Adhd

clinical practice
The new engl and journal o f medicine

n engl j med 370;9 nejm.org february 27, 2014
838
An audio version
of this article is
available at
NEJM.org
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.
Caren G. Solomon, M.D., M.P.H., Editor
Attention DeficitHyperactivity Disorder
in Children and Adolescents
Heidi M. Feldman, M.D., Ph.D., and Michael I. Reiff, M.D.
From the Department of Pediatrics, Stan-
ford University School of Medicine, Stan-
ford, CA (H.M.F.); and the Department of
Pediatrics, University of Minnesota, Min-
neapolis (M.I.R.). Address reprint requests
to Dr. Feldman at the Department of Pedi-
atrics, Stanford University School of Med-
icine, 750 Welch Rd., Suite 315, Palo Alto,
CA 94304, or at hfeldman@stanford.edu.
N Engl J Med 2014;370:838-46.
DOI: 10.1056/NEJMcp1307215
Copyright 2014 Massachusetts Medical Society.
A 9-year-old boy who received a diagnosis of attention deficithyperactivity disorder
(ADHD) at 7 years of age is brought to your office by his parents for a follow-up visit.
He had had behavioral problems since preschool, including excessive fidgeting and
difficulty following directions and taking turns with peers. Parent and teacher
ratings of behavior confirmed elevated levels of inattention, hyperactivity, and im-
pulsivity that were associated with poor grades, disruptions of classroom activities,
and poor peer relationships. He was treated with sustained-release methylphenidate.
Although parent and teacher rating scales after treatment showed reduced symp-
toms, he still makes many careless mistakes and has poor grades and no friends.
What would you advise?
The Clinical Problem
ADHD in children is characterized by inattention, hyperactivity, impulsivity, or a
combination of these symptoms, which compromise basic everyday functions such
as learning to read and making friends.
1,2
In the absence of biomarkers, diagnostic
criteria focus on behavioral symptoms. Since the same characteristics may be ob-
served in children and adolescents during typical development, the diagnosis of
ADHD calls for symptoms that are severe, out of proportion to expectations accord-
ing to the childs age or developmental level, and persistent and for which there are
no appropriate alternative explanations. The disorder is typically diagnosed in
childhood, but affected persons frequently remain symptomatic into adulthood.
3

ADHD is associated with low rates of high-school graduation and completion of
postsecondary education
4
and poor peer relationships,
5
even when it is appropriately
managed,
6
leading to high economic and social burdens.
7,8
ADHD is the most prevalent neurodevelopmental disorder among children. In
the United States, approximately 5.4 million children between 6 and 17 years of
age (9.5% of all U.S. children) have received an ADHD diagnosis.
9
The prevalence
of this condition increased by 33% between 19971999 and 20062008.
10
High
prevalence rates suggest overdiagnosis. Studies of regional variation in the United
States have shown that higher prevalence is associated with increased physician
supply,
11
and total sales of medications to treat ADHD have soared with marketing
to physicians and directly to the general public
12
findings that are consistent
with overdiagnosis or overreporting. However, there are also indications of under-
diagnosis. Children with disruptive and hyperactive behaviors are the most likely
to be referred for clinical evaluation, and in children who do not have these be-
haviors, ADHD may remain unidentified or untreated.
13,14
In community-based
samples, the prevalence of this condition is higher among boys than among girls,
and more boys than girls have a combination of inattention and hyperactivity
rather than inattention alone.
The New England Journal of Medicine
Downloaded from nejm.org on July 8, 2014. For personal use only. No other uses without permission.
Copyright 2014 Massachusetts Medical Society. All rights reserved.
clinical practice
839
An international meta-regression analysis
showed an aggregate prevalence of ADHD of 5.3%
(95% confidence interval, 5.0 to 5.6); var iations
in prevalence were related to diagnostic criteria.
The prevalence in Africa and the Middle East is
lower than in other regions of the world.
15
Classification
In community-based samples, among children
who do not meet diagnostic criteria for ADHD,
symptoms of inattention and overactivity corre-
late inversely with academic performance
16,17
;
this finding indicates that the severity threshold
in this disorder is arbitrary. Criteria from the
Diagnostic and Statistical Manual of Mental Disorders
(DSM) of the American Psychiatric Association
guide diagnosis in the United States.
1,2
The crite-
ria in the fifth and most recent version, the DSM-5,
which was released in May 2013, have not
changed substantially from those of the DSM-IV.
In both editions, the diagnosis in children is
based on the presence of at least six of nine
symptoms in either or both of two domains: in-
attention and hyperactivityimpulsivity. The DSM-5
differs from the previous edition in that adoles-
cents and adults must present with at least five
symptoms in either or both of the two domains,
symptoms must be present before 12 years of
age, and the diagnosis of ADHD can be made in
persons who also have a diagnosis of autism
spectrum disorder.
2
A section of the DSM-5 on
risks and prognostic factors emphasizes the need
to take into account the childs environmental cir-
cumstances. Long-term life stressors such as pov-
erty and physical or emotional abuse may lead to
symptoms similar to ADHD or may increase the
severity of ADHD symptoms.
The International Classification of Diseases, 10th edi-
tion (ICD-10),
18
uses the alternative term hyper-
kinetic disorder. A diagnosis of ADHD accord-
ing to this classification requires the presence of
both impaired attention and activity problems
19
;
thus, there is a lower prevalence of ADHD ac-
cording to the ICD-10 criteria than according to
the DSM-5 criteria (Table 1).
Pathogenesis and Risk Factors
Family, twin, and adoption studies provide evi-
dence that ADHD has a genetic component.
Heritability has been estimated at 76%.
20
Meta-
analyses of candidate-gene association studies
have shown strong associations between ADHD
and several genes involved in dopamine and
serotonin pathways.
20
Multiple genes, each with
a small effect, may together mediate genetic
vulnerability. Nongenetic factors (e.g., maternal
smoking during pregnancy or exposure to envi-
ronmental lead or polychlorinated biphenyls)
may also interact with genetic predisposition in
the pathogenesis of ADHD.
21,22
key Clinical points
Attention DeficitHyperactivity Disorder in Children and Adolescents
Attention deficithyperactivity disorder (ADHD), the most prevalent neurobehavioral disorder in chil-
dren, is associated with adverse long-term functional outcomes.
Diagnostic evaluation relies on the use of validated parent and teacher rating scales that assess the
childs behavior in everyday situations in various environments. Adolescents provide self-report as part
of the diagnostic evaluation.
Coexisting conditions and problems, especially learning disorders, anxiety and depression (internalizing
disorders), and oppositional behaviors and conduct disturbance (externalizing disorders), must be con-
sidered in the evaluation and management of ADHD.
Treatment should address a childs areas of functional disability rather than focus exclusively on ADHD
core symptoms. Management plans developed with the child and family members, including parents,
should specify measurable target objectives that relate to broader functional outcomes and are moni-
tored in the evaluation of treatment effectiveness.
Stimulant medications reduce the symptoms of ADHD without necessarily improving corresponding
functional limitations.
Behavior management is not as effective as medication in reducing core symptoms, but it improves func-
tioning, which is important for subgroups of children with ADHD, and it increases parental satisfaction.
840
Neuroimaging studies have shown that
ADHD is associated with a delay in cortical
maturation.
23
ADHD has long been thought to re-
flect dysfunction of prefrontalstriatal circuitry.
24

Recent studies suggest that the pathophysiological
features also encompass large-scale neural net-
works, including frontal-to-parietal cortical con-
nections.
25
However, measures of brain struc-
ture and function in persons with ADHD overlap
substantially with those of the general popula-
tion and thus are not useful in diagnosis.
Strategies and Evidence
Diagnosis
Core symptoms that are diagnostic of ADHD are
not always observed in children in the clinical
setting. Therefore, parents, teachers, and others
with knowledge of the child must provide infor-
mation about the childs symptoms in everyday
situations. In adolescents, self-report is an addi-
tional element in assessment because overt
symptoms of inattention and hyperactivity sub-
side and adult observers cannot judge the inter-
nal challenges to maintaining attention or still-
ness. Quantification of behavioral traits with the
use of reliable, validated rating scales is impor-
tant to document the severity of symptoms be-
fore and after the initiation of treatment (see
Table 1 in the Supplementary Appendix, available
with the full text of this article at NEJM.org).
Other medical and psychosocial conditions
with manifestations similar to those of ADHD
should be considered in the diagnostic process.
These conditions include seizure disorders,
sequelae of central nervous system trauma or
infection, sleep disorders, hyperthyroidism, phys-
ical or sexual abuse, and substance abuse. How-
ever, no medical, psychological, or neuropsycho-
logical tests are required to establish the
diagnosis unless relevant signs or symptoms are
noted in the history or physical examination.
26
ADHD frequently presents with other condi-
tions and problems, primarily learning and
language disorders, oppositional behavior and
conduct disturbance (externalizing disorders),
anxiety and depression (internalizing disorders),
and coordination difficulties.
26
ADHD may also
accompany autism, the fragile X syndrome, epi-
lepsy, traumatic brain injury, Tourettes syn-
drome, and sleep disturbance. The diagnostic
process should identify any coexisting conditions
to modify the management plan accordingly.
The International Classification of Functioning, Dis-
Table 1. Criteria for the Diagnosis of Attention DeficitHyperactivity Disorder (ADHD) and Hyperkinetic Disorder.
Criteria DSM-IV* DSM-5 ICD-10
Symptoms
Inattention Six of nine symptoms Six of nine symptoms in children;
five of nine symptoms in adoles-
cents and adults (17 yr)
Three of five symptoms
Hyperactivity and
impulsivity
Six of nine symptoms Six of nine symptoms in children;
five of nine symptoms in adoles-
cents and adults (17 yr)
Three of five symptoms of hyperac-
tivity and one of four symptoms
of impulsivity
Age at onset <7 yr <12 yr <7 yr
Settings Either inattention or hyperactivity
impulsivity in 2 settings
2 settings Inattention and hyperactivity at
home and school
Duration 6 mo 6 mo 6 mo
Impairment Clinically significant impairment in
social, academic, or occupational
functioning
Interference with functioning or devel-
opment; specify mild, moderate, or
severe functional impairment or
symptoms
Clinically significant distress or im-
pairment in social, academic, or
occupational functioning
Subtypes ADHD: combined type (inattentive
and hyperactiveimpulsive),
predominantly inattentive type,
or predominantly hyperactive
type
ADHD: combined inattentive and hy-
peractiveimpulsive presentation,
predominantly inattentive presenta-
tion, or predominantly hyperactive
impulsive presentation
Hyperkinetic syndrome, hyperkinet-
ic conduct disorder, or other hy-
perkinetic disorders
* The criteria are based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).
1
The criteria are based on the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5).
2
The criteria are based on the International Classification of Diseases, 10th edition (ICD-10).
19
clinical practice
841
ability and Health
27,28
provides a systematic approach
for cataloguing the range of functional conse-
quences of ADHD and coexisting conditions
with respect to body function and structures,
activities of daily living, and participation in the
community.
4,29
Specific functions that may be
impaired in ADHD are listed in Figure 1 in the
Supplementary Appendix. Functional assessment
at the time of diagnosis is useful for documenting
the type and extent of functional difficulties and
identifying meaningful goals for management.
Management
ADHD is a long-term condition. As such, treatment
should take place within a medical home,
30,31

where the health care team collaborates and co-
ordinates with the family, other health and men-
tal health clinicians, educators, and the patient
to develop comprehensive plans that address
symptoms and function over time. Management
plans should specify measurable target objectives
that relate to broader functional outcomes and
that guide the evaluation of treatment effective-
ness.
26
Objectives may include quantifiable in-
creases in academic accuracy and productivity,
prosocial behaviors, and decreased classroom
disruptions.
Medications
Short-term randomized, placebo-controlled trials
(generally <4 months in duration) involving chil-
dren with ADHD have shown a clinically signifi-
cant benefit of stimulant medications (derived
from methylphenidate or amphetamines) in reduc-
ing inattention, hyperactivity, and impulsivity.
32-34

Comparative-effectiveness studies have shown
that various stimulants are similar in terms of
effect size and adverse-effect profiles, though in-
dividual patients may have greater positive effects,
fewer adverse effects, or both with particular
medications than with others.
33,35
Sustained-
release and long-acting preparations of stimu-
lant medications are generally preferred over
short-acting agents because they allow adminis-
tration of a single morning dose to improve
symptoms for the entire school day without in-
creasing adverse effects. Table 2 lists medica-
tions for the treatment of ADHD, their recom-
mended doses, and potential adverse effects. The
two most common side effects are appetite sup-
pression and delayed onset of sleep.
One selective norepinephrine-reuptake inhibitor
(atomoxetine) and two selective
2
-adrenergic ago-
nists (extended-release guanfacine and extended-
release clonidine) have been shown to be effective
in reducing core symptoms in short-term placebo-
controlled clinical trials, but they have weaker
effects than those reported with stimulants
(Table 2).
36
Nonstimulant medications play an
important role in the management of ADHD
when parents do not want their children to re-
ceive stimulants, when stimulants are contrain-
dicated or have adverse effects, or when there is
a history or high likelihood of addiction or di-
version of medication for recreational use.
Behavioral Therapy
Behavioral therapy is central to the management
of ADHD.
37
Efficacy has been established in clin-
ical trials, crossover studies, and studies with
single-subject designs.
37
Behavioral therapies en-
hance motivation by using rewards and other
consequences and by providing models and op-
portunities for social learning.
38
Parental training
in behavioral management (called behavioral
parent training) is a systematic approach that
teaches parents to shape their childs behaviors
with the use of the basic principles of behavior
modification and social learning theory (Table 3).
Program features associated with better out-
comes include teaching parents how to commu-
nicate about their emotions, promoting positive
parentchild interaction skills, and requiring par-
ents to practice applying behavior-modification
techniques with their children during training
sessions.
39
Behavioral peer interventions that have
been found to be effective in randomized clinical
trials involve daylong, intensive social-skills train-
ing in natural settings such as summer school.
Peer interventions are often instituted concur-
rently with behavioral parent training.
37
In nonrandomized studies, behavioral class-
room management at school has been associat-
ed with moderate-to-large improvements in aca-
demic and behavioral functioning in children
with ADHD (Table 3).
40
School-based strategies
have been successful in positive environments
where punishment is minimized.
40
Because ADHD
is a disability, U.S. schools can provide accom-
modations, including behavior-management ser-
vices, for children with this disorder under
section 504 of the Rehabilitation Act of 1973.
ADHD is not an eligibility category for special-
education services under the Individuals with
Disabilities Education Act. Children with ADHD
may be eligible for an individualized educational
842
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3
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clinical practice
843
program under other criteria (such as other health
impairment or specific learning disability) if
their symptoms interfere with learning.
The Multimodal Treatment of ADHD Study
(MTA), the longest trial of ADHD treatment
(14 months), compared the use of medication
(with monthly visits after the initial dose adjust-
ment), intensive behavioral therapy, the combi-
nation of medical and behavioral therapy, and
community-based care in children who were 7.0
to 9.9 years of age at study entry.
41
Symptoms
improved after treatment in all groups. Medi-
cation (predominantly methylphenidate hydro-
chloride) was superior to behavioral therapy for
reducing the core symptoms of ADHD; the com-
bination of medical and behavioral therapy was
not significantly more effective than medication
alone for these symptoms. Secondary analyses
showed that, as compared with medication alone,
combined therapy resulted in greater improve-
ments in academic performance and reductions
in conduct problems, higher levels of parental sat-
isfaction, and the use of lower doses of stimulant
medication. Combined therapy was also superior
for treating children of low socioeconomic sta-
tus and those with coexisting anxiety.
42
Treatment of Preschool Children
The medical treatment of preschoolers with ADHD
is controversial. An 8-week randomized, placebo-
controlled trial of medication (the Preschool
ADHD Treatment Study) enrolled preschoolers
who remained symptomatic after their parents
had received required behavior-management train-
ing.
43
Stimulant medication improved symptoms.
The American Academy of Pediatrics (AAP) rec-
ommends that behavior management precede any
consideration of medication for preschoolers.
26,36
Longitudinal Care
The AAP recommends monthly visits for adjust-
ing medication in children and adolescents with
ADHD, followed by at least semiannual visits un-
til steady progress toward behavioral and func-
tional goals has been achieved.
36
Follow-up care
requires monitoring of symptoms, concurrent con-
ditions, measurable objectives, and general func-
tional outcomes. Routine monitoring in children
receiving medication should include measure-
ments of height, weight, blood pressure, and
heart rate. Adverse reactions may change over
time and should be assessed routinely. The dura-
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844
tion of medication use depends on its effects on
behavior and function over time. As children ap-
proach adulthood, objectives shift increasingly
toward social relationships, completing high
school and receiving higher education, employ-
ment, and other relevant functional domains
(Fig. 1 in the Supplementary Appendix).
Many studies show that children and adoles-
cents switch forms of treatment over time and
often discontinue the use of medication after
2 to 3 years.
44
Follow-up of the MTA cohort
6 to 8 years after the trial, when participants
were 13 to 18 years of age, showed that the
original study groups did not continue to re-
ceive their randomly assigned treatment and
did not differ significantly from each other
with respect to any variables, including grades,
arrests, and psychiatric hospitalizations.
6
The
study participants fared worse on outcomes
than local age-matched, normative comparison
groups. The best predictors of functioning in
adolescents were the severity of symptoms at
enrollment, the socioeconomic status of the
participants family, and the degree of his or
her response to any of the initial assigned study
treatments.
Areas of Uncertainty
Concerns have been raised about increased car-
diovascular risk and decreased height after pro-
longed use of stimulant medication for ADHD.
Although in 2008 the American Heart Associa-
tion recommended electrocardiography in chil-
dren before they begin to receive stimulant med-
ications, subsequent studies showed that the
frequency of unexpected death among children
receiving stimulants was no higher than the fre-
quency in the general population of children.
45,46

Before stimulants are prescribed, it is prudent to
inquire about the patients cardiac history and
family history of syncope or unexplained death.
34

A meta-analysis of cohort studies and clinical
trials concluded that height attenuation with the
use of stimulant medication is dose-dependent
and is approximately 1 cm per year for up to
3 years of medication use. The amount of catch-
up growth after discontinuation of medical ther-
apy was inconsistent across studies.
47
Long-term
studies are needed to assess the risks and bene-
fits of ongoing treatment with medication.
Another area of uncertainty is whether vari-
ous broad-based interventions might reduce the
prevalence or severity of ADHD.
38
Examples in-
clude training preschool children to use execu-
tive-function skills, such as response inhibition
and working memory,
48
which has led to im-
provements in executive function at older ages;
reducing noise in classrooms
49
; and altering
adverse factors associated with living in poverty,
such as reducing food insecurity or increasing
access to high-quality early education. Short-
and long-term effects of interventions that tar-
get family, social, and environmental factors
(e.g., increasing structure at home and school)
also warrant evaluation.
A total of 12 to 64% of families with a child
who has ADHD have reported the use of comple-
mentary and alternative therapies in their chil-
dren. These therapies include dietary supple-
mentation with essential fatty acids and high
doses of vitamins, changes in diet, and electro-
encephalographic biofeedback.
50
The evidence is
insufficient to recommend these therapies. Che-
lation and megavitamins may have adverse ef-
fects and are contraindicated.
51
Careful study of
new educational interventions, social-skills train-
ing, and life coaching is needed before these ap-
proaches can be recommended.
Adolescents who do not meet criteria for
ADHD are increasingly using stimulant medica-
tions to improve cognitive skills (referred to as
neuroenhancement, though performance en-
hancement may be more accurate).
51
Strategies
are needed to ensure that stimulant medications
are appropriately prescribed, used as directed,
and not diverted for nonmedical use.
Guidelines
The AAP reissued practice guidelines for the di-
agnosis and management of ADHD,
36
highlight-
ing differences in the treatment of preschool,
school-age, and adolescent patients. A supple-
ment to these guidelines provides information
on how to ascertain the relevant data and engage
the child in clinical care.
36
The American Acad-
emy of Child and Adolescent Psychiatry (AACAP)
has also published guidelines for the diagnosis
and management of ADHD.
52
The AAP recom-
mends direct contact between clinicians and
teachers, whereas the AACAP permits parental
reports of school performance. In addition, the
AACAP recommends medication as first-line treat-
clinical practice
845
ment and psychosocial therapies if medication pro-
vides a less-than-satisfactory response, whereas the
AAP promotes both types of management.
Conclusions and
Recommendations
The child described in the vignette has the core
symptoms of ADHD inattention, hyperactivity,
and impulsivity with functional impairment in
academic performance and social relationships.
He had improvement in core symptoms of ADHD
when he received stimulant medication, as has
been shown in randomized trials of these medica-
tions. However, the use of stimulants alone did
not substantially improve his educational and so-
cial functioning. We recommend that the treating
physician suggest a comprehensive psychoeduca-
tional assessment to determine whether he has
learning disabilities. In addition, his academic
productivity and social difficulties should be tar-
geted for interventions; given the demonstrated
benefits of these methods in clinical studies, we
would recommend behavioral parental training,
behavioral classroom management, peer interven-
tion approaches, or a combination of these meth-
ods. Specific, individualized, measurable objectives
should be established and progress toward those
objectives carefully monitored in collaboration
with his family and teachers, as well as counselors,
coaches, and other advisors in the community.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
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