IACAPAP Textbook of Child and Adolescent Mental Health

EXTERNALIZING DISORDERS

Chapter

D.1

ATTENTION DEFICIT
HYPERACTIVITY DISORDER
2020 Edition
Anthony de Freitas de Sousa, Isabel Meneghetti Coimbra,
Julia Marrone Castanho, Guilherme V Polanczyk &Luis Augusto Rohde

Anthony de Freitas de
Sousa
ADHD Outpatient Program,
Hospital de Clínicas de Porto
Alegre, Federal Universityof Rio Grande do Sul,
Brazil; National Institute ofDevelopmental Psychiatry,Brazil.
Conflict of interest: nonereported

Isabel Meneghetti Coimbra
ADHD Outpatient Program,
Hospital de Clínicas de Porto
Alegre, Federal Universityof Rio Grande do Sul,
Brazil; National Institute ofDevelopmental Psychiatry,BrazilConflict of interest: nonereported
This publication is intended for professionals training or practicing in mental health and not for the general public. The opinions
expressed are those of the authors and do not necessarily represent the views of the editors or IACAPAP. This publication seeks todescribe the best treatments and practices based on the scientific evidence available at the time of writing as evaluated by the authorsand may change as a result of new research. Readers need to apply this knowledge to patients in accordance with the guidelines andlaws of their country of practice. Some medications may not be available in some countries and readers should consult the specific drug
information since not all dosages and unwanted effects are mentioned. Organizations, publications and websites are cited or linked toillustrate issues or as a source of further information. This does not mean that authors, the Editor or IACAPAP endorse their content or
recommendations, which should be critically assessed by the reader. Websites may also change or cease to exist.
©IACAPAP 2020. This is an open-access publication under the Creative Commons Attribution Non-commercial License. Use,
distribution and reproduction in any medium are allowed without prior permission provided the original work is properly cited andthe use is non-commercial. Send comments about this book or chapter to jmreyATbigpond.net.au
Suggested citation: de Freitas de Sousa A, Coimbra I M, Castanho J M, Polanczyk GV, Rohde LA. Attention deficit hyperactivity
disorder. In Rey JM & Martin A (eds), JM Rey’s IACAPAP e-Textbook of Child and Adolescent Mental Health. Geneva: International
Association for Child and Adolescent Psychiatry and Allied Professions 2020.

ADHD D.1

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IACAPAP Textbook of Child and Adolescent Mental HealthAttention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental
condition characterized by frequent, pervasive and impairing inattention
and/or hyperactivity/impulsivity (American Psychiatric Association, 2013).
This chapter summarizes evidence-based data on ADHD, from epidemiology totreatment.

Julia Marrone Castanho

HISTORICAL NOTE

Conflict of interest: nonereported

Until recently, two publications competed for the title of providing the firstdescription of ADHD: the fictional Struwwelpeter, written by the pediatrician
Heinrich Hoffmann in 1845, and the 1902 Goulstonian Lecture, “An abnormal
Psychical Condition in Children”, by George F. Still, published in The Lancet.
There are other ADHD descriptions published between these two. The conceptof what we now call ADHD was introduced as a “mental instability” by DésiréMagloire Bourneville in France in 1885 (Bader & Hadjikhani, 2014). Two otherFrench physicians, Georges Paul-Boncour and Jean Philippe, described a group ofabnormal school children who presented symptoms of hyperactivity, impulsivity,and inattention, which would currently be diagnosed as having ADHD andcomorbid oppositional defiant disorder or conduct disorder.
Two other authors described ADHD features even earlier—more than
two centuries ago. Palmer and Finger (2001) introduced the work of Alexander
Crichton, a Scottish physician who had written a text in 1798 entitled “An Inquiry
into the Nature and Origin of Mental Derangement: Comprehending a Concise
System of Physiology and Pathology of the Human Mind and a History of the
Passion and their Effects”, in which he described a clinical condition similar towhat currently would be described as
ADHD in adults. Weikard, a German
physician, published a medical textbook
in 1775 (Der Philosophische Arzt), which
included a chapter on attention deficits inwhich he described symptoms of ADHD
like “often fails to give close attention
to details or makes careless mistakes inschoolwork, work, or other activities”,“often has difficulty organizing tasks andactivities”, “often avoids, dislikes, or isreluctant to engage in tasks that require
sustained mental effort”. Reports of acondition similar to ADHD can be foundeven earlier. The oldest is attributed to the
Greek philosopher Theophrastus in the
4th century BC (Victor et al, 2018).

ADHD Outpatient Program,
Hospital de Clínicas de Porto
Alegre, Federal Universityof Rio Grande do Sul,
Brazil; National Institute ofDevelopmental Psychiatry,BrazilGuilherme V Polanczyk MD,
PhD
Departamento de Psiquiatria,
Hospital das Clinicas
HCFMUSP, Faculdade de
Medicina, Universidade de
Sao Paulo; National Instituteof Developmental Psychiatry,BrazilConflict of interest: Received
conference support, speaking
fees, and consultancy feesfrom Takeda (formerly Shire),
consultancy fees from Medice,and royalties from Editora
Manole.

Luis Augusto Rohde MD,
PhD
Department of Psychiatry,
Federal University of Rio
Grande do Sul; Director, ADHD
Program, Hospital de Clínicas
de Porto Alegre, Brazil
Conflict of interest: Grants or
research support from, served
as a consultant to, and servedon the speakers’ bureau of
Medice, Novartis/Sandoz andShire/Takeda in the last three
years. The ADHD and Juvenile
Bipolar Disorder Outpatient
Programs chaired by Dr Rohde
have received unrestrictededucational and researchsupport from the following
pharmaceutical companies in
the last three years: Novartis/
Sandoz and Shire/Takeda. Dr
Rohde has received authorshiproyalties from Oxford Press andArtMed and travel grants from
Shire to take part in the 2018
APA annual meeting

After Still’s description, ADHD
was believed to be associated with brain
For those interested in learning morelesions and called minimal brain damage
about different aspects of ADHD, the World(Hohman, 1922; Kahn & Cohen, 1934).
Federation of ADHD has a free guide
Later, recognizing that not all children had
available in the Internet in English, Spanish
physical lesions, it was renamed minimal
and Chinese (click on the image to access)

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IACAPAP Textbook of Child and Adolescent Mental Healthbrain dysfunction (Clements & Peters, 1962). In
1934, Kramer-Pollnow described a syndrome called
hyperkinetische Erkrankung (hyperkinetic disease)characterized by restlessness and distractibility(Sharkey & Fritzgerald, 2007).
In 1937, Bradley described the first effective
treatment for ADHD. He reported that benzedrine
could decrease hyperactivity and improve attention
and academic performance (Bradley, 1937).
Hyperactivity was the symptom used to name thedisorder when first included in the International
Classification of Diseases, 9th edition (ICD-9) as“hyperkinetic syndrome of childhood” (subsequently
called “hyperkinetic disorder” in ICD-10) and in
the Diagnostic and Statistical Manual of Mental
Disorders, second edition (DSM-2) (“hyperkinetic
reaction of childhood”). It was only in 1980 that therole of inattention was recognized and the disorderrenamed “attention-deficit disorder with or without
hyperactivity” (DSM-III) and subsequently as“attention deficit hyperactivity disorder” (DSM-III-R
and DSM-IV).

EPIDEMIOLOGY
Meta-analytic data suggest a worldwide
prevalence of ADHD in children and adolescents
between 5% (Polanczyk et al, 2007) and 7%(Thomas et al, 2015). Both meta-analyses found highheterogeneity among the studies due to methodologicalfactors, such as different diagnostic approaches,
information sources, and whether impairment wasconsidered (Polanczyk et al, 2014).

Der Struwwelpeter, an illustrated book portraying children

misbehaving (“Impulsive Insanity/Defective Inhibition”) by
Heinrich Hoffman (1854).

Prevalence rates vary according to sex. Studies found a male-to-female ratioof 4:1 in clinical samples and 2:1 in general population studies (Polanczyk et al,2007), suggesting referral biases.
Regarding socioeconomic status, Larsson et al (2014) found that low family
income predicted an increased probability of ADHD in a Swedish population
cohort. This finding does not necessarily prove that lower socioeconomic statusincreases the risk of ADHD, it could be the opposite (reverse causation). Since thedisorder runs in families and causes various impairments—including educationaland occupational problems—that could lead to socioeconomic disadvantage.
Also, prevalence does not seem to vary with ethnicity. The association foundin some studies may be related to referral patterns and barriers affecting recognitionin particular ethnic groups (Faraone et al, 2015).
Does prevalence vary according to country? Did it increase in the last few
decades? Previous meta-analyses show that prevalence neither varies by geographic
region nor by the time of publication of the studies (Polanczyk et al, 2007, 2014).
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ETIOLOGY
Multiple theories about the etiology of ADHD have been proposed, fromsingle-cause explanations to models that characterize ADHD as a multifactorial
disorder, including genetic and environmental factors.

Genetic Factors
ADHD is a familial disorder; first-degree relatives of patients show a five- toten-fold increased risk of developing the disorder themselves when compared withthe general population. Twin studies have demonstrated a heritability of 70% to
80% in both children and adults (Thapar & Cooper, 2016; Posner et al, 2020).
A large genome-wide study including 20,000 individuals with and over
35,000 without ADHD found at least 12 different loci, with many genetic risk
variants involved in the development of ADHD. Each variant making a small
contribution to the risk (Demontis, 2019). These associations account for
approximately 22% of the disorder’s heritability (Posner et al, 2020).

Environmental Factors
Many environmental risk factors have been associated with ADHD.
However, none are specific to this condition. Due to the high heritability of
ADHD, gene-environment interactions might be the main mechanism by which
environmental factors increase the risk of developing the disorder. Epigenetics
is currently being brought into focus since it provides mechanisms by which
environmental risk factors modify gene function (Faraone et al, 2015; Posner etal, 2020).
The following are examples of environmental factors associated with ADHD
in meta-analytic or large population studies:
•

•
•
•
•

Prenatal and perinatal factors: low birth weight, prematurity—the
two more researched, see Franz et al, 2018—in-utero exposure tomaternal stress, maternal obesity, hypertension, cigarette smoking,alcohol, prescribed drugs (e.g., acetaminophen, valproate), and illicit
substances.
Environmental toxins (in-utero or during early childhood): lead,organophosphate pesticides, and polychlorinated biphenyls.
Nutritional deficiencies: zinc, magnesium, iron, omega-3 polyunsaturated
fatty acids.
Nutritional surpluses: sugar, artificial food colorings, low or high IgGfoods.
Psychosocial factors: low income, family adversity, harsh or hostileparenting.

Heritability
Heritability is a difficult tounderstand concept. There
are many misconceptions
about what it can andcannot tell us about a given
trait. Heritability does notindicate what proportionof a trait is determinedby genes and what
proportion is determinedby the environment. So, aheritability of 0.7 (or 70%)
does not mean that a trait
is 70% caused by genetic
factors; it means than 70%of the variability in the trait
in a population is due togenetic differences amongpeople.
To clarify this, imagine thatheight is 80% heritable.
This does not mean that
only 80% of people havetheir height geneticallyshaped. It would also be
erroneous to think thata particular height (e.g.,
165cm) can be broken
down in to 132cm ofgenetically determined
growth and 33cm ofenvironmentally caused
growth (Lynch K, 2013).

It is important to highlight that some of the associations detected might be
a product of gene/environment correlations. For example, the association between
maternal smoking and ADHD disappears after adjusting for family history of
ADHD, which suggests that this association is due to genetic factors that increase
the risk for both smoking and ADHD. The same applies to parenting style: achild’s behavior may elicit harsh and unsupportive parenting, which leads to an
escalation of problems and the development of coercive cycles within families(Posner et al, 2020).
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NEUROBIOLOGY
Neurotransmitters
The monoaminergic systems, specifically the dopaminergic and thenoradrenergic pathways, have been the most researched in ADHD; they are
intimately related to brain processes affected by the disorder. The dopamine
system plays an important part in planning and in the initiation of motor
responses, activation, switching, reaction to novelty and processing of reward.
The noradrenergic system influences arousal modulation, signal-to-noise ratios in
cortical areas, state-dependent cognitive processes, and cognitive preparation ofurgent stimuli (Faraone et al, 2015).
These systems were implicated in ADHD due to their involvement in
the mechanism of action of drugs used in treatment. They have been extensively
investigated in genetic studies using candidate gene approaches. Methylphenidate
and amphetamines target the sodium-dependent dopamine transporter,
atomoxetine targets the sodium-dependent noradrenaline transporter, and both
extended-release guanfacine and clonidine target the α2A-adrenergic receptor.
However, the complexity of ADHD pathophysiology extends beyond the
dopaminergic and noradrenergic systems. New research has implicated otherpathways, such as the nicotinic acetylcholine, glutamate, γ-aminobutyric acid
(GABA), serotonin, neurite outgrowth or endosomal systems (Faraone et al, 2015).

Structural Neuroimaging
Many studies have been published in the past two decades on brain
structure in ADHD. Earlier studies found a 3% to 5% difference in brain size
between individuals with and without ADHD (Castellanos et al, 2002; Durston
et al, 2004). Regarding subcortical regions, a meta-analysis reported smaller sizes
in the basal ganglia and limbic areas (Frodl & Skokauskas, 2012). The most recent
meta-analytic data by the ENIGMA-ADHD Working Group, which includes 36
cohorts and over 4,100 individuals, confirms these differences although notingthat they might be more subtle than previously described. Moreover, differences
are pronounced only in children and not significant in adults and adolescents(Hoogman et al, 2019).
Several studies found that the ADHD brain matures more slowly thanthe brain from typically developing children. In an important study, age of peakcortical thickness was delayed among children with ADHD (mean age at peak
thickness 10.5 years) when compared with normal controls (mean age 7.5 years)(Shaw et al, 2007). This delay was more significant in the prefrontal regions. In
relation to white matter, a meta-analysis of ten diffusion tensor imaging studies
showed differences between ADHD and non-ADHD brains (Chen et al, 2016).

Functional Neuroimaging
Task-based fMRI studies in patients with ADHD that used inhibitory
control, working memory, and tasks that required attention have shown under-activation of frontostriatal, frontoparietal, and ventral attention networks. The
fronto-amygdalar circuits, the limbic brain and the posterior areas of the brain

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IACAPAP Textbook of Child and Adolescent Mental Healthalso seem to be involved. Furthermore, in numerous studies, patients with ADHD
show lower activation in reward processing paradigms of the ventral striatum thancontrols. Also, they present hyperactivation of the somatomotor and visual systems,
which is possibly a mechanism to compensate impairment in the functioning of
the prefrontal and anterior cingulate cortex (Faraone et al, 2015).
Resting state MRI also suggests that the ADHD brain connects its functional
networks differently than the typically developing brain and that some networks
related to ADHD mature later (Sripada et al, 2014).
Findings of both structural and functional imaging vary considerably amongstudies, suggesting that the neurobiology of ADHD is heterogenous, which might
be reflected in the multiple symptoms of the condition. Despite evidence thatpatients with ADHD show differences from the “typical brain”, these biologicalmarkers are not sufficiently sensitive and specific to diagnose the disorder or toascertain if an individual has the disorder.

Neuropsychological data
It is important to highlight from the start that there is no neuropsychologicaltest with sufficient predictive power to diagnose ADHD. The most widely accepted
theory about neuropsychological deficits in ADHD emphasizes deficits on
behavioral inhibition (Barkley, 1997), including disruption of working memory,
sustained attention, motor control, and affect regulation. Some studies suggest
also that there are deficits on non-executive functions such as delay aversion(Sonuga-Barke et al, 2010). In addition, difficulties regulating arousal in response
to environmental circumstances are frequent. Clinically, this would mean that
ADHD symptoms are exacerbated during lengthy and tedious tasks (Posner et al,2020).
Regarding cognitive deficits, Frazier et al (2004) found a moderateassociation between lower reading and IQ scores with ADHD as well as large
impairments in arithmetic and spelling performance. These results were found ina meta-analysis of 137 studies with patients of all ages.
Again, the most important finding is the large heterogeneity in theneuropsychological profile of individuals with ADHD. As highlighted by Posner etal (2020): “While some individuals might show an extensive pattern of impairment
across different executive functions, others will display profound impairment in aparticular executive function (e.g., working memory) but be unaffected in otherareas (e.g., the ability to inhibit). Some patients will show no executive function
impairment at all.” More importantly, several other disorders might present aheterogeneous pattern of neuropsychological deficits and no specific deficit ispathognomonic of ADHD.

fMRI
Functional Magnetic
Resonance Imaging (fMRI)
measures brain activity
by detecting changes
associated with blood
flow, relying on the factthat cerebral blood flow
and neuronal activation go
together. When an area ofthe brain is in use, bloodflow to that region also
increases. fMRI is a variantof Magnetic ResonanceImaging (MRI) that seeks
to measure brain activity
and connectivity. It is noninvasive and provides amethod to assess brain
function.
The experimental designs
used in fMRI are restingstate and task-based.
In resting state fMRI
participants are not
performing any explicit
task, while using a stimulus
or performing a task is thecharacteristic of task-based
fMRI. In resting state fMRI
the most traditional design
consists of instructing
participants to keep theireyes closed, not to think
about anything in particularand not to fall asleep(Soares et al, 2016).

CLINICAL PRESENTATIONADHD is defined by the presence of a persistent pattern of inattention
and/or hyperactivity-impulsivity that interferes with normal functioning ordevelopment. Manifestations of inattention are numerous, including mind
wandering while performing a task, lack of persistence, and disorganization.

ADHD D.1

Click on the picture to viewa short clip about ADHD andthe brain

6

IACAPAP Textbook of Child and Adolescent Mental HealthHyperactivity manifests itself as excessive motor activity when not appropriate,fidgeting, tapping, or talkativeness. Impulsivity refers to making decisions or
actions without planning. Also, it can appear as social intrusiveness or making
important decisions without considering its consequences. It is important toemphasize that these behavioral patterns should not be due to defiance or lack ofcomprehension (American Psychiatric Association, 2013).
Research about the factor structure of ADHD symptoms across the lifespan,using different information sources (e.g., teachers and parents) and cultures,
suggests a two-factor model for ADHD, with inattentive and hyperactive/impulsive
dimensions (Bauermeister et al, 2010). DSM-5 (American Psychiatric Association,2013) suggests that there are three ADHD presentations: predominantly
inattentive, predominantly hyperactive/impulsive, and combined. Although thisdescription provides convenient clinical prototypes that have specific associations
with functional and behavioral correlates of inattention and hyperactivityimpulsivity symptoms, it does not identify robust subgroups with sufficient longterm stability to justify the classification of distinct types of the disorder (Willcutt
et al, 2012). The key symptoms of ADHD are listed in Table D.1.1
Table D.1.1

Click on the picture to view
Russell Barkley PhD arguingthat the core problem in
ADHD is not inattention but adisorder of self-regulation

Symptoms of ADHD

Inattention•

Difficulty paying attention to details and consequent careless mistakes•

Difficulty sustaining attention in tasks or activities•

Struggling to listen when spoken to•

Struggling to accomplish and to finish tasks or activities•

Difficulty organizing tasks and activities•

Avoidance of tasks that need more mental effort•

Misplacing objects needed to perform tasks or activities•

Distractibility by external stimuli•

Forgetfulness about daily activities

Hyperactivity or impulsivity•

Fidgeting or tapping hands or feet or squirming in seat•

Standing up when expected to remain seated•Running about or climbing (mostly in children) or subjective feelings ofrestlessness (mostly in adolescents and adults)•

Inability to play quietly•

Often “on the go”, “driven by a motor”•

Inappropriate talkativeness•Blurting out answers before a question has been finished•

Difficulty waiting their turn in games or activities•

Interrupting others or intruding

ADHD D.1

Individuals affected by
ADHD and their families
commonly misinterpret
symptoms as “part oftheir personality” or their“way of being.” In thesecircumstances, parents
are unlikely to seek
medical attention unlessthe behavior is associatedwith impaired functioning
noticed by others, likeacademic failure; in thiscase, teachers are the ones
who suggest parents toseek treatment.

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IACAPAP Textbook of Child and Adolescent Mental Health

It is important to highlight that children affected by ADHD might be able
to remain focused when performing specific tasks such as playing videogames,
watching television, or in certain situations which they enjoy. Motivation,
relevance, and attractiveness of the task for the child influence the manifestationof symptoms. Also, careful parents might provide structured environments andstimulation for their children with ADHD, creating a situation where symptoms
are only evidenced later in adolescence when they become more independent.

Differences According to Developmental Stage
The developmental stage must be considered when assessing individual
clinical presentations since symptoms vary according to age. Although there arestudies showing that current criteria can be used to diagnose ADHD even in 3-yearold children, there are intrinsic difficulties in diagnosing ADHD in preschoolers.
A degree of impulsivity and hyperactivity is developmentally appropriate in thisage group, which makes it hard to disentangle age-normal from inappropriate
hyperactive/impulsive behaviors. Also, since they might not be exposed to
substantial environmental demands (e.g., sticking to a task for any length of time),
inattention is even more difficult to assess.

Click on the image to viewa short clip with Guilherme
Polanczyk speaking about
the essentials for diagnosing
ADHD in pre-schoolers

In school-age children, inattentive and hyperactive/impulsive symptoms canbe detected, particularly in the classroom, in different combinations and varying
degrees of severity using information from different sources. ADHD symptoms
tend to decline in late adolescence and adulthood—hyperactive/impulsive

Table D.1.2 Changes in ADHD symptoms from childhood to adulthood
Primary school
years

Preschool years•

Inattention

Overactivity

Impulsivity••

Short playsequences (<3min)
Leaving activities
incomplete
Not listening•“Whirlwind”••

Does not listen
No sense of
danger (hard to
distinguish from
oppositionality)•

Adolescence

Brief activities (<10min)
Premature changes ofactivity
Forgetful;
disorganized;
distracted
environment••

Restless when calm
expected•

Acting out of turn;interrupting otherchildren and blurtingout answers
Thoughtless rulebreaking
Intrusions on peers;
accidents

•
•

•
•

AdulthoodLess persistence
than peers (<30min)
Lack of focus on
the details of atask
Poor planning
ahead

•

•

Fidgety•

Subjective
feelings ofrestlessness••

Poor self-control
Reckless risktaking•

Motor and otheraccidents
Premature andunwise decisionmaking
Impatience

•
•

•
•

•
•

Details notcompleted
Appointments
forgotten
Lack of foresight

Source: Taylor E, Sonuga-Barke E (2008), “Disorders of attention and activity” In Rutter M et al (eds), Rutter’s Child andAdolescent Psychiatry, p. 522. ©Blackwell Publishing Limited, with permission.

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IACAPAP Textbook of Child and Adolescent Mental Healthsymptoms lessening more than inattentive ones across development (Rohde et al,2019). See Table D.1.2.

Comorbidity
Individuals with ADHD from clinical and community samples often
suffer from other psychiatric disorders. The patterns of comorbidity depend on
the developmental stage. The most common comorbid conditions in children
are oppositional defiant disorder (ODD), conduct disorder (CD), intellectual
disability, learning disorders, language disorders, sleep disorders, enuresis,
developmental motor coordination disorders, depressive and anxiety disorders, tic
disorders, and autism spectrum disorders.
A meta-analysis found that children with ADHD are 10 times more likely
to have CD or ODD, five times more likely to suffer from depression, and threetimes more likely to have anxiety disorders compared with those without ADHD.
There was no significant difference in comorbidity profiles between boys and girls.
In adolescents and adults, eating disorders, substance use disorders, bipolar
disorder, and personality disorders are also more frequent. Recently, ADHD has
been associated with medical conditions beyond psychiatric disorders such as
obesity, asthma and atopic conditions, epilepsy, and diabetes (Rohde et al, 2019).

DIAGNOSIS
Currently, the diagnosis of ADHD, usually following a classification system,
predominantly DSM-5 or ICD-11, relies exclusively on a clinical assessment(see table D.1.3 and box in page 10) (American Psychiatric Association, 2013;
ICD-11). DSM-5 differs from ICD-11 in that it provides explicit statements ofsymptoms, other features, and decision rules to determine whether a child qualifies
for the diagnosis. DSM-5 is quite prescriptive and allows the creation of diagnostic
algorithms useful for research. ICD-11 relies largely on clinicians’ experience andsubjective judgement (see also Chapters A.3 and A.9 of the eBook).

Sources of Information
Different informants have different perspectives about the individual
assessed. Neither DSM-5, nor ICD-11 guide on how to proceed when faced withconflicting data from different sources. Despite a lack of consensus about thismatter, the current clinical wisdom is that diagnosis should be based on informationfrom as many sources as possible. Also, it is clear that some informants will beable to evaluate some of the symptoms more accurately than others (e.g., parents
can report about their child’s development and behavior at home, while teachers,by being constantly surrounded by children of similar age, can better report on
differences from peers and about behavior at school) (Rohde et al, 2019). Clinicians
should also examine the child, even though symptoms are often absent during
the assessment interview. It would be unrealistic to require a child to demolishor run amok in the doctor’s office to make a diagnosis of ADHD. Furthermore,examining the child is important to exclude other problems. Adolescents should be
asked about symptoms they experienced during childhood. However, they often
deny symptoms in the past, interpreting them as normal behaviors or minimizing
their impact. Parents’ information and school reports may help to determine theage of onset of symptoms.
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Table D.1.3

Diagnostic criteria for ADHD according to DSM-5

Criterion••••

6 or more out of 9 symptoms of inattention
OR
6 or more out of 9 symptoms of hyperactivity/impulsivity
For older adolescents (aged 17 or more) and adults, the threshold is at least 5
symptoms

Age of symptom onset*•

Before 12 years of age

Minimal duration ofsymptoms•

6 months

Pervasiveness•

Symptoms present in two or more settings (e.g., school, work, home)

Functioning•

There is clear evidence that symptoms cause significant impairment

Sources of information
required•

Not mentioned•

Symptoms occur exclusively during the course of pervasive developmental
disorder, schizophrenia or other psychotic disorder, and are not better accounted
for by another mental disorder (e.g., mood disorder, anxiety disorder, dissociative
disorder or a personality disorder)•••

Attention deficit hyperactivity disorder predominantly inattentive type
Attention deficit hyperactivity disorder predominantly hyperactive-impulsive type
Attention deficit hyperactivity disorder combined type

Number of symptoms
needed for diagnosis

Exclusion of thediagnosis if

Possible diagnoses*Note that this criterion refers to age of onset of symptoms and not to impairment

ADHD according to ICD-11
Attention deficit hyperactivity disorder is characterized by a persistent pattern (at least 6months) of inattention and/or hyperactivity-impulsivity, with onset during the developmental
period, typically early to mid-childhood. The degree of inattention and hyperactivityimpulsivity is outside the limits of normal variation expected for age and level of intellectual
functioning and significantly interferes with academic, occupational, or social functioning.
Inattention refers to significant difficulty in sustaining attention to tasks that do not provide ahigh level of stimulation or frequent rewards, distractibility, and problems with organization.
Hyperactivity refers to excessive motor activity and difficulties with remaining still, mostevident in structured situations that require behavioral self-control. Impulsivity is a tendency
to act in response to immediate stimuli, without deliberation or consideration of the risks
and consequences. The relative balance and the specific manifestations of inattentive andhyperactive-impulsive characteristics varies across individuals and may change over thecourse of development. In order for a diagnosis of disorder the behavior pattern must be
clearly observable in more than one setting.
Unlike DSM-5, ICD-11 excludes ADHD diagnosis when the individual suffers from autism
spectrum disorder, disruptive behavior or dissocial disorders.

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Additional Investigations
Regrettably, there are no auxiliary tests, investigations, or biomarkers
with sufficient predictive power to confirm or exclude this disorder. Likewise,
neuroimaging (MRI, PET, SPECT) and EEG are not recommended in routine
clinical evaluation, although they may be useful in differential diagnosis in rarecases. Neuropsychological, IQ, and achievement tests are helpful to estimate
intellectual impairment, severe executive function deficits, and potential learning
disorders (Rohde et al, 2019), which are important for management.
Rating scales are useful to quantify the severity of symptoms and to monitor
response to treatment. One of the most widely used is SNAP-IV (Swanson, Nolanand Pelham Rating Scale-fourth revision); for adults, ASRS (Adult ADHD SelfReport Scale) is recommended (see table D.1.4) (Faraone et al, 2015).

Differential Diagnosis
It is essential to conduct a complete physical exam to exclude other clinicalconditions (e.g., hyperthyroidism) that might cause inattentive and/or hyperactive/
impulsive symptoms, as well as to evaluate visual and auditive acuity and sleep
patterns.
Sleep disorders can be the cause, a consequence, or co-occur with ADHD
(see Chapter I.4 of the eBook). Several genetic conditions may present with
ADHD symptoms (i.e., neurofibromatosis type I, fragile X syndrome). Several
psychiatric disorders that can be comorbid with ADHD must be considered also inthe differential diagnosis (i.e., generalized anxiety disorder, bipolar disorder, major
depression). Although ADHD can be comorbid with PTSD (Spencer et al, 2016),
it is important to note that some traumatic events such as sexual abuse or severe
neglect might result in a clinical picture that resembles ADHD.
Table D.1.4 Selected Scales for ADHD freely available for clinical use
SCALE(age range)

RATER

COMMENTS

SNAP IV(5–18 years)
Swanson, Nolan andPelham Rating Scale-fourth
revision (Swanson et al,
2001)

•
•
•

Self
ParentTeacher•••••

A rating scale for symptoms of ADHD and ODD
Sensitive to changes relating to treatment
Short scale: 26 items
Full scale: 90 items
Versions in French, Portuguese, and Spanish

SWAN(5–18 years) Strengths
and Weaknesses of ADHD
Symptoms and Normal
Behavior Scale(Swanson et al, 2001)

•
•
•

Self
ParentTeacher•••

Based on DSM-IV criteria
26 items
Versions in French and Spanish

Self

•
•
•
•

Developed by the WHO
A 6-item version for screening
An 18-item version based on DSM-IV symptoms
Both versions have been translated into many languages

ASRS(adults)
Adult ADHD Self-Report
Scale

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There are steps to be followed by clinicians in the differential diagnoses inthese situations:•••

Consider the age of onset of the ADHD symptoms and of the symptomsof the other psychiatric problems,Examine the trajectory of the symptoms (e.g., some disorders are
episodic while ADHD is not), andAssess if the symptoms cannot be better explained by the comorbid
condition (Rohde et al, 2019).

For example, age-of-onset of symptoms can be clinically relevant whendisentangling inattention as manifestation of ADHD or as a symptom of a chronic
depressive disorder (e.g., dysthymia). Onset of the inattentive symptoms before
the onset of mood symptoms would suggest an ADHD diagnosis.
Relative immaturity. Interest in the relationship between relative immaturity
and ADHD has increased recently. Children in the same grade at school are aheterogeneous group with some, born earlier, being older than others, born later.
Age difference can be as large as 12 months, representing up to 15% of their young
lives. Studies have shown that children who are younger than their classmates
are more likely to be diagnosed with ADHD (Caye et al, 2019a). Although thereasons for this are not clear, it could be due to younger (less mature) children
being incorrectly diagnosed as having ADHD (false positives), or younger children
with ADHD in the same school grade having a more severe clinical presentation,
making easier its recognition. Irrespective of the reason, this issue should be taken
into consideration not just by clinicians but also by teachers.

Flow of Assessment
The diagnostic process is based on clinical approaches that rely on different
sources of information. This process might be conducted using standard psychiatricinterviews with the patient and their relatives, and with other appropriate
informants, such as teachers (see Chapter A.5 of the eTextbook).
The interview is designed to elicit the symptoms and understand how theyaffect the individual’s life as well as whether family or social factors may contributeto the symptoms. In addition, it allows capturing relevant medical and family
history of mental disorders. The search for impairment in the various areas of life
is crucial, such as school and relationship problems with parents and friends. In
addition, it is essential to comprehensively search for comorbidities (Rohde et al,2019).
To assist with diagnosis, particularly in research settings, different
standardized interviews can be used with the aim of increasing reliability, such as
the Schedule for Affective Disorders and Schizophrenia for School-age Children(K-SADS), or the Development and Wellbeing Assessment (DAWBA). Both can be
downloaded from the Internet free of charge and are available in several languages.
The K-SADS is a semi-structured interview, that is, it allows clinical judgment by
the interviewer who needs to be a clinician trained in the use of the instrument.
The DAWBA can be administered by trained non-clinical interviewers, online orby telephone, which is useful in epidemiological research.

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COURSE
Until recently, ADHD was seen as a disorder specific to children. The
belief was that individuals outgrew ADHD in adolescence. In the last two decades,
substantial work has documented its persistence into adulthood in a substantial
proportion of cases.

Persistence
There is no consensus on the extent in which ADHD persists from childhood
to adulthood. Longitudinal studies following children with ADHD to a mean ageof 18 years found rates that varied between 4% and 76% (Caye et al, 2016). A
meta-analysis suggested that 15% of childhood cases met full diagnostic criteria
by the age of 25, up to 65% showed symptoms causing impairment but did notmeet full diagnostic criteria, and 20% showed neither symptoms nor impairment
during adulthood (Faraone et al, 2006).
Despite the numerous studies on the trajectory of ADHD during thelifespan, there are only a few reports on childhood risk factors associated withremission or persistence into adulthood. A meta-analysis indicated that severe
ADHD, comorbid conditions (such as conduct disorder and major depressive
disorder), and treatment for ADHD were the main predictors of persistence. The
Multimodal Treatment of ADHD study (MTA) reported that parental mental
health problems could be a significant risk factor. However, IQ, socioeconomic
status, parental education, and parent-child relationship problems were notassociated with persistence (Roy et al, 2016).

Adolescent and Adult-Onset
According to DSM-5 (American Psychiatric Association, 2013), to makea diagnosis of ADHD, symptoms must have been present before the age of 12(until 2013, before seven years of age). Some studies (Caye et al, 2016; Moffitt
et al, 2015; Agnew-Blais et al, 2016) question this and suggest that ADHD may

ADHD D.1

Click on the picture to accessthe guideline on ADHD by the
National Institute for Healthand Care Excellence (NICE)

13

IACAPAP Textbook of Child and Adolescent Mental Healthoccasionally start during adolescence or even adulthood. Whether ADHD of lateonset may exist or not requires more research (Asherson & Agnew-Blais, 2019).

OUTCOMES
It is widely accepted that ADHD is associated with negative outcomes. A
wide range of studies has found that a diagnosis of ADHD is strongly associatedwith emotional problems and social impairments (Faraone et al, 2015), such as:••Less ability to cope with stressful events, to express empathy, and tosocialize with peers
More likelihood to bully others, to drop out of school, to be unemployed,
to have a lower income, to be involved in accidents—especiallymotor vehicle accidents—to be convicted of criminal offenses, to be
imprisoned, to misuse substances, to have unwanted pregnancies andsexually transmitted diseases, and to die younger.

Risk calculator
Click here to access arisk calculator to estimate
the chance of persistenceof ADHD from childhood
to young adulthood forchildren aged less than 12
years living in the UK or in
the US (Caye et al, 2019b).

These negative outcomes result in a worse quality of life and higher suicide
rates (Chen et al, 2019; Fitzgerald et al, 2019). In addition, ADHD has a negative
impact on families. For example, a Danish study found that having a child with
ADHD doubled the chances of parental separation (Kousgaard et al, 2018).
Despite all the negative outcomes associated with ADHD, some studies
give a glimpse of potentially positive aspects. For example, adults with the disorder
may have higher entrepreneurial traits (Verheul et al, 2016; Sônego et al, 2020), be
more tolerant of risk, more open to new experiences, and more creative (Antshel,
2018; White & Shah, 2011; Boot et al, 2017).

Financial Burden
Large, systematic reviews have estimated the annual cost attributed to
ADHD as between $143 and $266 billion in the US and more than €1 billion
in the Netherlands (Doshi et al, 2012; Le et al, 2014). In Sweden, children with
ADHD doubled or trebled the cost to the healthcare system when compared withpeers without the condition (Du Rietz et al, 2020). Similar financial burden has
been estimated for South Korea and Australia, among others.

TREATMENT
We present here the optimal treatment in an ideal world, something toaspire to. In many cases, however, due to lack of time, resources, skilled clinicians,
and for other reasons, shortcuts are made. This is particularly so in low income
countries where there is an acute lack of trained personnel. In any case, this should
not be a justification for using treatments that are unsafe or have been shown not
to be effective.
There are various treatment strategies that can ameliorate ADHD symptoms
which are supported by evidence. Given the variation among patients, anindividualized treatment plan is needed, taking into account age, comorbidities,
severity, family and social circumstances, and preferences of the patient and family.
The patient and family must always be involved in this process.

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Psychoeducation
Because ADHD is a chronic, potentially lifelong condition, psychoeducationis the foundation for any treatment. Clinicians should pay attention to giving
information in a way that families can understand, using language, comparisons,and metaphors at the patient educational level and in a culturally sensitive manner.
This would include:
•
•
•
•
•

•
•
•

Asking the family and the patient to explain their understanding of
ADHD
Giving an accurate explanation of what is ADHD, debunking myths
and misconceptions, which are widespread
Explaining that there is no “test” to diagnose ADHD, that diagnosis isbased on clinical assessment
Explaining at a level they can understand what causes the disorder
Listing the various treatment options, including medication, with theirbenefits and side effects, the likelihood of response, expected course ofaction, and short and long-term effects
Discussing pros and cons of the treatment chosen and if treatment isrejected
With parents’ permission, inform teachers about the disorder and what
they can do to support their students
Informing about self-help resources, support groups, voluntaryorganizations, websites, and support for education and employment(NICE, 2018).

Non-Pharmacological Treatments
Non-pharmacological treatments may be used as an alternative or as
an addition to medication when patients do not respond to the medication or
have significant adverse effects, to address certain comorbidities, when patients
do not have access to pharmacological treatment or when patients are too young

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IACAPAP Textbook of Child and Adolescent Mental Healthto take medication (Faraone et al, 2015). This evolves as patients grow up. For
instance, parental interventions have more impact on younger children, while
psychoeducation regarding substance misuse or motor vehicle accidents is more
relevant for adolescents or young adults. A more detailed description of thesetreatments can be found in Chapter D.1.1 of the eBook.

Behavioral and Psychosocial Treatment
Most guidelines recommend behavioral interventions (especially behavioral
parent training) combined with medication. Behavioral interventions areindicated as the first line of treatment mainly for younger children and for those
who have mild symptoms and impairment (Caye et al, 2019). However, the moreconservative analyses of the literature for school-aged children and adolescents,
considering evidence from randomized clinical trials relying on blind evaluations,suggest that effect sizes of ADHD symptoms are not substantial (Rimestad, 2019)
but it is important to highlight that they are relevant to improving the qualityof parenting and to treat comorbid conditions, especially oppositional defiant
disorder and conduct problems (Faraone et al, 2015).
Other psychological approaches used for treating ADHD include behavior
classroom interventions, social and organizational skills training, meditation-based
therapy, and cognitive therapy. The last three might be particularly suitable foradolescents.

Neurofeedback
Neurofeedback uses reward-based techniques to normalize elements of thepatient’s electrophysiological profile that are thought to be associated with attention
problems (Faraone et al, 2015). In summary, patients are trained to improve theirself-control over brain activity patterns while being monitored via EEG obtained
when they concentrate on a task (for instance, a simple computer game). Results ofresearch regarding the positive effects of neurofeedback in ADHD are ambiguous
at best (Caye et al, 2019).     Computerized Cognitive Training
Cognitive training approaches hypothesize a reduction of ADHD
symptoms by enhancing achievement in specific neuropsychological functions
related to ADHD (e.g., inhibitory control, attention, working memory). They areusually administered via computers or mobile phones and designed to be appealing
to children, similar to videogames (Caye et al, 2019). These interventions train
specific functions over multiple sessions, challenging the individual and increasing
difficulty as they evolve (Faraone et al, 2015). A meta-analysis found that thistreatment shows moderate effectiveness in improving the neuropsychological
functions targeted but a less clear impact on the core symptoms of the disorder(Caye et al, 2019). Recently, the US Food and Drug Administration (FDA)
approved the first videogame for treating ADHD in children (Kollins et al, 2020).
Although promising, more studies are needed before this intervention can berecommended.

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IACAPAP Textbook of Child and Adolescent Mental Health

Dietary Interventions
Dietary interventions are divided into exclusions and supplements. Exclusion
diets generally target artificial additives (mainly artificial food colorings). They havea positive but small effect, especially in patients that already had food intolerances(Faraone et al, 2015).
Polyunsaturated fatty acids are the supplements with the best positiveeffects (Caye et al, 2019). The use of other supplements (e.g., vitamins, herbs,
homeopathy) is not supported by research evidence (Faraone et al, 2015).

Brain Stimulation
Since the trigeminal nerve conducts afferent inputs to multiple
connections in the locus coeruleus, reticular activating system, and nucleus tractus
solitarius—areas associated with attention—it is theorized that external trigeminal
nerve stimulation may be a non-invasive, minimal risk treatment for ADHD
(McGough et al, 2019). Despite having been approved by the FDA, the efficacyof this intervention is supported only by a 5-week randomized controlled trial thatinvolved just 30 patients experiencing active trigeminal nerve stimulation. Morestudies are needed before it can be recommended.

PHARMACOLOGICAL TREATMENT
Stimulants
Psychostimulants—methylphenidate and amphetamines—are themost studied drugs for ADHD and among the best researched in psychiatry(e.g., table D.1.5). Methylphenidate is the most widely available. They have thelimitation of a short half-life, thus requiring two or three doses during the day for
optimal benefit—creating considerable practical problems particularly at school.
Extended release preparations—which only require a single morning dose—
use different mechanisms for slowing down absorption or release. For example,
Concerta utilizes an “osmotic pump” mechanism with 22% of the dose available
as immediate release.
Although more potent than methylphenidate, the amphetamines are lessoften used and, due to concerns about potential for abuse, are not commerciallyavailable in a number of countries. Apart from immediate release formulations,
there are several longer acting, extended release amphetamine products. For
example, Vyvanse (lisdexamfetamine) has an extended duration of action (seeTable D.1.5).
All stimulants are thought to act, at least in part, through their impact
on dopamine and/or noradrenaline pathways. Both neurotransmitters are key
modulators of the brain circuits that support attention, reward processing, andactivity. Whilst there are similarities between these medications, there are also
differences. Methylphenidate and the amphetamines inhibit both the dopamineand noradrenaline reuptake transporters. Amphetamine derivatives also promote
the release and reverse pre-synaptic transport of dopamine.
Although Concerta and Vyvanse (lisdexamfetamine) are considered first-line
treatment in the majority of international guidelines (see below) and have many

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Table D.1.5 Stimulant drugs available to treat ADHD

Drug

Methylphenidate

Typicalstarting
dose(mg)

Maximum
daily dose(mg)

Duration type

Brand name*

Short-acting

Ritalin
Metadate
Methylin

BID to TID

3-5

5

60

Focalin

BID to TID

2-3

2.5

20

Ritalin SR
Metadate ER
Methylin ER

QD to BID

3-8

10

60

Metadate CD
Ritalin LA

QD

6-8

10

60

Concerta

QD

8-12

18

72

Focalin SR

QD

12

5

30

Intermediateacting

ExtendedreleaseDaytrana

Patch worn for up to 9 hours

1030

Dexedrine
Dextrostat

BID to TID

4-6

5

30

Adderall

QD to BID

4-6

5

40

Intermediateacting

Dexedrine
spansule

QD to BID

10

5

40

ExtendedreleaseAdderal-XR

QD

10

10

30

Vyvanse

QD

13

30

70

Dosageschedule

Typical starting dose(mg)

Maximum
daily dose(mg)

Short-acting
Amphetamines

Approximate
durationof action(hours)Dosageschedule

QD: once a day; BID: twice a day; TID: three times a day.
*All may not be available in some countries and brand names may be different.

Table D.1.6 Non-stimulant drugs used to treat ADHDDrug

Duration type

Brand name*

Guanfacine

Extended release

Intuniv

QD

1

age 8-12: 4
13-17: 7

Clonidine

Extended release

KapwayCatapresBID

0.1

0.4 split in two
doses

QD to BID

70 kg or less: 0.5 mg/kg
over 70 kg: 40 mg

70 kg or less: 1.4
mg/kg or 100
over 70 kg: 100
mg

Atomoxetine

Short acting

Strattera

QD: once a day; BID: twice a day; TID: three times a day.
*All may not be available in some countries and brand names may be different.

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IACAPAP Textbook of Child and Adolescent Mental Healthsimilarities, they also have differences. Lisdexamfetamine has both a slightly larger
effect size than methylphenidate in clinical trials with children and adolescents, ahigher rate of irritability, and a bigger decrease in appetite. Concerta has a quicker
onset of action but a slightly shorter duration in pharmacokinetic studies, although
there is large inter-individual variability.

Non-Stimulants
There are two classes of non-stimulant medication used in ADHD, thenoradrenaline reuptake inhibitor atomoxetine and the ɑ2-adrenergic agonists
clonidine and guanfacine. See table D.1.6. Other medications have been used
off-label such as tricyclic antidepressants (imipramine), bupropion (anotherantidepressant), and modafinil (usually administered to treat narcolepsy),
with limited efficacy. Their use for ADHD is not approved in the US and theEuropean Union (Caye et al, 2019). Recently, there is growing interest in the useof cannabinoids.

WHICH MEDICATION TO USE?
Based on EffectivenessA meta-analysis including 133 studies with 24,000 participants foundthat psychostimulants were highly effective in reducing ADHD symptoms.
Methylphenidate and amphetamines have a slightly different effect according
to age group. Methylphenidate achieves a greater improvement in children andadolescents than in adults, while the amphetamines show similar benefit inboth age groups. Among non-stimulant medications, atomoxetine produces amoderate improvement in both children and adults. Guanfacine and clonidine,both extended release, lead to a moderate reduction of symptoms in children only(Cortese et al, 2018).
Various well-designed studies, most based on large datasets, have investigatedthe extent to which reducing ADHD symptoms was associated with better
outcomes in real life. They clearly documented the effectiveness of stimulants,
mainly methylphenidate, in different functional outcomes such as improved
quality of life (Jonsson et al, 2017; Coghill et al, 2017; Coghill, 2010) and higher
academic achievement (Lu et al, 2017), reduced criminality (Lichtenstein et al,2012; Mohr-Jensen et al, 2019), reduced vehicle accidents (Chang et al, 2017),
reduced emergency room admissions related to substance abuse or trauma (Quinn
et al, 2017; Chang et al, 2014), reduced risk of injuries and brain lesions (Ghirardi
et al, 2020; Dalsgaard et al, 2015), fewer sexually transmitted diseases (Chen etal, 2018), fewer suicides (Liang et al, 2018), and reduced mortality rates (Chen etal, 2020).

Based on side Effects
Adverse effects must always be discussed in detail with the patient and parents
before prescribing medication. The most common adverse effects of stimulants are
insomnia, headaches, irritability, agitation, nervousness, tremor, loss of appetite,
nausea, and weight loss. These tend to be mild, dose dependent and transitory.
Stimulants can exacerbate tics, psychotic and manic symptoms, and seizures inchildren at risk for such conditions. Most of them can be managed by adjusting theADHD D.1

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Table D.1.7

Monitoring and managing medication side effects

Side effectMay occur with:

Monitoring

Management

Loss ofappetite or
weight loss•••

Methylphenidate
Atomoxetine
Amphetamines••

Methylphenidate
Atomoxetine
Amphetamines•

Methylphenidate
Amphetamines•

Growthretardation

Insomnia

•
•
•

•
•

•

•

•
Hepatotoxicity•

Atomoxetine••

Abnormalblood pressure
or cardiac
function•••

Methylphenidate
Atomoxetine
Amphetamines•

Seizures

Tics

•
•

•
•

Methylphenidate
Atomoxetine

Methylphenidate
Amphetamines••

Measure weight before
treatment and then every
3-6 months
Plot on a growth chart
Measure height before
treatment and then every
3-6 months
Plot on a growth chart

Gather information about
sleep patterns before andafter starting treatment
Inform parents about risk ofliver damage
Monitor ALT and AST levels
before and after starting
treatment
Before starting medication,collect detailed information
about:− Personal and family
history of cardiovascular
events (particularly
sudden cardiac death)− Physical findings
suggestive of Marfan’s
syndrome or long Q-T
syndrome
At follow up appointments
monitor heart rate, bloodpressure and the presenceof abnormal murmurs
Warn parents about risk ofseizures

Monitor the presence of tics
before and after starting
treatment

•
•
•

•
•
•
•
•

•

Anxietysymptoms

ADHD D.1••

Methylphenidate
Amphetamines

Investigate presence ofanxiety symptoms before
and after starting treatment

Consider stopping medication
during weekends and school
holidays
Consider dosage reduction orstop medication if there is clear
evidence of growth retardation
Consider changing the doseschedule avoiding medication in
the afternoon
Reduce dose
Change to atomoxetine
Stop atomoxetine immediately if
jaundice or laboratory evidence ofliver damage emerges
Change to another medication but
do not resume atomoxetine•

In case of suspectedcardiovascular abnormality referpatient to a cardiologist before
commencing medication
In case of blood pressure higher
than the 95th percentile (or any
clinically relevant increase) or
arrhythmia/tachycardia, stop
the medication and refer to a
cardiologist••

Stop medication.
Consider using dexamphetamine.

•

Reduce/stop the stimulant if tics
get worse
Discuss with parents and patient
the benefits and risks of continuing
stimulant treatment
Consider atomoxetine•••

Avoid taking the medication before
meals
Give patient and parents dietaryadvice or refer for dietary advice•••

Titrate the dose more slowly
In case of worsening or emerging
anxiety symptoms consider
concomitant treatment of anxiety
Change to atomoxetine

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Table D.1.7

Monitoring and managing medication side effects (continuation)

Side effectPsychotic
symptoms

May occur with

Monitoring•••

Methylphenidate
Amphetamines

Monitor psychotic
symptoms before andafter starting treatment

Management••••

Aggressive or
hostile behavior
and suicidal
thinking•

Atomoxetine••
Drug misuse ordiversion••

Methylphenidate
Amphetamines•

Ask patients aboutsuicidal or aggressive
ideation or impulses

Monitor the numberof pills prescribed andgather information
about behaviors that
may suggest abuse/diversion
Do family members
abuse substances?

•
•

•
•

In case of high risk for, or emerging
psychotic symptoms, stop stimulants
Consider atomoxetine
If symptoms persist after stopping
stimulants, treat psychotic symptoms.
Warn parents about risk for such
behaviors before starting treatment
Discuss with parents how to keep
their child safe from self-harm
If symptoms persists after one
month consider changing to anothermedication
Ask parents to monitor or supervise
taking the medication
In case of high risk for abuse,suspected abuse or diversion,
atomoxetine should be prescribed

dose or changing the stimulant drug (see also Table D.1.8). Growth suppression
and cardiovascular effects are the long-term adverse effects most relevant.
Growth retardation. Stimulants can stunt children’s growth and may reduce
final adult height (by up to 4 cm of expected adult height; Greenhill et al, 2019).
This risk needs to be discussed with parents and patients, and children’s growthmonitored regularly while on stimulants. Growth might resume once stimulants
are stopped. Thus, ceasing taking the drug during summer school holidays may
minimize this risk. Other options include reducing the dose, switching to a nonstimulant medication, or stopping it.
Sudden death. Despite concerns in this regard, several large studies andmeta-analyses have shown no evidence that current use of an ADHD medication
is associated with an increased risk of serious cardiovascular events. Although therisk cannot be ruled out altogether, its magnitude is very low (Cooper et al, 2011).
Nevertheless, as part of the clinical history, it is necessary to ascertain cardiac
risk factors. Additionally, heart rate and blood pressure should be monitored atbaseline, after each dose change, and every six months. ECGs are not required
except when there are cardiac risk factors, particularly a family history of sudden
death before the age of 40 years (NICE, 2018). An option in these cases is toprescribe a non-stimulant. Atomoxetine can lead to an increase in blood pressureand heart rate, while guanfacine and clonidine may decrease these two parameters.

Diversion of ADHD Medication
Diversion of stimulant medication (i.e., by selling it, giving it to friends orrelatives, having it stolen by others) has increased in the last decades, especially in

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IACAPAP Textbook of Child and Adolescent Mental Healthhigh income countries, where stimulants are more often prescribed. While in mostof these cases stimulants are used to improve academic performance, recreationaluse also happens. Parents and patients need to be made aware of this risk andtake appropriate precautions monitoring and keeping the medication in a safe
place (Faraone & Wilens, 2007). If there are substance misusing individuals in thehousehold, clinicians may consider prescribing long-acting stimulants, which havelower abuse potential than immediate-release stimulants.

Implications of Comorbidities
Specific disorders such as depression and bipolar disorder may present withor exacerbate ADHD symptoms. In these cases, the best course of action may be
to treat the comorbid disorder first; the clinician can then assess the ADHD byfocusing on the remaining symptoms (Caye et al, 2019).
Generally, stimulants do not exacerbate comorbid tic disorders. However,this can happen in some patients and should be monitored (Caye et al, 2019). If
that were the case, treatment with atomoxetine or alpha agonists is an alternative(Pringsheim & Steeves, 2011). It is widely accepted that atomoxetine might be an
option when ADHD co-occurs with anxiety disorders due to its positive effect onanxiety symptoms, while stimulants might make them worse.

Table D.1.8 Summary of Recommendations for Treatment
Severity

4–5 years of age

6–11 years of age•••

Mild toModerate••••

Psychoeducation
Parent training
programs
Teacheradministeredbehavior therapy
If noimprovement andsymptoms aresevere, consider
methylphenidate.

•
•

•
•
•

Severe•ADHD D.1

Psychoeducation & parent training
programs
If no access to parent training:
stimulants
If no adequate response to a firststimulant or significant adverse
effects, switch to a different stimulant
If no adequate response orsignificant side effects: switch toatomoxetine
If no adequate response orsignificant side effects, try othermedications (e.g., guanfacine,clonidine)
Psychoeducation
Stimulants and, if possible, combinewith parent training program
If no adequate response orsignificant side effects: switch to adifferent stimulant
If no adequate response orsignificant side effects: try
atomoxetine, and after, othermedications (e.g., guanfacine,clonidine)

12–18 years of age
•
•
•
•
•

•
•
•
•

Psychoeducation & CBT
If no access to CBT: stimulants
If no adequate response orsignificant side effects: switch
to another stimulant
If no adequate response orsignificant side effects, try
atomoxetine
If no adequate response orsignificant side effects, try othermedications (e.g., guanfacine,clonidine)
Psychoeducation
Stimulants and, if possible,
combine with CBT
If no adequate response orsignificant side effects: switch
to another stimulant
If no adequate response orsignificant side effects: try
atomoxetine, and after, othermedications (e.g., guanfacine,clonidine)22IACAPAP Textbook of Child and Adolescent Mental Health

Recommendations by Guidelines
Based on the findings presented, stimulants are the first-line
psychopharmacological option in all international guidelines (e.g.,
Wolraich et al, 2019; NICE, 2018). According to NICE guidelines, thefirst line pharmacological treatment for children aged five years and over ismethylphenidate, either short- or long-acting.
Lisdexamfetamine is the second choice if the patient does not show
enough benefit after 6 weeks of treatment with methylphenidate. If poorly
tolerated, lisdexamfetamine can be replaced by dexamfetamine.
Atomoxetine and guanfacine can be offered if the patient cannot
tolerate or accept methylphenidate or lisdexamfetamine or if there is
no improvement in ADHD symptoms after 6 weeks of treatment withmethylphenidate and lisdexamfetamine. A summary of treatment strategies
according to developmental stage can be found in table D.1.8

SPECIAL CLINICAL ISSUESUse of Apps to Improve Adherence to Medication
Adherence to medication is always a problem in chronic conditions,particularly in the young. That is also the case for ADHD treatment. A recent
meta-analysis identified a growing use of Apps for ADHD (Păsărelu et al, 2020).
A pilot study indicated improved medication adherence when using smartphone
apps designed to act as a pill reminder as well as providing psychoeducation(Weisman et al, 2018).

Medication Holidays
A double-blind trial randomized children with ADHD into two groups,
one taking methylphenidate seven days a week and the other taking it only on
weekdays and receiving placebo on weekends. Taking methylphenidate only
during weekdays reduced complaints of insomnia and appetite suppression
without a significant increase of ADHD symptoms during the weekend or in thefirst day of school (Martins et al, 2004). Thus, clinicians may consider medicationfree weekends in cases where symptoms are pronounced mostly at school or if
medication causes significantly decreased appetite or insomnia. Longer drug
holidays—e.g., stopping medication during the summer vacation—should beassessed taking into consideration the cost-benefit (i.e., more problem behaviors
versus fewer adverse effects). In addition, this allows to test if the child still needs
the medication. However, this is an area that needs more research; a clinical trial
did not find benefits in relation to height with drug holidays (Waxmonsky et al,2019).

There is growing interest in
the development of apps
to assist with, and monitor
adherence to medication andother practical issues. Clickon the image to access one
such app in Portuguese.

Pregnancy
There are considerable data showing that ADHD medications are largely
safe during pregnancy, although there appears to be a slightly increased risk ofpre-eclampsia and of higher neonatal morbidity, especially central nervous system-

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IACAPAP Textbook of Child and Adolescent Mental Healthrelated disorders such as seizures (Cohen et al, 2017; Nörby et al, 2017). Thus,
clinicians should make patients who are, or plan to become, pregnant aware of thisrisk and possibly recommend ceasing medication during pregnancy.

Pharmacogenetics
There are many studies on the role of pharmacogenetics in ADHD using
gene-gene, gene-environment, genome-wide associations, neuroimaging, andpharmacokinetic approaches. Currently, there are no genetic markers with sufficient
diagnostic accuracy or capable to predict response to treatment to incorporate indaily clinical practice (Zayats & Neale, 2019).

Duration of treatment
There are no evidence-based guidelines about when treatment should cease.
Good clinical practice suggests that it is important to assess the need for medication
periodically (e.g., once a year) particularly when patients get older, taking into
account the response, the young person’s opinion, and side effects. A substantial
number of patients may benefit from continuing treatment into adultood (Posneret al, 2020).

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IACAPAP Textbook of Child and Adolescent Mental Health

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