). Inter-study inconsistencies in lightweight, unobtrusive and convenient. Despite the
whether REM sleep is increased or decreased in patients with increasing use of actigraphy in pediatric studies, variations
ADHD compared with controls have been ascribed to chan- remain in the device used, the point of attachment, the
ges in REM sleep during maturation (Kirov and Brand 2014). parameters measured and the method for storing and ana-
However, three meta-analyses of polysomnographic studies lyzing the signals (Meltzer et al. 2012). Actigraphy is
found no significant alterations in REM sleep parameters in unable to provide information on sleep architecture, PLMS,
children with ADHD compared with controls (Cortese et al. snoring or apnea/hypopnea. Compared with polysomnog-
2006a, 2009; Sadeh et al. 2006). The most recent and inclu- raphy, actigraphy may overestimate waking after sleep
sive of these ruled out inter-study heterogeneity as being onset and underestimate total sleep time, and may also
responsible for the lack of any detectable pooled difference in underestimate sleep onset latency (presumably because
REM sleep parameters (Cortese et al. 2009). immobility generally precedes sleep) (Spruyt et al. 2011).
In summary, the available evidence from polysomno- Nevertheless, actigraphy has the unique advantage of
graphic studies is most concordant for associations of providing a non-invasive means of measuring sleep–wake
ADHD with apnea/hypopnea and PLMS/nocturnal motor patterns objectively over extended periods of time under
activity in children (Cortese et al. 2006a; Spruyt and Gozal everyday conditions.
2011). The number of studies is limited, and some A meta-analysis of four actigraphic studies reported
parameters have been reported in only one or two studies, statistically significantly longer mean sleep onset latency
indicating a need for additional research (Cortese et al. and shorter true sleep time in non-medicated children with
2009). For example, two studies of sleep microstructure ADHD than in typically developing controls (Cortese et al.
(the cyclic alternating pattern) in patients with ADHD have 2009). Figure 1 illustrates data from one of these studies
yielded inconsistent results (Miano et al. 2006; Prihodova and shows that mean actigraphic sleep onset latency was
et al. 2012). Furthermore, current polysomnographic indi- longer in children with ADHD than in community controls
ces may not be sensitive enough to detect subtle patterns of and children with other psychiatric conditions (Hvolby
sleep fragmentation (Owens et al. 2013; Yoon et al. 2012). et al. 2008). Mean longest sleep latency was also highest in
For example, episodes of PLMS in children with ADHD children with ADHD, but total sleep time did not signifi-
are reportedly characterized by atypical, low periodicity cantly differ among the three groups (Hvolby et al. 2008).

123
4 A. Hvolby

70 greater proportions of children with ADHD fell asleep


Actigraphic measure
Sleep onset latency (minutes)
Parental estimate
during testing than did controls (Golan et al. 2004; Le-
60
cendreux et al. 2000). More recent studies have found no
50 significant differences between children with ADHD and
controls in MSLT outcomes (Prihodova et al. 2010; Wiebe
40 et al. 2013), although one of these reported statistically
30
significant inter-test variability in the ADHD group (Pri-
hodova et al. 2010). There is also little agreement among
20 three studies that have investigated the question of whether
MSLT results correlate with objective measures of noc-
10
turnal sleep in individuals with ADHD (Golan et al. 2004;
0 Lecendreux et al. 2000; Wiebe et al. 2013).
Psychiatric Psychiatric Randomly
referral and referral selected from
ADHD diagnosis (non-ADHD) local school Subjective assessments
(n = 45) (n = 64) (n = 97)

Fig. 1 Sleep onset latency assessed by parental estimation and Subjective measures of sleep in children are based on
actigraphy (Hvolby et al. 2008). Data are shown as means ± standard parent or child reports and include the BEARS sleep
deviations. Differences between the three groups were statistically screening tool (Owens and Dalzell 2005), the Children’s
significant for both the actigraphic measure (p \ 0.01) and the
parental measure (p \ 0.001), as was the difference between the two
Sleep Habits Questionnaire (CSHQ) (Owens et al. 2000),
measures (p \ 0.001) across all groups (three-way analysis of the Children’s Sleep Behavior Scale (CSBS) (Fisher et al.
variance, adjusted for sex and family type) (Hvolby et al. 2008). 1989) and sleep diaries (Hvolby et al. 2008, 2009). Adult
ADHD attention-deficit/hyperactivity disorder instruments include the Pittsburgh Sleep Quality Index
(Buysse et al. 1989). Instruments for subjective assessment
In subsequent actigraphic studies, differences between of daytime sleepiness include the Epworth Sleepiness
children with and without ADHD in sleep latency, sleep Scale.
efficiency and total sleep time were statistically significant The most recent meta-analysis of subjective studies
in one study (Moreau et al. 2013) but not in another (Wiebe found that ADHD was associated with statistically signif-
et al. 2013). Waking after sleep onset was found to be icant greater impairments in six parent-reported subjective
increased in adolescents with ADHD (Mullin et al. 2011), measures of sleep in children than in controls (Cortese
and several actigraphic measures of sleep have also been et al. 2009). The largest standardized mean difference was
reported to differ significantly in adults with ADHD, observed for bedtime resistance, followed by difficulty
compared with controls (Boonstra et al. 2007; Gamble with morning awakenings, sleep onset difficulties, sleep-
et al. 2013; Kooij et al. 2001; Van Veen et al. 2010). Ac- disordered breathing, night awakenings and daytime
tigraphic studies have also reported instability or increased sleepiness. Other sleep problems reportedly associated with
night-to-night variability in sleep parameters in patients ADHD in children and/or adults include early and middle
with ADHD compared with controls (Gruber and Sadeh insomnia, nocturnal awakening, nocturnal activity, snoring,
2004; Gruber et al. 2000; Hvolby et al. 2008; Moreau et al. breathing difficulties, restless sleep, parasomnias, night-
2013). mares, daytime sleepiness, delayed sleep phase, short sleep
time and anxiety around bedtime (Hansen et al. 2013;
Multiple sleep latency test Hvolby et al. 2008, 2009; Spruyt and Gozal 2011; Yoon
et al. 2012).
The MSLT provides a measure of daytime sleepiness by
timing the first signs of sleep during daytime nap periods Association of particular sleep problems with ADHD
(Spruyt and Gozal 2011). The technique is subject to subtypes
substantial heterogeneity, possibly due to differences in
methodology and patient populations among studies (Cor- Different patterns of sleep impairment may be character-
tese et al. 2009; Golan et al. 2004; Lecendreux et al. 2000). istic of ADHD subtypes (Gruber 2009). Some studies show
In meta-analyses (Cortese et al. 2006a, 2009), the average that parent-reported sleep disturbances are more common
time taken to fall asleep in MSLTs was statistically sig- in combined-type ADHD than in predominantly inattentive
nificantly shorter in patients with ADHD than in controls, ADHD (Corkum et al. 1999; Mayes et al. 2009), while
based on two included studies (Golan et al. 2004; Le- others describe greater daytime sleepiness in predomi-
cendreux et al. 2000). Both studies also reported that nantly inattentive ADHD than in combined-type ADHD

123
Associations of sleep disturbance with ADHD 5

(Chiang et al. 2010; LeBourgeois et al. 2004; Lecendreux Relationship of sleep disorders to ADHD
et al. 2000). However, differences in symptom severity
between subtypes may confound the associations with Diagnosis of sleep disorders is based on formal subjective
sleep problems (Corkum et al. 2011). Hyperkinetic disorder and/or objective criteria, such as the International Classi-
(HKD) diagnosed according to the ICD-10 criteria is fication of Sleep Disorders (American Academy of Sleep
generally regarded as a more severe form of combined-type Medicine 2005). Specific sleep disorders are associated
ADHD than that described by the DSM, and children with with ADHD or ADHD-like symptoms, and systematic
HKD exhibited profound sleep-related problems in a study screening for sleep problems and disorders has been rec-
using subjective parent ratings (Gomes et al. 2013). If ommended during initial assessment and ongoing man-
different sleep problems are associated with different agement of patients with ADHD (Cortese et al. 2013a).
ADHD subtypes, then this represents another potentially Inadequate sleep in children is known to have neurocog-
uncontrolled variable in studies investigating the relation- nitive, neurobehavioral and functional manifestations that
ship between sleep and ADHD (Kirov et al. 2004). overlap with the core features of ADHD (O’Brien 2009;
Owens et al. 2013). Experimental sleep restriction impacts
Agreement and disagreement between subjective on attention and higher-level cognitive function (Beebe
and objective measures of sleep 2011), and has been shown to affect neurobehavioral
functioning in typically developing children (Gruber et al.
While laboratory studies are susceptible to artifacts (e.g., 2011). No experimental study has yet shown that sleep
first-night effects), naturalistic studies are subject to restriction induces hyperactivity, impulsivity or external-
uncontrolled variables such as parents’ work schedules, izing behaviors in children (Beebe 2011), despite the per-
parenting style, family structure, child habits and ception that ‘paradoxical’ hyperactivity exists as a
employment in teenagers (Beebe 2011). Several studies behavioral response to daytime sleepiness (Owens et al.
have revealed discrepancies between results obtained 2013; Owens 2008). Recent observational studies in typi-
using objective and subjective measures of sleep in cally developing children have, however, shown that short
patients with ADHD (Choi et al. 2010; Corkum et al. sleep duration correlates with ADHD-like symptoms and
2001; Hvolby et al. 2008; Lim et al. 2008; Owens et al. behaviors scored by parents (Paavonen et al. 2009; Pesonen
2009; Wiggs et al. 2005; Yoon et al. 2012). In one study et al. 2010) and teachers (Gruber et al. 2012b).
in children, parental estimates of sleep onset latency
exceeded actigraphic estimates in about 75 % of cases, Sleep-disordered breathing and obstructive sleep apnea
although mean sleep onset latency was longer in children
with ADHD than in controls using both measures (Fig. 1) The term sleep-disordered breathing (SDB) describes a
(Hvolby et al. 2008). Subjective reports may emphasize spectrum of conditions ranging from obstructive sleep
particularly problematic nights, which may not be cap- apnea (OSA) to primary snoring (O’Brien 2009; Owens
tured in a single night’s objective measurement, or by 2008). SDB has been consistently associated with neuro-
averaging objective measurements over several nights: behavioral and neurocognitive deficits, including inatten-
indeed, intra-individual variability in sleep parameters is tive or ADHD-like symptoms (Beebe 2006; Beebe et al.
reportedly higher in patients with ADHD than in controls 2004; Chervin et al. 2002, 2012; Gottlieb et al. 2003; Lal
(Gruber and Sadeh 2004; Gruber et al. 2000; Lecendreux et al. 2012; O’Brien 2009; Owens 2008; Rosen et al. 2004;
and Cortese 2007; Moreau et al. 2013; Tsai and Huang Soylu et al. 2013; Suratt et al. 2011). Furthermore, a recent
2010). Parental sensitivity to behavioral problems at systematic review indicated that the prevalence of OSA in
bedtime may also lead to differences compared with patients with ADHD (25–30 %) is higher than in the
objective assessments (Hvolby et al. 2008; Owens et al. general population (about 3 %) (Youssef et al. 2011).
2009; Yoon et al. 2012). In adults with ADHD, self- Indeed, US guidelines recommend that children undergo-
reported sleep time, quality and efficiency were lower ing evaluation for ADHD are assessed for sleep apnea
than in controls, but this was found to correlate with (Wolraich et al. 2011).
polysomnographic measures of PLMS and not with Surgical treatment of children with OSA via adenoton-
polysomnographic measures of sleep efficiency, length or sillectomy in prospective, interventional studies has been
onset latency (Philipsen et al. 2005). In summary, the reported to be associated with improvements in neuropsy-
available methods for assessing sleep each present their chological behavior (Beebe 2006), academic performance
own advantages and disadvantages, with no single tech- (Gozal 1998) and ADHD-like symptoms (Soylu et al.
nique providing a complete picture of the complex 2013; Youssef et al. 2011). In children with diagnoses of
interactions between sleep and ADHD. ADHD and OSA, two prospective studies have

123
6 A. Hvolby

demonstrated significant improvements in ADHD symp- resulted in decreased total sleep time and daytime sleepi-
toms, including hyperactivity, following adenotonsillec- ness (Gradisar et al. 2011). There is evidence to suggest
tomy (Chervin et al. 2006; Huang et al. 2007). There is also that ADHD may be associated with disturbances of the
some evidence that positive airway pressure ventilation in circadian rhythm. A delayed pattern of melatonin secretion
patients with OSA may also be associated with improve- in children with ADHD compared with controls has been
ments in ADHD-like symptoms (Youssef et al. 2011). described (Van der Heijden et al. 2005, 2007). Children
Large-scale, randomized, controlled studies are warranted with ADHD have also been reported to exhibit stronger
to investigate further the effect of OSA treatment in circadian evening tendencies than controls, as assessed
patients with ADHD (Youssef et al. 2011). using the child morning-evening preference scale. Scores
on this parent-rated instrument were correlated with both
Restless legs syndrome and periodic limb movement parental and polysomnographic measures of sleep onset
disorder latency (Gruber et al. 2012a). In adults with ADHD, dis-
turbances in diurnal rhythms of endocrine secretion,
Restless legs syndrome (RLS) is a neurological disorder CLOCK gene expression and physical activity have been
characterized by an irresistible urge to move the legs to reported (Baird et al. 2012; Bijlenga et al. 2013). Fur-
relieve uncomfortable sensations at rest (Picchietti and thermore, delayed sleep timing in adults with ADHD and
Picchietti 2010). Periodic limb movement disorder comorbid insomnia compared with controls has been doc-
(PLMD) is a clinical syndrome characterized by PLMS of a umented (Van Veen et al. 2010) and shown to correlate
specific nature and frequency determined by polysomnog- with the severity of ADHD symptoms (Gamble et al.
raphy (Picchietti and Picchietti 2010). While 2 % of typi- 2013).
cally developing children and adolescents (aged
8–17 years) are reported to meet the diagnostic criteria for Interaction of obesity with sleep disorders and ADHD
RLS (Picchietti et al. 2007), up to 44 % of children with
ADHD have symptoms of RLS, and 26 % of children with There is good evidence from cross-sectional studies for an
RLS have symptoms of ADHD (Cortese et al. 2005; Owens association of ADHD with obesity: The prevalence of
2008). Accordingly, Cortese et al. have emphasized the ADHD is higher than expected in people with obesity
importance of identifying RLS during clinical evaluation of sampled at obesity clinics, and the body mass index of
children with ADHD symptoms (Cortese et al. 2006b). The patients with ADHD is higher than average (Cortese et al.
recently revised diagnostic criteria for RLS in children 2008a). Furthermore, in a 33-year longitudinal study,
introduced pediatric terms and prompts to allow the clini- 41.4 % of adults who had combined-type ADHD as chil-
cian to recognize typical descriptions of RLS symptoms, dren were obese, compared with 21.6 % of those without a
which must be in the child’s own words (Picchietti et al. childhood diagnosis of ADHD (Cortese et al. 2013c).
2013). As described previously, increased PLMS in Obesity is, in turn, correlated with sleep-disordered
patients with ADHD compared with controls is a common breathing and other sleep disorders (Cortese et al. 2008b),
finding in polysomnographic studies. The impact of RLS or short sleep duration (Taheri et al. 2004) and short time in
PLMD on sleep could lead not only to the diurnal mani- bed (Hart et al. 2013). Abnormal eating behaviors associ-
festation of ADHD-like symptoms but also to bedtime ated with ADHD (e.g., impulsive eating) might contribute
resistance, which may be mistaken for opposition or defi- to obesity (Cortese and Vincenzi 2012), and in adolescents
ance, due to the unpleasant symptoms (Cortese et al. with obesity but without diagnosed ADHD, daytime
2006b). sleepiness has been reported to correlate with ADHD
symptom ratings (Cortese et al. 2007). Together, these data
Circadian-rhythm sleep disorders suggest a complex interplay between ADHD, obesity and
sleep problems.
The major feature of circadian-rhythm sleep disorders is
the misalignment of sleep pattern timing with the terrestrial
cycle, leading to disrupted sleep and impaired functioning. Effects of ADHD medications on sleep
In delayed sleep-phase disorder, sleeping and waking occur
later than normal, and this may manifest as sleep onset ADHD medications are known to affect sleep in many
insomnia, evening diurnal preference and difficulty wak- individuals, and guidelines recommend that sleep is care-
ing. Such sleep problems are common, especially during fully assessed before starting ADHD pharmacotherapy
adolescence: a meta-analysis of adolescent sleep studies (Graham et al. 2011; Wolraich et al. 2011). Sleep distur-
revealed a worldwide delayed sleep–wake behavior pattern bances in patients with ADHD, including those associated
that was consistent with delayed sleep-phase disorder and with ADHD medications, may be addressed via

123
Associations of sleep disturbance with ADHD 7

pharmacological and behavioral interventions, with the doses of immediate-release methylphenidate (Swanson
latter forming part of the recommended multimodal strat- et al. 2003). In an open-label polysomnographic study in
egy (Cortese et al. 2013a). children with ADHD, the only statistically significant
effects of OROS-MPH treatment were a decrease in the
Pharmacotherapy with stimulants number of night-time awakenings and an increase in the
percentage of stage 2 sleep, compared with pre-treatment
The effects of stimulants on sleep in patients with ADHD baseline (Kim et al. 2010). Based on parental sleep diaries,
differ from patient to patient and reflect the underlying both OROS-MPH and another extended-release methyl-
complexity of the links between ADHD and sleep distur- phenidate formulation led to statistically significant
bance (Graham et al. 2011). The sympathomimetic action reductions in total sleep time 1–4 weeks after initiation of
of stimulants promotes wakefulness in most people, treatment in a randomized study in children with ADHD
underlying their use in the treatment of narcolepsy (Mor- (Lee et al. 2012). In a randomized, double-blind, placebo-
genthaler et al. 2007). While there is evidence that stimu- controlled study, the majority of children in all three
lants are associated with disrupted or disturbed sleep in treatment groups (OROS-MPH, placebo or immediate-
patients with ADHD (Ironside et al. 2010; Nutt et al. 2007; release methylphenidate three times daily) continued to
Spruyt and Gozal 2011; Stein 1999), clinical experience have good or excellent sleep quality based on parent ratings
also indicates that stimulants produce paradoxical effects at 2 and 4 weeks after initiation of treatment (Wolraich
(Bradley 1937), whereby alleviation of symptoms can calm et al. 2001). Sleep quality was also rated as good or
patients and promote sleep (Jerome 2001; Kinsbourne excellent by parents after 1 and 12 months of open-label
1973; Kooij et al. 2001; Kratochvil et al. 2005). Further- OROS-MPH treatment in children with ADHD (Wilens
more, because of the potential for symptom rebound as et al. 2003). Table 1 shows a summary of the proportions
blood drug concentrations wane (Carlson and Kelly 2003), of patients experiencing TEAEs of insomnia in random-
an additional dose of a short-acting stimulant, or the use of ized, double-blind, placebo-controlled, parallel-group
a formulation with an increased duration of action, may clinical studies of OROS-MPH.
prevent sleep disturbances resulting from worsening of LDX is the only stimulant prodrug. After oral admin-
hyperactivity or behavioral difficulties at bedtime (Cortese istration, rate-limiting enzymatic hydrolysis of LDX in the
et al. 2013a, b; Lecendreux et al. 2000). bloodstream releases the pharmacologically active d-am-
In clinical trials using objective sleep measures, imme- fetamine moiety from the lysine conjugate (Steer et al.
diate-release methylphenidate has been reported to increase 2012). LDX treatment was not associated with impairments
sleep onset latency and/or to decrease total sleep time in in sleep quality or quantity in clinical trials using objective
patients with ADHD (Boonstra et al. 2007; Galland et al. sleep measures in adults with ADHD (Adler et al. 2009a;
2010; Greenhill et al. 1983; Sangal et al. 2006), with sleep Surman and Roth 2011) and children with ADHD (Giblin
quality either unaffected (Galland et al. 2010) or improved and Strobel 2011) (Fig. 2). Table 2 shows a summary of
(Boonstra et al. 2007; Sobanski et al. 2008). A recent meta- the proportions of patients experiencing TEAEs of
analysis of six actigraphic studies in children with ADHD insomnia in randomized, double-blind, placebo-controlled,
reported statistically significant lower daytime activity, parallel-group clinical studies of LDX.
longer sleep onset latency, lower total sleep time and lower
sleep efficiency with immediate-release methylphenidate Pharmacotherapy with non-stimulants
treatment than with placebo (De Crescenzo et al. 2014).
Both amfetamine and methylphenidate are associated with In contrast to stimulants, somnolence is the most common
treatment-emergent adverse events (TEAEs) of insomnia in sleep-related adverse event associated with atomoxetine (a
clinical studies (Efron et al. 1997; Stein et al. 2011). noradrenaline reuptake inhibitor approved for treatment of
Long-acting stimulants are available in many different ADHD). In a 2009 systematic review, the frequency of
formulations (Hodgkins et al. 2012). This section focuses somnolence reported as a TEAE in placebo-controlled
on osmotic-release oral system methylphenidate (OROS- clinical trials of atomoxetine was reported to range from 15
MPH) and lisdexamfetamine dimesylate (LDX), both of to 17 % (Garnock-Jones and Keating 2009). In a random-
which are recently developed and widely used ADHD ized, double-blind trial, atomoxetine was associated with a
medications with daily durations of efficacy of at least 12 h smaller increase in sleep onset latency, a lower frequency
post-dose (Coghill and Seth 2006; Lakhan and Kirchgess- of insomnia, a higher frequency of somnolence and smaller
ner 2012; Setyawan et al. 2013a, b; Steer et al. 2012). effects on subjective measures of sleep than methylpheni-
OROS-MPH combines an immediate-release bolus with date taken three times daily (Sangal et al. 2006). Lower
a two-stage extended-release technology to provide an frequencies of insomnia and higher frequencies of som-
ascending profile of drug delivery similar to three daily nolence with atomoxetine than with long-acting stimulants

123
8 A. Hvolby

Table 1 Frequency of TEAEs of insomnia (or similar) in randomized, double-blind, placebo-controlled, parallel-group clinical studies of
OROS-MPH in patients with ADHD
Study Age of population, years Duration, weeks Treatment (n) Proportion of patients
reporting a TEAE, %

Medori et al. (2008) 18–65 5 Placebo (96) 7.3


OROS-MPH (305) 13.4
Biederman et al. (2006) 19–60 6 Placebo (74) 5a
OROS-MPH (67) 18a
Biederman et al. (2010) 19–60 6b Placebo (109) 4c
OROS-MPH (114) 11c
Adler et al. (2009b) 18–65 7 Placebo (116) 5.2 (3.4)d
OROS-MPH (110) 9.1 (7.3)d
Newcorn et al. (2008) 6–16 6 Placebo (74) 1e
OROS-MPH (219) 13e
Atomoxetine (221) 7e
Findling et al. (2008) 6–12 7 Placebo (85) 4.7
OROS-MPH (91) 7.7
Transdermal methylphenidate (98) 13.3
Casas et al. (2013) 18–65 13 Placebo (97) 11.3 (2.1)d
OROS-MPH 54 mg (89) 14.6 (7.9)d
OROS-MPH 72 mg (92) 16.3 (9.8)d
Randomized-withdrawal studies are excluded
ADHD attention-deficit/hyperactivity disorder, OROS-MPH osmotic-release oral system methylphenidate, TEAE treatment-emergent adverse
event
a
Frequency of ‘sleep problems’
b
Acute efficacy phase
c
TEAEs reported on two or more visits
d
Frequency of initial insomnia
e
Includes insomnia, initial insomnia, middle insomnia and late insomnia

have been reported as TEAEs in randomized, double-blind, Management of sleep problems in patients with ADHD
parallel-group efficacy studies (Dittmann et al. 2013;
Newcorn et al. 2008). Dosing in the evening rather than in Both European and US guidelines recommend assessment
the morning has been found to reduce daytime somnolence of sleep disturbance during evaluation of an individual for
with atomoxetine (Block et al. 2009). suspected ADHD, and before initiation of pharmacother-
An extended-release formulation of guanfacine, a apy (Graham et al. 2011; Wolraich et al. 2011). This
selective a 2-adrenoceptor agonist, is approved in North approach enables any effects of the disorder on sleep to be
America for the treatment of children and adolescents distinguished from those of medication (Cortese et al.
with ADHD, both as a monotherapy and as an adjunct to 2013b). Clinicians have been advised to use sleep diaries
stimulant treatment. Somnolence is one of the most and questionnaires for routine screening and follow-up,
commonly reported TEAEs in clinical trials of exten- together with specific screening for RLS and polysom-
ded-release guanfacine (either alone or when co- nography when a physical sleep disorder is suspected
administered with a stimulant) (Faraone et al. 2013). (Cortese et al. 2013b). In developing a multimodal treat-
The effects of guanfacine on ADHD symptoms have ment plan for patients with ADHD, consideration should be
been suggested to be independent of its sedative prop- given to interventions focused on improving sleep and
erties (Kollins et al. 2011). Extended-release clonidine bedtime behavior (Lecendreux and Cortese 2007). Both
(another selective a 2-adrenoceptor agonist) is also non-pharmacological and pharmacological interventions
approved in North America with a similar indication are available for improving sleep in patients with ADHD,
(Childress and Sallee 2012) and is associated with and are applicable to sleep disturbance associated with
somnolence (Cortese et al. 2013b). ADHD medication and with the disorder itself. Potential

123
Associations of sleep disturbance with ADHD 9

Fig. 2 a, b Polysomnographic, a c
c parent-rated subjective and Baseline Week 7 Change Baseline Week 7 Change

Latency to persistent sleep (minutes)


50 50
d actigraphic outcomes from a
double-blind, randomized, 45 41.00 45
parallel-group study of the 40 40

Mean CSHQ score


effects of LDX treatment on 35 35
sleep in 24 children with ADHD 30
28.79
30
(Giblin and Strobel 2011). 25 25
*p \ 0.0001 versus baseline. 19.00 18.71
20 20
ADHD attention-deficit/
15 12.21 15
hyperactivity disorder, CSHQ
Children’s Sleep Habits 10 10
Questionnaire, LDX 5 5
lisdexamfetamine 0 0
–0.29
–5 –5
Placebo LDX Placebo LDX

b Baseline Week 7 d Baseline Week 7


10 100 93.27
91.28 90.17
85.76
7.93
Number of awakenings

8 80

Sleep efficiency (%)


6 60

4 3.57
3.29*
40
3.00

2 20

0 0
Placebo LDX Placebo LDX

strategies for managing sleep disturbances during treatment Behavioral interventions


with ADHD medications are summarized in Table 3.
Established behavioral interventions for insomnia in typi-
Sleep hygiene cally developing children include parent education, grad-
uated extinction (ignoring disruptive behaviors for a
Healthy sleep practices include the following: a regular predetermined period) and bedtime fading, which involves
sleep/wake schedule; adequate opportunity for sleep; identifying a bedtime at which the child falls asleep within
calming and structured bedtime routines; avoidance of about 15 min, and gradually setting bedtime earlier until
caffeine, large amounts of liquids, naps, exercise and the desired bedtime is achieved, while keeping wake time
alerting activities (e.g., use of electronic devices) soon fixed and disallowing sleep at other times (Mindell et al.
before bedtime; sleeping only in bed and using the bed 2006; Vriend and Corkum 2011). Clinical studies of
only for sleeping; and attention to environmental factors behavioral interventions to improve sleep in children with
such as bedroom furniture, lighting and temperature ADHD are limited and have not demonstrated any effect on
(Cortese et al. 2013a; Owens 2008; Yoon et al. 2012). In a ADHD symptoms (Cortese et al. 2013a). A pilot study
study of children with ADHD and initial insomnia indicated that a sleep program involving face-to-face and
receiving stimulants, implementing sleep hygiene reduced telephone contact with a specialist pediatrician or child
sleep onset delay to below 60 min in about 20 % of psychiatrist improved children’s sleep, quality of life and
patients, with an overall effect size of 0.67 (Weiss et al. psychosocial functioning, based on parent reports after
2006). Implementing healthy sleep practices is the rec- 5 months (Sciberras et al. 2011). This approach is under
ommended first-line option for addressing problems with evaluation in a larger randomized, controlled study (Scib-
sleep in both medicated and un-medicated patients with erras et al. 2010). Case reports also indicate efficacy of
ADHD (Cortese et al. 2013b; Lecendreux and Cortese behavioral programs in reducing the severity of dyssomnia
2007). in children with ADHD (Mindell et al. 2006).

123
10 A. Hvolby

Table 2 Frequency of TEAEs of insomnia (or similar) in randomized, double-blind, placebo-controlled, parallel-group clinical studies of LDX
in patients with ADHD
Study Age of population, Duration, Treatment Proportion of patients
years weeks (n) reporting a TEAE, %

Biederman et al. (2007) 6–12 4 Placebo (72) 2.8


LDX (218) 18.8
Adler et al. (2008) 18–55 4 Placebo (62) 5
LDX (358) 17–21a
Findling et al. (2011) 13–17 4 Placebo (77) 3.9
LDX (223) 11.2
Coghill et al. (2013) 6–17 7 Placebo (110) 0.0 (0.9)c
LDX (111) 14.4 (2.7)c
OROS-MPH (111)b 8.1 (6.3)c
d
Adler et al. (2013) 18–55 10 Placebo (80) 3.8
LDX (79) 12.7
Randomized-withdrawal studies are excluded
ADHD attention-deficit/hyperactivity disorder, LDX lisdexamfetamine dimesylate, TEAE treatment-emergent adverse event
a
Range across forced-dose groups (30, 50 or 70 mg/day)
b
Reference arm (active control)
c
Frequency of initial insomnia
d
Patients with ADHD and executive function deficits

Table 3 Recommended strategies for managing sleep disturbances Pharmacological strategies


during treatment with ADHD medications (Cortese et al. 2013b)
Monitoring: insomnia associated with stimulants may attenuate In addition to adjusting dose, class, formulation or regimen
after 1–2 months (Lecendreux and Cortese 2007) of ADHD medications, sleep problems in patients with
Considering if it is possible to stop the medication ADHD may be addressed via additional medications
Implementing sleep hygiene/behavioral measures (Table 3). In patients with psychiatric comorbidities, it
Reviewing the possible causes of sleep problems should be borne in mind that other medications (e.g.,
Treating RLS antidepressants) may also affect sleep. Implementation of
Adding small, short-acting stimulant doses in the early evening healthy sleep practices should precede pharmacological
(if rebound effect occurs) interventions targeted at specific sleep disorders in patients
Reducing stimulant dose with ADHD (Cortese et al. 2013a).
Switching to an alternative class of stimulant Iron deficiency has been implicated in the etiology of
Switching to an alternative stimulant formulation both RLS and ADHD, with potential links to alteration of
Considering use of a non-stimulant (e.g., atomoxetine) dopamine transporter expression and the synthesis and
Considering melatonin treatment catabolism of monoaminergic neurotransmitters (Allen and
ADHD attention-deficit/hyperactivity disorder, RLS restless legs
Earley 2007; Cortese et al. 2005, 2012). A small, ran-
syndrome domized study of iron supplementation in children with
ADHD detected a statistically significant reduction of
ADHD symptoms (Konofal et al. 2008). Monitoring serum
The ball blanket ferritin levels has been proposed for children with sus-
pected RLS (Picchietti and Picchietti 2010), and there is
Ball blankets (Fig. 3) are filled with loose balls to stimulate some evidence that iron supplementation may be effective
sensory receptors in the skin, muscles and joints, which in relieving the symptoms of RLS in children (Cortese
transmit inhibitory signals to the central nervous system et al. 2013a). The role of monoamine neurotransmission in
(Hvolby and Bilenberg 2011). In a study in children with ADHD and RLS was investigated more directly in a dou-
ADHD, the use of ball blankets was found to reduce sleep ble-blind, placebo-controlled trial in 29 children with
onset latency, the number of awakenings and intra-indi- ADHD or ADHD and RLS/PLMS. In this study, levodopa
vidual variability in sleep parameters (Hvolby and Bilen- treatment slightly improved PLMS and/or RLS symptoms,
berg 2011). but did not affect other sleep parameters, ADHD symptoms

123
Associations of sleep disturbance with ADHD 11

release formulation used as an ADHD therapy) (Prince


et al. 1996; Wilens et al. 1994).
Real-world data on sleep medication use in patients with
ADHD is scarce. In observational study in a population of
children with ADHD, 63 % of whom had moderate or
severe sleep problems, 19 % took clonidine and 9 % took
melatonin during the 1-week reporting period (none took
antihistamines, benzodiazapenes or dopamine agonists)
(Efron et al. 2014).

A conceptual model of the interactions of ADHD


with sleep

Associations between ADHD and sleep disorders and


subjective or objective measures of sleep or sleep distur-
bance do not provide information on causation. As an
interpretative aid, this section presents a conceptual model
of the potential relationships between sleep problems and
ADHD or ADHD-like symptoms (Fig. 4). This theoretical
framework is made up of four hypothetical scenarios.
In one scenario, ADHD leads directly to problems with
Fig. 3 Ball blanket. a Plastic balls, diameter 49 mm and b cotton sleep (Fig. 4, left-hand panel). This may be due to hyper-
blanket containing 7 kg of balls and measuring 140 9 200 cm activity, nocturnal motricity or behavior (e.g., bedtime
resistance). This scenario may be more pertinent to patients
with hyperactive symptoms than to those with predomi-
or performance in neuropsychometric tests (England et al. nantly inattentive ADHD. If sleep problems are a conse-
2011). However, a subsequent subgroup analysis of this quence of ADHD symptoms, treatment with stimulants
study failed to confirm the effect of levodopa on PLMS may help a patient to sleep by reducing these symptoms.
(Ferri et al. 2013). These results suggest that further work Insufficient duration of efficacy may, however, lead to
is needed to unravel the relationship, if any, between symptom rebound at bedtime.
dopamine, ADHD and RLS/PLMS. No therapies have yet In a contrasting scenario, disturbed sleep is responsible
received regulatory approval for treating RLS in children for daytime symptoms, behaviors and functional impair-
(Cortese et al. 2013a). ments that are characteristic of ADHD (Fig. 4, right-hand
Patients with ADHD and circadian-rhythm disorder are panel). The strongest evidence for a sleep disorder giving
reported to exhibit a delayed pattern of melatonin secre- rise to ADHD or ADHD-like symptoms is the amelioration
tion. Melatonin is classified as a dietary supplement in the of such symptoms after surgical intervention to improve
USA but is subject to drug regulation in Europe (Bendz and nocturnal breathing. It has been recommended that primary
Scates 2010). Two randomized, double-blind, placebo- sleep disorders are excluded before diagnosing ADHD
controlled trials (Van der Heijden et al. 2007; Weiss et al. (Cortese et al. 2006b, 2013a; Lecendreux and Cortese
2006) and a preliminary open-label study (Tjon Pian Gi 2007). In this situation, psychostimulant medications might
et al. 2003) have indicated that melatonin treatment is be ineffective or could even exacerbate sleep problems. In
effective in reducing sleep onset delay in children with contrast, treating an underlying sleep disorder could result
ADHD (Cortese et al. 2013a). in daytime improvements (O’Brien 2009). That successful
Hypnotic agents, including zolpidem, mirtazapine, treatment of OSA, RLS and delayed sleep-phase disorder
trazodone and antihistamines, have been used off-label in can lead to improvements in ADHD symptoms is borne out
clinical practice to treat insomnia in children with ADHD by case studies (Miano et al. 2013).
(Kratochvil et al. 2005) and some have been evaluated in In another scenario, sleep disturbances and ADHD are
clinical trials (Cortese et al. 2013b), but their use does not coincident, but may exacerbate each other in a feed-for-
form part of current clinical guidelines. Clonidine has also ward loop (Fig. 4, upper-middle panel). Individuals with
been suggested as a treatment option for stimulant-associ- ADHD could be both more vulnerable to the effects of
ated sleep onset delay in patients with ADHD (in an sleep disturbance and more prone to disturbed sleep than
immediate-release formulation rather than the extended- typically developing children (Owens et al. 2013). The

123
12 A. Hvolby

Fig. 4 Conceptual model of the


ADHD primary Interaction and complexity Sleep problem primary
modes of interaction between
ADHD and sleep. ADHD ADHD symptoms lead to Sleep disorders or
Reciprocal causation or
sleep disturbances disturbances cause
attention-deficit/hyperactivity common aetiology
or disorders or mimic ADHD
disorder

ADHD

Neuro- Comorbidity
behavioural (depression,
morbidity anxiety)
ADHD ADHD
or ADHD-like symptoms
Sleep problem

ADHD
Sleep problem Sleep problem
Common underlying
pathophysiology

Sleep problem

Treating ADHD may Integrated


alleviate sleep problem treatment Treating sleep disorder
approach may alleviate ADHD

choice of treatment in this situation is complex because at least a subset of individuals with ADHD (Owens et al.
medications could have opposing or mixed effects on sleep. 2013). Intra-individual variability in neuropsychological
Psychiatric comorbidities are common in children with tasks, rather than a constant level of impairment, is char-
ADHD, and these may be associated with sleep problems. acteristic of ADHD (Spencer et al. 2009; Tamm et al.
Furthermore, daytime sleepiness has been reported to be 2012), and a similar picture of volatility and unpredict-
associated with worsened internalizing symptoms in chil- ability is observed in sleep patterns in children with ADHD
dren with anxiety disorder, suggesting that poor sleep may (Gruber and Sadeh 2004; Gruber et al. 2000; Lecendreux
negatively affect emotional regulation as well as attentional and Cortese 2007; Tsai and Huang 2010). Furthermore,
functioning (Hansen et al. 2013). The possible interplay sleep duration decreases during development, and a more
between sleep, ADHD and anxiety in children may be rapid decrease compared with normative centiles at
related to the alterations observed in sleep-deprived indi- 3–5 years of age has been reported to be a significant
viduals in overlapping brain mechanisms involved in predictor of subsequent ADHD (Scott et al. 2013).
alertness and reward pathways (Gruber 2014). Sleep dis-
turbances in ADHD can, however, occur independently of
psychiatric comorbidities, as demonstrated in studies Conclusions
employing psychiatric control groups (Hvolby et al. 2008).
Nevertheless, comorbid psychiatric disorders (both inter- ADHD is commonly associated with specific sleep disor-
nalizing and externalizing) may further exacerbate both ders and objectively or subjectively assessed sleep distur-
sleep problems and ADHD symptoms in patients with bances. The relationship between ADHD and sleep
ADHD. problems is complex and bidirectional, and is modulated by
In a final scenario, common or overlapping neurobio- interactions with ADHD medications and by psychiatric
logical disease mechanisms are hypothesized to give rise to comorbidities and associated medications. Understanding
both ADHD and sleep disturbance (Fig. 4, lower-middle these associations and relationships is important when
panel). Circadian-rhythm disorders, sleep/wake disorders assessing and managing patients with ADHD. As recom-
and delayed sleep-phase disorder could share pathophysi- mended in current guidelines, primary sleep disorders
ological mechanisms with ADHD. There may be a genet- (specifically SDB/OSA and PLMD/RLS) should be ruled
ically determined predisposition to sleep dysregulation in out before diagnosing or treating ADHD. Obesity and

123
Associations of sleep disturbance with ADHD 13

psychiatric comorbidities (e.g., anxiety and depression) can submission was also provided by Oxford PharmaGenesisTM Ltd. Shire
also lead to sleep problems, and need to be identified and develops and markets drugs to treat psychiatric disorders, including
ADHD.
treated appropriately. The multifaceted effects of stimulant
pharmacotherapy on sleep in patients with ADHD are Conflict of interest The author declares he has no conflict of
particularly important for clinicians to understand when interest.
evaluating treatment options for patients. Stimulant medi-
Open Access This article is distributed under the terms of the
cations may disrupt or improve sleep in different patients,
Creative Commons Attribution License which permits any use, dis-
depending not only on the nature of the patient’s illness, tribution, and reproduction in any medium, provided the original
but also on the drug dose, class, formulation and duration author(s) and the source are credited.
of efficacy. Effective management of sleep problems
associated with ADHD and its treatment may not only
alleviate sleep-related symptoms, but also improve quality
of life in parents or carers of children with disruptive
References
bedtime behavior or insomnia.
In the near term, new understanding of how sleep Adler LA, Goodman DW, Kollins SH, Weisler RH, Krishnan S,
interacts with ADHD and how this affects treatment Zhang Y, Biederman J (2008) Double-blind, placebo-controlled
choices is likely to come from clinical studies. Polysom- study of the efficacy and safety of lisdexamfetamine dimesylate
nographic studies need to be larger and better controlled in adults with attention-deficit/hyperactivity disorder. J Clin
Psychiatry 69:1364–1373
than previous studies, and should not overlook subtle Adler LA, Goodman D, Weisler R, Hamdani M, Roth T (2009a)
polysomnographic signals such as microarousals and the Effect of lisdexamfetamine dimesylate on sleep in adults with
time structure of PLMS. There is also a need to follow up attention-deficit/hyperactivity disorder. Behav Brain Funct 5:34.
the recent data indicating a link between ADHD, obesity, doi:10.1186/1744-9081-5-34
Adler LA, Zimmerman B, Starr HL, Silber S, Palumbo J, Orman C,
daytime sleepiness and circadian-rhythm alterations. Con- Spencer T (2009b) Efficacy and safety of OROS methylpheni-
spicuously absent from the current literature is any con- date in adults with attention-deficit/hyperactivity disorder: a
vincing demonstration that pharmacological or non- randomized, placebo-controlled, double-blind, parallel group,
pharmacological intervention to improve sleep actually dose-escalation study. J Clin Psychopharmacol 29:239–247.
doi:10.1097/JCP.0b013e3181a390ce
leads to improved ADHD symptoms or reduced functional Adler LA, Dirks B, Deas PF, Raychaudhuri A, Dauphin MR, Lasser
impairment associated with the disorder. Similarly, as RA, Weisler RH (2013) Lisdexamfetamine dimesylate in adults
children become adolescents, they may experience sleep with attention-deficit/hyperactivity disorder who report clinically
loss, but do any adolescents benefit from more or better significant impairment in executive function: results from a
randomized, double-blind, placebo-controlled study. J Clin Psy-
sleep in terms of preventing worsening of ADHD? Crucial chiatry 74:694–702. doi:10.4088/JCP.12m08144
to both these questions is the possibility that specific Allen RP, Earley CJ (2007) The role of iron in restless legs syndrome.
ADHD phenotypes are associated with, or characterized Mov Disord 22(Suppl 18):S440–S448. doi:10.1002/mds.21607
by, particular types of sleep-related problems. In addition American Academy of Sleep Medicine (2005) The international
classification of sleep disorders, 2nd edn. American Academy of
to helping clinicians make treatment decisions, the ability Sleep Medicine, Westchester
to subcategorize patients with ADHD based on their sleep American Psychiatric Association (1980) Diagnostic and statistical
phenotype may help shed light on areas where current data manual of mental disorders, 3rd edn. American Psychiatric
are conflicting. Furthermore, such phenotypic classification Association, Washington
American Psychiatric Association (2013) Diagnostic and statistical
is probably essential for increased sensitivity in genomic manual of mental disorders, 5th edn (DSM-5). American
screens for ADHD-associated polymorphisms. The over- Psychiatric Publishing, Arlington
lapping neurochemical and neuroanatomical systems Baird AL, Coogan AN, Siddiqui A, Donev RM, Thome J (2012)
involved in regulating sleep, attention, arousal and circa- Adult attention-deficit hyperactivity disorder is associated with
alterations in circadian rhythms at the behavioural, endocrine
dian rhythms are the subjects of current basic research and molecular levels. Mol Psychiatry 17:988–995. doi:10.1038/
(Owens et al. 2013). Whether enhanced understanding of mp.2011.149
these mechanisms in health and disease or the use of state- Barkley RA (1990) Attention-deficit-hyperactivity disorder: a hand-
of-the-art genetic and neuroimaging tools will lead to the book for diagnosis and treatment. Guildford Press, New York
Beebe DW (2006) Neurobehavioral morbidity associated with
development of new therapies or preventative strategies for disordered breathing during sleep in children: a comprehensive
ADHD are questions for the future. review. Sleep 29:1115–1134
Beebe DW (2011) Cognitive, behavioral, and functional conse-
Acknowledgments Shire provided funding to Oxford PharmaGen- quences of inadequate sleep in children and adolescents. Pediatr
esisTM Ltd for writing and editorial support for this publication. Dr. Clin North Am 58:649–665. doi:10.1016/j.pcl.2011.03.002
M. Cottingham and Dr. E. Southam of Oxford PharmaGenesisTM Ltd Beebe DW, Wells CT, Jeffries J, Chini B, Kalra M, Amin R (2004)
provided writing assistance under the direction of the author. Editorial Neuropsychological effects of pediatric obstructive sleep apnea.
assistance in editing, fact checking, formatting, proofreading and J Int Neuropsychol Soc 10:962–975

123
14 A. Hvolby

Bendz LM, Scates AC (2010) Melatonin treatment for insomnia in Choi J, Yoon IY, Kim HW, Chung S, Yoo HJ (2010) Differences
pediatric patients with attention-deficit/hyperactivity disorder. between objective and subjective sleep measures in children with
Ann Pharmacother 44:185–191. doi:10.1345/aph.1M365 attention deficit hyperactivity disorder. J Clin Sleep Med
Bessey M, Richards J, Corkum P (2013) Sleep lab adaptation in 6:589–595
children with attention-deficit/hyperactivity disorder and typi- Coghill D, Seth S (2006) Osmotic, controlled-release methylpheni-
cally developing children. Sleep Disord 2013:698957. doi:10. date for the treatment of ADHD. Expert Opin Pharmacother
1155/2013/698957 7:2119–2138. doi:10.1517/14656566.7.15.2119
Biederman J et al (2006) A randomized, placebo-controlled trial of Coghill D et al (2013) European, randomized, phase 3 study of
OROS methylphenidate in adults with attention-deficit/hyper- lisdexamfetamine dimesylate in children and adolescents
activity disorder. Biol Psychiatry 59:829–835. doi:10.1016/j. with attention-deficit/hyperactivity disorder. Eur Neuropsy-
biopsych.2005.09.011 chopharmacol 12:1208–1218. doi:10.1016/j.euroneuro.2012.
Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL (2007) 11.012
Efficacy and tolerability of lisdexamfetamine dimesylate (NRP- Corkum P, Tannock R, Moldofsky H (1998) Sleep disturbances in
104) in children with attention-deficit/hyperactivity disorder: a children with attention-deficit/hyperactivity disorder. J Am Acad
phase III, multicenter, randomized, double-blind, forced-dose, Child Adolesc Psychiatry 37:637–646. doi:10.1097/00004583-
parallel-group study. Clin Ther 29:450–463 199806000-00014
Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Kotarski Corkum P, Moldofsky H, Hogg-Johnson S, Humphries T, Tannock R
M, Spencer T (2010) A randomized, 3-phase, 34-week, double- (1999) Sleep problems in children with attention-deficit/
blind, long-term efficacy study of osmotic-release oral system- hyperactivity disorder: impact of subtype, comorbidity, and
methylphenidate in adults with attention-deficit/hyperactivity stimulant medication. J Am Acad Child Adolesc Psychiatry
disorder. J Clin Psychopharmacol 30:549–553. doi:10.1097/JCP. 38:1285–1293. doi:10.1097/00004583-199910000-00018
0b013e3181ee84a7 Corkum P, Tannock R, Moldofsky H, Hogg-Johnson S, Humphries T
Bijlenga D, Van Someren EJ, Gruber R, Bron TI, Kruithof IF, (2001) Actigraphy and parental ratings of sleep in children with
Spanbroek EC, Kooij JJ (2013) Body temperature, activity and attention-deficit/hyperactivity disorder (ADHD). Sleep
melatonin profiles in adults with attention-deficit/hyperactivity 24:303–312
disorder and delayed sleep: a case–control study. J Sleep Res Corkum P, Davidson F, Macpherson M (2011) A framework for the
22:607–616. doi:10.1111/jsr.12075 assessment and treatment of sleep problems in children with
Block SL et al (2009) Once-daily atomoxetine for treating pediatric attention-deficit/hyperactivity disorder. Pediatr Clin North Am
attention-deficit/hyperactivity disorder: comparison of morning 58:667–683. doi:10.1016/j.pcl.2011.03.004
and evening dosing. Clin Pediatr (Phila) 48:723–733. doi:10. Cortese S, Vincenzi B (2012) Obesity and ADHD: clinical and
1177/0009922809335321 neurobiological implications. Curr Top Behav Neurosci
Boonstra AM, Kooij JJ, Oosterlaan J, Sergeant JA, Buitelaar JK, Van 9:199–218. doi:10.1007/7854_2011_154
Someren EJ (2007) Hyperactive night and day? Actigraphy Cortese S, Konofal E, Lecendreux M, Arnulf I, Mouren MC, Darra F,
studies in adult ADHD: a baseline comparison and the effect of Dalla Bernardina B (2005) Restless legs syndrome and attention-
methylphenidate. Sleep 30:433–442 deficit/hyperactivity disorder: a review of the literature. Sleep
Bradley C (1937) The behavior of children receiving benzedrine. Am 28:1007–1013
J Psychiatry 94:577–585 Cortese S, Konofal E, Yateman N, Mouren MC, Lecendreux M
Breslau N, Roth T, Rosenthal L, Andreski P (1996) Sleep disturbance (2006a) Sleep and alertness in children with attention-deficit/
and psychiatric disorders: a longitudinal epidemiological study hyperactivity disorder: a systematic review of the literature.
of young adults. Biol Psychiatry 39:411–418 Sleep 29:504–511
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ (1989) Cortese S, Lecendreux M, Mouren MC, Konofal E (2006b) ADHD
The Pittsburgh Sleep Quality Index: a new instrument for and insomnia. J Am Acad Child Adolesc Psychiatry 45:384–385.
psychiatric practice and research. Psychiatry Res 28:193–213 doi:10.1097/01.chi.0000199577.12145.bc
Carlson GA, Kelly KL (2003) Stimulant rebound: how common is it Cortese S et al (2007) Parent reports of sleep/alertness problems and
and what does it mean? J Child Adolesc Psychopharmacol ADHD symptoms in a sample of obese adolescents. J Psychosom
13:137–142. doi:10.1089/104454603322163853 Res 63:587–590. doi:10.1016/j.jpsychores.2007.08.005
Casas M et al (2013) Efficacy and safety of prolonged-release OROS Cortese S et al (2008a) Attention-deficit/hyperactivity disorder
methylphenidate in adults with attention deficit/hyperactivity (ADHD) and obesity: a systematic review of the literature. Crit
disorder: a 13-week, randomized, double-blind, placebo-con- Rev Food Sci Nutr 48:524–537. doi:10.1080/104083907015
trolled, fixed-dose study. World J Biol Psychiatry 14:268–281. 40124
doi:10.3109/15622975.2011.600333 Cortese S, Konofal E, Dalla Bernardina B, Mouren MC, Lecendreux
Chervin RD, Archbold KH, Dillon JE, Panahi P, Pituch KJ, Dahl RE, M (2008b) Does excessive daytime sleepiness contribute to
Guilleminault C (2002) Inattention, hyperactivity, and symptoms explaining the association between obesity and ADHD symp-
of sleep-disordered breathing. Pediatrics 109:449–456 toms? Med Hypotheses 70:12–16. doi:10.1016/j.mehy.2007.04.
Chervin RD et al (2006) Sleep-disordered breathing, behavior, and 036
cognition in children before and after adenotonsillectomy. Cortese S, Faraone SV, Konofal E, Lecendreux M (2009) Sleep in
Pediatrics 117:e769–e778. doi:10.1542/peds.2005-1837 children with attention-deficit/hyperactivity disorder: meta-ana-
Chervin RD et al (2012) Esophageal pressures, polysomnography, lysis of subjective and objective studies. J Am Acad Child
and neurobehavioral outcomes of adenotonsillectomy in chil- Adolesc Psychiatry 48:894–908. doi:10.1097/CHI.0b013e3181
dren. Chest 142:101–110. doi:10.1378/chest.11-2456 ac09c9
Chiang HL et al (2010) Association between symptoms and subtypes of Cortese S, Angriman M, Lecendreux M, Konofal E (2012) Iron and
attention-deficit hyperactivity disorder and sleep problems/disorders. attention deficit/hyperactivity disorder: what is the empirical
J Sleep Res 19:535–545. doi:10.1111/j.1365-2869.2010.00832.x evidence so far? A systematic review of the literature. Expert
Childress AC, Sallee FR (2012) Revisiting clonidine: an innovative Rev Neurother 12:1227–1240. doi:10.1586/ern.12.116
add-on option for attention-deficit/hyperactivity disorder. Drugs Cortese S et al (2013a) Assessment and management of sleep
Today (Barc) 48:207–217. doi:10.1358/dot.2012.48.3.1750904 problems in youths with attention-deficit/hyperactivity disorder.

123
Associations of sleep disturbance with ADHD 15

J Am Acad Child Adolesc Psychiatry 52:784–796. doi:10.1016/j. Golan N, Shahar E, Ravid S, Pillar G (2004) Sleep disorders and
jaac.2013.06.001 daytime sleepiness in children with attention-deficit/hyperactive
Cortese S et al (2013b) Practitioner review: current best practice in disorder. Sleep 27:261–266
the management of adverse events during treatment with ADHD Gomes AA, Parchao C, Almeida A, Clemente V, Pinto de Azevedo
medications in children and adolescents. J Child Psychol MH (2013) Sleep–wake patterns reported by parents in hyper-
Psychiatry 54:227–246. doi:10.1111/jcpp.12036 active children diagnosed according to ICD-10, as compared to
Cortese S, Ramos Olazagasti MA, Klein RG, Castellanos FX, Proal E, paired controls. Child Psychiatry Hum Dev. doi:10.1007/s10578-
Mannuzza S (2013c) Obesity in men with childhood ADHD: a 013-0422-6
33-year controlled, prospective, follow-up study. Pediatrics Gottlieb DJ et al (2003) Symptoms of sleep-disordered breathing in
131:e1731–e1738. doi:10.1542/peds.2012-0540 5-year-old children are associated with sleepiness and problem
De Crescenzo F et al (2014) The use of actigraphy in the monitoring of behaviors. Pediatrics 112:870–877
methylphenidate versus placebo in ADHD: a meta-analysis. Atten Gozal D (1998) Sleep-disordered breathing and school performance
Defic Hyperact Disord 6:49–58. doi:10.1007/s12402-013-0122-x in children. Pediatrics 102:616–620
Dittmann RW et al (2013) Efficacy and safety of lisdexamfetamine Gradisar M, Gardner G, Dohnt H (2011) Recent worldwide sleep
dimesylate and atomoxetine in the treatment of attention-deficit/ patterns and problems during adolescence: a review and meta-
hyperactivity disorder: a head-to-head, randomized, double- analysis of age, region, and sleep. Sleep Med 12:110–118.
blind, phase IIIb study. CNS Drugs 27:1081–1092. doi:10.1007/ doi:10.1016/j.sleep.2010.11.008
s40263-013-0104-8 Graham J et al (2011) European guidelines on managing adverse
Efron D, Jarman F, Barker M (1997) Side effects of methylphenidate effects of medication for ADHD. Eur Child Adolesc Psychiatry
and dexamphetamine in children with attention deficit hyperac- 20:17–37. doi:10.1007/s00787-010-0140-6
tivity disorder: a double-blind, crossover trial. Pediatrics Greenhill L, Puig-Antich J, Goetz R, Hanlon C, Davies M (1983)
100:662–666 Sleep architecture and REM sleep measures in prepubertal
Efron D, Lycett K, Sciberras E (2014) Use of sleep medication in children with attention deficit disorder with hyperactivity. Sleep
children with ADHD. Sleep Med 15:472–475. doi:10.1016/j. 6:91–101
sleep.2013.10.018 Gruber R (2009) Sleep characteristics of children and adolescents
England SJ et al (2011) L-dopa improves restless legs syndrome and with attention deficit-hyperactivity disorder. Child Adolesc
periodic limb movements in sleep but not attention-deficit- Psychiatr Clin N Am 18:863–876. doi:10.1016/j.chc.2009.04.
hyperactivity disorder in a double-blind trial in children. Sleep 011
Med 12:471–477. doi:10.1016/j.sleep.2011.01.008 Gruber R (2014) ADHD, anxiety and sleep: a window to understand-
Faraone SV, McBurnett K, Sallee FR, Steeber J, Lopez FA (2013) ing the interplay between sleep, emotional regulation and
Guanfacine extended release: a novel treatment for attention- attention in children? Behav Sleep Med 12:84–87. doi:10.
deficit/hyperactivity disorder in children and adolescents. Clin 1080/15402002.2014.862089
Ther 35:1778–1793. doi:10.1016/j.clinthera.2013.09.005 Gruber R, Sadeh A (2004) Sleep and neurobehavioral functioning in
Ferri R, Bruni O, Novelli L, Picchietti MA, Picchietti DL (2013) boys with attention-deficit/hyperactivity disorder and no reported
Time structure of leg movement activity during sleep in breathing problems. Sleep 27:267–273
attention-deficit/hyperactivity disorder and effects of levodopa. Gruber R, Sadeh A, Raviv A (2000) Instability of sleep patterns in
Sleep Med 14:359–366. doi:10.1016/j.sleep.2012.12.012 children with attention-deficit/hyperactivity disorder. J Am Acad
Findling RL, Bukstein OG, Melmed RD, Lopez FA, Sallee FR, Child Adolesc Psychiatry 39:495–501. doi:10.1097/00004583-
Arnold LE, Pratt RD (2008) A randomized, double-blind, 200004000-00019
placebo-controlled, parallel-group study of methylphenidate Gruber R, Xi T, Frenette S, Robert M, Vannasinh P, Carrier J (2009)
transdermal system in pediatric patients with attention-deficit/ Sleep disturbances in prepubertal children with attention deficit
hyperactivity disorder. J Clin Psychiatry 69:149–159 hyperactivity disorder: a home polysomnography study. Sleep
Findling RL, Childress AC, Cutler AJ, Gasior M, Hamdani M, 32:343–350
Ferreira-Cornwell MC, Squires L (2011) Efficacy and safety of Gruber R, Wiebe S, Montecalvo L, Brunetti B, Amsel R, Carrier J
lisdexamfetamine dimesylate in adolescents with attention- (2011) Impact of sleep restriction on neurobehavioral function-
deficit/hyperactivity disorder. J Am Acad Child Adolesc Psy- ing of children with attention deficit hyperactivity disorder.
chiatry 50:395–405. doi:10.1016/j.jaac.2011.01.007 Sleep 34:315–323
Fisher BE, Pauley C, McGuire K (1989) Children’s Sleep Behavior Gruber R, Fontil L, Bergmame L, Wiebe ST, Amsel R, Frenette S,
Scale: normative data on 870 children in grades 1 to 6. Percept Carrier J (2012a) Contributions of circadian tendencies and
Mot Skills 68:227–236 behavioral problems to sleep onset problems of children with
Galland BC, Tripp EG, Taylor BJ (2010) The sleep of children with ADHD. BMC Psychiatry 12:212. doi:10.1186/1471-244x-12-
attention deficit hyperactivity disorder on and off methylpheni- 212
date: a matched case-control study. J Sleep Res 19:366–373. Gruber R, Michaelsen S, Bergmame L, Frenette S, Bruni O, Fontil L,
doi:10.1111/j.1365-2869.2009.00795.x Carrier J (2012b) Short sleep duration is associated with teacher-
Gamble KL, May RS, Besing RC, Tankersly AP, Fargason RE reported inattention and cognitive problems in healthy school-
(2013) Delayed sleep timing and symptoms in adults with aged children. Nat Sci Sleep 4:33–40. doi:10.2147/NSS.S24607
attention-deficit/hyperactivity disorder: a controlled actigraphy Hansen BH, Skirbekk B, Oerbeck B, Wentzel-Larsen T, Kristensen H
study. Chronobiol Int 30:598–606. doi:10.3109/07420528.2012. (2013) Associations between sleep problems and attentional and
754454 behavioral functioning in children with anxiety disorders and
Garnock-Jones KP, Keating GM (2009) Atomoxetine: a review of its ADHD. Behav Sleep Med 12:53–68. doi:10.1080/15402002.
use in attention-deficit hyperactivity disorder in children and 2013.764525
adolescents. Paediatr Drugs 11:203–226. doi:10.2165/00148581- Hart CN, Larose JG, Fava JL, James BL, Wing RR (2013) The
200911030-00005 association between time in bed and obesity risk in young adults.
Giblin JM, Strobel AL (2011) Effect of lisdexamfetamine dimesylate Behav Sleep Med 11:321–327. doi:10.1080/15402002.2012.700289
on sleep in children with ADHD. J Atten Disord 15:491–498. Hodgkins P, Shaw M, Coghill D, Hechtman L (2012) Amfetamine and
doi:10.1177/1087054710371195 methylphenidate medications for attention-deficit/hyperactivity

123
16 A. Hvolby

disorder: complementary treatment options. Eur Child Adolesc disorder: misuse, cognitive impact, and adverse effects. Brain
Psychiatry 21:477–492. doi:10.1007/s00787-012-0286-5 Behav 2:661–677. doi:10.1002/brb3.78
Hodgkins P et al (2013) Management of ADHD in children across Lal C, Strange C, Bachman D (2012) Neurocognitive impairment in
Europe: patient demographics, physician characteristics and obstructive sleep apnea. Chest 141:1601–1610. doi:10.1378/
treatment patterns. Eur J Pediatr 172:895–906. doi:10.1007/ chest.11-2214
s00431-013-1969-8 LeBourgeois MK, Avis K, Mixon M, Olmi J, Harsh J (2004) Snoring,
Huang YS, Guilleminault C, Li HY, Yang CM, Wu YY, Chen NH sleep quality, and sleepiness across attention-deficit/hyperactiv-
(2007) Attention-deficit/hyperactivity disorder with obstructive ity disorder subtypes. Sleep 27:520–525
sleep apnea: a treatment outcome study. Sleep Med 8:18–30. Lecendreux M, Cortese S (2007) Sleep problems associated with
doi:10.1016/j.sleep.2006.05.016 ADHD: a review of current therapeutic options and recommen-
Hvolby A, Bilenberg N (2011) Use of ball blanket in attention-deficit/ dations for the future. Expert Rev Neurother 7:1799–1806.
hyperactivity disorder sleeping problems. Nord J Psychiatry doi:10.1586/14737175.7.12.1799
65:89–94. doi:10.3109/08039488.2010.501868 Lecendreux M, Konofal E, Bouvard M, Falissard B, Mouren-Simeoni
Hvolby A, Jorgensen J, Bilenberg N (2008) Actigraphic and parental MC (2000) Sleep and alertness in children with ADHD. J Child
reports of sleep difficulties in children with attention-deficit/ Psychol Psychiatry 41:803–812
hyperactivity disorder. Arch Pediatr Adolesc Med 162:323–329. Lee SH et al (2012) Effect of methylphenidate on sleep parameters in
doi:10.1001/archpedi.162.4.323 children with ADHD. Psychiatry Investig 9:384–390. doi:10.
Hvolby A, Jorgensen J, Bilenberg N (2009) Parental rating of sleep in 4306/pi.2012.9.4.384
children with attention deficit/hyperactivity disorder. Eur Child Lim CG, Ooi YP, Fung DS, Mahendran R, Kaur A (2008) Sleep
Adolesc Psychiatry 18:429–438. doi:10.1007/s00787-009-0750-z disturbances in Singaporean children with attention deficit
Ironside S, Davidson F, Corkum P (2010) Circadian motor activity hyperactivity disorder. Ann Acad Med Singap 37:655–661
affected by stimulant medication in children with attention- Lorenzo JL, Barbanoj MJ (2002) Variability of sleep parameters
deficit/hyperactivity disorder. J Sleep Res 19:546–551. doi:10. across multiple laboratory sessions in healthy young subjects: the
1111/j.1365-2869.2010.00845.x ‘‘very first night effect’’. Psychophysiology 39:409–413. doi:10.
Ivanenko A, Crabtree VM, Gozal D (2004) Sleep in children with 1017/s0048577202394010
psychiatric disorders. Pediatr Clin North Am 51:51–68 Mayes SD et al (2009) ADHD subtypes and comorbid anxiety, depression,
Jerome L (2001) Can methylphenidate facilitate sleep in children with and oppositional-defiant disorder: differences in sleep problems.
attention deficit hyperactivity disorder? J Child Adolesc Psy- J Pediatr Psychol 34:328–337. doi:10.1093/jpepsy/jsn083
chopharmacol 11:109. doi:10.1089/104454601750143564 Medori R et al (2008) A randomized, placebo-controlled trial of three
Katz ES, Greene MG, Carson KA, Galster P, Loughlin GM, Carroll J, fixed dosages of prolonged-release OROS methylphenidate in
Marcus CL (2002) Night-to-night variability of polysomnogra- adults with attention-deficit/hyperactivity disorder. Biol Psychi-
phy in children with suspected obstructive sleep apnea. J Pediatr atry 63:981–989. doi:10.1016/j.biopsych.2007.11.008
140:589–594. doi:10.1067/mpd.2002.123290 Meltzer LJ, Montgomery-Downs HE, Insana SP, Walsh CM (2012)
Kim HW et al (2010) The effect of OROS methylphenidate on the sleep of Use of actigraphy for assessment in pediatric sleep research.
children with attention-deficit/hyperactivity disorder. Int Clin Psy- Sleep Med Rev 16:463–475. doi:10.1016/j.smrv.2011.10.002
chopharmacol 25:107–115. doi:10.1097/YIC.0b013e3283364411 Miano S et al (2006) NREM sleep instability is reduced in children
Kinsbourne M (1973) Stimulants for insomnia. N Engl J Med with attention-deficit/hyperactivity disorder. Sleep 29:797–803
288:1129. doi:10.1056/NEJM197305242882121 Miano S et al (2013) Case reports of sleep phenotypes of ADHD:
Kirov R, Brand S (2014) Sleep problems and their effect in ADHD. from hypothesis to clinical practice. J Atten Disord 17:565–573.
Expert Rev Neurother 14:287–299. doi:10.1586/14737175.2014. doi:10.1177/1087054713497254
885382 Mick E, Biederman J, Jetton J, Faraone SV (2000) Sleep disturbances
Kirov R, Pillar G, Rothenberger A (2004) REM-sleep changes in associated with attention deficit hyperactivity disorder: the impact
children with attention-deficit/hyperactivity disorder: methodo- of psychiatric comorbidity and pharmacotherapy. J Child Adolesc
logic and neurobiologic considerations. Sleep 27:1215 Psychopharmacol 10:223–231. doi:10.1089/10445460050167331
Kirov R, Uebel H, Albrecht B, Banaschewski T, Yordanova J, Mindell JA, Kuhn B, Lewin DS, Meltzer LJ, Sadeh A (2006)
Rothenberger A (2012) Attention-deficit/hyperactivity disorder Behavioral treatment of bedtime problems and night wakings in
(ADHD) and adaptation night as determinants of sleep patterns infants and young children. Sleep 29:1263–1276
in children. Eur Child Adolesc Psychiatry 21:681–690. doi:10. Moreau V, Rouleau N, Morin CM (2013) Sleep of children with
1007/s00787-012-0308-3 attention deficit hyperactivity disorder: actigraphic and parental
Kollins SH et al (2011) Psychomotor functioning and alertness with reports. Behav Sleep Med 12:69–83. doi:10.1080/15402002.
guanfacine extended release in subjects with attention-deficit/ 2013.764526
hyperactivity disorder. J Child Adolesc Psychopharmacol Morgenthaler TI et al (2007) Practice parameters for the treatment of
21:111–120. doi:10.1089/cap.2010.0064 narcolepsy and other hypersomnias of central origin. Sleep
Konofal E et al (2008) Effects of iron supplementation on attention 30:1705–1711
deficit hyperactivity disorder in children. Pediatr Neurol Mullin BC, Harvey AG, Hinshaw SP (2011) A preliminary study of
38:20–26. doi:10.1016/j.pediatrneurol.2007.08.014 sleep in adolescents with bipolar disorder, ADHD, and non-
Kooij JJ, Middelkoop HA, van Gils K, Buitelaar JK (2001) The effect patient controls. Bipolar Disord 13:425–432. doi:10.1111/j.1399-
of stimulants on nocturnal motor activity and sleep quality in 5618.2011.00933.x
adults with ADHD: an open-label case-control study. J Clin Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore
Psychiatry 62:952–956 RJ, Michelson D (2008) Atomoxetine and osmotically released
Kratochvil CJ, Lake M, Pliszka SR, Walkup JT (2005) Pharmaco- methylphenidate for the treatment of attention deficit hyperac-
logical management of treatment-induced insomnia in ADHD. tivity disorder: acute comparison and differential response. Am J
J Am Acad Child Adolesc Psychiatry 44:499–501. doi:10.1097/ Psychiatry 165:721–730. doi:10.1176/appi.ajp.2007.05091676
01.chi.0000155322.32500.3a Nutt DJ et al (2007) Evidence-based guidelines for management of
Lakhan SE, Kirchgessner A (2012) Prescription stimulants in attention-deficit/hyperactivity disorder in adolescents in transi-
individuals with and without attention deficit hyperactivity tion to adult services and in adults: recommendations from the

123
Associations of sleep disturbance with ADHD 17

British Association for Psychopharmacology. J Psychopharmacol Prince JB, Wilens TE, Biederman J, Spencer TJ, Wozniak JR (1996)
(Oxford, England) 21:10–41. doi:10.1177/0269881106073219 Clonidine for sleep disturbances associated with attention-deficit
O’Brien LM (2009) The neurocognitive effects of sleep disruption in hyperactivity disorder: a systematic chart review of 62 cases.
children and adolescents. Child Adolesc Psychiatr Clin N Am J Am Acad Child Adolesc Psychiatry 35:599–605. doi:10.1097/
18:813–823. doi:10.1016/j.chc.2009.04.008 00004583-199605000-00014
O’Brien LM, Ivanenko A, Crabtree VM, Holbrook CR, Bruner JL, Rosen CL, Storfer-Isser A, Taylor HG, Kirchner HL, Emancipator JL,
Klaus CJ, Gozal D (2003a) The effect of stimulants on sleep Redline S (2004) Increased behavioral morbidity in school-aged
characteristics in children with attention deficit/hyperactivity children with sleep-disordered breathing. Pediatrics
disorder. Sleep Med 4:309–316 114:1640–1648. doi:10.1542/peds.2004-0103
O’Brien LM, Ivanenko A, Crabtree VM, Holbrook CR, Bruner JL, Rowland AS, Lesesne CA, Abramowitz AJ (2002) The epidemiology
Klaus CJ, Gozal D (2003b) Sleep disturbances in children with of attention-deficit/hyperactivity disorder (ADHD): a public
attention deficit hyperactivity disorder. Pediatr Res 54:237–243. health view. Ment Retard Dev Disabil Res Rev 8:162–170.
doi:10.1203/01.PDR.0000072333.11711.9A doi:10.1002/mrdd.10036
Owens JA (2005) The ADHD and sleep conundrum: a review. J Dev Sadeh A, Pergamin L, Bar-Haim Y (2006) Sleep in children with
Behav Pediatr 26:312–322 attention-deficit hyperactivity disorder: a meta-analysis of poly-
Owens JA (2008) Sleep disorders and attention-deficit/hyperactivity somnographic studies. Sleep Med Rev 10:381–398. doi:10.1016/
disorder. Curr Psychiatry Rep 10:439–444 j.smrv.2006.03.004
Owens JA, Dalzell V (2005) Use of the ‘BEARS’ sleep screening tool Sangal RB, Owens J, Allen AJ, Sutton V, Schuh K, Kelsey D (2006)
in a pediatric residents’ continuity clinic: a pilot study. Sleep Effects of atomoxetine and methylphenidate on sleep in children
Med 6:63–69. doi:10.1016/j.sleep.2004.07.015 with ADHD. Sleep 29:1573–1585
Owens JA, Spirito A, McGuinn M (2000) The Children’s Sleep Saxby H, Morgan H (1993) Behaviour problems in children with
Habits Questionnaire (CSHQ): psychometric properties of a learning disabilities: to what extent do they exist and are they a
survey instrument for school-aged children. Sleep 23:1043–1051 problem? Child Care Health Dev 19:149–157
Owens J, Sangal RB, Sutton VK, Bakken R, Allen AJ, Kelsey D Scholle S, Scholle HC, Kemper A, Glaser S, Rieger B, Kemper G,
(2009) Subjective and objective measures of sleep in children Zwacka G (2003) First night effect in children and adolescents
with attention-deficit/hyperactivity disorder. Sleep Med undergoing polysomnography for sleep-disordered breathing.
10:446–456. doi:10.1016/j.sleep.2008.03.013 Clin Neurophysiol 114:2138–2145
Owens J et al (2013) Future research directions in sleep and ADHD: Sciberras E, Efron D, Gerner B, Davey M, Mensah F, Oberklaid F,
report of a consensus working group. J Atten Disord Hiscock H (2010) Study protocol: the sleeping sound with
17:550–564. doi:10.1177/1087054712457992 attention-deficit/hyperactivity disorder project. BMC Pediatr
Paavonen EJ et al (2009) Short sleep duration and behavioral 10:101. doi:10.1186/1471-2431-10-101
symptoms of attention-deficit/hyperactivity disorder in healthy Sciberras E, Fulton M, Efron D, Oberklaid F, Hiscock H (2011)
7- to 8-year-old children. Pediatrics 123:e857–e864. doi:10. Managing sleep problems in school aged children with ADHD: a
1542/peds.2008-2164 pilot randomised controlled trial. Sleep Med 12:932–935. doi:10.
Pesonen AK et al (2010) Sleep duration and regularity are associated 1016/j.sleep.2011.02.006
with behavioral problems in 8-year-old children. Int J Behav Scott N, Blair PS, Emond AM, Fleming PJ, Humphreys JS, Henderson
Med 17:298–305. doi:10.1007/s12529-009-9065-1 J, Gringras P (2013) Sleep patterns in children with ADHD: a
Philipsen A et al (2005) Sleep in adults with attention-deficit/ population-based cohort study from birth to 11 years. J Sleep Res
hyperactivity disorder: a controlled polysomnographic study 22:121–128. doi:10.1111/j.1365-2869.2012.01054.x
including spectral analysis of the sleep EEG. Sleep 28:877–884 Setyawan J, Guerin A, Hodgkins P, Gauthier G, Cloutier M, Wu E,
Picchietti MA, Picchietti DL (2010) Advances in pediatric restless Haim Erder M (2013a) Treatment persistence in attention deficit/
legs syndrome: iron, genetics, diagnosis and treatment. Sleep hyperactivity disorder: a retrospective analysis of patients
Med 11:643–651. doi:10.1016/j.sleep.2009.11.014 initiated on lisdexamfetamine versus other medications. J Med
Picchietti D, Allen RP, Walters AS, Davidson JE, Myers A, Ferini- Econ 16:1275–1289. doi:10.3111/13696998.2013.839947
Strambi L (2007) Restless legs syndrome: prevalence and impact Setyawan J, Hodgkins P, Guerin A, Gauthier G, Cloutier M, Wu EQ,
in children and adolescents—the Peds REST study. Pediatrics Erder MH (2013b) Comparing treatment adherence of lis-
120:253–266. doi:10.1542/peds.2006-2767 dexamfetamine and other medications for the treatment of
Picchietti DL, Bruni O, de Weerd A, Durmer JS, Kotagal S, Owens attention deficit/hyperactivity disorder: a retrospective analysis.
JA, Simakajornboon N (2013) Pediatric restless legs syndrome J Med Econ 16:962–975. doi:10.3111/13696998.2013.800524
diagnostic criteria: an update by the International Restless Legs Silvestri R et al (2009) Sleep disorders in children with attention-
Syndrome Study Group. Sleep Med 14:1253–1259. doi:10.1016/ deficit/hyperactivity disorder (ADHD) recorded overnight by
j.sleep.2013.08.778 video-polysomnography. Sleep Med 10:1132–1138. doi:10.
Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) 1016/j.sleep.2009.04.003
The worldwide prevalence of ADHD: a systematic review and Sobanski E, Schredl M, Kettler N, Alm B (2008) Sleep in adults with
metaregression analysis. Am J Psychiatry 164:942–948. doi:10. attention deficit hyperactivity disorder (ADHD) before and
1176/appi.ajp.164.6.942 during treatment with methylphenidate: a controlled polysom-
Prihodova I, Paclt I, Kemlink D, Skibova J, Ptacek R, Nevsimalova S nographic study. Sleep 31:375–381
(2010) Sleep disorders and daytime sleepiness in children with Soylu E, Soylu N, Yildirim YS, Sakallioglu O, Polat C, Orhan I
attention-deficit/hyperactivity disorder: a two-night polysomno- (2013) Psychiatric disorders and symptoms severity in patients
graphic study with a multiple sleep latency test. Sleep Med with adenotonsillar hypertrophy before and after adenotonsil-
11:922–928. doi:10.1016/j.sleep.2010.03.017 lectomy. Int J Pediatr Otorhinolaryngol 77:1775–1781. doi:10.
Prihodova I, Paclt I, Kemlink D, Nevsimalova S (2012) Sleep 1016/j.ijporl.2013.08.020
microstructure is not altered in children with attention-deficit/ Spencer T, Biederman J, Wilens TE, Faraone SV (1998) Adults with
hyperactivity disorder (ADHD). Physiol Res/Academia Scien- attention-deficit/hyperactivity disorder: a controversial diagno-
tiarum Bohemoslovaca 61:125–133 sis. J Clin Psychiatry 59(Suppl 7):59–68

123
18 A. Hvolby

Spencer SV, Hawk LW Jr, Richards JB, Shiels K, Pelham WE Jr, Van der Heijden KB, Smits MG, Van Someren EJ, Gunning WB
Waxmonsky JG (2009) Stimulant treatment reduces lapses in (2005) Idiopathic chronic sleep onset insomnia in attention-
attention among children with ADHD: the effects of methylphe- deficit/hyperactivity disorder: a circadian rhythm sleep disorder.
nidate on intra-individual response time distributions. J Abnorm Chronobiol Int 22:559–570. doi:10.1081/cbi-200062410
Child Psychol 37:805–816. doi:10.1007/s10802-009-9316-2 Van der Heijden KB, Smits MG, Van Someren EJ, Ridderinkhof KR,
Spruyt K, Gozal D (2011) Sleep disturbances in children with Gunning WB (2007) Effect of melatonin on sleep, behavior, and
attention-deficit/hyperactivity disorder. Expert Rev Neurother cognition in ADHD and chronic sleep-onset insomnia. J Am
11:565–577. doi:10.1586/ern.11.7 Acad Child Adolesc Psychiatry 46:233–241. doi:10.1097/01.chi.
Spruyt K, Gozal D, Dayyat E, Roman A, Molfese DL (2011) Sleep 0000246055.76167.0d
assessments in healthy school-aged children using actigraphy: Van Veen MM, Kooij JJ, Boonstra AM, Gordijn MC, Van Someren
concordance with polysomnography. J Sleep Res 20:223–232. EJ (2010) Delayed circadian rhythm in adults with attention-
doi:10.1111/j.1365-2869.2010.00857.x deficit/hyperactivity disorder and chronic sleep-onset insomnia.
Steer C, Froelich J, Soutullo CA, Johnson M, Shaw M (2012) Biol Psychiatry 67:1091–1096. doi:10.1016/j.biopsych.2009.12.
Lisdexamfetamine dimesylate: a new therapeutic option for 032
attention-deficit hyperactivity disorder. CNS Drugs 26:691–705. Vriend J, Corkum P (2011) Clinical management of behavioral
doi:10.2165/11634340-000000000-00000 insomnia of childhood. Psychol Res Behav Manag 4:69–79.
Stein MA (1999) Unravelling sleep problems in treated and untreated doi:10.2147/PRBM.S14057
children with ADHD. J Child Adolesc Psychopharmacol Weiss MD, Wasdell MB, Bomben MM, Rea KJ, Freeman RD (2006)
9:157–168 Sleep hygiene and melatonin treatment for children and adoles-
Stein MA, Waldman ID, Charney E, Aryal S, Sable C, Gruber R, cents with ADHD and initial insomnia. J Am Acad Child
Newcorn JH (2011) Dose effects and comparative effectiveness Adolesc Psychiatry 45:512–519. doi:10.1097/01chi.0000205706.
of extended release dexmethylphenidate and mixed amphet- 78818.ef
amine salts. J Child Adolesc Psychopharmacol 21:581–588. Wender PH (1998) Attention-deficit hyperactivity disorder in adults.
doi:10.1089/cap.2011.0018 Psychiatr Clin North Am 21:761–774
Sung V, Hiscock H, Sciberras E, Efron D (2008) Sleep problems in Wiebe S, Carrier J, Frenette S, Gruber R (2013) Sleep and sleepiness
children with attention-deficit/hyperactivity disorder: prevalence in children with attention deficit/hyperactivity disorder and
and the effect on the child and family. Arch Pediatr Adolesc Med controls. J Sleep Res 22:41–49. doi:10.1111/j.1365-2869.2012.
162:336–342. doi:10.1001/archpedi.162.4.336 01033.x
Suratt PM, Diamond R, Barth JT, Nikova M, Rembold C (2011) Wiggs L, Montgomery P, Stores G (2005) Actigraphic and parent
Movements during sleep correlate with impaired attention and reports of sleep patterns and sleep disorders in children with
verbal and memory skills in children with adenotonsillar subtypes of attention-deficit hyperactivity disorder. Sleep
hypertrophy suspected of having obstructive sleep disordered 28:1437–1445
breathing. Sleep Med 12:322–328. doi:10.1016/j.sleep.2010.10. Wilens TE, Biederman J, Spencer T (1994) Clonidine for sleep
007 disturbances associated with attention-deficit hyperactivity dis-
Surman CB, Roth T (2011) Impact of stimulant pharmacotherapy on order. J Am Acad Child Adolesc Psychiatry 33:424–426
sleep quality: post hoc analyses of 2 large, double-blind, Wilens T et al (2003) ADHD treatment with once-daily OROS
randomized, placebo-controlled trials. J Clin Psychiatry methylphenidate: interim 12-month results from a long-term
72:903–908. doi:10.4088/JCP.11m06838 open-label study. J Am Acad Child Adolesc Psychiatry
Swanson J et al (2003) Development of a new once-a-day formulation 42:424–433. doi:10.1097/01.CHI.0000046814.95464.7D
of methylphenidate for the treatment of attention-deficit/ Wolraich ML et al (2001) Randomized, controlled trial of OROS
hyperactivity disorder: proof-of-concept and proof-of-product methylphenidate once a day in children with attention-deficit/
studies. Arch Gen Psychiatry 60:204–211 hyperactivity disorder. Pediatrics 108:883–892
Taheri S, Lin L, Austin D, Young T, Mignot E (2004) Short sleep Wolraich M et al (2011) ADHD: clinical practice guideline for the
duration is associated with reduced leptin, elevated ghrelin, and diagnosis, evaluation, and treatment of attention-deficit/hyper-
increased body mass index. PLoS Med 1:e62. doi:10.1371/ activity disorder in children and adolescents. Pediatrics
journal.pmed.0010062 128:1007–1022. doi:10.1542/peds.2011-2654
Tamm L, Narad ME, Antonini TN, O’Brien KM, Hawk LW Jr, World Health Organization (1992) International statistical classifica-
Epstein JN (2012) Reaction time variability in ADHD: a review. tion of diseases and related health problems (ICD-10), 10th edn.
Neurotherapeutics 9:500–508. doi:10.1007/s13311-012-0138-5 World Health Organization, Geneva
Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG (2003) Yoon SY, Jain U, Shapiro C (2012) Sleep in attention-deficit/
Melatonin for treatment of sleeping disorders in children with hyperactivity disorder in children and adults: past, present, and
attention deficit/hyperactivity disorder: a preliminary open label future. Sleep Med Rev 16:371–388. doi:10.1016/j.smrv.2011.07.
study. Eur J Pediatr 162:554–555. doi:10.1007/s00431-003- 001
1207-x Youssef NA, Ege M, Angly SS, Strauss JL, Marx CE (2011) Is
Tsai MH, Huang YS (2010) Attention-deficit/hyperactivity disorder obstructive sleep apnea associated with ADHD? Ann Clin
and sleep disorders in children. Med Clin North Am 94:615–632. Psychiatry 23:213–224
doi:10.1016/j.mcna.2010.03.008

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