1 Adhd

Attention
AttentionDeficit/Hyperactivity
Deficit/Hyperactivity
Disorder
Disorder
Desalegn Feyissa(B.Pharm., MSc, RPh. Assistant Professor of Clinical

Pharmacy)
06/27/2024 Attention Deficit/Hyperactivity Disorder 1

Introduction
• The common childhood psychiatric disorders where the
onset of symptoms explicitly occurs during childhood
are:
– Attention deficit/hyperactivity disorder (ADHD)
– Tourette's disorder
– Enuresis
• Treating children with psychotropic drugs requires a very

different approach than treating adults.
– Age-related pharmacodynamic and pharmacokinetic
differences can alter drug disposition and response
Cont…
• Children may not be able to articulate symptom
response or adverse effects of a medication.
• Psychotropic drug treatment of children is intended to

control symptoms or behaviors that impair learning
and development.
• The psychiatric assessment of a child requires

obtaining information from:
– the child, parents, caregivers and teachers.

Definition
• A diagnosis of ADHD should be considered whenever a

child presents with developmentally inappropriate
inattention, impulsivity, and/or hyperactivity.
• Symptom presence and severity vary with the situation.
• It is unusual for a child to display signs of the disorder in

all settings or even in the same setting at all times.

Clinical Presentation and Epidemiology
• Several inattentive or hyperactive-impulsive symptoms

have to present prior to age 12 years to meet the
diagnostic criteria of DSM-V
• ADHD occurs in 6% to 9% of children and is estimated
to be present in 4% of adults.
• In the United States, four boys are diagnosed with ADHD
for every girl.
• Symptoms can persist lifelong for both sexes, but
hyperactivity is much less prominent in adolescence and
adulthood
Cont…
• Inattention and distractibility can be symptoms of an
anxiety, mood, or psychotic disorder.
• In some cases, other disorders coexist with ADHD;

learning deficiencies and conduct or oppositional
disorders are common comorbid conditions.
• The presence of multiple comorbid conditions,

particularly conduct or mood disorder, can increase the
likelihood of ADHD chronicity into adulthood

Etiology and Pathophysiology
• Both genetic and non-genetic factors are implicated in
the pathogenesis.
• First-degree relatives of an individual with ADHD have a

four- to eightfold increased chance of developing
ADHD compared with the general population
– monozygotic twins have up to a 90% concordance rate for ADHD.
• Children with fetal alcohol syndrome, lead poisoning

and meningitis have a higher incidence of ADHD
symptomatology.
Cont…
• ADHD is associated with a variety of environmental
risks, including:
– obstetric adversity, maternal smoking, and adverse parent–
child relationships.
• Although there are no definitive pathophysiologic
markers for ADHD,
– imaging studies show subjects with ADHD have decreased
total brain volume

Cont…
• Brain changes are thought to impair executive
functioning necessary for
– prioritization of tasks, decision making, motor control, and an
awareness of space and time.
• Genetically mediated changes in serotonergic,

cholinergic, and most notably dopaminergic function
have been documented in children and adults with
ADHD.
– Deficits in the dopaminergic reward pathway in the ADHD brain
impair the ability to delay gratification, resist distractions, regulate
arousal, and attend to information or tasks that are dull or repetitive
Cont…
• This dysfunction involves multiple dopaminergic
receptors (D2, D3, D4 and D5) and dopamine active
transporter protein (DAT), which is pre-synaptic.
• Norepinephrine and epinephrine are agonists at

dopaminergic receptors and are modulated by DAT as
well.
• Treatment with stimulants has been shown to improve

the rate of cortical thickening, and pharmacotherapy
can improve or normalize dopaminergic receptor
function.
Cont…
• Those with demonstrated abnormalities in DAT seem to
respond better to methylphenidate and atomoxetine
• Effective treatments modulate dopamine and

norepinephrine
– to improve executive functioning, regulate arousal, and sustain
attention for improved performance.
• The clinical response associated with stimulants is not
diagnostic for ADHD
– because stimulants can increase attention, decrease motor activity, and
improve learning tasks in those with subclinical ADHD or in
individuals with such problems from other sources (e.g., fatigue).

Treatment
Stimulants
• Stimulants are considered first-line therapy in most
cases of ADHD; however, comorbid conditions impact
the drug selection process.
• Pharmacotherapy should be considered whenever a

thorough diagnostic assessment results in a diagnosis of
ADHD.
• Several studies demonstrate the superiority of

stimulants over behavioral interventions in alleviating
core symptoms of ADHD.

Cont…
• Emerging literature shows improvement in academic
performance in medicated children with ADHD versus
those un-medicated
• Multimodal treatment, individualized to the specific needs

of the child and family, is crucial for an overall positive
therapeutic outcome which includes:
– parent training
– family therapy
– classroom interventions and
– contingency management (e.g., rewards for good behavior).
Behavioral Interventions for ADHD
Technique Description Example
Positive reinforcement Providing rewards or privileges Child completes an assignment
contingent on the child’s and is permitted to play on the
performance computer
Time-out Removing access to positive Child hits sibling impulsively
reinforcement contingent on the and is required to sit 5 minutes
child’s performance of unwanted or in the corner of the room
problem behavior
Response cost Withdrawing rewards or privileges Child loses free-time privileges
contingent on the child’s for not completing homework
performance of unwanted or
problem behavior
Token economy Combining positive reinforcement Child earns stars for
and response cost. The child earns completing assignments and
rewards and privileges contingent loses stars for getting out of
on performing desired behaviors seat. The child cashes in the
and loses the rewards and privileges sum of stars at the end of the
based on undesirable behaviors week for a prize

Cont…
• Stimulants are the most effective drug treatment options,
with efficacy ranging from 70% to 96%.
– e.g., methylphenidate, dexmethylphenidate, mixed amphetamine
salts, and dextroamphetamine
• Methylphenidate and amphetamines block dopamine

and norepinephrine reuptake
– amphetamines also increase catecholamine release.
• Both drugs inhibit monoamine oxidase (MAO), or

amphetamines, more potently than methylphenidate
Cont…
• Because different stimulants work through slightly
different mechanisms, the lack of response to one chemical
class of stimulant does not preclude response to another
class
• Stimulant dosing should be titrated for maximum

individual efficacy and minimum side effects
• With immediate-release stimulants, most patients require a

two or three times daily dosing schedule because of the
short half-lives of these drugs
Cont…
• Immediate-release formulations have the advantage of
lower cost, less insomnia, and potentially fewer growth
effects versus extended-release products.
• Drug response is maximal during the absorption phase, is

evident in 15 to 30 minutes, and lasts 2 to 6 hours
• Methylphenidate transdermal system provides 12 hours of

symptom control when worn for 9 hours.

Cont…
• Drug delivery systems of once-daily products provide 8
to 12 hours of symptom control
• Once-daily stimulant formulations are the preferred

treatment for ADHD in most individuals
– due to convenience and better medication adherence.
• Adolescents and adults with ADHD are also responsive

to stimulants.

Adverse Effects: Stimulants
Psychiatric
• The Food and Drug Administration (FDA) has added
warnings to the labeling of all stimulants &
atomoxetine.
• Hundreds of post-marketing reports of three broad
categories of psychiatric adverse events have been
associated with stimulants:
– psychosis or mania
– aggression or violent behavior and
– severe anxiety or panic attacks.
• All of these reactions require dose reduction or cessation

of stimulant therapy and supportive treatment
Cardiac
• A boxed warning for cardiovascular risks including
sudden unexplained death has been added to ADHD
stimulant drug labeling
• Stimulant products generally should not be used in
pediatrics or adults with known structural cardiac
abnormalities.
• AHA recommends careful screening of all children and
adolescents prior to initiating pharmacologic therapy for
ADHD, including a detailed patient and family history
and physical examination
Cont…
• Ideally, a baseline electrocardiogram (ECG) should
also be obtained, along with routine monitoring of pulse
and blood pressure.
• The FDA did not find the risk of sudden unexplained

death to be greater in those taking stimulants than in the
general population;
– therefore, no restriction in stimulant use has been
recommended

Growth
• Stimulant treatment of ADHD can affect growth, but the
effects are minimal or insignificant for most children.
• Amphetamine products may be associated with more

prominent growth effects than methylphenidate
• 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.

Cont…
• In most cases, children should be given a drug-free trial
every year.
• Time off stimulant appears to lessen stimulant growth

suppressant effects,
– but evidence is lacking to firmly determine the impact of
drug holidays on growth.

Cont…
• Consideration must be given to the risks of negative
effects on learning, socialization, and self-image while off
stimulant therapy when determining the frequency and
duration of the drug-free trial
• Drug holidays are important because they provide time

to reassess the need for continued treatment.
• Drug dosage often varies from year to year, largely

because of age-related pharmacokinetic changes.

Cont…

Cont…

Cont…

Treatment
Non-stimulants
• Extended-release atomoxetine and guanfacine are
second-line alternatives to the stimulants for treatment of
ADHD in children and adolescents.
• Their potential benefits relative to stimulants include:

– no abuse potential
– less potential for growth effects and
– less sleep disturbance

Cont…
• Atomoxetine
– is a selective NERI
– Twice-daily dosing is optimal in children and adolescents
to improve tolerability.
– also approved in adults.
– Adults can take it once daily, usually in the morning.
– has a significantly slower onset of therapeutic effect than
stimulants (2–4 weeks vs 1 hour )
– sometimes combined with a stimulant in partially
responsive patients
• describing fewer late-day rebound effects and better sleep when
it is given in the evening; however, adverse effects are additive
Cont…
• Guanfacine and clonidine
– are central alpha 2-adrenergic agonists, acting post-
synaptically to increase blood flow in the prefrontal cortex.
– Increased blood flow in the prefrontal cortex has been
shown to enhance working memory and executive
functioning.
– Both interact with a multitude of neurotransmitter systems,
including:
• catecholamine, indolamine, alpha2-receptors on
parasympathetic neurons, opioids, imidazole, and amino acid
systems.

Cont…
• Guanfacine has a longer elimination half-life (12–18
hours) compared with clonidine (2.5–4 hours), and its
greater selectivity for the alpha2a-receptor, compared with
clonidine, imparts less sedation.
• Clonidine and immediate-release guanfacine are not as

effective as stimulants for monotherapy treatment.
– They are prescribed frequently as adjuncts to reduce
disruptive behavior, control aggression, or improve
sleep

Cont…
• Extended-release guanfacine
– is approved for children and it appears at least as effective
as other non-stimulants and is an acceptable second-line
agent
• for children and adolescents unresponsive to or unable to
tolerate stomach upset or insomnia with stimulant
medications.
– is more sedating than stimulants or atomoxetine

• therefore, sleepiness during the school day requires careful
monitoring.

Cont…
• Bupropion,
– a monocyclic antidepressant, is a weak dopamine and
norepinephrine reuptake inhibitor with no significant direct
effect on serotonin or MAO.
– has less appetite suppression compared with stimulants
but has a greater risk of seizures.
– metabolized faster in prepubertal children, making twice
daily dosing optimal for efficacy (even for bupropion SR)
– It also may be effective in adults at antidepressant doses.
• Once-daily dosing is possible for most adults.

Cont…
• Tricyclic antidepressants (TCAs)
– last-line agents because they are the most dangerous in
overdose and pose the greatest risk for cardiovascular
side effects.
– Imipramine and desipramine are the most systematically

studied TCAs in the treatment of ADHD, although
nortriptyline is also effective.
– The onset of TCA clinical response occurs within the first 2

to 4 weeks

Cont…
• Lithium and anticonvulsants
– are used increasingly to control aggression and explosive
behavior in patients with a diagnosis of ADHD.
– Lithium, valproate, and carbamazepine are effective for
explosive behavior, aggression, and impulsivity,
• but they are not beneficial treatments for a child with the
inattentive subtype of ADHD.
– Dosing starts in low divided doses with titration over 1 to 2
weeks to therapeutic response

Cont…
• Antipsychotics
– Conventional antipsychotics improve symptoms of
hyperactivity and impulsivity
• but can have negative effects on learning and cognitive
functioning and can cause extrapyramidal side effects (e.g.,
dystonia and tardive dyskinesia) that limit their usefulness.
– atypical antipsychotics have been used to control severe
aggression in refractory cases of ADHD, particularly if
conduct disorder or bipolar disorder coexists.
• E.g. risperidone, olanzapine, quetiapine, ziprasidone, and
aripiprazole

Cont…
• If multiple drugs are started simultaneously, it is
impossible to determine the impact of each drug.
• The predominance and urgency of symptoms guide the

drug-selection process
• For example, if a child presents as severely anxious or

depressed with associated attentional problems,
– then an antidepressant should be initiated first with
monitoring to determine if attentional symptoms improve

Cont…
• When a child presents with severe ADHD and associated
anxiety or depression,
– a stimulant should be initiated to treat the more severe ADHD.
• If ADHD symptoms improve significantly, but anxiety or

depression persists,
– then an antidepressant can be added.
• Careful monitoring is needed to detect drug

interactions that lead to higher drug plasma levels and
increased adverse effects.
Adverse Effects
Non Stimulants
• Atomoxetine
– Possible adverse effects of atomoxetine, and their
management, are similar to those of stimulants, including
psychiatric and cardiac adverse effects
– It has been associated with less growth suppression

compared with stimulants,
• 0.44 cm over 2 years of treatment.

Cont…
– It has a greater risk of fatigue, sedation, and dizziness
compared with stimulants and bupropion
– Unlike stimulants, atomoxetine labeling includes a bolded

warning of potential for severe liver injury
– It is the only FDA-approved ADHD medication with a

labeled warning for new onset suicidality,
• 0.4% in atomoxetine treated patients versus 0% in patients
receiving placebo

Cont…
• Clonidine and guanfacine
– The most common side effects of clonidine and guanfacine
are dose-dependent sedation, hypotension, and
constipation.
• Sedation usually subsides after 2 to 3 weeks of therapy.
– Of concern are reports of bradycardia, syncope, rebound
hypertension, heart block, and sudden death with
clonidine.
– Extended-release guanfacine appears to pose a lower risk
of cardiac adverse effects

Cont…
• Bupropion
– Nausea can resolve over time or with slower dosage
titration
– rash, which can require discontinuation of therapy if
severe
– Bupropion should not be used in children with a seizure
because of unacceptable risk of seizures in these patients.
– Bupropion can cause or exacerbate tics

Cont…
• TCA
– Possible CNS adverse effects of TCAs include
• dizziness, aggressiveness, excitement, nightmares, insomnia,
forgetfulness and irritability.
– Similar to other antidepressants, TCAs carry a warning of

the risk of new-onset suicidality in pediatric patients.
– TCA-withdrawal effects are severe in children and include

nausea, vomiting and diarrhea.

Cont…

Cont…
DEX, dextroamphetamine; DMPH, dexmethylphenidate; MPH, methylphenidate;

47
MXA, mixed amphetamine salts;
Evaluation of Therapeutic Outcomes
• Careful documentation of baseline symptoms and
complaints over a 1-month pre-drug 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
• The benefits of drug therapy must outweigh the potential

for adverse effects.
Cont…
• After the initiation and titration of any drug
treatment, it is necessary that parents, teachers, and
clinicians assess the overall functioning of the child
– using standardized rating scales to determine if
significant therapeutic benefit justifies continuing
medication.
• Therapeutic effects of the stimulants include

decreased motor activity and impulsivity and
increased attention span.

Reading Assignment (1%)
• Tourette's Disorder
• Enuresis
• Conduct disorder


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Attention

Desalegn Feyissa(B.Pharm., MSc, RPh. Assistant Professor of Clinical

06/27/2024 Attention Deficit/Hyperactivity Disorder 1

• Treating children with psychotropic drugs requires a very

• Psychotropic drug treatment of children is intended to

• The psychiatric assessment of a child requires

06/27/2024 Attention Deficit/Hyperactivity Disorder 3

• A diagnosis of ADHD should be considered whenever a

• Symptom presence and severity vary with the situation.

• It is unusual for a child to display signs of the disorder in

06/27/2024 Attention Deficit/Hyperactivity Disorder 4

• Several inattentive or hyperactive-impulsive symptoms

• In some cases, other disorders coexist with ADHD;

• The presence of multiple comorbid conditions,

06/27/2024 Attention Deficit/Hyperactivity Disorder 7

• First-degree relatives of an individual with ADHD have a

• Children with fetal alcohol syndrome, lead poisoning

06/27/2024 Attention Deficit/Hyperactivity Disorder 9

• Genetically mediated changes in serotonergic,

• Norepinephrine and epinephrine are agonists at

• Treatment with stimulants has been shown to improve

• Effective treatments modulate dopamine and

06/27/2024 Attention Deficit/Hyperactivity Disorder 12

• Pharmacotherapy should be considered whenever a

• Several studies demonstrate the superiority of

06/27/2024 Attention Deficit/Hyperactivity Disorder 13

• Multimodal treatment, individualized to the specific needs

06/27/2024 Attention Deficit/Hyperactivity Disorder 15

• Methylphenidate and amphetamines block dopamine

• Both drugs inhibit monoamine oxidase (MAO), or

• Stimulant dosing should be titrated for maximum

• With immediate-release stimulants, most patients require a

• Drug response is maximal during the absorption phase, is

• Methylphenidate transdermal system provides 12 hours of

06/27/2024 Attention Deficit/Hyperactivity Disorder 18

• Once-daily stimulant formulations are the preferred

• Adolescents and adults with ADHD are also responsive

06/27/2024 Attention Deficit/Hyperactivity Disorder 19

• All of these reactions require dose reduction or cessation

• The FDA did not find the risk of sudden unexplained

06/27/2024 Attention Deficit/Hyperactivity Disorder 22

• Amphetamine products may be associated with more

• Proposed mechanisms of stimulant effects on growth

06/27/2024 Attention Deficit/Hyperactivity Disorder 23

• Time off stimulant appears to lessen stimulant growth

06/27/2024 Attention Deficit/Hyperactivity Disorder 24

• Drug holidays are important because they provide time

• Drug dosage often varies from year to year, largely

06/27/2024 Attention Deficit/Hyperactivity Disorder 25

06/27/2024 Attention Deficit/Hyperactivity Disorder 26

06/27/2024 Attention Deficit/Hyperactivity Disorder 27

06/27/2024 Attention Deficit/Hyperactivity Disorder 28

• Their potential benefits relative to stimulants include:

06/27/2024 Attention Deficit/Hyperactivity Disorder 29

06/27/2024 Attention Deficit/Hyperactivity Disorder 31

• Clonidine and immediate-release guanfacine are not as

06/27/2024 Attention Deficit/Hyperactivity Disorder 32

– is more sedating than stimulants or atomoxetine