DISEASE MANAGEMENT

Pharmacological treatment of attention-deficit hyperactivitydisorder in preschool-age children requires care

Adis Medical Writers

Published online: 15 June 2013

� Springer International Publishing Switzerland 2013

Abstract Preschool-age children with attention-deficit

hyperactivity disorder (ADHD) have high rates of aggres-

sive and disruptive behaviours. Although symptom

improvement may be achieved with nonpharmacological

management, there is often a need for pharmacological

intervention, which is controversial, especially in very

young children. Improvements in ADHD symptoms have

been reported in preschoolers receiving methylphenidate or

atomoxetine, but further studies are required.

Common problem in preschool-age children

Attention-deficit hyperactivity disorder (ADHD) is a neu-

robehavioral developmental disorder that is chronic,

impairing and common, with estimates of its prevalence in

preschool-age children in the USA ranging from 0.5 to

6.5 %, depending on the diagnostic instruments and criteria

used [1]. This article summarizes a review by Ghuman and

Ghuman [1] on the pharmacological interventions for

ADHD in preschoolers. An overview of ADHD in pre-

schoolers is shown in Table 1.

Preschoolers who do not receive appropriate treatment

for ADHD are at risk of significant behavioural and func-

tional impairment throughout childhood, adolescence and

into adulthood [1]. Although the routine use of drug

treatment for school-age children with ADHD is well

established and is included among management strategies

in treatment guidelines [2–4], there is less published clin-

ical evidence regarding the use of these drugs in the

treatment of preschool-age children.

Parents and caregivers of preschoolers with ADHD are

often also affected, commonly experiencing considerable

stress and depression related to difficulties in looking after

the affected child [5]. For example, they may have prob-

lems finding suitable childcare and demands on their time

spent caring for their difficult-to-manage child may lead to

worries about job security. Importantly, parents of pre-

schoolers with ADHD need appropriate professional

assistance and guidance in the management of the behav-

iour of their young child [1].

Consider nonpharmacological management

Nonpharmacological interventions (psychosocial and die-

tary interventions) may be used as an alternative to, or in

conjunction with, pharmacological therapy in the man-

agement of ADHD in preschoolers [1]. Regardless of the

approach to treatment, evidence-based recommendations

for the diagnosis and treatment of ADHD should be

followed.

Parent, child and parent-child psychosocial interventions

have improved difficult behaviours in preschoolers with

oppositional, aggressive, non-compliant and disruptive

behaviours together with hyperactivity and inattention [1].

In the randomized Preschool ADHD Treatment Study

(PATS), 7.2 % of preschoolers had significant improve-

ments in ADHD symptoms (without methylphenidate

therapy) during an initial 10-week course of group parent

training; these children were then no longer eligible to

participate in the medication arm of the study [6]. More-

over, a further 6.9 % of the study participants did not start

Adis Medical Writers (&)

Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,

North Shore, 0754 Auckland, New Zealand

e-mail: dtp@adis.com

Drugs Ther Perspect (2013) 29:241–244

DOI 10.1007/s40267-013-0053-9

drug therapy because of improvements in their behaviour

during the initial 10-week parent-training phase, even

though they still met the criteria for receiving methylphe-

nidate treatment [6]. Significant improvement in ADHD

symptoms in preschoolers were also evident with man-

agement that utilized a combined parent- and child-training

programme in a recent randomized, controlled trial [7].

Despite these documented benefits of non-pharmacological

management for preschoolers with ADHD, poor compli-

ance by parents with psychosocial intervention recom-

mendations may adversely affect management of the

affected child [1].

Alternative therapies for preschoolers with ADHD

include restricted elimination diets consisting of only a few

foods, such as rice, meat, vegetables. Significant

improvements in parent- and teacher-rated symptoms of

ADHD have been reported with restricted diet in a con-

trolled trial [8]; however, it is important that adherence to

this type of diet is closely monitored to ensure that nutri-

tional deficiencies do not occur.

Pharmacological interventions often used ‘off-label’

Most drugs used in the treatment of ADHD address

imbalances in the noradrenergic and dopaminergic systems

that are present in affected children [1]. However, in pre-

school children with ADHD, pharmacological therapy is

often used ‘off-label’, because of the general lack of reg-

ulatory approval for the use of these agents in this age

group [9, 10]. Good quality data on the efficacy and tol-

erability of drug therapy to treat ADHD, especially that of

long-term treatment, are currently limited in preschoolers.

Moreover, little is known about the effects of these drugs

on the developing brain.

Recent American Academy of Pediatrics clinical prac-

tice guidelines provide recommendations on the use of

pharmacotherapy for children with ADHD aged C4 years

[4]. In very young preschool-age children, the use of

pharmacotherapy is controversial and nonpharmacological

approaches, when available, may be preferred [1].

On the basis of available data and current guidelines, a

cautious trial of drug therapy is indicated for preschoolers

only if there is no symptom improvement with behavioural

therapy [1]; however, preschoolers receiving drug therapy

should be monitored closely for treatment-related adverse

effects and treatment should be temporarily interrupted at

6-month intervals to allow drug therapy-free assessments

of symptoms. Identification of predictors and moderators of

treatment response for use in guiding therapy in pre-

schoolers requires further study [1].

Methylphenidate can be beneficial …

Clinical evidence relating to use of drug therapy in pre-

schoolers with ADHD largely relates to methylphenidate, a

dopamine transporter blocker and a CNS stimulant [1, 11].

Methylphenidate is available as oral immediate-release and

modified-release formulations and a transdermal patch.

Significant improvements in symptoms have been

reported in several randomized clinical trials of oral

methylphenidate in preschoolers with ADHD [6, 12–14].

PATS (the largest randomized, placebo-controlled, double-

blind clinical trial of methylphenidate in preschoolers) had

strict criteria for the diagnosis of ADHD and study eligi-

bility [6]. After an initial 10-week phase of parent behav-

iour training phase, eligible children aged 3.5–5 years

(n = 165) received treatment with methylphenidate

immediate-release 1.25, 2.5, 5, or 7.5 mg three times daily

during a 5-week titration phase, followed by a longer

10-month maintenance treatment period (n = 140) [6].

After the first 5 weeks of methylphenidate treatment,

ADHD symptoms significantly (p \ 0.01) improved with

methylphenidate (with the exception of the lowest dosage)

relative to placebo [6]. Nevertheless, the effect size was

Table 1 Overview of attention-deficit hyperactivity disorder (ADHD) in preschool-age children, as reviewed by Ghuman and Ghuman [1]

Most common symptoms Hyperactivity, impulsivity, temper tantrums, aggressive behaviour, defiance, inattention

Most common co-

morbidities

Speech delay, oppositional defiant disorder, learning difficulties, social disorders

Underlying causes Imbalances in noradrenergic and dopaminergic systems, and dysfunction in fronto-subcortical pathways have

been implicated

Nonpharmacological

interventions

Psychosocial approaches, parent behaviour management (e.g. increased consistency in approaches to managing

the child’s disruptive behaviour), dietary interventions (e.g. restricted elimination diet)

Pharmacological

interventions

Usually prescribed off-label in preschool children

Oral methylphenidate is the most commonly used agent

Other options include methylphenidate transdermal system patch and oral atomoxetine

Controversial issues Perceived difficulty with, and objections to, diagnosing ADHD

Concerns regarding a lack of data on the long-term safety of drugs administered to very young children

242

small (0.4–0.8 for different doses of methylphenidate) and

less than that reported for children of school age in another

study [15]; however, the effect was sustained during the

10-month open-label follow-up period [16]. The mean

optimal daily dose of methylphenidate was 14 ± 8 mg/day

at the end of the titration phase and 20 ± 10 mg/day at the

end of the 10-month treatment period. The presence of co-

morbid disorders appeared to have an effect on methyl-

phenidate treatment response, with preschoolers having B1

co-morbid disorder having a better treatment response, and

those with C3 co-morbid disorders not appearing to benefit

from methylphenidate treatment [17].

The methylphenidate transdermal patch has been suc-

cessfully used to treat school-age children with ADHD, and

is a potential option for preschoolers, particularly those

having difficulty swallowing pills. However, clinical evi-

dence of the effectiveness of this formulation in pre-

schoolers with ADHD is limited to a prospective case

series study in three preschool boys [18].

… but adverse effects are common

A high rate (30 %) of adverse events occurred in the pre-

schoolers who received methylphenidate in PATS [6, 19].

Consistent with older children, documented adverse events

included reduced appetite, difficulty falling asleep, and a

decrease in growth velocity. Certain adverse events (more

irritability and mood changes) were observed more often in

the methylphenidate preschoolers, suggesting that the drug

may have a unique adverse effect profile in younger chil-

dren. Notably, the rate of methylphenidate treatment dis-

continuation was markedly higher in the preschoolers than

in older children with ADHD treated with the drug [6, 15,

19]. Long-term data from PATS showed that the pre-

schoolers treated with methylphenidate had an annual

height gain of 20 % less than expected and an annual

weight gain of 55 % less than expected [20].

Atomoxetine may improve symptoms and functional

impairment

Preliminary data suggest that atomoxetine may be useful in

the treatment of preschoolers with ADHD, but information

is very limited on its use in young children with this con-

dition. In a study in 101 children aged 5 and 6 years, sig-

nificant reductions in core symptoms of ADHD were

reported for children treated with atomoxetine relative to

those treated with placebo [21]. However, 62 % of the

atomoxetine-treated children continued to have functional

impairment and residual symptoms. A higher (75 %)

response rate was reported in a smaller, prospective, open-

label study in 12 preschool children with ADHD (mean age

5.0 years) treated with atomoxetine [22].

Of note, treatment with atomoxetine may be limited by

its tolerability profile, as a relatively high incidence of

gastrointestinal adverse effects, including gastrointestinal

upset, was reported with the drug in both studies. More-

over, unlike some other ADHD medications, atomoxetine

capsules must be taken whole with water or other liquids

[23]. The capsules should not chewed, crushed, or opened

and sprinkled on food or made into a suspension [23], thus

making administration and dosage titration potentially

challenging in younger children.

Controversies about pharmacological treatment remain

Notwithstanding the published clinical evidence that drug

therapy can be effective in preschoolers with ADHD, there

is a general lack of data on the short- and long-term safety

of drugs used in ADHD, which explains why there may be

a reluctance to prescribe these drugs to preschoolers [1].

Concerns have been raised regarding the pharmacolog-

ical management of ADHD in young children who are

typically undergoing a period of fast growth and matura-

tion in emotional, neuronal and cognitive development [1].

Many complex neurological processes occur in the brain

from birth until childhood; cortical synaptic density

increases and synaptic elimination and connectivity

rewiring take place through to late childhood, together with

a marked increase in cerebral glucose utilization that

coincides with the phase of synaptic proliferation, between

birth and 4 years of age [1]. The transient phase of limited

attention span, limited self-regulatory behaviour, naturally

high levels of energy and motor activity often seen in

preschoolers may lead to the premature diagnosis and

‘wrongful’ ADHD labelling of an active child and result in

inappropriate drug treatment [24].

There is a general lack and inconsistency of data

addressing the effects of psychopharmacological agents on

the brain in school-age children, and no published studies

have reported data on the effect of these drugs on the brains

of preschoolers with ADHD relative to untreated pre-

schoolers with ADHD. Weak evidence of mild cortical

atrophy was reported in one controlled study in 24 adults

diagnosed with minimal brain dysfunction or hyperkinetic

syndrome who had taken stimulant drugs for various

periods of time for hyperactivity during childhood [25]. By

contrast, imaging studies showed a normalization in the

rate of cortical thinning in school-age and older children

with ADHD after psychostimulant treatment (compared

with healthy matched controls), whereas cortical thinning

was evident in 19 children with ADHD who did not receive

psychostimulants [26].

243

Pharmacological treatments for ADHD also have central

and peripheral catecholaminergic effects that may result in

statistically significant increases in heart rate and blood

pressure [27]. However, serious cardiovascular events

related to ADHD medications are considered rare, and are

usually associated with the presence of potential cardiac

risk factors (e.g. history of syncope, family history of

ventricular arrhythmia, evidence of undiagnosed congenital

heart disease). The US FDA has issued a black box

warning for all stimulants concerning the use of these

agents in children or adolescents with cardiac problems.

Although identifying and managing underlying cardiovas-

cular pathology may not eliminate the risk of serious car-

diovascular events, it may increase the safety of using

pharmacological treatments for ADHD [27].

Disclosure This article was adapted from Pediatric Drugs

2013;15(1):1–8 [1]. The preparation of these articles was not sup-

ported by any external funding.

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