Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in Preschool-Aged Children

Abstract

Objectives:

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder defined as a persistent pattern of inactivity and/or hyperactivity that interferes with behavioral function or development. Diagnosis and treatment of ADHD in the preschool-aged population (children 3–5 years old) is more complicated compared with older children because of developmental and physiological differences. This article reviews the available literature regarding the challenges associated with ADHD diagnosis and treatment in preschool-aged children, as well as the unmet needs of preschool-aged children with ADHD.

Methods:

Key considerations for ADHD diagnosis and treatment patterns in preschool-aged children are summarized in this review, including the need for early intervention, the association with comorbidities, and the differences in pharmacokinetic profiles between preschool-aged children and older children.

Results:

Efficacy and safety data are lacking, as clinical trial design and execution pose unique challenges in this population. Preschool-aged children often have difficulty with pill swallowing and tolerating phlebotomy necessary for the collection of pharmacokinetic and safety data. However, early diagnosis and treatment are essential to mitigate ADHD symptoms and comorbidities that may develop during childhood and adolescence in patients with persistent ADHD.

Conclusion:

This review describes the established diagnostic and treatment modalities, along with the unmet needs of preschool-aged children with ADHD.

Introduction

Attention-deficit/hyperactivity disorder (ADHD), one of the most common neurodevelopmental disorders in children, is defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5™; American Psychiatric Association 2013) as a persistent pattern of inattention and/or hyperactivity that interferes with behavioral function or development. Both genetic and environmental factors contribute to the complex etiology of ADHD (Curatolo et al. 2010; Pingault et al. 2015; Akutagava-Martins et al. 2016). ADHD is often treated with stimulant drugs that increase the neurocirculation of norepinephrine and dopamine through transporter blockade (Keenan and Wakschlag 2000).

The American Academy of Pediatrics (AAP) recommends a comprehensive evaluation of any child (4–18 years) with symptoms of inattention, hyperactivity, or impulsivity (American Academy of Pediatrics 2011). The DSM-5 criteria for a diagnosis of ADHD requires the presence of symptoms for at least 6 months, with six or more symptoms in two or more settings (home, school, extracurricular activities, social activities, etc.) that are inappropriate for developmental level and impair academic or social progression.

ADHD can be classified into three subtypes based on the number of inattentive or hyperactive/impulsive symptoms present. Children with combined type display a similar number of inattentive and hyperactive/impulsive symptoms, while others may present as predominantly inattentive or predominantly hyperactive/impulsive. However, symptom presentation and, therefore, ADHD subtype often change throughout childhood (Lahey et al. 2005; Galera et al. 2011). For 66.7%–91.3% of children diagnosed at age 4–6 years, the ADHD subtype changed one or more times over the subsequent 7 years (Lahey et al. 2005). ADHD is associated with impairment of academic, social, and behavioral functioning in childhood (DuPaul et al. 2001; Schoemaker et al. 2012; Sjowall and Thorell 2014; Cak et al. 2017). Children referred for further assessment may demonstrate sensory problems and spatial awareness issues (Ren et al. 2014). Additionally, ADHD is associated with a modified sensitivity to reward and punishment (Groen et al. 2013; Gong et al. 2014; Furukawa et al. 2017).

Worldwide, the prevalence of ADHD in the preschool population (3–5 years) based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV; American Psychiatric Association 1994) criteria is 10.5%, which is higher than the 5.9%–7.1% overall prevalence of ADHD in children and adolescents, according to a 2012 meta-analysis (Willcutt 2012). Additionally, the worldwide prevalence of ADHD was greater in males relative to females (1.8:1) in preschool children (Willcutt 2012).

In the United States, historic community and clinical estimates of DSM-defined ADHD in preschool-aged children (2–6 years) range from 2% to 7.9%, with a mean prevalence of 4.2% (Egger et al. 2006). More recently, the National Survey of Children's Health reported a U.S. prevalence of current ADHD in preschool-aged children (2–<6 years) of 1.0% in 2007–2008, 1.5% in 2011–2012 (∼237,000), and 2.1% in 2016 (∼335,000), suggesting that prevalence is increasing (Danielson et al. 2017, 2018). According to parent reports, ADHD prevalence in U.S. children aged 4–17 years increased by 42% from 2003 to 2011, and the percentage of children taking medication increased by 28% from 2007 to 2011 (Visser et al. 2014).

Aside from a significant impairment in global functioning, social behavior, and learning, the Preschoolers with Attention-Deficit/Hyperactivity Treatment Study (PATS) showed that nearly 70% of referred preschool-aged children with ADHD had a comorbidity (Posner et al. 2007). Common concurrent disorders include oppositional defiant disorder, autism spectrum disorder, communication disorders, and anxiety disorders (Posner et al. 2007; Canals et al. 2018). Furthermore, for children enrolled in PATS, comorbid oppositional defiant disorder or conduct disorder predicted the stability of an ADHD diagnosis after 6 years of follow-up, and parent- and teacher-reported ratings of hyperactivity and inattention were significantly higher in children with these comorbidities compared with children with no reported comorbidities during both 3- and 6-year follow-up (p < 0.005; Riddle et al. 2013). An earlier age of ADHD onset increases the likelihood of a comorbidity, which negatively impacts ADHD treatment (Wilens et al. 2002; Connor et al. 2003; Ghuman et al. 2007).

Difficulties in behavior during preschool years are predictive of impairments in social and academic functioning throughout childhood and adulthood, highlighting the need for early intervention and treatment (Altszuler et al. 2016; Lahey et al. 2016; Meinzer et al. 2016; Sjöwall et al. 2017). Preschool-aged children with ADHD display continued impairment across all settings and relationships (Lahey et al. 2004), with disruptive behavior potentially leading to suspensions from school or daycare (Egger et al. 2006). In a 12-year follow-up study, hyperactive preschool-aged children continued to demonstrate disruptive and inattentive behaviors both at home and school, as well as poor cognition and reading abilities as they aged (McGee et al. 1991). In addition, hyperactive children have a higher likelihood of not completing high school, unemployment, and financial difficulties, as well as increased social problems relative to community control subjects (Barkley et al. 2006; Altszuler et al. 2016).

As they grow, preschool-aged children with ADHD are more likely to develop risk-seeking behaviors relative to community control children, resulting in significant consequences during adulthood. ADHD in childhood (4–15 years) was associated with a greater likelihood of developing comorbid psychiatric disorders, teenage pregnancy, criminal behavior, and substance or alcohol use later in life as compared with non-ADHD control subjects (Dalsgaard et al. 2013; Caye et al. 2016).

Physical health risks are higher in preschool-aged children with ADHD, as indicated by increased injuries and mortality rates (Dalsgaard et al. 2015a, 2015b). At age 5, the rate of injury for a child with ADHD is 19.3%, compared with 10.9% of children without ADHD. The rate of injuries is reduced by up to 43.5% and the rate of emergency room visits is reduced by as much as 45.7% when ADHD is treated with medication (Dalsgaard et al. 2015a).

Treatment of ADHD in Preschool-Aged Children

The AAP and the American Academy of Child and Adolescent Psychiatry recommend evidence-based parent- and/or teacher-administered behavioral therapy as the first line of treatment for ADHD in preschool-aged children (Pliska 2007; American Academy of Pediatrics 2011). A parent management program or behavioral intervention therapy is recommended for at least 8 weeks before pharmacotherapy for preschool-aged children (Gleason et al. 2007). The goal of behavioral treatment is to improve ADHD symptoms as well as parent–child interaction and compliance to assigned tasks. The most effective treatments are individually delivered, developmentally appropriate, and multimodal in practice. Four examples of behavioral therapy programs include the New Forest Parenting Package (Abikoff et al. 2015), the Incredible Years Program (Fernandes Azevedo et al. 2014), the Positive Parenting Program (Triple P; Sanders 2012), and Parent–Child Interaction Therapy (PCIT; Abrahamse et al. 2012).

The New Forest Parenting Package is a program specifically directed toward treatment of ADHD in preschool-aged children. The program involves 8-weekly home-delivered intervention sessions combining behavioral training with parental procedures to support positive behaviors in children, such as self-regulation, attention, impulse control, and working memory (Abikoff et al. 2015). ADHD symptoms of inattention and hyperactivity based on parent ratings improved with the New Forest Parenting Package, though these observations were not supported by teacher or clinician commentary (Abikoff et al. 2015). The Incredible Years Program is a 12- to 24-week program that reinforces supportive parenting tactics and positive parent–child interactions resulting in improved ADHD symptoms over a period of 12 months, as well as comorbid conduct disorder symptoms (Hartman et al. 2003; Jones et al. 2008).

The Triple P intervention includes five levels of support for parents with various delivery methods operating along a continuum of intensity in approach (Sanders 2012). At short- and long-term follow-up, this intervention decreased behavioral problems and increased parenting confidence and positive parent–child interactions compared with preintervention ratings (Bor et al. 2002; Sanders et al. 2007; Sanders et al. 2014).

PCIT improves a child's social behavior and fosters parent–child attachment through a two-phase system where parents master techniques for child- and parent-directed interactions (Wagner and McNeil 2008). Disruptive behaviors are reduced and overall stress outcomes are better with PCIT (Abrahamse et al. 2012; Thomas et al. 2017). In general, behavioral training programs used as monotherapy decreased ADHD symptoms in preschoolers, and their effectiveness may be enhanced by ADHD pharmacotherapy (Mulqueen et al. 2015; Pelham et al. 2016).

If ADHD symptoms persist or worsen despite behavioral therapy, the AAP recommends the psychostimulant methylphenidate (MPH) as second-line treatment. Though not approved by the U.S. Food and Drug Administration (FDA), MPH has been found to be effective in reducing ADHD symptoms in preschool-aged children (Gleason et al. 2007). Symptoms of ADHD and behaviors in preschool-aged children improved with MPH treatment, as evidenced by assessments including variations of the Conners' Parent Rating Scale, Nisonger Child Behavior Rating Form, Clinical Global Impression-Severity, the teacher Social Competence Scale, and the Gordon Diagnostic System Delay and Vigilance Tasks (Musten et al. 1997; Abikoff et al. 2007; Ghuman et al. 2009b). Likewise, MPH was more effective in reducing ADHD symptoms in preschool-aged children when compared with the PCIT behavioral program, though the sample size was small (van der Veen-Mulders et al. 2018).

Findings from the PATS have contributed to the understanding of the efficacy and safety of MPH in preschool-aged children with ADHD. The study was a National Institutes of Mental Health-funded, multicenter, randomized trial investigating the short-term efficacy (5 weeks) and long-term safety (40 weeks) of MPH in preschool-aged children with ADHD who did not respond adequately to behavioral treatment (Kollins et al. 2006). The PATS trial enrolled 303 subjects (3–5.5 years of age), of which 165 entered the crossover titration phase where MPH was titrated to 1.25, 2.5, 5.0, or 7.5 mg three times daily based on parent and teacher ratings. Optimized MPH treatment resulted in significant dose-dependent improvements in ADHD symptoms in PATS participants relative to baseline levels based on parent and teacher ratings (Greenhill et al. 2006).

During a 10-month open-label continuation of the PATS study, 95 preschoolers maintained improvements in ADHD symptoms of hyperactivity, impulsivity, inattention, and social skills; mean doses of MPH increased from 14.04 ± 7.57 mg/day at month 1 to 19.98 ± 9.56 mg/day at month 10 (Vitiello et al. 2007). Most children enrolled in PATS continued an ADHD stimulant medication regimen over a 6-year period (Vitiello et al. 2015).

Adverse events (AEs) from MPH treatment reported in PATS and other studies underscore the importance of careful evaluation of the benefits versus risks of its use in preschool-aged children. According to parent reports, 30% of children had moderate to severe AEs and 11% discontinued due to AEs (Wigal et al. 2006). The five most common AEs reported in preschool-aged children included repetitive behaviors or thoughts, emotional outbursts, decreased appetite, irritability, and insomnia (Wigal et al. 2006); in older children, common side effects include mood swings, decreased appetite, irritability, and insomnia (Wigal et al. 2017).

In PATS, moderate and severe AEs were reported for 15%–20% of subjects randomized to placebo compared with 25%–30% of subjects on a total daily dose of 22.5 mg MPH (Wigal et al. 2006). In addition, cardiovascular effects, including increased blood pressure, have been observed in preschool-aged children treated with MPH, though the risk remains low (Wigal et al. 2006; Dalsgaard et al. 2014). As preschool years are accompanied by dramatic changes in developmental landmarks, a major concern with MPH use is the negative impact on growth rate. Out of nearly 100 children studied in PATS who continued MPH treatment, annual growth rates were 20.3% and 55.2% lower than expected for weight and height, respectively (Swanson et al. 2006).

The use of another stimulant, amphetamine (AMPH), and nonstimulants, atomoxetine and risperidone, have also been explored. Studies in school-aged children support the efficacy of AMPH in improving ADHD symptoms compared with placebo treatment (Childress et al. 2017; Brams et al. 2018). Immediate-release AMPH is FDA-approved as a mixed AMPH salts tablet (Adderall^®; Teva Select Brands, Horsham, PA), racemic AMPH sulfate tablet (Evekeo^®; Arbor Pharmaceuticals, Atlanta, GA), or dextroamphetamine sulfate oral solution (ProCentra^®; Independence Pharmaceuticals, Newport, KY) for children 3–5 years of age; all three are given at an initial daily dose of 2.5 mg with weekly increments of 2.5 mg, if needed.

Despite FDA approval for use in preschool-aged children, controlled clinical trial data on AMPH in this population are lacking when compared with studies on nonapproved MPH. In one study of 28 preschool-aged children taking stimulant medication (6 AMPH, 22 MPH), ADHD symptoms reduced relative to placebo as validated by parent and teacher ratings (Short et al. 2004). Common side effects in this study were decreased appetite, irritability, crying, and rebound effects (Short et al. 2004); in older children and adolescents, decreased appetite, insomnia, abdominal pain, and nausea/vomiting were common with AMPH usage (Punja et al. 2016).

Atomoxetine, a norepinephrine reuptake inhibitor, was evaluated in preschoolers in a few small trials. In an open-label pilot study with 12 children aged 3–5 years, ADHD symptoms of hyperactivity and impulsivity improved in 75% of subjects relative to baseline levels according to parent-rated evaluations (p < 0.0001) and Children's Global Assessment Scale scores (p < 0.001); however, 66.7% of subjects experienced AEs, including defiance, tantrums, aggression, irritability, and gastrointestinal effects (Ghuman et al. 2009a). In a placebo-controlled, short-term treatment trial (8 weeks), atomoxetine significantly reduced ADHD symptoms in 5- and 6-year-old children compared with placebo control subjects based on ADHD-IV subscales of parent-rated hyperactivity/impulsivity (p = 0.005) and parent- and teacher-rated inattentiveness (p = 0.002 and 0.04, respectively); subjects treated with atomoxetine were significantly more likely to experience decreased appetite (p = 0.008), sedation (p = 0.02), and gastrointestinal upset (p = 0.02) relative to control subjects (Kratochvil et al. 2011).

Risperidone, an antipsychotic agent, was also studied in preschoolers with ADHD. It significantly reduced ADHD symptoms of inattention and hyperactivity/impulsivity over a 6-week outpatient study in 33 children (3–6 years) based on the Parent ADHD Rating Scale (p < 0.001) and Parent Conners Rating Scale (p < 0.001) and was noninferior to MPH treatment (Arabgol et al. 2015). The most common AEs following risperidone treatment were drowsiness and anorexia (20% of subjects); anorexia was the most commonly reported AE in MPH-treated subjects and occurred in 55% of participants (Arabgol et al. 2015).

The combination of risperidone treatment (maximum dose 2 mg/day) with doses of MPH up to 20 mg daily was compared with MPH treatment alone in 42 children aged 3–6 years (Safavi et al. 2016). In both groups, ADHD symptoms significantly improved on the Parent Conners Rating Scale after 6 weeks of treatment (p < 0.001), but there was no significant difference in symptom improvement with monotherapy versus combination therapy. The combination therapy group required significantly lower doses of MPH at week 6 (p = 0.002). The most common AEs following MPH monotherapy were insomnia (33%) and anorexia (25%), whereas anorexia (21.7%) and daytime drowsiness (17.4%) were the most commonly reported AEs with combination therapy.

These risperidone studies focused on small populations and did not address the long-term safety concerns of risperidone, which can cause serious AEs such as weight gain, elevated prolactin levels, neuroleptic malignant syndrome, metabolic changes, agranulocytosis, seizures, and tardive dyskinesia (Arabgol et al. 2015; Masi et al. 2017; Risperdal^®; Janssen Pharmaceuticals, Inc., Titusville, NJ).

Unmet Needs of Preschool-Aged Children with ADHD

The FDA has issued guidelines in accordance with the Best Pharmaceuticals for Children Act and Pediatric Research Equity Act to encourage proper study design and execution for medications in all relevant pediatric populations (Food and Drug Administration 2014, 2016). The FDA has emphasized that pharmacokinetics, pharmacodynamics, safety, and efficacy must be considered in pediatric drug development.

A recent evaluation revealed that only 7.4% of child and adolescent psychiatrists adhere to current guidelines in the diagnosis and treatment of ADHD in preschool-aged children (Chung et al. 2016). In 2012, 91.4% of preschool-aged children were prescribed off-label ADHD medication, whereas 15.6% of children 6–11 years of age were taking off-label ADHD medications, reflecting the increased availability of approved ADHD medications for children aged over 5 years (Panther et al. 2017). Off-label prescription is concerning considering the lack of safety and efficacy studies in preschool-aged children, and it further emphasizes the need for more studies to support effective and safe prescription practices for young children.

Guidelines for ADHD treatment in preschool-aged children lack robust supportive data (Gleason et al. 2007; American Academy of Pediatrics 2011). Both pharmacokinetic and efficacy studies in preschool-aged children pose challenges due to difficulties enrolling an adequate number of subjects. Studies on young children require resources that may not be readily available, including special facilities, equipment, nurses, laboratories, and expertise. In an ethical context, young children cannot consent to study participation, and both parental permission and the assent of the child are needed.

The immediate-release formulations of AMPH (Adderall, Evekeo, ProCentra) are approved by the FDA for the treatment of ADHD in children 3–5 years of age, although there are no efficacy and safety trials supporting their use. Given the unfamiliarity with solid, oral-dosage forms and known difficulties with pill swallowing in this age group (Beck et al. 2005), it may be difficult for caregivers to administer the medication daily. Clinicians may alter dosages or suggest that caregivers crush tablets into smaller pieces for easier administration; however, this can lead to changes in bioavailability. The novel option of a flavored spray to act as a pill glide decreases swallowing difficulty in children 6–16 years of age and may increase treatment adherence in preschool-aged children (Jagani et al. 2016).

Alternatively, ADHD medications are available in other dosage forms that may circumvent these difficulties (Fig. 1). Orally disintegrating tablets are another option for young children who have difficulty with pill swallowing. Both AMPH and MPH are available as extended-release, orally disintegrating tablets (Adzenys XR-ODT™; Neos Therapeutics, Inc., Grand Prairie, TX; Cotempla XR-ODT™; Neos Therapeutics, Inc.); however, these are only FDA-approved for children ≥6 years of age. Further studies are needed to evaluate the safety and efficacy of orally disintegrating tablets in preschool-aged children to support FDA approval of their use. ProCentra, approved for preschool-aged children by the FDA, has a bubblegum flavor that may increase ease of administration and medication adherence, as children typically prefer sweet taste and have aversions to bitter-tasting medications (Mennella and Beauchamp 2008).

FIG. 1.

Available stimulant formulations for attention-deficit/hyperactivity disorder treatment.

Pharmacokinetic factors due to differences in body water content and the developmental maturation of organ systems affect drug exposure in preschool-aged children and should be taken into consideration when initiating pharmacotherapy with ADHD treatments (Table 1; Kearns et al. 2003; Wells et al. 2005). Relative to older children, preschool-aged children have higher maximum concentration values and significantly slower clearance rates (Table 1; Wigal et al. 2007). The pharmacokinetic differences indicate an overall greater drug exposure in preschool-aged children with the same weight-adjusted dose (Wigal et al. 2007). One report has noted an inverse relationship for AMPH exposure and child age (6–12 years) that was independent of weight, which may be explained by an observed decrease in clearance and increase of half-life in younger subjects (Sikes et al. 2018).

Table 1.

Pharmacokinetic Factors that Influence Age-Related Drug Exposure

Pharmacokinetic process	Pharmacokinetic factors
Absorption
Oral	Levels of gastric acidity (Kearns et al. 2003)
	Gastric emptying rate and intestinal motility (Bowles et al. 2010)
	Gastrointestinal drug-metabolizing enzyme systems (Kearns et al. 2003)
	Gastrointestinal permeability (McOmber et al. 2010)
	Biliary function (Kearns et al. 2003)
	Transporter expression (Lu and Rosenbaum 2014)
Transdermal	Skin perfusion and hydration (Kearns et al. 2003)
Transdermal	Body surface area–weight ratio (Kearns et al. 2003)
Inhalation	Variation in pulmonary routes (Kearns et al. 2003)
Distribution	Changes in total body water (Wells et al. 2005)
	Changes in total body adipose tissue (Wells et al. 2005)
	Plasma protein binding (Ehrnebo et al. 1971)
	Blood flow to organs (i.e., brain; Wu et al. 2016)
Metabolism	Bioavailability (Kearns et al. 2003)
Metabolism	Hepatic enzyme systems (CYP3A; Fakhoury et al. 2005)
Excretion	Maturation of renal function processes (Chen et al. 2006)

CYP3A, cytochrome P450 3A.

Studies that focus on both short-term and long-term safety and efficacy implications of ADHD medications on growth, sexual development, cognition, learning, and behavior will provide a clearer understanding of ADHD treatment in preschool-aged children. Though limited in number, several trials in preschool-aged children have been completed or are currently being conducted (Table 2).

Table 2.

Study Design of Clinical Trials for ADHD Treatment in Preschool-Aged Children

ID number	Type	Study start date	Title
NCT00018863	Pharmacological intervention	2001	Treatment of attention-deficit/hyperactivity disorder in preschool-aged children (PATS)
NCT00517504	Pharmacological intervention	2001	Methylphenidate study in young children with developmental disorders
NCT00414921	Pharmacological intervention	2003	Preschool-aged supplement to clonidine in ADHD (Kiddie-CAT)
NCT00517647	Pharmacological intervention	2004	Atomoxetine pilot study in preschool-aged children with ADHD
NCT01462032	Pharmacological intervention	2011	Non-pharmacological interventions for preschoolers with attention-deficit/hyperactivity disorder (ADHD) (NIPA)
NCT02402166	Pharmacological intervention	2015	Safety, tolerability, pharmacokinetic, and efficacy study of SPD489 in preschool children with attention-deficit/hyperactivity disorder
NCT02466386	Pharmacological intervention	2015	Safety and tolerability study of SPD489 in preschool children aged 4–5 years, diagnosed with attention-deficit/hyperactivity disorder
NCT02677519	Pharmacological intervention	2016	A 12-month open label safety study of Aptensio XR^® in children ages 4–5 years diagnosed with ADHD (EF004)
NCT02683265	Pharmacological intervention	2016	A flexible-dose titration study of Aptensio XR in children ages 4 to under 6 years diagnosed with ADHD (EF003)
NCT02470234	Pharmacological intervention	2016	Pharmacokinetic study of methylphenidate HCl extended-release capsules in children 4 to under 6 years of age with ADHD (PK003)
NCT03260205	Pharmacological intervention	2017	Safety and efficacy study in preschool children aged 4–5 years with attention-deficit/hyperactivity disorder (ADHD)
NCT02807870	Pharmacological intervention and behavioral training	2016	Early interventions in children with attention-deficit/hyperactivity disorder
NCT01320098	Behavioral training	2007	Parent training for attention-deficit/hyperactivity disorder (ADHD) preschoolers
NCT01684644	Behavioral training	2012	A controlled study of parent training in the treatment of ADHD in young children (D'SNAPP)
NCT01919073	Behavioral training	2012	Efficacy of a brief behavioral intervention to treat ADHD and disruptive behaviors in preschoolers
NCT02642666	Behavioral training	2015	The effects of yoga on attention, impulsivity and hyperactivity in pre-school age children
NCT02588365	Behavioral training	2015	Brain training in children with/at-risk for attention-deficit/hyperactivity disorder and executive function impairment
NCT02433145	Neuropsychological	2014	Explore the association between neuropsychological functions and ADHD diagnosis and comorbid using longitudinal study in preschool children

ADHD, attention-deficit/hyperactivity disorder; ID, identification; XR, extended release.

Due to slower clearance rates, lower doses of MPH (0.76 mg/kg per day) and atomoxetine (1.59 mg/kg per day) were used to treat ADHD symptoms in preschool-aged children (Ghuman et al. 2009a, 2009b). In PATS, the average dose in preschool-aged versus school-aged children did not differ (5.89 ± 1.89 vs. 6.94 ± 3.3 mg, respectively; p = 0.33); however, dose-normalized maximum concentration levels were significantly higher (p = 0.003) and clearance was significantly slower (p = 0.0002) for preschoolers (Wigal et al. 2007). AEs were also higher in preschoolers than is typically seen with older children (Wigal et al. 2006).

These data will need to be replicated with other formulations, such as products with both immediate- and extended-release properties, that provide the benefit of immediate onset of therapeutic effect and the adequate duration required to avoid a midday dose (Greenhill et al. 2002; Wigal et al. 2014; Childress et al. 2017, 2018). Limitations of these studies include small sample sizes, absence of titration protocols, and loss to follow-up (Greenhill et al. 2006; Ghuman et al. 2009a, 2009b; Vitiello et al. 2015). Some of these limitations were addressed in PATS by providing extensive information on MPH use in preschool-aged children with ADHD with a large sample size and follow-up data, though additional studies are needed (Vitiello et al. 2015).

Conclusion

ADHD is a common neurodevelopmental disorder in preschool-aged children and is characterized by patterns of inattention and hyperactivity or impulsivity that can lead to disruptions in social behavior and cognition, as well as mental and physical health risks. It can be challenging to diagnose ADHD in preschool-aged children. Currently, the AAP recommends MPH if unresponsive to behavioral therapy; however, despite evidence in support of its safety and efficacy in preschool-aged children, MPH is not approved by the FDA in this population. Only AMPH is approved by the FDA for use in preschool-aged children, though clinical trial data are lacking.

Rigorous placebo-controlled clinical trials with formulations designed for children must be conducted to establish the short- and long-term efficacy and safety of medications in preschool-aged children with ADHD. Pharmacokinetic studies are needed to understand the correct dosage regimen, as the same weight-adjusted dose of extended-release MPH formulations led to increased exposure in preschool-aged compared with school-aged children (Wigal et al. 2007). Long-term follow-up data show that early diagnosis of ADHD and intervention in preschool-aged children are critical toward decreasing the development of comorbidities and impairment as children grow up.

Clinical Significance

ADHD, a common neurodevelopmental disorder in preschool-aged children, is characterized by patterns of inattention and hyperactivity or impulsivity that can lead to disruptions in social behavior and cognition, as well as mental and physical health risks. Although diagnosis of ADHD can be challenging in preschool-aged children, early intervention is critical toward decreasing the development of comorbidities and impairment later in life. Rigorous placebo-controlled clinical trials with formulations designed for children are needed to establish the short- and long-term efficacy and safety of medications for preschool-aged children with ADHD. Additionally, pharmacokinetic studies are needed to determine the correct dosage regimen in preschool-aged children, who may experience increased drug exposure relative to school-aged children.

Footnotes

Acknowledgments

Medical writing and editorial support was provided by Caryne Craige, PhD, of AlphaBioCom, LLC and was funded by Neos Therapeutics, Inc.

Disclosures

Dr. J.G.S. is an employee of Worldwide Clinical Trials and reports no competing interests. Dr. A.C.C. has received research support from, consulted with, acted as invited speaker for, and/or served on advisory boards of Akili; Alcobra Pharma; Arbor Pharmaceuticals; Forest Research Institute; Ironshore Pharmaceuticals; KemPharm, Inc.; Lilly USA; Lundbeck; Neos Therapeutics; Neurovance; NextWave Pharmaceuticals; NLS Pharma Group; Noven Pharmaceuticals; Otsuka Pharmaceutical; Pfizer; Purdue Pharma; Rhodes Pharmaceuticals; Shire Pharmaceuticals; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Theravance Biopharma; and Tris Pharma.

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