Pada PPDGJ III, Attention deficit-Hyperkinetic disorder termasuk dalam F 90 (gangguan

hiperkinetik). Adapun ciri utama gangguan hiperkinetik adalah berkurangnya perhatian

dan adanya aktivitas berlebihan.
Berkurangnya perhatian
Hiperaktivitas
F90 sendiri terbagi menjadi F90.0 (Gangguan aktivitas dan perhatian), F90.1 (Gangguan
tingkah laku hiperkinetik), F90.2 (Kombinasi gangguan atensi dan hiperkinetik), F90.8
(Gangguan hiperkinetik lainnya), dan F90.9 (Gangguan hiperkinetik YTT).
F90.9 adalah kategori sisa, yang hanya boleh digunakan bila adanya kesulitan dalam
membedakan F90.0 dan F90.1, tetapi masih memenuhi keseluruhan kriteria F90.
.

KAPLAN:

ALMA M. SPANIARDI, M.D., LAURENCE L. GREENHILL, M.D., AND LILY I.

HECHTMAN, M.D.
INTRODUCTION (EPID)
Attention-deficit/hyperactivity disorder (ADHD) is the most common
childhood behavioral disorder diagnosed in outpatient settings in the
United States. It is a chronic disorder which can cause impairment into
adolescence and adulthood. In 2007, Polanczyk and colleagues estimated
worldwide prevalence of ADHD in children and adolescents to be 5.29
percent using a comprehensive meta-analysis including hundreds of
articles and more than 100,000 patients. Similarly, a meta-analysis from
2012 by Willicut using full DSM-IV diagnostic criteria found the prevalence
of ADHD to be 5.9 to 7.1 percent. It has been suggested that the prevalence
of ADHD is higher in males and younger children. The National Survey of
Children’s Health (NSCH), which showed that 11 percent of US school-aged
children had been diagnosed with ADHD by 2011, an increase of 42 percent
since the previous survey in 2003. It has been suggested that the increasing
rates of diagnosis and treatment may be due to increased awareness and
access to care as opposed to an increase in the number of children in the
population meeting criteria for ADHD.
HISTORY
ADHD first was described by George Still in 1902, who wrote about
children who were restless, impulsive, and inattentive, with intense
affective responses and conduct problems. After the influenza pandemic
and the epidemic of encephalitis lethargica in 1919 to 1920, children who
survived the flu frequently developed severe behavior problems and are
now thought to have suffered organic brain damage. For that reason, the
childhood condition was termed “minimal brain damage syndrome,” even
though brain damage could not be proven. In the early 1960s, the condition
was renamed “minimal brain dysfunction.” Not only did these terms postulate unproven
etiological mechanisms, they were also stigmatizing.
The ninth revision of the International Classification of Diseases and
Related Health Problems (ICD-9) and the second edition of the DSM
adopted the same descriptive term for the condition—hyperkinetic
syndrome of childhood. The 1980 version of the APA classificatory system,
DSM-III, renamed this diagnosis attention-deficit disorder (ADD) due to
research suggesting that the main disability was the difficulty of
maintaining sustained attention and impulsivity. Much of the diagnostic
criteria for ADHD has remained the same between DSM-IV in 1994, the
text revision, DSM-IV-TR in 2000, and the most recent version, DSM-5,
released in May 2013.
DIAGNOSIS AND DEFINITION
The fifth edition of the American Psychiatric Association’s (APA)
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5), published in May 2013, describes ADHD as a pattern of
inattentive and/or hyperactive–impulsive behavior inconsistent with
developmental level which interferes with functioning in social,
educational, or work settings. Symptoms are divided into two categories:
inattention and hyperactivity and impulsivity. There are five main
diagnostic criteria: (1) onset before age 12 years old; (2) duration greater
than 6 months; (3) children must have at least six symptoms from the
inattention and/or hyperactive/impulsive symptom list, while older
adolescents and adults must have at least five; (4) several symptoms must
be present in two or more settings and interfere with functioning; and (5)
symptoms that do not occur exclusively during the course of schizophrenia
or other psychotic disorder and are not better accounted for by another
mental disorder, such as depression. DSM-5 has no exclusion criteria for
those with Autism Spectrum Disorder (ASD), allowing both Autism and
ADHD to be diagnosed simultaneously in the same patient. Possible
specifiers for the disorder in DSM-5 include combined presentation
(criterion met for both inattention and hyperactivity–impulsivity),
predominantly inattentive presentation or predominantly
hyperactive/impulsive presentation. Other specifiers describe current
severity of the disorder being mild (few to no symptoms in excess of those
required), moderate or severe (many symptoms in excess of those
required), or to specify if the disorder is in partial remission (fewer than
full criteria met in past 6 months, but still result in impairment).
The inattention symptom criteria list includes: (a) Often fails to give
close attention to details or makes careless mistakes in schoolwork, at
work, or during other activities; (b) Often has difficulty sustaining attention
in tasks or play activities; (c) Often does not seem to listen when spoken to
directly; (d) Often does not follow through on instructions and fails to
finish schoolwork, chores, or duties in the workplace; (e) Often has difficulty organizing
tasks and activities; (f) Often avoids, dislikes, or is
reluctant to engage in tasks that require sustained mental effort; (g) Often
loses things necessary for tasks or activities; (h) Often easily distracted by
extraneous stimuli (or unrelated thoughts for adolescents and adults); and
(i) Often forgetful in daily activities.
Hyperactivity and impulsivity symptoms criteria include: (a) Often
fidgets with or taps hands or feet or squirms in seat; (b) Often leaves seat in
situations when remaining seated is expected; (c) Often runs about or
climbs in situations where it is inappropriate; (d) Often unable to play or
engage in leisure activities quietly; (e) Often “on the go,” acting as if “driven
by a motor”; (f) Often talks excessively; (g) Often blurts out an answer
before a question has been completed; (h) Often has difficulty waiting his
or her turn; and (i) Often interrupts or intrudes on others.
In the DSM-5 enhanced item descriptors were added to diagnostic
criteria to demonstrate symptoms across the lifespan. For example, motor
hyperactivity appears far less frequently in affected adolescents and adults,
who continue to have attentional and organizational problems, poor anger
management, job instability, and problems with social relationships and
self-esteem. All 18 of the DSM-IV-TR symptoms of ADHD were retained in
the DSM-5, but enhanced elaborators of each were added to better describe
difficulties experienced by adolescents and adults. For instance, the
inattention criteria “Often avoids, dislikes, or is reluctant to engage in tasks
that require sustained mental effort” now includes specific examples of this
symptom “(preparing reports, completing forms, reviewing lengthy
papers)” to be applied to older adolescents and adults in addition to
“(schoolwork or homework)” which is primarily specific to children.
Concerns about Changes in DSM-5
DSM-5 addresses limitations in the prior edition. There is a concern that
the decision in DSM-5 to increase the age of onset allowed for diagnosis
from 7 years old to 12 years old may inflate the prevalence of positive
diagnoses in adults. The onset criterion of age 7 used in three prior editions
of the DSM lacked empirical validation. The aim of the 5-year extension in
upper age limit for diagnosis was to improve diagnosis of adults, while still
maintaining ADHD as a neurodevelopmental disorder with childhood
onset. However, there is concern that the prevalence of ADHD will increase
as a result, especially in older children, adolescents, and adults (McKeown
et al., 2015). The prevalence rate may also increase in individuals with
inattentive subtype, as inattention has been found to have a later onset. A
recent study by Matte et al. has suggested a 27 percent increase in the
expected prevalence of ADHD among young adults when comparing DSMIV
to DSM-5 criteria while Polanczyk et al. found that the age adjustment to
12 would have minimal impact. COMPARATIVE NOSOLOGY
Clinicians in Europe use a very different diagnostic description of ADHD
than that in the DSM-5: The ICD-10 diagnosis of “hyperkinetic disorder
(HD).” The differences include the extent to which medication should be
used and the algorithm used to diagnose the disorder. The DSM-5
diagnosis of ADHD and the ICD-10 diagnosis of HD are based on the same
18 symptoms, but the two systems use different decision rules. Fewer
children are classified with ADHD using ICD-10 than in DSM-IV. For
example, investigators in the United Kingdom applied an algorithm to the
579 children with DSM-IV ADHD Combined Subtype who had been
recruited into the National Institute of Mental Health (NIMH) Multimodal
Treatment Study of Attention-Deficit/Hyperactivity Disorder (MTA trial) in
order to generate an ICD-10 diagnosis of HD. Only 25 percent of the MTA
sample continued to meet the diagnostic criteria for HD. This suggests that
cultural differences in referral practices and clinician preferences play a
role in determining international differences in diagnoses of ADHD and
HD.
ETIOLOGY
ADHD is a complex disorder of multifactorial etiology, thought to have
multiple genetic and environmental variables of small effect acting together
to produce vulnerability to ADHD. Although the etiology of ADHD yet has
to be determined, there is a growing consensus that the condition involves
functional and anatomical dysfunction in the brain’s cortico-basal gangliathalamo-
cortical circuitry. These areas support the regulation of attentional
resources, the programming of complex motor behaviors, and the learning
of responses to reinforcement. Theories involving these areas have been
examined in series involving neurobiological studies of healthy humans,
humans with ADHD, and animal models.
Genetics
Twin, sibling, adoption, and family studies all suggest a strong genetic
component in the development of hyperactivity, inattention, and
impulsivity, with heritability index estimated to range from 0.6 to 0.98.
Heritability estimates include both genetic influences, as well as the effects
of gene–environment interaction. ADHD-like behaviors have been
reported in rare genetic disorders such as fragile X syndrome,
neurofibromatosis type 1, DiGeorge syndrome, tuberous sclerosis, Turner
syndrome, Williams syndrome, Angelman and Prader-Willi.
Twin Studies. Twin studies suggest that 76 percent of the variance in
the transmission of ADHD is attributable to genetics, making ADHD one of
the most heritable psychiatric disorders. Monozygotic twins have been found to be more
concordant for ADHD symptoms of hyperactivity,
inattention, and impulsivity than are same-sex dizygotic twins. The
concordance rate among monozygotic twins ranges from 59 to 92 percent,
whereas the concordance rate in dizygotic twins ranges from 29 to 42
percent.
Sibling and Half-Sibling Studies. MRI studies have found reduced
volumes in right prefrontal gray matter and left occipital gray and white
matter in both ADHD subjects and their unaffected siblings. An early study
compared the incidence of ADHD symptoms in 29 full-sibling and 22 halfsibling
pairs for evidence of minimal brain dysfunction. Each pair had been
raised together by a common mother. More than half (10) of the 19 full-sib
pairs were concordant for ADHD, compared with only 2 of the 22 half-sib
pairs, a significant difference, supporting the genetic influence on the
transmission of ADHD in families.
Adoption Studies. Studies have found that the biological relatives of
hyperactive children are more likely to be hyperactive themselves. This
relationship is not seen in adoptive relatives of hyperactive children.
Adoptive relatives of children with ADHD have risk of ADHD similar to
relatives of control children, while the biological relatives of children with
ADHD are more likely to have ADHD or associated disorders. In a study of
international adoptees aged 10 to 15 years, Van den Oord and colleagues
estimated that genes accounted for 47 percent of the variance of inattention
scores on the Child Behavior Checklist. Eighteen percent of biological
relatives of adopted-away children with ADHD were found to be at risk for
the disorder versus 6 percent of the child’s adopted relatives.
Family Studies. Family studies have shown that first-degree relatives of
children with ADHD are two to eight times more likely to have the disorder.
First-degree relatives of children with ADHD have a 20 to 25 percent risk
for ADHD, compared with 4 to 5 percent for relatives of controls. If a
parent has ADHD, 50 percent of his or her offspring are likely to have that
condition. The increased incidence of ADHD is also extended to seconddegree
relatives.
Mode of Inheritance. Several hypotheses of ADHD’s mode of
transmission have been advanced. Omenn explored the possibility of sexlinked
transmission because of the male preponderance in the condition.
Other theories include a polygenetic inheritance model, including those of
Morrison and Stewart, but limitations in sample size made this hard to
prove. Rhee and colleagues postulated a polygenetic multiple threshold
model after analyzing sex differences in an Australian twin and sibling-pair
study. However, differences in fit between genetic models were modest, as led to the
suggestion that symptoms of ADHD may be caused by several
interacting genes of modest effect. This hypothesis is consistent with
ADHD’s high population prevalence and high concordance in monozygotic
twins, but modest recurrence risk for first-degree relatives. However,
diagnostic uncertainty impedes progress in developing genetic models of
inheritance.
Molecular Genetic Studies. There has been increasing interest in
attempting to identify the specific “risk” genes that may be implicated in
the development of ADHD. This search has yielded generally inconsistent
results due to complexity of the trait and heterogeneity across studies.
Candidate genes have been chosen for study based on theoretical
considerations related to their function and the majority of studies have
concentrated on dopamine-related genes given the implication of
dopamine dysfunction in ADHD. Candidate genes discovered so far are
responsible for less than 5 percent of genetic variation in ADHD. Genomewide
association studies (GWAS) of ADHD have not yet revealed any
genome-wide significant association to common variation, indicating that
the effect sizes of risk variants are likely very small.
The dopamine transporter gene (DAT1) codes for a sodium-dependent
dopamine transporter protein that regulates reuptake of dopamine from
the synaptic cleft. Cook et al. were the first to show an association between
ADHD and DAT1 with 480–ase-pair allele. Several studies have indicated
that DAT1 might be more strongly associated with the
hyperactive/impulsive or combined subtypes of ADHD. Another early gene
studied was the dopamine type D2 receptor gene (DRD2). The gene is not
specific to ADHD and is not believed to be a primary cause of the disorder.
The dopamine 4 receptor seven-repeat allele gene (DRD4) has been linked
to novelty seeking and connected to the impulsivity seen in ADHD. DRD4
has also been related to the inattentive subtype of ADHD. The
synaptosomal-associated protein 25 gene (SNAP25) codes for a protein
involved in neurotransmitter regulation and axonal growth. McGough et al.
found an association between SNAP25 and sensitivity to methylphenidate
(MPH) adverse events in preschoolers with ADHD. Genes that code for
dopamine β-hydroxylase (DBH), catechol-O-methyltransferase (COMT),
dopamine 5 receptor gene, norepinephrine transporter gene (SLC6A2),
serotonin transporter gene (SLC6A4), α-2A adrenergic receptor (ADRA2A),
thyroid receptor B gene, androgen receptors and factors in immune
function and regulation have also been reported to correlate with ADHD
symptoms. Subsequent studies and meta-analysis have not sufficiently
supported the association between ADHD and these genes.
Neuroanatomical Aspects
Investigators have postulated the presence of an anterior attention network
for promoting multiple aspects of attention, including focusing, executing,
sustaining, and shifting functions. The attention networks are widespread
through the cortex of the brain and are closely related to the default mode
network described by Castellanos and others. MRI studies suggest that
there are structural abnormalities in the brains of children with ADHD,
including differences in the frontostriatal areas, temporoparietal lobes,
cerebellum, basal ganglia, corpus callosum, amygdala, hippocampus, and
thalamus. A meta-analysis of voxel-based morphometric (VBM) studies by
Nakao and colleagues of children and adults with ADHD found global
reductions in gray matter volumes, especially the right lentiform nucleus
extending to the caudate nucleus, with slightly larger gray matter volumes
in the left posterior cingulate cortex. These areas were demonstrated to
normalize with age as well as with stimulant medication treatment.
Developmentally, children with ADHD have a 3- to 5-year delay in cortical
thickness maturation, particularly in the frontal and temporal brain
regions. Diffusion tensor imaging (DTI) studies show white matter tract
abnormalities and dysfunctional connectivity in ADHD during rest and
while engaging in cognitive tasks.
Deficits in neural activity within frontostriatal and frontoparietal
circuits are consistent findings in ADHD. fMRI studies using cognitive
tasks to target the neural circuits show significantly reduced frontal lobe
activity in subjects with ADHD compared to controls. Meta-analysis shows
hypoactivation in the frontoparietal and ventral attention networks in
children with ADHD, areas which control goal-directed executive processes
and decision making. Hart and colleagues found that right dorsolateral
prefrontal cortex activation was reduced in medication-naive patients, but
normal in long-term stimulant-medicated patients.
Electroencephalography (EEG) studies have reported an elevated
theta/beta ratio (TBR) in subjects with ADHD versus controls, however,
increased theta band activity has also been associated with substance use
and bipolar disorder. Recent meta-analysis determined that excess theta
and elevated TBR was not a reliable diagnostic measure for ADHD, but
could have prognostic value for treatment outcome.
Neurotransmitters in ADHD
The nonspecific catecholamine hypothesis of ADHD posits that the
psychophysiology of ADHD symptomatology emerges from an imbalance
among various neurotransmitters, including norepinephrine, epinephrine,
and dopamine. Human studies investigating the catecholamine hypothesis
of ADHD produced conflicting results, possibly due to the difficulty of
measuring brain levels of these neurotransmitters in peripherally obtained
samples.
Dysfunction in brain norepinephrine systems, particularly a lack of inhibition of locus
coeruleus neurons, could explain the inattention,
cognitive deficits, and higher levels of gross motor activity seen in children
with ADHD. Randomized clinical trials (RCTs) have suggested that the
norepinephrine reuptake inhibitors (NRIs), tricyclic antidepressants
(TCAs) and atomoxetine, are effective in reducing ADHD symptoms by
restoring a more normal ratio of epinephrine and norepinephrine.
Molecular genetic studies have targeted genes that code for dopamine
receptors and PET scans in adults with ADHD have provided imaging data
that correlate stimulant-driven increases in dopamine concentration. There
is weak evidence for serotonin’s role in ADHD. Medications that exclusively
affect serotonin function, such as the selective serotonin reuptake
inhibitors (SSRIs), have no efficacy in the treatment of children with
ADHD. For that reason, serotonin is thought to play a secondary role in the
pathology of ADHD.
Environmental Factors
ADHD has been associated with numerous environmental factors, although
it is difficult to conclusively determine causality. In utero risk factors
include prenatal exposure to alcohol, nicotine, recreational drugs,
glucocorticoids, the toxins hexachlorobenzene and polychlorinated
biphenyls (PCBs), poor maternal diet and maternal stress during
pregnancy. Perinatal ADHD risks include prematurity, low birth weight,
and obstetric complications. ADHD has been associated with childhood
illnesses such as meningitis, encephalitis, cardiac disease, thyroid disease,
epilepsy, head trauma, and autoimmune and metabolic disorders. High
blood lead levels have also been linked with ADHD diagnosis, however, this
is likely not a major factor in the disorder. Psychosocial adversity including
poverty, childhood maltreatment, negative parenting, family discord, and
bullying have all been associated with ADHD. It has been difficult for
investigators working with children affected by adversity to determine
whether their ADHD symptoms reflect a response to negative parenting, a
harsh environment, a genetically influenced biological problem, or some
interaction among these factors.
Dietary Influences. Dietary factors as a cause and possible treatment of
ADHD are controversial. There have been reports of a connection between
ADHD and nutritional deficiencies of iron, zinc, and essential fatty acids
(omega-3 and omega-6), but the beneficial effects of supplementation are
inconclusive. Some studies have indicated that a small subset of children
may have sensitivity to certain foods, additives, excess sugar or nutritional
deficiencies, causing behavioral effects. There has been some support for
elimination diets to treat ADHD, such as the Feingold (additive and
salicylate-free) diet, oligoantigenic (hypoallergenic) diet, and ketogenic
diet. In 2011, the U.S. Food and Drug Administration determined that existing data do not
support a causal link between additives and behavioral
disturbance in children.
DIAGNOSIS AND CLINICAL FEATURES
The diagnosis of ADHD requires the integration of data from multiple
sources, including clinical interview, direct observation, behavioral rating
scales, and the subjective observations of parents and teachers. Most
children with ADHD are referred for care because of impairment in
academic, family, and/or peer relationship functioning. Symptoms of
impulsivity, overactivity, and inattention drive this impairment across the
lifespan.
Clinical Features
DSM-5 Diagnostic Criteria. DSM-5 diagnostic criteria for ADHD defines
three types of presentations based on two criteria lists of nine symptoms of
inattention and nine symptoms of hyperactivity/impulsivity. Children with
six or more symptoms of inattention and fewer than six symptoms of
hyperactivity–impulsivity are diagnosed with ADHD predominantly
inattentive presentation, while those with six or more symptoms of
hyperactivity/impulsivity and fewer than six symptoms of inattention meet
criteria for ADHD predominantly hyperactive/impulsive presentation.
ADHD combined presentation is diagnosed if full criteria from both lists
are met. Older adolescents and adults require only five symptoms from
either (or both) of the two criteria lists. For formal diagnosis of ADHD it is
necessary for symptoms be present prior to age 12, persist for at least 6
months, have a negative impact on social, academic, or occupational
activities and be present in two or more settings. The diagnosis is not
appropriate if the symptoms occur exclusively during the course of another
primary psychotic, mood, anxiety, or substance or personality disorder, but
ADHD may coexist with pervasive developmental disorder. DSM-5 has
included expanded item descriptors of symptoms to better represent the
experience of adolescents and adults of ADHD across the lifespan. There
are specifiers available to indicate severity of the disorder as mild,
moderate, or severe.
Hyperactivity. Hyperactivity describes the inappropriate excessive
motor activity observed in ADHD, including restlessness, fidgeting, and
appearing to be “driven by a motor.” These behaviors are often first noticed
when the child is a toddler, but can be normative before age 4. The level of
gross motor activity usually decreases with age, however, the inner sense of
restlessness may continue into young adult life. Children with ADHD
display sustained levels of high activity in different settings such as home,
school, and playgroup. Activity increases occur during sleep as well. Hyperactivity may
be absent in novel situations or when child is engaged in
an activity they find particularly engrossing such as playing videogames.
Impulsivity. Impulsive actions occur without forethought about
consequences and may be associated with desire for immediate rewards or
to avoid delay. Impulsivity might be seen when the child engages in
dangerous activities, yells out in class, or interrupts or intrudes on others
during games or conversations. Impulsive behavior might also result in
trouble with parents, teachers, or other children, including verbal or
physical fights. Children with ADHD can demonstrate overly quick and
error-prone performance on standardized tasks. Symptoms of impulsivity
can persist into adulthood, even after hyperactive symptoms have
diminished.
Attentional Difficulties. Inattention includes difficulty sustaining focus,
trouble maintaining organization, and being easily distracted by extraneous
stimuli. The symptoms of inattention often become prominent in
elementary school when the child is approximately 8 to 9 years old and
symptoms can be lifelong. Attentional difficulties are most often seen in
routine settings in which the youth with ADHD must sit and carry out tasks
that involve repetition under conditions of low levels of reinforcement and
external motivation. Sluggish Cognitive Tempo (SCT) is a type of
attentional difficulty that has been closely associated with the inattentive
subtype of ADHD. SCT describes a constellation of symptoms such as
daydreaming, staring, tendency toward confusion, mental fogginess,
sleepiness, apathy, and physical hypoactivity. There is growing evidence
suggesting that SCT is a condition distinct from ADHD, however, SCT is
currently not considered a separate disorder or diagnostic subtype.
Associated Factors. Children with ADHD might have areas of
impairment that are not listed under the DSM-5 symptom criteria covered
exactly by the 18 symptom exemplars of hyperactivity, impulsivity, or
inattention. Children and adolescents with ADHD often show difficulty
with time management and do not develop an internal sense of pace in
planning tasks. This poor sense of time leads to problems in estimating the
actual difficulty of waiting in line, planning how much time a task requires,
or even knowing when to come home when out playing with other children.
Children with ADHD often lack persistence and can become bored playing
interactive games with peers. They also find it difficult to delay
gratification.
Neuropsychological testing has found that individuals with ADHD
demonstrate impaired executive functioning including abnormal response
inhibition. On any given measure of executive function, less than half of
children with ADHD have been found to be impaired. Executive functioning problems
also occur in other psychiatric disorders of
childhood, such as depression, and are not specific to ADHD. It has been
shown that academic functioning is more strongly affected by an impulsive
need to get through tests quickly, a deficit closely linked to poor behavioral
inhibition, rather than poor executive functioning.
ADHD is often associated with problems in emotion regulation,
resulting in temper outbursts, mood lability, and reactivity. Moods can
change dramatically with no obvious connection with what is going on in
the environment. Social skills are often significantly impaired in children
with ADHD compared to controls. Individuals with ADHD may have
problems accurately interpreting nonverbal social cues and have trouble
cooperating with other children and following rules in games. Peers
identify these individuals as intrusive, bossy, and insensitive to the needs of
others. Children with ADHD often overreact and respond to frustration in
social situations which can lead to verbal or physical aggression. This is a
strong stimulus for peer rejection, which has been shown to be a reliable
long-term negative predictor of development, particularly in adolescence.
MEDICAL AND LABORATORY EXAMINATION
Children with ADHD should be given a medical evaluation, including a
thorough history and physical examination, to rule out physical disorders
that can mimic the symptoms of ADHD. The medical history should cover
the prenatal, perinatal, toddler, and preschool phases of development.
Inquiries should be made about pregnancy complications, such as maternal
illness (eclampsia, diabetes), maternal smoking, alcohol, or illicit drug use.
The perinatal period should identify the presence of labor problems,
delivery complications, prematurity, jaundice, and low birth weight.
Feeding and sleeping routines during the perinatal and postnatal periods
need to be described. Developmental milestones, illnesses, injuries, and
symptomatology need to be reviewed. A detailed family, medical, and
psychiatric history should be completed.
The medical examination can identify physical problems (such as
arrhythmia, tachycardia, or hypertension) that can increase the risk of
serious adverse events should a stimulant medication treatment be
initiated. Height and weight at baseline should be recorded. Physical
examination of a child with ADHD may reveal nonlocalizing neurological
signs, such as poor coordination, dysrhythmias, and overflow movements.
Medical problems that might aid in the differential diagnosis, such as petit
mal epilepsy, hearing and vision difficulty, thyroid dysfunction, and
hypoglycemia, all need to be ruled out. There are no blood, genetic, or
neuroimaging tests available to diagnose ADHD.
RATING SCALES
Many standardized behavioral rating scales for ADHD have been developed. Rating
scales should not be used independently to diagnose
ADHD, but can be particularly helpful in establishing the presence of core
ADHD symptoms in more than one setting. ADHD-specific scales have
been found to have greater than 90 percent sensitivity and specificity if
used in the correct population. Commonly used rating scales for ADHD
include Conners Rating Scales for parents (CPRS-R) and teachers (CTRSR),
Conners Wells Adolescent Self-Report Scale, Vanderbilt ADHD
Diagnostic Parent and Teacher Scales, Swanson, Nolan and Pelham (SNAPIV),
and Brown ADD Rating Scales for Children, Adolescents, and Adults.
Only the Conners Comprehensive Behavior Rating Scales and the ADHD
Rating Scale IV have been validated in preschool-aged children.
DIFFERENTIAL DIAGNOSIS
A clinician must make a differential diagnosis when judging whether a
patient meets criteria for ADHD. The distinction between differential
diagnosis and comorbidity is not well defined in the DSM-5. If the
impairing condition is best accounted for by another disorder, that other
disorder rules out ADHD. For children with intellectual disability,
inattention may be a natural accompaniment of the intellectual limitations,
so the diagnosis of ADHD should only be applied if that symptom is
excessive for the mental age of the child. Children from chaotic,
disorganized, or inadequate home environments may also show symptoms
of overactivity or inattention. The symptoms of children with oppositional
defiant behavior must be distinguished from the reluctance and resistance
that children with ADHD exhibit when they avoid effortful mental tasks.
Symptoms of impulsivity, gross motor hyperactivity, or inattention may
appear during the use of medications, such as the akathisia that
accompanies second-generation antipsychotics or from bronchodilators.
Such children should not receive a diagnosis of ADHD, but one of Other
Substance-Related Disorder.
COURSE AND PROGNOSIS
Parents often notice very high levels of gross motor activity when the child
with ADHD is a toddler, just when the child has learned to walk
independent of the parent’s help. However, the energy, oppositionality, and
curiosity of toddlers can be confused with the excessive, almost random
motion of older children with ADHD, so that one must be cautious when
applying the ADHD diagnosis to a preschooler. Usually, the ADHD
diagnosis is first applied in primary school, during grades 1 to 6, when
adjustment to the sedentary learning style is compromised. Thus the
school-aged child often experiences academic failure and peer rejection.
Behavior problems at school and at home are not infrequent with
oppositional defiant disorder (ODD) being a common comorbidity.
In childhood 65 to 75 percent of children with ADHD have one or more comorbid
conditions, which in addition to ODD, can include conduct
disorder (CD), anxiety and mood disorders, tics or Tourette syndrome,
learning disorders, and autistic spectrum disorders. Many of these
comorbidities continue into adolescence.
In adolescents, the external overactivity lessens but the internal
restlessness does not. The adolescent with ADHD continues to have
academic and social problems, which erode his/her self-esteem and at
times promote the gravitation to a negative peer group. Thus, adolescents
with ADHD who are untreated, compared to peers with no mental disorder,
have a threefold increase in substance use and abuse, more frequent
delinquent acts and trouble with the law, and increased rates of car
accidents when they begin to drive. Adolescents with ADHD also start
sexual intercourse earlier with a higher number of sexual partners and
greater frequency of unprotected sex with corresponding higher rates of
sexually transmitted diseases and unwanted pregnancy. The rate of
depression and anxiety also increases in adolescence because of the many
functional problems.
Approximately 60 percent of children with ADHD continue to be
impaired well into adult life with prevalence estimates suggesting that 4
percent of adults may suffer from ADHD. In adulthood, hyperactivity may
be expressed by inner feelings of restlessness, inability to relax and excess
talkativeness, fidgeting, and inability to remain seated for long periods of
time, for example, meetings, symposia, church. Impulsivity may be
expressed in impatience, interrupting others, acting without thinking,
ending or starting ventures on impulse, for example, jobs, relationships,
and at times sensation-seeking behavior.
Inattention is seen in distractibility, disorganization, chronic lateness,
or missing appointments. The distraction and disorganization often results
in careless mistakes and forgetfulness. Procrastination is another
important problem. Even when things are started, they are often not
finished and so deadlines are thus missed.
The inattention and distractibility also make it appear that the adult
with ADHD is not interested and not listening to what is being said. This
can strain relationships at home and at work. Some adults with ADHD also
suffer from labile moods and “short fuses.” These characteristics coupled
with the problems described above result in more frequent losses of jobs
and relationships. The consequences of this are lower job status and lower
income and a sense of underachievement or failure on the part of the adult
with ADHD. The inattentiveness and impulsivity also increases the
likelihood of driving accidents and infractions, other types of accidents are
also more prevalent. Generally, adults with ADHD may have an unhealthy
lifestyle, with smoking, alcohol, and drug abuse risky sexual behavior, and
chronic sleep problems frequently seen.
In adulthood, comorbidity is the rule, with more than 75 percent of adults with ADHD
having at least one comorbid condition. Anxiety,
depression, substance abuse, and some personality disorders are the most
common comorbidities. Gambling and other addictions are also frequently
seen.
It should be noted that even though the male/female ratio in children
with ADHD can be 3–4:1, in adulthood it is 1:1. It is possible that many
girls who tend to be less disruptive are not identified or referred in
childhood but have significant impairment as adults and seek help then.
TREATMENT OF ADHD
The efficacy of both medication and psychosocial interventions for the
treatment of ADHD has been well established. The preferences of families
and availability of services largely guide the choice of treatment.
Stimulants
Stimulants are considered first-line agents to treat ADHD symptoms based
on decades of proven safety and efficacy. Therapeutic effects of stimulants
include a decrease of hyperactivity, impulsivity, and inattention, as well as
improvement in associated behaviors. The two groups of stimulant
medication that have received U.S. Food and Drug Administration (FDA)
approval for the treatment of youth with ADHD are amphetamines and
MPHs. Many stimulants are available in both generic and branded
versions. Stimulants are classified with drugs that can be abused or cause
dependency under the category of schedule II controlled substances by the
United States Drug Enforcement Agency (DEA) (Table 45.1–1).
Pharmacology and Pharmacokinetics. Both MPH and amphetamine can
be described as psychostimulants, which refers to their ability to increase
central nervous system activity in brain regions and increase blood
pressure and pulse in the periphery. Although the exact mechanism of
action is not completely understood, stimulants increase the concentration
of dopamine and norepinephrine in the synaptic cleft. MPH appears to act
primarily as a dopamine–norepinephrine reuptake inhibitor, while
amphetamines block the reuptake of both norepinephrine and dopamine as
well as facilitate dopamine release through reverse transport. Berridge et
al. showed—during in vivo microdialysis in rodents—that low-dose MPH
substantially increased norepinephrine and dopamine reflux within the
prefrontal cortex (PFC) while enhancing PFC-dependent cognitive

Tabel Stimulant Drugs

FORMULATIONS
The racemic form of MPH is d,l-threo-methylphenidate, with d-threomethylphenidate
(d-MPH) being the more active isomer. Both racemic
MPH (including Ritalin, Metadate, and Methylin) and the monoisomer d-
MPH (Focalin) are commercial products. MPH is available in immediaterelease
tablet, chewable and liquid formulations.
Extended-release MPH is available in many different preparations. It is
manufactured using beaded technology, consisting of both immediate- and
delayed-release beads which are equivalent to two doses of immediaterelease
medication given 4 hours apart. The beads can be sprinkled on food
for children who have difficulty with swallowing pills. MPH is also available
as a transdermal patch (Daytrana), which has onset of action of 60 minutes
and can be worn up to 9 hours per day. MPH utilizing an osmotic-release
oral system (OROS-MPH or Concerta) releases the stimulant via an
osmotic pump in an ascending dose curve over a 10- to 12-hour period.
This allows for a single-dose product that is consistent with the effect of a
three times per day dose of immediate-release MPH hydrochloride. The
newly available MPH hydrochloride extended-release liquid suspension
(Quillivant XR) has demonstrated efficacy in reducing ADHD symptoms
for up to 12 hours, is well tolerated and is especially useful in children who
have difficulty swallowing pills.
Amphetamine is manufactured as immediate-release formulations,
including mixed amphetamine salts, which is a mixture of d- and lamphetamine,
or in the dextro isomer. With regard to just the dextro
isomers, dextroamphetamine (d-AMP) is 1.5 times more potent, milligram
for milligram, than is d-MPH. Another popular product, mixed salts of
amphetamine (MAS), is marketed as Adderall, and combines four different
salts of amphetamine, including both d-AMP and l-AMP. One small study
showed that there are no efficacy differences between d-AMP and MAS.
AMP is also available in extended-release beaded formulations, as the
isomer d-amphetamine sulfate (Zenzedi) and as a liquid (Procentra).
Lisdexamfetamine dimesylate (Vyvanse) is a therapeutically inactive
prodrug that is converted by enzymatic hydrolysis to inactive l-lysine and
active d-amphetamine predominantly by red blood cells, with a smaller
amount converted in the gastrointestinal tract. This formulation was
developed to decrease the potential for abuse, as lisdexamfetamine used
intranasally or intravenously has similar effects to oral administration.
Although absorption of MPH products is generally not affected by
foods, some long-duration preparations of d-AMP show decreased
concentrations when taken with high-fat meals. Whereas MPH is
metabolized in the gut wall and plasma by esterases, the metabolism of d-
AMP and MAS takes place in the liver. Variants in the humans CES-1 gene
coding for the hydrolyzing enzyme have led to interindividual variations in
MPH metabolism and plasma level. Amphetamine product package inserts approved by
the FDA warn that
urinary excretion of AMP metabolites can be increased by foods of acidic
content (vitamin C and orange juice), thus lowering plasma concentration.
Conversely, foods that shift urinary pH higher reduce excretion and thus
increase the plasma concentration of d-AMP or MAS.
Efficacy. Efficacy studies of stimulants consistently show high
numbers of children who are responders (Storebø et al., 2015). The MTA
study found that 77 percent responded to MPH, and an additional 10
percent of MPH nonresponders responded to d-AMP. Teacher rating scales
showed significant reductions in ADHD symptoms for stimulants
compared with placebo, with effect size ranging from 0.8 to 1.0 standard
deviation (SD) on behavioral measures and 0.5 SD for cognitive measures
for those children randomized to active drug. Placebo response rates in
controlled studies have tended to be low, generally less than 20 percent of
those randomized to that condition. The Preschool ADHD Treatment Study
(PATS) determined that preschool-aged children require a lower optimal
doses of IR methylphenidate, experienced much higher rates of adverse
events, do not respond as robustly showing a lower effect size, and had
slower clearance of the drug than school-aged children (Vitiello et al.,
2015).
Amphetamines and MPHs both share the ability to reduce gross motor
overactivity, increase sustained attention on tasks, and reduce impulsive
responses on laboratory measures. These characteristics have been shown
in more than 200 short-duration, double-blind, placebo-controlled clinical
trials involving patients with ADHD across a wide age range, including
preschoolers, school-aged children, adolescents, and adults. Some
individuals respond preferentially to MPH, whereas others respond
preferentially to the amphetamines. The majority of evidence indicates that
MPH and amphetamine are equally efficacious.
Cognitive and Behavioral Effects. Greater effects due to stimulants are
found to occur in behavioral domains rather than in cognitive areas.
Psychostimulant medications have been shown to reduce gross motor
overactivity, out-of-seat behavior, calling-out in the classroom,
disruptiveness, impulsive behavior, and noncompliance while improving
self-perception, academic productivity, peer nominations of the child and
mother–child interaction. Stimulants have been shown to improve
vigilance and reaction time and reduce variability, short-term memory, and
learning of verbal and nonverbal material in children with ADHD. The
MTA Titration Trial showed a linear dose–response curve for behavioral
measures between 0.5 and 1.0 mg/kg/day. Although earlier studies showed
no long-term academic benefit from stimulant treatment, recent controlled
trials revealed improvements in school-based productivity and accuracy in children with
ADHD consistently treated with stimulants.
Adverse Effects
SHORT-TERM ADVERSE EFFECTS. Common side effects of the stimulant
medications include decreased appetite, weight loss, delayed onset of sleep,
headaches, stomachaches, and small increases in blood pressure and pulse.
Most of the short-term side effects can often be dealt with by changing the
time or dose of medication, or both.
Infrequent side effects include motor tics, the unmasking of Tourette
syndrome, and late withdrawal effects, sometimes called rebound.
Rebound presents the sudden return of more severe overactivity,
impulsivity, and inattention in the late afternoon or evening than present at
baseline off medication. Attempts to demonstrate their presence in fullday,
laboratory classrooms have been unsuccessful, so these effects may be
generated as the child interacts with task demands in his or her natural
environment. Long-acting psychostimulant preparations or a small dose of
immediate-release medication may be given before onset of the rebound to
reduce this problem.
Stimulants rarely produce visual and tactile hallucinations, priapism,
choreiform movements, and self-directed behavior, such as lip licking, nail
biting, and rubbing of sores. These problems are first treated by
discontinuing the medication until the adverse event disappears.
Two large recent studies in children and one in adults found that ADHD
medications are not associated with an increased risk of severe
cardiovascular events. General cardiac side effects of stimulant drugs are
increase in heart rate of approximately 1 to 2 beats/minute and increase in
systolic and diastolic blood pressure of 3 to 4 mm Hg. Stimulants have not
been found to induce clinically significant changes in electrocardiographic
parameters. The evidence suggests a potential for severe adverse cardiac
events in some children with certain forms of congenital heart disease or
arrhythmias. Routine electrocardiograms are not recommended prior to
initiating stimulants in the absence of concerning physical examination
findings or personal or family cardiac history.
Long-Term Adverse Events
EFFECTS ON GROWTH. The use of stimulants in children has been associated
with growth suppression in some studies, but methodological issues
prevent a clear conclusion to be drawn. Two large-scale NIMH-supported
randomized, clinical trials have shown that MPH can reduce the rate of
height and weight gains in developing children with ADHD. This
suppression effect, which may be dose related in some children, has been
more pronounced in those children treated with d-AMP and occurs
predominately in the first year of treatment. The reductions in linear growth have been
minimal (approximately 1 cm in height and 2.5 kg in
weight during the first year of treatment with stimulants). There is growing
evidence of that this decrease in growth velocity diminishes after the first
year treatment. The effects on growth are thought to be secondary to
appetite suppression and reduction of caloric intake. Small, single-site
studies are discordant concerning whether psychostimulants suppress
human growth hormone (HGH) or effect prolactin levels. Some researchers
have suggested that the growth deficit may be associated with the disorder
itself, rather than stimulant medication. Clinicians are recommended to
regularly monitor height and weight of children with ADHD treated
chronically with psychostimulant medication. It is also encouraged to
institute drug holidays during summer vacations to increase the probability
of growth rebound.
SUBSTANCE ABUSE. There is no evidence to suggest that the use of
stimulants in young people increases the risk for later substance use
disorders (SUD). A meta-analytic study by Wilens and colleagues suggests
that stimulant treatment in childhood has a protective effect, bringing the
risk down to the level of the general population. Other studies have
revealed that stimulant therapy neither increases nor decreases the risk for
subsequent SUD in children and adolescents with ADHD. Clinicians should
take into consideration if family members are currently abusing
prescription medication before prescribing stimulants for ADHD.
Stimulant medication can be misused or diverted for the purpose of
academic performance enhancement or euphoric effects, with immediaterelease
stimulants more often misused compared to extended-release
formulations. A systematic review of 21 studies indicated prevalence of
psychostimulant misuse in the year prior to the study ranged from 5 to 9
percent in grade and high school–aged children and 5 to 35 percent in
college-aged individuals. Close monitoring, pills counts, or switch to
nonstimulant medication should be employed by the clinician if misuse or
diversion is suspected.
Summary of Stimulant Medication. Continuous treatment of children
with ADHD with psychostimulants is both effective and safe over the first 2
years. Long-acting preparations provide the convenience of once-daily
dosing, reduce stigma associated with taking medication at school and can
decrease the potential for abuse. Short-acting forms are useful for younger
children who often require smaller doses than is available in extendedrelease
preparations. Many adverse events can be handled by adjustment of
dose and/or the time of administration of the medication. Long-term
adverse events such as growth rate suppression concern parents but may be
managed by instituting drug holidays to permit growth rebound.
Nonstimulant Medication in the Treatment of Children with ADHD
Whereas psychostimulants constitute the first-line treatment for children
with ADHD, other medications need to be used for nonresponders or those
who experience moderate to severe adverse events. Some nonstimulant
medications, such as atomoxetine and long-acting clonidine or guanfacine,
have been approved by the FDA for the treatment of ADHD in children and
adolescents. Other nonstimulant medications are used off-label but are less
efficacious than the stimulants in treating ADHD symptoms. Advantages of
nonstimulant medications include a longer duration of action and the
absence of psychostimulant effects such as behavioral rebound or delay of
sleep onset.
Atomoxetine HCl. Atomoxetine (ATX), an NRI marketed under the
name Strattera, is an approved alternative to stimulants. It may be
considered first line in individuals where parents have a personal objection
to stimulants, or the child has comorbid anxiety symptoms or severe
stimulant side effects. Atomoxetine is well absorbed after oral
administration and is minimally affected by food. Maximum plasma
concentrations are reached approximately 1 to 2 hours after ingestion and
typical duration of action is 10 to 12 hours. Ninety-eight percent of
circulating ATX is bound to plasma protein, mainly albumin. ATX is dosed
by weight, with RCTs showing no benefit from exceeding total daily doses
of 1.4 mg/kg. The time to therapeutic effect is in the range of 1 to 4 weeks,
with full response at 6 to 12 weeks.
ATX has been shown to reduce ADHD behaviors in children,
adolescents, and adults with a medium effect sizes of 0.5 to 0.7. Common
adverse events associated with ATX involve abdominal discomfort, nausea,
decrease in appetite, sedation, daytime sleepiness, headache, dizziness,
vertigo, irritability, and mood swings. Daytime sleepiness and
gastrointestinal tract problems may be diminished by titration to full dose
over 1 week in twice-daily dosing. Minor increases in blood pressure and
pulse have been reported and thus should be regularly monitored. Rare
adverse events in youth include priapism, disturbances in sexual
functioning, increased suicidality and liver toxicity.
ATX is metabolized by the cytochrome P450 (CYP) 2D6 hepatic enzyme
system. A fraction of the population are poor metabolizers of CYP 2D6–
metabolized drugs. Such individuals may experience elevated plasma
concentrations and extended plasma half-life, therefore very slow initial
titration may be required to prevent excessive dosing of these patients.
Patients taking other medications metabolized by CYP 2D6, such as
fluoxetine (Prozac), paroxetine (Paxil), and quinidine (Cardioquin), might
show signs of competitive inhibition, namely increased plasma levels of
both ATX and the competing drug. α -Adrenergic Agonists. The α-adrenergic agonist
agents were
initially approved for the management of hypertension in adults. The longacting
α-adrenergic agents guanfacine ER (Intuniv) and clonidine ER
(Kapvay) have been FDA approved as monotherapy and adjunctive
treatment of ADHD in children 6 to 17 years old. The immediate-release
clonidine (Catapres) and guanfacine (Tenex) have not been approved to
treat ADHD, although they are commonly used off-label. The supposed
mechanism of action of the α-adrenergic agents involves stimulating α
(alpha) receptors in the PFC leading to improvement inattention,
impulsivity, and hyperactivity. The α-adrenergic agonists are clearly less
efficacious than the psychostimulants with several meta-analyses
suggesting a moderate effect size. However, a small multisite, double-blind,
RCT showed that children and adolescents comorbid for ADHD and
Tourette syndrome benefited from clonidine alone or in combination with
MPH, in both cases significantly better than placebo. Guanfacine has
proven efficacy in reducing oppositional symptoms in children with
comorbid oppositional behaviors and ADHD.
Common side effects of the α-adrenergic agents are sedation, fatigue,
somnolence, headache, hypotension, syncope, and bradycardia. There have
been rare reports of hallucinations in children treated with guanfacine.
Clonidine is very sedating and has been used to treat sleep difficulties of
children with ADHD, as well as to offset the delay in sleep onset caused by
stimulant medications. It is initiated at low doses, 0.05 mg at bedtime.
Guanfacine is a more selective α-adrenergic agonist and is slightly less
sedating than clonidine. It is used in higher total daily doses than clonidine,
between 1 and 3 mg. The α-adrenergic agonists need to be discontinued
very slowly to prevent rebound adrenergic overdrive, with hypertension,
agitation, fever, headache, tachycardia, chest pain, sleep disturbance,
nausea, and vomiting. This can create a problem if a family goes on holiday
and the parents forget the child’s medication.
Tricyclic Antidepressants. TCAs have data supporting their use in
ADHD, but are used infrequently as they have a much more serious sideeffect
profile. Spencer reviewed 29 studies of children and adults treated
with TCAs (imipramine, desipramine, and nortriptyline) and found
significant reductions in ADHD symptoms in 22 of the studies. There are
many adverse events associated with TCAs, including cardiovascular
adverse events, such as slowing of cardiac conduction and increasing the
electrocardiographic PR and QRS intervals indicating increased risk of
cardiac arrhythmias and heart block. There have been reported sudden
deaths in patients on stable therapeutic doses of TCAs. For that reason,
electrocardiograms at baseline and after each dose adjustment are
necessary for routine monitoring. Other side effects commonly experienced
with TCAs include lowering of seizure threshold and cholinergic side effects, such as
constipation, dry mouth, or blurred vision. When
discontinued, TCAs should be tapered over several weeks.
Bupropion. Bupropion is an antidepressant with dopaminergic and
noradrenergic properties that has shown modest efficacy in ADHD, but is
less effective than stimulants or atomoxetine. It is available in extendedrelease
preparations (Wellbutrin SR, Wellbutrin XL) that permit once-daily
dosing. It might be more effective in adolescents and is not recommended
for children. Starting dose for young adolescents is 75 mg twice a day to a
maximum of 200 to 300 mg/day. The doses can be increased once weekly
until improvement is noted. Bupropion usually takes 4 to 6 weeks to show
effect.
Side effects of bupropion include fatigue, dry mouth, insomnia,
headaches, nausea, vomiting, constipation, tremor, and skin rash. Seizures
will reliably occur if the adolescent’s dose exceeds 400 mg/day. This
medication is FDA approved for the treatment of depression and smoking
cessation, but not ADHD, in individuals older than 18 years of age.
Bupropion is considered a second-line, off-label treatment for ADHD.
Other Alternative Medications. Anticonvulsants, including
carbamazepine (Tegretol), lithium (Eskalith), SSRIs have not been shown
to be effective for the treatment of ADHD. Second-generation antipsychotic
medications such as risperidone have been shown to be effective for the
treatment of aggression when combined with parent training and MPH, but
not when used as the sole therapeutic agent. Modafinil (Provigil), an
antinarcoleptic stimulant agent, was shown to be effective in three doubleblind,
placebo-controlled RCT, but the manufacturer withdrew its
application to the FDA because of a severe Stevens–Johnson skin rash that
might have occurred in one patient and reported visual hallucinations in
registration trials. In summary, then, these medications might be useful in
treating some comorbid conditions that children with ADHD often have.
Summary of Medication Treatments. Most children with ADHD
respond to stimulant medication, so it continues to be the first-line
treatment choice for reducing the symptoms of ADHD. However, if
stimulants are ineffective, practice parameters first suggest turning to the
serotonin–norepinephrine reuptake inhibitor atomoxetine. Alternatively,
one can combine a stimulant medication with an α-2 agonist when the
youth shows only partial response to a stimulant. If the child shows severe
adverse events on stimulants, off-label medications can be tried. One must
keep in mind that bupropion is less effective than either the TCAs or
stimulants and carries a risk of seizures at high doses. Clonidine and
guanfacine are sedating and have significant cardiovascular side effects.
For all these drugs, careful monitoring and slow, cautious discontinuation are essential.
TCAs are not routinely used for the treatment of ADHD due
to the numerous side effects and high toxicity.
Treatment of ADHD Comorbidities
Tic Disorder. Stimulants alone or in combination with clonidine,
guanfacine, and atomoxetine appear to reduce ADHD symptoms in
individuals with both ADHD and Tourette syndrome or tic disorders.
Although stimulants have not been shown to worsen tics in most patients
with tic disorders, they may exacerbate tics in some individual cases. In
these instances, decreasing the dose of stimulants or treatment with α-
agonists or atomoxetine may be an alternative. Cognitive behavioral
therapy (CBT) with the use of opposing muscle contractions to address tics
has also shown some efficacy and can be considered to address problems
with tics.
Seizure Disorder. Children with seizure disorders may also suffer from
ADHD. Although there are concerns about psychostimulants, particularly
MPH, lowering the seizure threshold, experiencing a first seizure when
starting a psychostimulant is extremely rare. Studies of EEG epileptiform
activity, seizure rates, or interactions between antiepileptic drugs (AEDs)
and psychostimulants have not shown any additional seizure risk. On the
contrary, studies have shown that children with ADHD and a seizure
disorder that is adequately controlled on an AED show reduced ADHD
symptoms and no change in seizure frequency.
Aggression, Oppositional Defiant Disorder, and Conduct Disorder.
Individuals with ADHD and comorbid Aggression, ODD and/or CD require
comprehensive intervention which includes pharmacotherapy and
psychosocial treatments. Stimulants have been shown in randomized,
controlled trials to improve ADHD, aggression, ODD and CD symptoms. α-
Blockers (guanfacine and clonidine) alone or as adjuncts to stimulants have
also been shown to decrease ADHD, aggression, and oppositional
symptoms. Stimulants also reduced negative social interactions and covert
antisocial behavior (stealing and vandalism but not cheating). However,
one cannot solely rely on medication to treat children with ADHD and
these comorbid conditions. A comprehensive treatment approach which
may include parent training, social skills training, and anger management
for the child as well as an appropriate academic program and support may
also be needed. Treating Aggression, ODD, and CD early and effectively is
critical as long-term consequences of these disorders include later drug and
alcohol abuse and antisocial behavior with involvement of the criminal
justice system.
Anxiety Disorder. It had been suggested that children with ADHD and
comorbid anxiety may be less responsive to and experience more side
effects with stimulant medication (Coughlin et al., 2015). The large
Multimodal Study of ADHD (MTA) did not find this to be the case.
However, children with ADHD and anxiety disorder seemed to benefit
significantly from psychosocial treatment as well as medication. Thus for
children with ADHD and comorbid anxiety, slow and careful titration of
stimulant medication for the ADHD symptoms is recommended and
psychosocial treatments such as parent training, social skills training,
and/or CBT for the child combined with an appropriate academic program
and academic support is suggested. However, should all these measures
prove inadequate, addition of SSRIs (fluoxetine [Prozac] or sertraline
[Zoloft]) to address the anxiety can be added.
Mood Disorder. In community samples, major depressive disorder
(MDD) in youth with ADHD is more than five times higher than in youths
without ADHD. Depressive disorders in youth with ADHD usually occur
several years after the onset of ADHD and may be due to the cumulative
effects of ADHD-related impairments and negative environmental
circumstances they need to cope with. Youths with depression and ADHD
have greater levels of psychosocial impairment than those with either
condition alone. For individuals with both disorders, depressions start
earlier, last longer, are more likely to recur and have higher rates of
suicides and hospitalizations than those who have depression alone.
A combination of pharmacotherapy and psychosocial interventions is
recommended for patients who have both ADHD and major depression.
Generally, as per the Texas Children’s Medication Algorithm Project
(CMAP), it is suggested that the clinician begin with the most effective
medication for the most impairing condition for the patient. Only after the
full effect of this medication is determined for both conditions, should a
second medication be added to deal with residual symptoms of the second
condition. Thus, in some cases of the combination of ADHD and mood
disorders both stimulants and SSRIs may need to be used.
Psychosocial interventions both for the depression, for example, CBT,
and the ADHD, for example, organizational, study skills remediation, and
appropriate academic and/or vocational program may all be needed.
The question of ADHD and Bipolar Disorder is being resolved with the
introduction of the clinical entity of Disruptive Mood Dysregulation
introduced in DSM-5. As a result, mainly classical symptoms of Bipolar
Disorder such as severe elation of mood, grandiosity, racing thoughts, and
hypersexuality are used to confer the bipolar diagnosis. In these
circumstances, the Bipolar Disorder needs to be stabilized with mood
stabilizers and/or antipsychotics before stimulant treatment can be
introduced.
Developmental Disorders. ADHD symptoms of inattention and
hyperactivity are seen in children with mental retardation and ASD.
Stimulants have been shown to be beneficial in both groups, particularly in
those children with IQs greater than 50. A recent randomized, controlled
trial found that MPH was more effective than placebo in reducing
symptoms of ADHD in children with autism, while few effects were seen on
ASD symptoms.
Some studies suggest that these populations may be more susceptible to
adverse events of psychostimulants. While other studies do not suggest
this. However, if severe side effects occur, for example, severe agitation,
irritability, fearfulness, or stereotyped behavior, a low dose of secondgeneration
antipsychotic medication may need to be added.
There are few randomized, double-blind controlled trials with other
medications for patients with ADHD and ASD. Atomoxetine has been
shown to have some positive effects on ADHD symptoms with little effect
on ASD. The side effects associated with Atomoxetine appear to be less
problematic than with stimulants. There are some clinical suggestions that
some anticonvulsant medications and guanfacine may also be beneficial for
the ADHD symptoms in these populations but no well-controlled trials
have been reported to date. Although psychosocial interventions are also
suggested, again data on the efficacy of these approaches is also lacking.
Psychosocial Treatment of Children with ADHD
Psychosocial treatment of children with ADHD refers to nonmedication
treatment. This type of treatment includes different modalities, such as
psychoeducation, academic organization skill teaching and remediation,
parent training, behavior modification, CBT, social skills training, and
individual therapy. Of these modalities, parent training, intensive behavior
modification, social skills training, and academic organizational skills have
shown efficacy for children with ADHD in controlled trials.
Among nonpharmacological treatments, direct contingency
management uses systematic manipulation of punishments and rewards,
often in specialized settings. Although it can produce impressive effects on
behavior and performance in the classroom, its effects tend not to
generalize or be maintained outside of the settings in which they are
applied. In addition, published outcomes are achieved through single-case
designs. In the field, behavior therapy often is carried out in consultation
with teachers and parents regarding in-school and home management.
Published trials often depend on parent and teacher ratings of
improvement but do not include independent evaluators. However, a
recent review showed that even with blinded assessments, significant
effects persisted for improving parenting and decreasing childhood conduct
problems. Although controlled studies of systematic combinations of direct
contingency management plus intensive behavior therapy have yielded
significant improvement, effect sizes of clinical change are smaller than
those found with stimulant medication.
Intensive behavioral interventions are based on a number of principles.
These begin with psychoeducation about the course, risk factors, and longterm
outcomes of ADHD. Second, the parents are encouraged to attend
more carefully to their child’s behavior, particularly when the child
complies. Third, the parents are trained to use time out effectively. Fourth,
the parents are instructed in establishing a contingency management or
token economy system at home. Then the parents learn how to manage
noncompliant behaviors in public settings. Finally, advances in prosocial
behavior in school are supported by use of a daily report card.
It is crucial to evaluate the parents and family for dysfunction related to
the child’s ADHD. Parental ADHD may interfere with behavioral
modification programs, indicating that treatment of the affected parent
may be necessary before the child’s intervention can be successful. Other
dysfunctions might be present in the family as well, such as marital
problems, substance abuse, or parental depression.
Behavior modification has been successfully applied to the classroom,
with a meta-analysis of 70 studies showing an effect size of 0.6 SD
compared to an attention control condition. In contrast, CBT has not been
shown to be effective (Vidal et al., 2015). Practice parameters published for
child and adolescent psychiatrists strongly suggest that behavior therapy in
the form of behavioral parent training and behavioral classroom
management be added to psychopharmacological treatment if the child is
shown to be a partial responder to stimulant medications or exhibits a
comorbid psychiatric disorder whose impairment does not respond to the
medication.
SUMMARY AND CONCLUSIONS
ADHD is a prevalent condition which begins in childhood but often
continues into adolescence and adulthood. It is accompanied by significant
academic, occupational, social, and emotional impairment. The patients
with ADHD are often comorbid with other conditions. These comorbidities
include oppositional defiant, conduct, learning, and anxiety disorders in
childhood, and anxiety, depression, and substance use and abuse in
adolescence and adulthood.
Treatment must include the ADHD and the various comorbidities.
Thus, pharmacotherapy and psychosocial treatment as well as appropriate
academic programs and support are needed for optimal outcome. It must
be stressed that ADHD is a chronic condition for which ongoing long-term
monitoring and treatment is required to optimize functioning.
SPECIFIC CASE OF CHILDHOOD ADHD
Ben is an 8.5-year-old African-American adopted boy who lives with his parents and 11-
yearold
brother. He attends third-grade regular education in his local public school and received
special services including speech, physical, and occupational therapy. Although his drug
screen
at birth was negative, Ben’s biological mother was said to have used crack and
methadone
during her pregnancy. No information was available about his biological father. Ben had
suffered several upper respiratory infections at age 2 years requiring several rounds of
antibiotics. Developmentally, some motor delays were reported, with crawling by 1 year
and
walking by age 2 years. He was speaking one word by his first birthday, but by age
3½years his
expressive language was behind his peers in fluency. He demonstrated difficulties
following
multipart directions, even though his hearing tested in the normal range.
Ben has had difficulty with daydreaming and wandering about since kindergarten. His
teachers complained that Ben did “not seem to listen,” had “poor concentration,” and was
constantly “out of his seat.” Ben had never had close friends and other children seemed to
avoid him because he could not stick with an activity for very long and he was always “in
their
space.” Ben’s adoptive parents were drained from the nightly battles over homework and
discouraged by his lack of focus and “spaciness.” His inattention and impulsivity put him
in
danger and caused injury. He had run into traffic on several occasions, even after being
hit by a
truck with resulting injuries.
Ben’s parents and his third-grade teachers completed the SNAP Rating Scale. Clinician
assessment revealed seven symptoms of inattention. His mother also endorsed all nine
symptoms of hyperactivity/impulsivity. These symptoms were moderately to severely
impairing across multiple settings, including home, peer relations, personal safety, and
during
athletics.
Ben was started on extended-release MPH at 18 mg daily which was later increased to 27
mg daily. His teachers reported improvement in attention and hyperactive behavior at
school.
Homework was no longer such a struggle and he was noted to play quietly with his toys
in the
evenings.