Module 8
ADHD Assignment
a. Epidemiology
ADHD is the most well-known and researched neurodevelopmental disorder
of childhood. It occurs in approximately 5% to 10% of children and approximately
2.5% to 5% of adults.12–14 Non-Hispanic Caucasian and African-American children
are more likely diagnosed with ADHD compared with children of Hispanic or Asian
descent according to CDC and National Children’s Health survey data.12,15 ADHD is
more prevalent in males than females with a ratio of 2:1 in children and 1.6:1 in
adults.1 In 2016, 6.1 million children in the United States or 9.4% of those aged 2 to
17 years were diagnosed with ADHD: almost twice the actual rate according to
worldwide prevalence studies and the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5).1,5,16 Methodological inconsistencies in diagnostic assessments
likely contribute to increasing diagnosis and differences in prevalence rates
internationally. Investigators evaluating 135 ADHD prevalence studies representing
seven regions (North America, South America, Europe, Asia, Africa, Oceania, and the
Middle East) found when consistent diagnostic criteria from the DSM-5 are applied,
the prevalence of ADHD for children and adolescents is similar among countries
globally, at approximately 5.5%.5,13,14,16 There is increasing concern among
healthcare professionals and the public regarding the overdiagnosis of ADHD leading
to stigmatization and potentially inappropriate treatment.
Increasing rates of ADHD diagnosis in the United States is likely a factor
associated with the observed increased prescribing of ADHD medications. In 2016,
the U.S. Centers for Disease control (CDC.gov) reported 2 million of the 6.1 million
children with ADHD were first diagnosed at 2 to 5 years of age.12,16 Of concern is
the mode of treatment for these toddlers, as CDC data showed three out of four 2- to
5-year olds with ADHD were prescribed medications and only one out of two were
prescribed behavioral interventions. The American Academy of Pediatrics (AAP)
recommends a 6-month trial of behavioral interventions and parent training prior to
pharmacotherapy in children ages 2- to 4-years old.12,16 In addition to young
children, adolescents and young adults are increasingly being diagnosed with ADHD.
A large U.S. pharmacy benefits management company, Express Script’s, analysis of
pharmacy claims representing 400,000 privately insured individuals younger than 65
years showed that ADHD medication use increased by 35.5% for all age groups
between 2008 and 2012. In addition, while the number of adults using ADHD
medications was up 53.4% from 2008 to 2012, children still received a higher
percentage of ADHD prescriptions compared to adults as 80% of these were
stimulants.In 2015, 4% of privately insured women ages 15 to 44 filled a prescription
for an ADHD medication, most often a stimulant such as amphetamine salts or
methylphenidate. This represents a 344% increase in ADHD medication prescribing
in 2015 compared to 2003. Of note, filled prescriptions for nonstimulant ADHD
medications did not increase.
Therefore, it is imperative that healthcare professionals and educators
advocate for a comprehensive and thorough assessment of Attention Deficit
Hyperactivity Disorder (ADHD) by an experienced clinician. This assessment should
utilize standardized diagnostic criteria and encompass a detailed investigation of all
possible causes of inattention, impulsivity, and hyperactivity. Such an approach is
essential to avoid the pitfalls of overdiagnosis and the potential for inappropriate
treatment.
ADHD is a complex neurodevelopmental disorder that manifests with
symptoms of inattention, hyperactivity, and impulsivity. These symptoms can
significantly impact a child's academic performance, social interactions, and overall
quality of life. However, these behaviors can also be indicative of other underlying
issues, such as learning disabilities, anxiety disorders, depression, or environmental
factors. Therefore, a thorough assessment by a clinician who is well-versed in ADHD
and its differential diagnoses is critical.
The assessment process should begin with a detailed medical, developmental,
and family history. This helps to identify any genetic predispositions or environmental
factors that might contribute to the child's symptoms. The clinician should conduct
structured interviews with the child, parents, and teachers to gather comprehensive
information about the child's behavior across different settings and over time.
Standardized rating scales and questionnaires, such as the Conners' Rating Scales or
the ADHD Rating Scale-IV, should be employed to systematically evaluate the
presence and severity of symptoms.
Additionally, a thorough assessment should include a comprehensive physical
and neurological examination to rule out any medical conditions that might mimic or
exacerbate ADHD symptoms. For instance, conditions such as thyroid disorders, sleep
apnea, or hearing and vision impairments can lead to inattention and hyperactivity. In
some cases, laboratory tests or imaging studies might be warranted to exclude these
medical conditions.
Cognitive and psychological assessments are also integral to the diagnostic
process. These assessments can help identify coexisting conditions such as learning
disabilities, intellectual disabilities, or emotional disturbances that might be
contributing to the child's symptoms. For example, psychoeducational testing can
assess cognitive abilities, academic skills, and processing deficits, providing a clearer
picture of the child's strengths and weaknesses.
In the educational setting, teachers play a vital role in the assessment process.
They should be encouraged to provide detailed observations of the child's behavior,
academic performance, and social interactions. Teachers can offer valuable insights
into how the child's symptoms manifest in the classroom and how they impact
learning and peer relationships. Collaboration between healthcare providers and
educators is essential to ensure a holistic understanding of the child's behavior across
different contexts.
It is also important to consider cultural and socioeconomic factors that might
influence the presentation and interpretation of ADHD symptoms. Clinicians should
be culturally competent and sensitive to the diverse backgrounds of the children they
assess. Cultural norms and expectations can affect how behaviors are perceived and
reported, and socioeconomic challenges might contribute to stressors that impact a
child's behavior and performance.
Once the assessment is complete, the clinician should integrate all the gathered
information to arrive at a diagnosis. This involves determining whether the child's
symptoms meet the criteria for ADHD as outlined in standardized diagnostic manuals
such as the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition) or the ICD-11 (International Classification of Diseases, Eleventh Revision).
The clinician should also consider the presence of any comorbid conditions and how
they might interact with ADHD symptoms.
The goal of a thorough assessment is not only to establish an accurate
diagnosis but also to guide appropriate treatment planning. If ADHD is diagnosed, the
treatment plan should be comprehensive and individualized, addressing the unique
needs of the child. Treatment options might include behavioral interventions,
educational accommodations, and, when appropriate, pharmacological treatment.
Behavioral interventions can include parent training programs, cognitive-behavioral
therapy, and classroom management strategies. Educational accommodations might
involve individualized education plans (IEPs), 504 plans, or other supports tailored to
the child's learning needs.
In cases where ADHD is not diagnosed, the clinician should work with the
child, family, and educators to address the identified issues. This might involve
interventions for other mental health conditions, academic support for learning
disabilities, or strategies to manage environmental stressors.
In conclusion, the recommendation for a thorough assessment of ADHD by an
experienced clinician is crucial to ensure accurate diagnosis and appropriate
treatment. Utilizing standardized criteria, investigating all potential causes of
symptoms, and incorporating a multidisciplinary approach can help avoid
overdiagnosis and the risks associated with inappropriate treatment. Through careful
and comprehensive evaluation, healthcare professionals and educators can support the
well-being and development of children exhibiting symptoms of inattention,
impulsivity, and hyperactivity.
b. Etiology and Pathophysiology
There has been substantial progress in understanding the role of both genetics
and the environment, as well as their interaction, in the pathophysiology of ADHD.
An extensive review of twin studies over the past 40 years has shown that the
heritability of ADHD (the amount of variance in ADHD symptoms attributable to
genetics) averages around 74%.19 The most extensive genome-wide association study
(GWAS) to date was a meta-analysis of 12 studies comparing 20,183 persons with
ADHD and 35,191 controls.20 This study discovered twelve regions that achieved
genome-wide significance with none of the genes identified in previous candidate
gene studies (ie, dopamine transporter) being found to be significant.19 It remains to
be seen exactly how the newly identified genes might be involved in ADHD. Despite
the size of the study, all 12 loci identified accounted for only 22% of the genetic
variance as the remaining ~50% of the heritability is “missing.
Some of the missing heritability may occur because patients have copies or
deletions in the genome that cover multiple genes called copy number variants
(CNV). Current CNV studies have implicated a number of systems in ADHD:
cholinergic receptors, and genes for central nervous system (CNS) development21
and on an area of chromosome 15q13.22 The CNVs affecting the metabotropic
glutamatergic receptor 5 gene were found to be enriched in cohorts of patients with
ADHD relative to controls.23 Fasoracetam (NFC) is a metabotropic glutamate
receptor activator that recently was administered to 30 adolescents with ADHD in an
open trial.24 All patients had been genotyped for variations in metabotropic
glutamatergic genes and after 5 weeks of treatment, there was a statistically
significant improvement from baseline to endpoint in ADHD symptoms, with the
greatest improvement seen in those with CNVs in the glutamatergic genes. Despite
these initial positive results, further double-blind studies are needed.
Increasingly, there is clear evidence that genes involved in ADHD are also
involved in other major psychiatric disorders, including schizophrenia, and affective
disorders. A significant genetic correlation has been found between ADHD and autism
spectrum disorder (ASD) in a large GWAS of individuals with ASD. Thus, genes for
neurodevelopmental disorders are not specific to ADHD and may show considerable
pleiotropy (one gene influences two or more seemingly unrelated phenotypic
traits).27 Since gene by environment interaction may also be important, it is critical to
examine environmental factors. Twin studies can estimate the amount of variance
related to the environment and further subdivide environmental effects into “shared”
(an event both twins experience, such as neighborhood) and “non-shared” (one twin
has a head injury, the other does not).
Surprisingly, shared environmental factors do not appear to have a relationship
to ADHD symptoms.28 In an Australian population-based control study, over 12,000
children with ADHD were compared to over 30,000 controls on maternal, pregnancy,
and birth data.29 Mothers of children with ADHD were significantly more likely to be
younger, single, or to have smoked in pregnancy. Additionally they had a higher level
of induced labor, preterm labor, preeclampsia, or early term delivery. Antidepressant
use in pregnancy is not related to ADHD,30 and in an extensive review of prenatal
factors in ADHD, Sciberras et al.31 noted that carefully done prospective studies are
needed to determine causality of these factors.
Genetics and environment work together to shape the brain and there is an
emerging picture of differences in brain structure, function, and connectivity that
occur across the life span in individuals with ADHD. Cortical surface area is reduced
in ADHD versus controls in both childhood and adulthood; in addition, the age of
peak thickness occurs later in ADHD, with the most pronounced delay occurring in
the prefrontal cortex.32 Cortical thickness is also reduced in children with ADHD
relative to controls, but when adults with ADHD remit, their cortical thickness is not
different from controls. There is evidence that continued use of stimulants for the
treatment of ADHD is associated with greater normalization of cortical thickness.34
Reduced cerebellar volume is the most pronounced difference in ADHD versus
controls.35 The ENIGMA ADHD study obtained structural MRI in 1,713 individuals
with ADHD and 1,529 controls, both children and adults.36 Subcortical structures
(accumbens, amygdala, caudate, hippocampus, and putamen) were reduced in those
with ADHD relative to controls, with effect sizes of around 0.2. Effects were larger in
children than adults. In totality, the structural imaging data suggest ADHD is caused
by a wide scale process affecting many regions of the brain.
Functional MRI has shown that the brains of children with ADHD fail to
activate a network of regions involved in attention and impulse control relative to
controls.37 During inhibitory tasks, children with ADHD fail to activate the right
inferior frontal cortex and anterior cingulate cortex. When performing attention tasks,
children with ADHD have reduced activation in the basal ganglia, prefrontal cortex,
and parietal lobe, while they have increased activation of cuneus. There is increasing
interest in the role of the default mode network (DMN) in many psychiatric
disorders.38 The DMN consists of the medial prefrontal cortex, medial parietal lobe,
or precuneus, as well as the posterior cingulate. These areas are active during the
“resting state” when attention is not engaged; this system is actively suppressed
during active attention.
A lack of connectivity between the prefrontal cortex and precuneus is
associated with failure of suppression of the DMN, causing lapses in attention and
inhibitory control. Multiple studies in ADHD have shown that relative to controls,
both children and adults do not have the same degree of anti-correlation of the DMN
and attention/control areas. Liddle et al. showed that treatment with stimulants can
normalize this situation. Functional MRI can be used to assess general connectivity
between a very large number of brain regions. A major review showed that children
with ADHD have stronger short-range connections (particularly with limbic areas)
than controls, but reduced number of long-range connections in the attention and
control systems of the brain.
c. Clinical Presentation
The American Academy of Pediatrics (AAP) guideline for the diagnosis,
evaluation, and treatment of ADHD in children and adolescents recommends an
evaluation for any child between ages 4 and 18 years who presents with academic or
behavioral problems and symptoms of inattention, hyperactivity, or impulsivity.3 At
least six symptoms of inattention or hyperactivity and impulsivity causing impairment
in more than one major setting (eg, home, school) for 6 months and an onset of
symptoms before age 12 are currently required by the DSM-5 for a diagnosis of
ADHD in children 4 to 12 years only. Only five symptoms are required for older
adolescents and adults (age 17 and over). Validated rating scales, such as the Connors
Rating Scales—revised (CRSrevised), and the Vanderbilt ADHD diagnostic scale, are
recommended for objective symptom ratings from parents and teachers in different
age groups.3–5 To make a diagnosis of ADHD, the clinician should rule out
alternative causes of symptoms (eg, learning disability, situational stressor) and assess
for other conditions that may coexist with ADHD including oppositional defiant and
conduct disorders, Tourette disorder, ASD, sleep and mood disorders.
Preschool-age onset of ADHD may be more likely in children with multiple
risk factors including maternal smoking, lead exposure, iron deficiency,
developmental delay, ASD, intellectual disability, or genetic loading.43,44 The DSM-
5 diagnostic criteria for ADHD can be applied to preschool-age children, although it
may be difficult to document symptoms in multiple settings with different caregivers
if the child does not attend preschool.1,3,12,44 Enrollment in a qualified preschool
and a parent training program is often recommended. Both can help parents develop
reasonable expectations for their child’s development and foster the development of
management skills for problem behaviors while diagnostic assessment is underway.
Most cases of ADHD are first realized during ages 6 to 9 years, with the child
having difficulty academically and/or socially in school and at home. Most children
have combined inattentive and hyperactive or impulsive symptoms that cause
functional impairment. This period is crucial to the child’s success in school,
socialization, and the development of his or her sense of self; therefore, accurate
diagnosis and treatment is critical. Comorbid oppositional defiant disorder (ODD),
conduct disorder (CD), and aggression are indicators that the child is at greater risk
for delinquency and substance abuse in adolescence.8,10,45 This is the most well-
studied age group, with strong data showing benefits of recognition and treatment
with behavioral interventions and medications.
Hyperactivity decreases in adolescents, and inattention and impulsivity are the
more prominent functionally impairing symptoms. There may be fewer numbers of
symptoms of ADHD in adolescence, but the symptoms present cause significant
functional impairment.1,8,10 Adolescents with ADHD are increasingly identified as
“moody” or having a temper. They are easily overwhelmed by demands and may
avoid tasks or approach multiple tasks in a disorganized manner.8 Decision making is
impaired (eg, discontinues ADHD treatment despite functional impairment) and
decisions are made based on peer approval.8 Higher rates of delinquency, drug and
alcohol use, and psychiatric comorbidity have been documented in adolescents with
ADHD compared with those without ADHD.3,4,10,11,46 Assessment for substance
abuse and risk of diversion must be considered before starting stimulant
medication.8,46 Speeding and increased motor vehicle accidents occur at higher rates
in teens with ADHD compared to those without the disorder.
The presence of multiple comorbid conditions, particularly conduct disorder or
mood disorder, can increase the likelihood of ADHD chronicity into adulthood. DSM-
5 criteria for ADHD in childhood and adolescence also apply to adults. Inattentive
symptoms are the most common and functionally impairing in adults, but
hyperactive/restless and impulsive symptoms such as being overly talkative,
impatient, and intrusive are experienced by many and are associated with higher rates
of bipolar disorder and psychosis.1,2,10,11,48 Cognitive deficits (eg, executive
functioning, working memory, task prioritization, lower IQ) have been documented in
adults with ADHD in addition to a greater risk for unstable relationships,
unemployment, psychiatric hospitalization, and incarceration compared with those
without ADHD.2,10,11,48 In 2017, the World Health Organization published a 6-item
questionnaire to update the Adult ADHD SelfReport Scale (ASRS) with DSM-5
diagnostic criteria. This validated screening tool can be used as a first step to a more
thorough diagnosis with an experienced clinician. Gathering collateral information
from family and friends is recommended to either support or refute the diagnosis.
Adult-onset ADHD is increasingly recognized although still controversial. A
Brazilian study evaluated 5,249 youth in 1993 at age 11 and found 393 (8.9%) met
criteria for ADHD. Evaluation of the group in 2015 at age 18 to 19 years revealed 492
(12.2%) youth with no symptoms in childhood met criteria for ADHD.50
Interestingly, the childhood-onset group was predominantly male and the young adult-
onset group was predominantly female. Both groups had increased levels of
impairment (eg, comorbidities, incarceration, suicide attempts) compared to those
without ADHD. United Kingdom investigators studied 2,040 twins longitudinally
between 1994 and 2015. In adulthood, 166 met criteria for ADHD; 111 of these (67%)
had no symptoms during childhood.51 Adult-onset ADHD raises many questions
about potential causes (eg, marijuana use, alcohol use, chronic anxiety), diagnostic
categorization, and treatment. Is young adult-onset ADHD a different brain disorder
with similar symptoms to childhood-onset ADHD; is the course different? More
research is needed.
Specific goals of treatment or desired outcomes must be identified (eg, able to
sit in chair for 20 minutes, completes homework assignments, or no longer blurts out
comments in class without being called upon).3,42 For adults, the desired outcome
may be to read an entire newspaper before starting another project, improving safety
while driving, or successfully completing tasks on time at school or at work.2,8,48
Treatment for ADHD may decrease the rate of some serious injuries in youth.
Investigators evaluated a large German healthcare database (reflecting 20% of the
population) and found that in children with ADHD ages 3 to 17 years, treated with a
stimulant or atomoxetine there was no difference in overall injury rates requiring
hospital admission compared to untreated children; however, there was a 34%
decrease in severe brain injury in the treated group.53 Similarly, an international
review and meta-analysis of about 13,000 youth found that pharmacologic treatment
in pediatric patients with ADHD likely has a protective effect, with a 10% reduction
in the incidence of any unintentional injury. Of note, traumatic brain injury was
excluded as an endpoint, given the potential to increase a patient’s likelihood for
being diagnosed with ADHD.
Improvement in academic performance and on-task behavior in the classroom
has been associated with stimulant treatment of ADHD.55 A study of 930 young
adults with ADHD found treatment with pharmacotherapy (eg, stimulants and
atomoxetine) was associated with significantly improved scores on higher education
entrance exams compared to never-medicated peers. Review of the Icelandic
Medicines Registry and the Database of National Scholastic Examinations revealed
that delayed initiation of pharmacologic treatment may be associated with academic
decline among youth age 9 to 12 years, particularly in math. Additionally other
studies have demonstrated improvement in math productivity, accuracy, and reading
speed with methylphenidate treatment, though academic improvements were thought
to be small compared to overall symptom improvement.
Education on ADHD as a biologic disorder with brain-derived causes is
essential for destigmatizing ADHD and improving treatment acceptance. Parent
training and behavioral interventions such as positive rewards for good behavior and
structured limit setting are recommended as first-line interventions before medication
trials in preschoolers (3- to 5-year-olds) with ADHD. It is crucial to get parents,
teachers, and clinicians involved to coordinate care and provide consistent behavioral
management for the child at home and at school. Although methylphenidate has been
found safe and effective for ADHD in 4- and 5-year-olds, behavioral interventions are
recommended first by most clinicians and guidelines.3,59 Schoolage children (6–11
years) also benefit from these behavioral interventions in addition to strategies, such
as breaking up homework assignments into shorter, manageable segments. Although it
varies by state, children and adolescents with ADHD may qualify for an
individualized educational program (IEP) that allows for more time to take an exam,
preferred seating, and modified work assignments.3,4,45 It is noteworthy that most
studies comparing behavioral intervention with stimulant therapy in youth found a
much stronger effect on ADHD core symptoms from stimulants.4,5,7,60 Combined
behavioral and stimulant therapy resulted in greater improvements on academic and
conduct measures in some studies with greater parent and teacher satisfaction ratings.
Lower doses of stimulant were effective when behavioral interventions were
administered according to several studies.
Recommended behavioral interventions for adolescents and adults include
keeping an external organizer (eg, smart phone, notebook with “to-do” lists) and
breaking up activities into short, manageable tasks. Recognizing triggers for
distraction and making a point of thinking before acting are useful interventions and
are recommended during cognitive behavioral therapy (CBT) sessions designed to
manage adult ADHD.52,62 Controlled studies have shown that ADHD-specific CBT
was more effective than psychoeducation and relaxation in adults with ADHD whose
symptoms were only partially responsive to medication.62 One study in 88 adults
compared 12 weekly sessions (1.5-h long) of manualized CBT administered with a
long-acting formulation of methylphenidate or amphetamine salts to CBT alone and
found greater benefit in ADHD symptoms, organizational skills, and self-esteem in
the combination CBT and medication group at the end of 12 weeks. Of note, the CBT
alone group continued to improve according to unblinded clinician assessment and
self-report after 6 months of treatment.52 Yoga, meditation, and some dietary
supplements have been recommended for ADHD as well, but they should not take the
place of more established effective treatments, such as medications and cognitive
interventions.
Extensive research has evaluated dietary interventions for ADHD, primarily in
children with some adolescent data. When iron and zinc are supplemented in youth
with known deficiencies, the therapeutic benefit of stimulant therapy can be
enhanced, frequently allowing lower effective doses.64–66 The role of gingko biloba,
vitamin D, Memoemet syrup, and other complementary and alternative products has
also been evaluated, with variable efficacy and tolerability.5 While some evidence is
promising, ongoing evaluations are needed before recommending these products,
given variability in study design (eg, use of concomitant pharmacotherapy, rating
scales to assess symptom improvement, and variability among products used).
Although scientific evidence is lacking, there is a universal belief among families that
the avoidance of sugar and artificial sweeteners improves ADHD symptoms. The
attention paid to sugar avoidance and healthy diet is the more likely reason for
improved behavior. An overall healthy diet with the proper balance of protein, fresh
produce, and fiber is recommended.
Several studies demonstrate the superiority of stimulants over other
pharmacotherapies and behavioral interventions in alleviating core symptoms of
ADHD in schoolage children, adolescents, and adults.5,17,59 Although the United
Kingdom’s 2018 National Institute for Health and Care Excellence (NICE) guidelines
recommend considering medication as early as 5 years of age, the clinician needs to
weigh the risks of starting medication at an early age against the harm of delaying
diagnosis and treatment.3,4,42,44 Clinicians should educate all parents and caregivers
regarding realistic expectations of drug therapy, goals of treatment, and the need for
adverse effect monitoring in children. Adolescents and adults should be actively
engaged in shared decision making regarding drug therapy and monitoring in an
attempt to improve treatment persistence. Studies show higher rates of medication
non-adherence in adolescents (50%)8 and adults (30%) compared to children (10–
30%). Preventing misuse and diversion of stimulants through frequent communication
with patients and family, use of a controlled substance agreement, and by tracking
state-wide prescription drug monitoring databases is recommended.
Stimulants are broadly divided into two main chemical classes,
methylphenidate (includes dexmethylphenidate) and amphetamines (includes
dextroamphetamine and mixed amphetamine salts). Methylphenidate and
amphetamines block presynaptic dopamine and norepinephrine reuptake;
amphetamines also increase dopamine release.7,75 Both drugs inhibit monoamine
oxidase (MAO), amphetamines more potently than methylphenidate. Because
different stimulants work through slightly different mechanisms, the lack of response
to one chemical class of stimulant (eg, methylphenidate or dexmethylphenidate) does
not preclude response to another class (eg, mixed amphetamine salts,
dextroamphetamine, or lisdexamfetamine).
Stimulants are the most effective drug treatment options, with a pooled
average effect size of 0.7 to 1.0. This is in contrast to nonstimulant drug treatment
options such as guanfacine, clonidine, and atomoxetine whose effect sizes range from
0.35 to 0.5 signifying lower efficacy.4,68,71 A systematic review and meta-analysis of
133 double-blind randomized controlled trials (81 in children and adolescents [n =
11,018], 51 in adults [n = 5,362], 1 in both) was conducted to assess the efficacy and
tolerability of ADHD pharmacotherapy over 12 weeks in different age groups.
Overall, the analysis showed stimulants were more effective than nonstimulant
medications in all ages; however, stimulants were not as effective in adults compared
to children and adolescents.
Among children and adolescents, all approved ADHD medications were found
to be superior to placebo (clinician report), with amphetamines superior to
methylphenidate, modafinil, atomoxetine, and guanfacine. Methylphenidate was
superior to atomoxetine. Per teacher report, only methylphenidate and modafinil were
superior to placebo. Guanfacine and amphetamines were less well tolerated than
placebo, with amphetamines demonstrating a significant increase in systolic blood
pressure and weight loss among children and adolescents, more than methylphenidate.
Because the largest analysis of clinical trial data showed overall better tolerability
with methylphenidate in children and adolescents compared to amphetamine
compounds, many clinicians recommend methylphenidate first-line in younger age
groups. Nonetheless, amphetamine may be used first-line if patient and clinician
prefer it. In contrast to recommendations in pediatric patients, an amphetamine
compound is preferred over methylphenidate as a first-line medication for adults
based on the analysis of 12 week trials showing greater efficacy and acceptable
tolerability of amphetamine compounds in adults versus pediatric patients.68 In
adults, amphetamines, methylphenidate, bupropion, and atomoxetine were superior to
both placebo and modafinil. Modafinil did not demonstrate superiority in adults. With
the exception of bupropion, all agents in adults were less well tolerated than placebo.
Stimulants are available in diverse formulations (immediate release, delayed
release, extended release, liquids, orally disintegrating tablets and patches) to allow
for individualization of drug selection based on a child’s ability to swallow solid
formulations and in an attempt to individualize the duration of symptom control.
Oncedaily stimulant formulations are the preferred treatment for ADHD in most
individuals due to convenience and better medication adherence.5,71,79 Immediate-
release formulations have the advantage of lower cost, less insomnia, and potentially
fewer growth effects versus extended-release products; however, they also carry a
higher risk of diversion and abuse.2,45,71 Administration of stimulant medications
with food can delay the absorption and subsequently delay the onset of therapeutic
effect by 30 minutes to 1 hour for immediate-release preparations, and 1 to 2 hours for
extended-release preparations.7,71,78 Total bioavailability of stimulant can be
decreased by 10% to 30% with coadministration of food, more so for beaded
formulations of extended-release stimulant compared with OROS methylphenidate or
lisdexamfetamine.17,71,78 With immediate-release stimulants, most patients require a
two or three times daily dosing schedule because of the short half-lives and duration
of action of these drugs (2–4 hours for methylphenidate and dexmethylphenidate and
~4–6 hours for dextroamphetamine or mixed amphetamine salts).4,7 Drug response is
maximal during the absorption phase, is evident in 15 to 30 minutes, and lasts 2 to 6
hours.
Drug delivery systems of once-daily products (amphetamine aspartate,
amphetamine sulfate, dextroamphetamine sulfate, and dextroamphetamine saccharate
[Adderall XR]; methylphenidate [Concerta]; methylphenidate [Daytrana];
dexmethylphenidate [Focalin XR]; methylphenidate [Metadate CD]; and
methylphenidate long-acting [Ritalin LA]) provide 8 to 12 hours of symptom
control.71,77 Concerta uses an oral osmotic (OROS) controlled-release delivery
system, whereas other oral preparations use combinations of immediate-release and
extended-release beads. Concerta is a nondeformable tablet, and it should not be given
to children with gastrointestinal (GI) narrowing because of the risk of obstruction.
Mydayis, a long-acting mixed amphetamine salt, provides up to 16 hours of symptom
control in adolescents and adults via pH-dependent, triple bead technology.76,80
Adhansia XR is an extended release methylphenidate capsule with a duration of
action up to 16 hours.77 A novel evening-dosed delayed-release/extendedrelease
methylphenidate product (Jornay PM) has demonstrated improvement in early
morning functional impairment among youth with ADHD. DELXIS® technology
utilizes a dual-layer (outer delayedrelease, inner extended-release layer) microbead
delivery system that surrounds an inner methylphenidate loaded core.
For patients with trouble swallowing pills, several alternative stimulant
formulations are available. Methylphenidate transdermal system provides up to 12
hours of symptom control when worn for 9 hours. Dyanavel XR, an extended-release
amphetamine oral suspension, utilizes ion exchange chemistry (LiquiXR™
technology) to provide continuous release of amphetamine throughout the day.83
Adzenys ER oral suspension (MXA) is a long-acting mixed amphetamine salt that has
demonstrated efficacy in youth 6 to 17 years of age.84 Cotempla XR-ODT
(methylphenidate) and Adzenys XR-ODT MXA should also be considered for youth
with trouble swallowing pills. Both products utilize micro-particle technology and
have been shown to have effects for 10 to 12 hours. Lisdexamfetamine is a prodrug
conjugated to an amino acid that requires cleavage during metabolism to the active
dextroamphetamine. It has a longer time to onset of effect (~2 hours) but provides 10
to 12 hour symptom control. As a prodrug, it has lower risk for abuse compared to
other long-acting amphetamines where beads may be crushed or snorted. NICE
guidelines recommend it as a preferred long-acting amphetamine formulation due to
the extent of evidence for efficacy and safety in children, adolescents, and adults, and
a lower abuse risk.
At least 15 cases of priapism (painful prolonged erection), associated with
stimulant use, have been reported to the FDA in boys with a mean age of 12.5 years. A
few cases of priapism have been reported with atomoxetine, and all cases require
immediate medical attention. The FDA has received at least 51 reports of skin
discoloration associated with the methylphenidate transdermal system, also known as
chemical leukoderma, that may not be reversible.71 Psychiatric, cardiac, and growth
effects of stimulants have been extensively studied with key data and
recommendations in the sections below.
Although considered rare, the FDA has added warnings to the labeling of all
ADHD medications (ie, stimulants, atomoxetine, α2 -adrenergic agonists) regarding
three broad categories of psychiatric adverse effects: psychosis, mood disturbance (ie,
irritability, lability, or depression), and severe anxiety or panic attacks. Treatment-
emergent psychosis is estimated to occur in approximately 1.5% of youth with ADHD
treated with stimulant medications based on placebo-controlled trials.45
Hallucinations involving visual or tactile sensations of insects, snakes, or worms were
typical in children, with adolescents and adults experiencing hallucinations and
delusions.90 Multimodal Treatment Study of Children with ADHD (MTA), analyzing
available data on the emergence of psychosis in 509 youth diagnosed with ADHD at
age 7 to 9 years, showed that 5.1% reported psychosis which was not statistically
different than 3.9% of the 276 local normal controls who reported psychosis over the
same 10-year follow-up period. Therefore, investigators did not correlate stimulant
use or an ADHD diagnosis in either group with the emergence of psychosis, but
frequent cannabis use was associated with increased risk of psychosis in both groups.
Sadness from stimulants may in part be genetically mediated, as an association
was found between two single nucleotide polymorphisms (SNPS) in the gene
encoding for carboxylesterase (CES1), which may impact stimulant metabolism, and
the occurrence of sadness in 77 youth taking immediate-release methylphenidate for
ADHD.92 There is also evidence to suggest that preschool-aged youth are more
susceptible to sadness, irritability, and mood lability with stimulant treatment
compared with adolescents and adults.45,86 Literature reviews describe treatment
emergent mania, and psychosis with atomoxetine, primarily in those with underlying
bipolar disorder or depression.
Labeling for atomoxetine includes a warning of increased suicidality largely
because of its mechanism of action that is similar to antidepressants. A worldwide
analysis of clinical trial and post-marketing data show no increase in suicidality
(hazard ratio of 0.96).93 Both stimulant and atomoxetine have the potential to cause
or exacerbate mania, anxiety, panic attacks, or depression. In addition, stimulants and
atomoxetine should not be given to manage attention in individuals with a primary
psychotic illness such as schizophrenia or schizoaffective disorder due to the high risk
of worsening psychosis. Clonidine and guanfacine are much less likely than
stimulants or atomoxetine to cause psychosis, mania, or anxiety, but treatment-
emergent psychosis, irritability, depression, and nightmares have been reported.94
When psychiatric adverse effects occur, dose reduction or cessation of therapy and
supportive treatment is recommended.
Stimulants, atomoxetine, and α2 -adrenergic agonists have well-described
cardiac and cardiovascular side effects that are not significant for most youth but can
be intolerable in some, particularly in those with existing cardiac/cardiovascular
disease. Clinical trial data show that children who take stimulants for ADHD can have
an increased heart rate by 3 to 10 beats/min and/or increased systolic or diastolic
blood pressure by 2 to 14 mm Hg. To explore the extent of cardiac side effects more
thoroughly, investigators used ECG and echocardiography to evaluate cardiac
function in 58 children (ages 6–18 years old) with ADHD diagnosed for at least 6
months taking OROS methylphenidate (mean dose 39.40 mg or 0.93 mg/kg/day)
compared to 58 matched control group children diagnosed with ADHD but not yet
started on medication. Overall no significant differences were found in terms of blood
pressure or ECG findings including QTc measurements; however, youth taking
methylphenidate had lower E’septal values on echocardiography.96 This difference
was considered within normal limits and not indicative of cardiac dysfunction.
Clinical trial and post-marketing surveillance data shows atomoxetine
treatment has been associated with increased heart rate at an average of approximately
5 beats/min and increased systolic or diastolic blood pressure of approximately 12
mm Hg. An Eli Lilly cardiovascular safety review showed 8% to 10% of patients
taking atomoxetine had more significant increases in pulse at ≥20 bpm and increase in
systolic and/or diastolic blood pressure of >15 to 20 mmHg.93 Clonidine and
guanfacine may cause dose-related bradycardia and lowered blood pressure in youth
that may prevent upward titration in addition to modest widening of the QTc interval
(5–7 msec) that warrants monitoring, particularly if the child takes another agent
known to prolong QTc such as an antidepressant or antipsychotic.
A 9.5-year prospective cohort study of children with ADHD found that,
although rare, adverse cardiovascular events were twice as likely to occur in stimulant
users as in nonusers.97 There were 111 cardiovascular events in the 8,300 children
with ADHD included in this analysis with hypertension, heart disease not otherwise
specified, and cardiovascular disease not otherwise specified comprising 62% of
adverse cardiac events, while arrhythmias comprised 23%, and cardiac arrest
accounted for less than 1%.45 The same investigators looked at national rates of
stimulant use (n = 714,258) and found 1.8 times greater risk of cardiovascular events
in those taking stimulants with greater risk seen with higher doses compared with
lower doses.
The impact of ADHD medications on growth has been investigated
extensively over the past 40 years as dose-dependent growth deficits of 1 to 1.4
cm/year have been observed with shortterm stimulant treatment, mainly in the first 2
years. Weight deficits are more prominent with a mean 3 kg (6.6 lbs) weight decrease
in the first year of treatment and 1.2 kg (2.6 lbs) weight decrease in the second year of
treatment according to MTA data.98 Long-term studies on stimulants have reported
divergent effects on growth, with many studies showing no clinically significant
height deficits by adulthood. MTA study investigators assessed the largest cohort of
children with ADHD ranging in age from 7–9 years old to 25 years old (n=515), and
compared them to classmates without ADHD (n=258). These authors reported an
overall adult height deficit of 4.7 cm among those consistently taking stimulant
medication compared to those not taking a stimulant. Growth deficits were less when
stimulants were taken inconsistently. Those taking stimulants consistently were 2.36
cm ± 1.13 cm shorter than those in the “inconsistent” group. Proposed mechanisms of
stimulant effects on growth include alterations in growth hormone or growth factor,
decreased thyroxine secretion, and suppression of appetite leading to reduced caloric
intake.
Cases of stimulant-induced peripheral vasculopathy, including Raynaud’s
phenomenon, have been reported and are related to the peripheral release of
catecholamines, resulting in vasoconstriction. Symptoms are typically intermittent and
mild, but can include digital ulceration and/or soft tissue breakdown. A retrospective,
case–control study demonstrated that among children treated with stimulants, there
was a significant association between the development of Raynaud’s phenomenon and
past or current use of stimulants.89,100 This risk appears to be dose dependent, with
symptoms typically resolving after dose reduction or discontinuation of the
medication.89,101 Additionally, there is a case report of dosedependent Raynaud’s
phenomenon with atomoxetine use.102 Close monitoring for digital changes is
necessary during treatment with stimulants, α-2 agonists, and atomoxetine.
Rheumatology consultation may be required for some individuals.
Compared to the simulants, nonstimulant medications used for the treatment
of ADHD are less effective alternatives than simulants in both children and
adolescents. However, for most of these agents, the FDA has approved them both as
monotherapy and as adjuncts to stimulants in children and adolescents for improving
overall response and for managing behavioral symptoms and insomnia associated
with ADHD and some have received FDA for the treatment of ADHD in adults.
Potential advantages of non-simulants relative to stimulants include no abuse
potential, less potential for growth effects, and less sleep disturbance.
Atomoxetine is a selective norepinephrine reuptake inhibitor that should be
taken in divided doses in the morning or late afternoon by children for improved
tolerability.106 Adults can take it once daily, usually in the morning.106 Placebo-
controlled, short-term trials (6–12 weeks) have shown that atomoxetine is effective in
reducing ADHD symptoms in children, teens, and adults, and long-term studies show
ongoing benefit and safety for children and adolescent responders out to 4
years.93,106 A controlled trial comparing atomoxetine, OROS methylphenidate, and
placebo over 6 weeks in 6- to 16-year-old patients showed that both drugs were
significantly better than placebo at improving ADHD symptoms, but OROS
methylphenidate was superior to atomoxetine.106 There was evidence for a
preferential response to atomoxetine over stimulants in some individuals.106
Atomoxetine has a significantly slower onset of therapeutic effect than stimulants (2–
4 weeks vs 1–2 hours with an effective stimulant dose), and full benefit may not be
seen for 6 to 12 weeks.105,106 The practice of combining atomoxetine with a
stimulant in partially responsive patients is based on limited data from open trials and
case series describing fewer late-day rebound effects and better sleep when
atomoxetine is given in the evening; however, the adverse effects are additive.
Possible adverse effects of atomoxetine and their management are similar to
those of stimulants, including upset stomach and psychiatric and cardiac adverse
effects. Although atomoxetine has less potential for growth suppression compared
with stimulants, it has a greater risk of fatigue, sedation, and dizziness compared with
stimulants or bupropion. Studies show that adults experience overall similar adverse
effects as youth but they are less likely to report decreased appetite and are more
likely to report urinary hesitation/ retention and sexual side effects (decreased libido
and erectile disturbances) compared to youth.105 Unlike stimulants, atomoxetine
labeling includes a bolded warning of potential severe liver injury based on 2 cases (1
adult, 1 child) of hepatic injury leading to transplant. A comprehensive safety review
over 10 years described 133 cases of liver injury “possibly” related to atomoxetine,
with liver functioning returning to normal after atomoxetine discontinuation.
Although hepatotoxicity is considered rare, patients and families should be counseled
to report signs of liver injury including dark urine, jaundice, or right upper quadrant
pain.
d. Comorbidity and Polytherapy in ADHD
Childhood bipolar disorder may be difficult to distinguish from ADHD
because inattention, hyperactivity, and impulsivity are common with both conditions.
When ADHD is diagnosed in an individual with bipolar disorder, the mood must be
stabilized first with lithium, an anticonvulsant, or an atypical antipsychotic before
considering an ADHD-specific treatment.
Autism spectrum disorders (ASD) are estimated to occur in 20% to 50% of
youth with ADHD and 30% to 80% of youth with ASD exhibit symptoms of
inattention.110 Impairments can range from mild to severe with poor language
development, poor social skills, sensory over-responsivity, emotional dysregulation,
inattention, impulsivity, irritability, oppositional behavior, and aggression.110 There
are few studies to guide treatment of ADHD in individuals with ASD.
A Cochrane review of 4 U.S. randomized controlled trials involving 113 youth
with ASD and ADHD treated with methylphenidate for 4 to 6 weeks demonstrated
short-term benefit for hyperactivity and possibly inattention in children who could
tolerate methylphenidate. Of note, youth who could not tolerate a test-dose were
excluded and there was no evidence that methylphenidate was helpful for social
interaction or stereotypical behaviors.111 Available evidence shows that stimulants
are less effective and less well-tolerated for managing ADHD in youth with more
severe forms of ASD.110,111 If a stimulant trial is initiated, the child with ASD
should be monitored carefully for worsening stereotypies, obsessional symptoms,
sleep difficulties, poor appetite, irritability, or the emergence of seizures. Atomoxetine
was only slightly better than placebo in managing ADHD symptoms in children with
ASD according to a 8-week controlled trial that included 97 children between the ages
of 6 and 17 years.69 Clonidine and guanfacine have small, uncontrolled studies only
showing benefit in improving attention and decreasing aggressive/impulsive behavior
in children with ASD.
Patients with ADHD are two to three times more likely to experience seizures
than age-matched peers, and ADHD is the most common comorbidity in youth with
epilepsy.45,73 While some reviews have demonstrated seizure aggravation and EEG
changes related to stimulant treatment,112,113 most studies show methylphenidate is
safe and effective for managing ADHD in youth with epilepsy. A retrospective review
of 18,000 Medicaid-enrolled youth with epilepsy and ADHD treated with a stimulant
did not demonstrate an increased risk for seizure-related hospitalizations among
current or former stimulant users.114 Given the risk for stimulants to lower the
seizure threshold, all individuals should be stabilized and seizure-free on an
anticonvulsant prior to initiation of the stimulant.73,114,115 If new or worsening
seizures are suspected, discontinuation of the stimulant should be considered and
cautiously reintroduced once stabilized.59 The impact of atomoxetine, clonidine, and
guanfacine on seizure frequency requires further study. Bupropion use is
contraindicated in patients with a seizure disorder.
Genetics, age (14- to 25-year-olds), psychosocial factors, and comorbidities all
influence one’s risk for drug and alcohol abuse,46,116 with ADHD itself being a
known risk factor for the development of a substance use disorder. A review of 27
longitudinal studies that followed children with and without ADHD into adolescence
or adulthood found that compared with control subjects without ADHD, children with
ADHD were (1) nearly three times more likely to report nicotine dependence in
adolescence/adulthood, (2) almost two times more likely to meet diagnostic criteria
for alcohol abuse or dependence, (3) approximately 1.5 times more likely to meet
criteria for marijuana use disorder, (4) twice as likely to develop cocaine abuse or
dependence, and (5) more than 2.5 times more likely to develop a substance use
disorder overall.10,116 Observational follow-up of the Multimodal Treatment Study
of Children with ADHD (MTA) has provided additional information regarding long-
term substance use risk in children with ADHD. As reported on the Substance Use
Questionnaire (SUQ), youth with ADHD compared to their peers were more likely to
use marijuana weekly (32.8% vs 21.3%) and cigarettes daily (35.9% vs 17.5%) as
adults. Additionally, early substance use, specifically the use of alcohol, cigarettes,
and marijuana, was more common in the ADHD group compared to peers.10 This
highlights the need for early substance use screening in adolescence, particularly
among patients with ADHD.
Parents frequently express concern that treating their child with a stimulant,
particularly early treatment, may increase the risk of substance abuse. Follow-up
studies show that stimulant therapy for ADHD neither increases nor decreases the risk
of subsequent drug or alcohol abuse.10,46 There is evidence that individuals initiating
treatment early (before age 8) are less likely to use substances than those who have
delayed onset of treatment. Behavioral therapy may also confer some protection
against substance use and delinquency.10,46,116 Atomoxetine, an α2 -adrenergic
agonist, or bupropion are preferred agents for individuals with ADHD and active
substance use disorders.
Furthermore, other comorbid conditions including depression, anxiety, low
self-esteem, conduct disorder, and antisocial personality disorder all increase the risk
for developing a substance use disorder in an individual with ADHD.10,116 These
comorbidities also increase the risk for delinquency and incarceration that can prevent
treatment and lead to ongoing substance abuse. As youth with ADHD transition to
adolescence, parents and clinicians should pay attention to whether the teen could be
at risk for substance abuse or inappropriate use of their prescribed medication.116–
118 Several studies have evaluated protective factors against substance abuse and
delinquency for youth both with and without ADHD. These studies found that a
quality parent–youth relationship, involving good communication, regular time
together, consistent rules, and sharing of information (eg, how the child or adolescent
spends free time and who his or her friends are) can be effective in deterring alcohol
and substance abuse in youth with or without ADHD.46,116 Youth support groups at
high schools, such as the Gay/ Straight Alliance (GSA), are credited with assisting
schools with achieving lower rates of illicit drug use and the misuse of prescription
ADHD medications compared with schools without GSAs.
Oppositional defiant disorder (ODD) or conduct disorder (CD) occur in 30%
to 60% of youth diagnosed with ADHD and are commonly associated with severe
aggression and functional impairment.119 Causes of ODD, CD, and associated severe
aggression in youth with ADHD are multifactorial and include psychosocial adversity
factors (eg, maternal mental disorder, paternal criminality, violence in the home),
learning disability, disruptive mood dysregulation disorder (DMDD), or bipolar
disorder. Experts consider psychosocial interventions that include parent training and
support for the child’s family an essential part of the treatment plan for youth with
ADHD, co-occurring with ODD or CD.
Unfortunately optimizing ADHD-specific medication such as stimulant or
atomoxetine is not universally effective for aggression and over half of youth with
ADHD and ODD/CD need more than one medication for optimal symptom control.67
The treatment of severe childhood aggression (TOSCA) study included 168 youth
with ADHD and either ODD or CD (mean age of 9 years) and showed that adding
risperidone 1 to 3 mg daily to parent training, behavioral therapy, and optimized
stimulant resulted in moderate improvement in aggression. A 52-week follow-up of
study participants demonstrated an overall benefit for youth who remained on
medication, with the risperidone augmented-group demonstrating a small added
benefit (improved CGI-S scores). This warrants close evaluation considering the long-
term use of risperidone was associated with significant increased risk for weight gain
and increased serum prolactin.131 Overall, guidelines recommend that risperidone
should be considered as a short-term treatment for severe aggression and/or explosive
anger if not effectively managed by traditional ADHD medications.
ADHD occurs in 50% to 60% of youth with chronic tics or Tourette disorder,
and 20% of children with ADHD go on to develop chronic tics or Tourette
disorder.69,70,88 Until recently, experts cautioned that stimulants should not be first-
line treatments for ADHD in youth with tic disorders due to the stimulant’s ability to
increase central dopaminergic and noradrenergic activity, potentially exacerbating
tics. There is less need for concern according to investigators who conducted a meta-
analysis of 22 placebo-controlled trials involving 2,385 children with ADHD and
Tourette disorder. The analysis showed that stimulants were not more likely to worsen
tics than placebo, and the association between stimulants and new-onset tics was more
coincidental than a cause-and-effect relationship.88 Additionally the timing of tic
development in the context of ADHD may have led clinicians to inappropriately
attribute new onset tics to stimulant treatment, as epidemiologic studies show that
when ADHD and Tourette co-occur, symptoms of ADHD are present 2 to 3 years
before tics emerge. Tourette disorder is known for fluctuating symptom severity with
tics worsening and remitting in an unpredictable pattern, further diminishing the
ability to accurately attribute tic causality.
A double-blind, placebo-controlled trial compared monotherapy with
methylphenidate or clonidine with the combination of methylphenidate and clonidine
in patients with ADHD and Tourette disorder. Overall combination therapy
demonstrated the greatest benefit in reducing symptoms of ADHD and tics,72,88 and
clonidine appeared most helpful for impulsivity and hyperactivity, whereas
methylphenidate was most helpful for inattention. All treatments were well tolerated,
but sedation was common (28%) in those receiving clonidine.72 Furthermore,
guanfacine was administered to 34 children (mean age 10.4 years), with ADHD and
tic disorder during an 8-week, placebo-controlled trial at a dose of 1.5 to 3 mg/day.
Tic severity decreased by 31% in the guanfacine group compared with 0% in the
placebo group.72 There was a mean improvement of 37% on the teacher-rated ADHD
scale compared with 8% improvement with placebo. Therefore as previously stated,
clonidine or guanfacine alone is a less effective alternative to stimulants in the
treatment of children with ADHD and this holds true for those with comorbid Tourette
disorder.
Atomoxetine appears to be an effective treatment for ADHD and tics in
pediatric patients with comorbid Tourette syndrome or chronic motor tic disorder. For
this study, 148 children and adolescents were randomized to atomoxetine (0.5–1.5
mg/kg/day) or placebo for up to 18 weeks of treatment. Overall atomoxetine resulted
in improvements in the severity of ADHD (effect size = 0.6) and tics (effect size =
0.3).105 Individuals with Tourette disorder and ADHD are more prone to disruptive
behaviors including poor frustration tolerance, aggression, and impulsivity, often
requiring behavioral interventions and medications that may include second-
generation antipsychotics.72 Second-generation antipsychotics such as risperidone,
aripiprazole, and ziprasidone have evidence from controlled trials to support their use
in managing motor and vocal tics associated with Tourette disorder; however,
aripiprazole is the only agent currently FDA-approved for managing Tourette
disorder.
e. Personalized Pharmacotherapy
There are many things to consider when making therapeutic decisions in
patients with ADHD such as age, comorbidities, tolerability, potential for drug
interactions, and patient preference. In addition, there may be pharmacokinetic and
pharmacogenomic factors to consider when personalizing pharmacotherapy. In
looking specifically at pharmacogenomics, the functional activity of cytochrome P450
(CYP) 2D6, norepinephrine and dopamine transporters (SLC6A2, SLC6A3),
catechol-o-methyltransferase (COMT), dopamine receptor (DRD4), carboxylesterases
(CES1), and α2 -adrenergic receptor (ADRA2A) has been evaluated as a predictive
tool for ADHD medication response and tolerability.132–136 While formal clinical
pharmacogenomic guidelines do not exist for ADHD treatment at this time,
medication-specific recommendations exist in some manufacturer labeling (eg,
atomoxetine).
As the pharmacogenomics of ADHD treatments is a rapidly evolving field, an
evidence-based resource available to decipher this work is provided by the Clinical
Pharmacogenomics Implementation Consortium (CPIC, www. cpicpgx.org) or the
Pharmacogenomics Research Network (PGRN, www.pharmgkb.org).138 Specifically
the CPIC website contains evidence-based expert guidelines for interpretation of
specific gene drug pairs, which may be used when testing is completed. It is important
to note that CPIC does not recommend testing, but rather aims to serve as a reference
for when testing results are available. While routine use of pharmacogenomic testing
is not recommended prior to initiation of ADHD medication, consideration should be
made in particular clinical scenarios: (a) prior to the initiation of atomoxetine in
pediatric patients with previous poor response/tolerability to other substrates of
CYP2D6 and/or who are particularly sensitive to changes in HR/BP; (b) poor
tolerability to atomoxetine/stimulants at starting doses; (c) individuals presenting with
several psychiatric comorbidities and a history of psychotropic medication poor
response/tolerability; (d) family history of poor medication tolerability.
As methylphenidate is de-esterified prior to elimination it is less likely to have
metabolic drug interactions compared with mixed amphetamine salts. Gender has
been shown to influence the absorption of methylphenidate, with males having
increased bioavailability compared with females.7 Variability in dosage requirements
for amphetamine salts, atomoxetine, and bupropion, can be due to inter-individual
variability in plasma concentration achieved at a given dose. As all are metabolized
via CYP2D6, the bioavailability and half-life of CYP2D6 substrates can be four to
eight times greater in those taking a CYP2D6 inhibitor (eg, bupropion, fluoxetine, or
paroxetine). Additionally, in CYP2D6 poor metabolizers atomoxetine has a much
longer plasma half-life (20 hours compared to 5 hours), resulting in increased total
plasma exposure compared to extensive (normal) metabolizers. Some studies have
shown that CYP2D6 poor metabolizers may experience more insomnia, weight loss,
increased heart rate and blood pressure, constipation, and depression associated with
atomoxetine treatment compared to extensive metabolizers.
Additionally, it has been suggested that individuals who are classified as poor
metabolizers may demonstrate greater therapeutic benefit from certain medications
due to increased exposure to the active drug. This is particularly relevant for
medications metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme, such as
atomoxetine, which is commonly used in the treatment of Attention Deficit
Hyperactivity Disorder (ADHD).
The CYP2D6 enzyme is responsible for the metabolism of many drugs,
including atomoxetine. Genetic polymorphisms in the CYP2D6 gene can result in
different metabolizer phenotypes: poor metabolizers (PMs), intermediate metabolizers
(IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs). Poor
metabolizers have little to no functional CYP2D6 enzyme activity, leading to slower
drug metabolism and higher plasma concentrations of the medication. As a result,
these individuals might experience more pronounced therapeutic effects as well as an
increased risk of adverse effects.
For atomoxetine, increased drug exposure in poor metabolizers can enhance
the therapeutic benefits in managing ADHD symptoms. These patients may achieve
effective symptom control with lower doses of the medication compared to those with
normal or ultra-rapid metabolism. However, the heightened drug levels also
necessitate careful monitoring for potential side effects, such as increased heart rate,
elevated blood pressure, gastrointestinal disturbances, or neuropsychiatric symptoms.
Given the variability in drug metabolism due to CYP2D6 genetic differences,
the manufacturer of atomoxetine recommends dose adjustments based on the patient’s
CYP2D6 phenotype. For instance, lower starting doses may be advised for poor
metabolizers, with careful titration based on therapeutic response and tolerability.
Additionally, when atomoxetine is used concomitantly with potent CYP2D6 inhibitors
(such as fluoxetine, paroxetine, or quinidine), which can further reduce the metabolic
activity of CYP2D6, similar dose adjustments and increased monitoring are
warranted.
Despite these recommendations, the routine use of pharmacogenomic testing
prior to initiating atomoxetine treatment remains a topic of ongoing research and
debate. Pharmacogenomic testing involves analyzing a patient's genetic makeup to
predict their response to specific medications. While this approach holds promise for
personalized medicine, providing insights into the optimal drug choice and dosing for
individual patients, its implementation in clinical practice is still evolving.
Several factors contribute to the cautious adoption of routine
pharmacogenomic testing. Firstly, there is the consideration of cost and accessibility.
Genetic testing can be expensive and may not be readily available in all healthcare
settings, particularly in resource-limited environments. Secondly, the interpretation of
pharmacogenomic results requires specialized knowledge, and not all healthcare
providers may be adequately trained in this area. Additionally, the clinical utility and
cost-effectiveness of pharmacogenomic testing for atomoxetine need further
validation through large-scale studies.
Moreover, the relationship between CYP2D6 genotype and clinical outcomes
with atomoxetine treatment is complex. While poor metabolizers may benefit from
increased drug exposure, other factors, such as age, comorbid conditions, concurrent
medications, and individual variability in drug response, also play crucial roles in
determining therapeutic outcomes. Therefore, pharmacogenomic testing should be
considered as one of several tools in a comprehensive assessment rather than a
standalone determinant of treatment decisions.
The current standard of care emphasizes a tailored approach to ADHD
management, considering the patient's clinical profile, response to treatment, and side
effect burden. Clinicians often rely on a trial-and-error method to identify the optimal
medication and dosage for each patient, adjusting the treatment plan based on ongoing
assessments and feedback. This approach, while sometimes time-consuming, ensures
that therapeutic decisions are personalized and adaptive to the patient's needs.
In summary, poor metabolizers of CYP2D6 substrates, such as atomoxetine,
may experience greater therapeutic benefits due to increased medication exposure.
The manufacturer recommends dose adjustments based on CYP2D6 phenotype and
concomitant use of potent CYP2D6 inhibitors to mitigate the risk of adverse effects
and optimize therapeutic outcomes. However, the routine use of pharmacogenomic
testing prior to atomoxetine treatment requires further evaluation to determine its
clinical utility, cost-effectiveness, and feasibility in diverse healthcare settings. A
balanced approach, integrating pharmacogenomic insights with comprehensive
clinical assessment, holds the promise of enhancing personalized ADHD treatment
while ensuring patient safety and efficacy.
f. Evaluation of Therapeutic Outcomes
Careful documentation of baseline symptoms and complaints over a 1-month
predrug period is essential to the evaluation of therapeutic and adverse outcomes.
Investigation regarding family history of psychiatric disorders and cardiac disease is
essential to determine risk for related adverse drug reactions and to implement
appropriate monitoring.4,45,59 Baseline symptoms can be measured using
videotapes, clinician rating scales (eg, ADHD Rating Scale IV, Vanderbilt ADHD
Diagnostic Scale), or both. In addition, height, weight, and eating and sleeping
patterns should be recorded at baseline and every 3 months.
After the initiation and titration of any drug treatment, it is necessary that
parents, teachers, and clinicians assess the overall functioning of the child or adult
using standardized rating scales to determine if significant therapeutic benefit justifies
continuing medication.4,42 Therapeutic effects of the stimulants include decreased
motor activity and impulsivity and increased attention span. This suggests that
stimulants are indicated for ADHD symptoms and not for primary learning disorders.
The benefits of drug therapy must outweigh the potential for adverse effects to justify
continued treatment. There is a lack of standardized assessment tools for adults;
however, the adult ADHD screening tool can be useful.49 Short-term studies (1 year
or less) in adults with ADHD show that treatment with stimulants improves subjective
quality of life. Long-term studies are needed to better assess the risk versus benefit of
stimulant therapy on psychosocial and health outcomes.
Atomoxetine, α2 -adrenergic agonists, and bupropion also require monitoring
to detect changes in appetite, weight, and sleep patterns, as well as pulse and blood
pressure. A therapeutic trial of atomoxetine or bupropion consists of 6 weeks at
maximum tolerated doses unless response occurs at a lower dose.4,42 Atomoxetine’s
full therapeutic benefit may continue to build over weeks to months, but if there is no
significant benefit in the initial 6 weeks, it is unlikely that atomoxetine will be
effective; therefore, it can be tapered off. When guanfacine or clonidine is given,
careful clinical monitoring for fatigue, dizziness, and autonomic changes (eg, blood
pressure and pulse) is recommended. The American Heart Association has stated that
ECG monitoring is not required for α2 -adrenergic agonists treatment in children,
although many clinicians continue to assess for ECG changes, particularly if there is a
family history of cardiac disease, if the patient is taking other agents that impact
cardiac function, or if clinical symptoms warrant.
When discontinuing treatment with alpha-2 adrenergic agonists such as
clonidine and guanfacine, it is essential to proceed with caution to prevent adverse
effects, particularly rebound hypertension and behavioral dyscontrol. These
medications, often prescribed for conditions like hypertension, ADHD, and certain
anxiety disorders, work by stimulating alpha-2 receptors in the brain, which decreases
the sympathetic outflow from the central nervous system. This results in lowered
blood pressure and, in some cases, a calming effect on behavior.
Due to their mechanism of action, abrupt discontinuation of clonidine and
guanfacine can lead to a sudden surge in sympathetic activity, causing a rapid increase
in blood pressure (rebound hypertension) and potential exacerbation of behavioral
symptoms such as agitation, anxiety, and irritability. Therefore, it is recommended
that these medications be withdrawn gradually. The suggested tapering schedule
involves reducing the dose of clonidine by 0.05 mg and guanfacine by 0.5 mg every 3
to 7 days. This gradual reduction allows the body to adjust to the decreasing levels of
medication, minimizing the risk of withdrawal symptoms and ensuring a safer
transition off the drug.
In practice, this means if a patient is taking 0.3 mg of clonidine daily, the dose
would be reduced to 0.25 mg for 3 to 7 days, then to 0.2 mg for another 3 to 7 days,
and so on, until the medication can be safely discontinued. Similarly, for guanfacine,
if the patient is on a dose of 3 mg daily, the reduction would follow the same pattern:
decreasing to 2.5 mg for a few days, then to 2 mg, continuing in this manner until
cessation.
Furthermore, during this tapering period, healthcare providers should closely
monitor the patient for any signs of increased blood pressure or return of behavioral
symptoms. Regular blood pressure checks and assessments of the patient's mental and
behavioral status are crucial. If any concerning symptoms arise, the tapering process
might need to be slowed down further, or other therapeutic measures may need to be
considered to manage these symptoms effectively.
It is also important to communicate with the patient and their caregivers about
what to expect during the discontinuation process. They should be informed about the
potential symptoms of rebound hypertension and behavioral changes, and instructed
to contact their healthcare provider if they notice any significant issues. This
education can help in early detection and management of any adverse effects,
contributing to a smoother discontinuation process.
Regarding the initiation of clonidine and guanfacine, a therapeutic trial
typically requires 1 to 2 months to assess the full therapeutic response. This period
allows healthcare providers to determine the efficacy of the medication in managing
the patient's condition, be it hypertension, ADHD, or another disorder. The gradual
titration of the dose to the effective level helps in minimizing initial side effects and
ensuring that the patient tolerates the medication well. For instance, in the treatment
of ADHD, clonidine and guanfacine can help reduce symptoms of hyperactivity,
impulsivity, and inattention over this period.
Interestingly, one of the early noticeable effects of these medications,
particularly relevant in the treatment of ADHD and anxiety disorders, is an
improvement in sleep patterns. Increased sleep or better sleep quality often occurs
almost immediately after starting the medication, which can have a positive impact on
the patient's overall well-being and daily functioning. Improved sleep can also help in
better management of symptoms during the day, as adequate rest is crucial for
cognitive and emotional regulation.
However, it's worth noting that while improved sleep can be an immediate
benefit, the full behavioral and therapeutic effects of clonidine and guanfacine might
take longer to manifest. This delay underscores the importance of patience and
adherence to the prescribed regimen during the initial phase of treatment. Regular
follow-ups with the healthcare provider during this period are essential to adjust
dosages as needed and to monitor for any side effects or signs of improvement.
In summary, when discontinuing clonidine and guanfacine, a gradual tapering
process over several weeks is crucial to prevent rebound hypertension and behavioral
dyscontrol. A reduction of 0.05 mg of clonidine or 0.5 mg of guanfacine every 3 to 7
days is recommended, with close monitoring for adverse effects. During the initiation
of therapy, a therapeutic trial of 1 to 2 months is necessary to assess the full response,
though improvements in sleep are often observed immediately. Effective management
requires careful monitoring, patient education, and regular follow-ups to ensure safety
and efficacy.
