Diagnosis and Treatment Options for Preschoolers with Attention-Deficit/Hyperactivity Disorder

Abstract

Objective:

The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), classifies attention-deficit/hyperactivity disorder (ADHD) as a neurodevelopmental disorder, with symptoms becoming apparent as early as the preschool years. Early recognition can lead to interventions such as parent/teacher-administered behavior therapy, the recommended first-line treatment for preschool patients. There are few data, however, to inform the use of second-line, pharmacotherapy options in this population. In this review, we identified recent literature on the diagnosis and treatment of ADHD in preschool children.

Methods:

A PubMed and clinicaltrials.gov search was conducted for trials assessing efficacy or safety of ADHD medications in children aged <6 years. Diagnostic methods and criteria focusing on recognition of ADHD in preschool children were also surveyed.

Results:

The DSM-5 describes different manifestations of ADHD in preschool versus school-aged children, but does not list separate criteria by age group. Importantly, behaviors indicative of ADHD in older children may be developmentally appropriate in preschool children. Several behavioral rating scales have been validated in children younger than 6 years of age for assessing ADHD. The Preschool ADHD Treatment Study (PATS) has provided the most extensive efficacy and safety data on methylphenidate (MPH) for ADHD in preschoolers to date, with significant improvement in ADHD symptoms observed with MPH compared with placebo, although adverse event-related discontinuation was higher in PATS compared with studies of MPH for ADHD in school-aged children. Since PATS was conducted, few studies designed to assess ADHD medication effectiveness in preschool children have been published. One article reported significant improvement in ADHD symptoms with MPH (immediate release) versus placebo, two studies showed no difference between MPH and risperidone or MPH plus risperidone in relief of ADHD symptoms, and one study demonstrated the efficacy of atomoxetine versus placebo for ADHD symptoms in preschoolers.

Conclusions:

Further research is needed on pharmacotherapy for preschool children with ADHD.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is classified in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), as a neurodevelopmental disorder, with symptoms becoming apparent as early as the preschool years (American Psychiatric Association 2013). It is generally diagnosed in school-aged children; however, most parents of children referred for evaluation of ADHD symptoms report onset of symptoms at 4 years of age or earlier (Connor 2002), and anomalous cortical development has been observed in children with ADHD as early as the preschool years (Jacobson et al. 2018). The 2016 estimated prevalence of parent-reported ADHD diagnosis was 2.4% in preschool children, increasing to 9.6% in school-aged children (6–11 years), and 13.6% in adolescents (12–17 years) (Danielson et al. 2018).

Diagnosis of ADHD in preschool children may be complicated by developmental factors (American Psychiatric Association 2013). Symptoms of ADHD may differ over the course of the lifespan, and the “context” of symptoms differs for young children compared with school-aged children or adolescents (Egger et al. 2006b; Chacko et al. 2009). Preschool children function in more limited settings, and parents and other caretakers generally expect greater levels of activity and impulsivity in young children compared with older children. Nonetheless, early recognition of ADHD is key in providing interventions that can prevent the development of poor social and functional outcomes associated with ADHD. The American Academy of Pediatrics (AAP) guidelines support evaluating children as young as 4 years who have behavioral problems or symptoms of inattention, hyperactivity, or impulsivity, and for preschool-aged children diagnosed with ADHD, behavioral therapy and parent training are recommended first-line treatments (Klein et al. 2013; Sonnack and Brenneman 2014; Wolraich et al. 2019). Reviews of the literature conclude that parent behavioral training has demonstrated the strongest evidence of efficacy for treatment of preschool patients with ADHD (Charach et al. 2011, 2013).

In an analysis of data from children aged 2–5 years in the 1994–2009 National Ambulatory and National Hospital Ambulatory Medical Care Surveys (N = 43,598), 57.8% of 2- to 5-year-olds with an ADHD diagnosis received psychotropic medication (Chirdkiatgumchai et al. 2013). There are few data, however, to inform the use of second-line, pharmacotherapy options in this population (Charach et al. 2013). Best evidence for the effectiveness of pharmacotherapy in very young children comes from the Preschool ADHD Treatment Study (PATS), a multiphase placebo-controlled trial of methylphenidate (MPH) immediate release (IR) that enrolled 303 children with ADHD aged 3–5.5 years (Greenhill et al. 2006). Yet, MPH is not among the few medications that have received U.S. Food and Drug Administration (FDA) approval for treating ADHD in children younger than 6 years of age (Table 1) (The ADHD Medication Guide 2019).

Table 1.

Medications with an Indication for Treating Attention-Deficit/Hyperactivity Disorder in Children Younger Than 6 Years of Age (The ADHD Medication Guide 2019)

Brand name	Generic name	Indication age range, years	Formulation
Adderall^® (2017)	Mixed amphetamine salts (d,l-amphetamine [3:1])	≥3	Tablet
Adderall^® (2017)	Mixed amphetamine salts (d,l-amphetamine [3:1])	≥3	IR formulation only
Evekeo^® (2016)	Amphetamine sulfate (d,l-amphetamine [1:1])	≥3	Tablet
ProCentra^® (2017)	Dextroamphetamine sulfate (d-alpha-methylphenethylamine)	3–16	Oral solution
Zenzedi^® (2017)	Dextroamphetamine sulfate (d-alpha-methylphenethylamine)	3–16	Tablet

ADHD, attention-deficit/hyperactivity disorder; IR, immediate release.

Medications with an FDA indication for treating ADHD in children 3–5 years of age include an amphetamine tablet formulation, dextroamphetamine oral solution and tablets, and mixed amphetamine salts (Adderall, IR formulation only; The ADHD Medication Guide 2019). Adderall, approved in 1996, was the first ADHD medication with an indication in children as young as 3 years of age; however, no published efficacy data in preschool children were available at that time, when requirements for approval were less stringent (Vaughan and Kratochvil 2006; Wolraich et al. 2019), and clinical trial data supporting its use in this age group are limited to a single naturalistic study to this day (Short et al. 2004). For this reason, the AAP does not recommend the FDA-approved medications as first-line treatment for preschool children with ADHD (Wolraich et al. 2019). Because there are few FDA-approved ADHD medications with an indication in children younger than 6 years of age, off-label prescribing is often used (Wolraich et al. 2019). Indeed, more than 90% (2233/2442) of 3- to 5-year-old children with an ADHD diagnosis who were prescribed ADHD medications received an off-label prescription in a study based on Medicaid encounter and pharmacy claims data (Panther et al. 2017). Among U.S. child and adolescent psychiatrists who responded to a clinical practice survey (N = 339), 71% “often” or “very often” recommend pharmacotherapy for their preschool patients with ADHD when behavioral therapy is unsuccessful (Chung et al. 2016). Of respondents who prescribe medication, 64% report they prescribe MPH, 21% prescribe an amphetamine, and 16% prescribe a nonstimulant as their first-line medication (Chung et al. 2016). In an analysis of medical database records, 73% (86/118) of preschool-aged ADHD patients who received medication were prescribed stimulants, 22% were prescribed alpha-2 adrenergic agonists, and 5% were prescribed antidepressant drugs (DeBar et al. 2003).

Given these practice patterns, the use of psychotropic drugs in preschool patients with ADHD has come under FDA scrutiny, and in fact, the FDA now requests the collection of dosing and safety data in patients 4 years of age and older for new products approved to treat ADHD (Food and Drug Administration 2019). Because it has become clear that ADHD is a neurodevelopmental disorder that can be diagnosed and treated in the preschool years (American Psychiatric Association 2013; Wolraich et al. 2019), clinicians have opted to prescribe medications to treat ADHD in very young children when behavioral therapy is not effective (Chirdkiatgumchai et al. 2013; Chung et al. 2016). Although medication can be a beneficial part of ADHD treatment in some preschool patients, it should be used carefully in this population (Wolraich et al. 2019).

Children and adolescents, aged 6–18 years, have been the focus of much of the research literature on diagnosis and treatment of ADHD, including a substantial proportion of clinical studies on efficacy, safety, and tolerability of ADHD medications (Storebo et al. 2011, 2015; Zwi et al. 2011; Otasowie et al. 2014; Punja et al. 2016). However, due to the physical, emotional, and behavioral changes that occur during development from preschool- to school-age years, evidence derived from school-aged children may not provide the best guidance for the diagnosis and treatment of ADHD in very young children. It is important, therefore, for clinicians to understand both issues related to the diagnosis of ADHD in preschool-aged children and the evidence supporting pharmacotherapy options for children younger than 6 years of age. The objective of this article is therefore to review recent literature on the diagnosis and treatment of ADHD in preschool children, to outline what is known and, importantly, what remains to be learned regarding the pharmacological treatment of ADHD in this population.

Methods

PubMed and clinicaltrials.gov searches were conducted for trials assessing efficacy or safety of ADHD medications in children younger than 6 years of age. The term “preschool” is generally defined as ages 3–5 (Centers for Disease Control and Prevention 2019) or age 4 years to the sixth birthday (Wolraich et al. 2019); in this review, “preschool” refers to children younger than 6 years of age and includes data from children younger than 4 years old. PubMed search terms included ADHD; preschool or young children; school-based intervention, behavioral intervention, psychosocial intervention, or parent behavior training; pharmacotherapy; and clinical trial. Searches were also made for trials of specific drugs (MPH, amphetamine, methamphetamine, atomoxetine, clonidine, guanfacine). Because trials of ADHD medications in preschool children conducted before the PATS have been reviewed by Charach et al. (2011) and considered only fair in quality, this search was restricted to those published in 2006 or later.

The clinicaltrials.gov website was searched for phase 2, 3, or 4 interventional studies assessing the efficacy and safety of ADHD treatment medications. The search captured trials enrolling children aged 4 or 5 years; trials enrolling children older than 6 years were excluded. To exclude published trials, results of the clinicaltrials.gov search were compared against the PubMed search results.

Literature on diagnostic methods and criteria focusing on recognition of ADHD in preschool children was also surveyed.

Results

Diagnosis of ADHD in preschool children

The DSM-5 describes different manifestations of ADHD in preschool versus school-aged children (Appendix A1) (American Psychiatric Association 2013). However, the ADHD diagnostic criteria and specifiers do not differ by age group, even though ADHD symptoms and subtypes may not be consistent between preschool- and school-aged children (Lahey et al. 2005; Chacko et al. 2009). The possible differences in the presentation of ADHD in preschool- versus school-aged children raise important questions for diagnosis: Do preschool children diagnosed with ADHD continue to meet criteria as they mature? Can we identify any characteristics that may predict the developmental course of ADHD diagnosed in preschool-aged patients? Do DSM-5 diagnostic criteria adequately identify ADHD in preschool children?

ADHD is a neurodevelopmental disorder with multiple pathways through development (Berger and Nevo 2011). The neurodevelopmental course of ADHD may best be described in terms of an interplay of genetic, developmental, and environmental factors that contribute to the severity and persistence of symptoms through childhood and into adulthood (Halperin et al. 2012). Numerous longitudinal studies have examined persistence rates from school-age into adulthood, resulting in a wide range of estimates (from 5% to 76%) due to differences in sample characteristics and diagnostic system and assessment approach (Caye et al. 2016). Most studies suggest that in a substantial proportion of school-aged children diagnosed with ADHD, symptoms will persist into adulthood (median rate across reviewed studies, 41%) (Caye et al. 2016).

Trajectories in atypical brain development have been described with a goal of understanding differences in trajectory between patients with persistent ADHD in adulthood versus those whose symptoms remit (Shaw et al. 2013). Reviews of the evidence suggest that persisting versus remitting trajectories may have a significant heritable component, but early characteristics or risk factors may also predict the course of symptoms into adulthood (Berger and Nevo 2011; Friedman and Rapoport 2015; Pingault et al. 2015). Commonly reported predictors of persistence of ADHD diagnosis from school-age into adulthood include ADHD severity or impairment, comorbid disorders (oppositional defiant disorder [ODD], conduct disorder [CD], major depressive disorder, bipolar disorder, and anxiety disorders), as well as parental mental health (Biederman et al. 2011; Caye et al. 2016; Roy et al. 2016).

Although ADHD symptoms may have their onset in the preschool years (Connor 2002), few studies have examined the early course of ADHD in longitudinal studies of children who are preschool age at enrollment. As in studies enrolling older children, estimates of persistence in these studies varied considerably (Lahey et al. 2004; Tandon et al. 2011; Riddle et al. 2013; O'Neill et al. 2014). Based on an analysis of children followed through the PATS follow-up (F/U), PATS investigators concluded that the diagnosis of ADHD is moderately stable from preschool to school-age (Riddle et al. 2013). Of preschool children with moderate-to-severe ADHD enrolled in PATS (n = 207), the proportion that were diagnosed with ADHD at the end of the PATS F/U (year 6) was 77% (mean age at year 6, 10.4 years) (Riddle et al. 2013). After adjustment for medication during the follow-up period, ADHD rate was 89% at year 6.

The PATS F/U findings were consistent with an earlier analysis of 255 children aged 4–7 years, in which ∼80% of children diagnosed with ADHD met full diagnostic criteria for ADHD, based on parent and teacher ratings, at least twice in annual assessments over the following 4 years (Lahey et al. 2004). Other studies have reported lower rates of ADHD persistence in children followed from preschool to school age. In a longitudinal study of 79 children who met diagnostic criteria for ADHD at 3–4 years of age, 63% continued to have an ADHD diagnosis at age 6 (O'Neill et al. 2014), and among 48 children with an ADHD diagnosis at 3 to younger than 6 years of age, 31% had a positive diagnosis of ADHD at a 2-year follow-up (Tandon et al. 2011).

Changes in hyperactive and inattentive symptoms over the course of development show different trajectories beginning in the preschool years. In children with high hyperactive-impulsivity and inattentive symptoms assessed periodically from 1.5–8 years of age, hyperactivity decreased slightly with increasing age, while inattention increased substantially to a peak at age 6, although the authors suggested that the complexity of assessing inattention in very young children may have accounted for some of that change (Galera et al. 2011). In a longer duration study of children with ADHD aged 4–7 years at enrollment and diagnosed at age 4 (N = 125), hyperactive symptoms declined significantly from age 4–18 inattention declined more slowly beginning at age 9 or 10 (Lahey et al. 2016). Even as symptoms decline, on average, over development, an ADHD diagnosis in early childhood is associated with increased likelihood of arrest, unintentional injury, and risky behaviors with motor vehicles at 15–18 years of age (Lahey et al. 2016). “At risk” status as early as 54 months predicts “at risk” status at grades 1 and 3 (von Stauffenberg and Campbell 2007).

Some of the same factors that predict persistence of ADHD from adolescence into adulthood, including severity of ADHD symptoms and comorbid ODD (von Stauffenberg and Campbell 2007; Tandon et al. 2011; Law et al. 2014; O'Neill et al. 2014; Breaux et al. 2016), may indicate stability of a preschool diagnosis or predict a later ADHD diagnosis in at risk preschool children, although predictors were generally more complex than those in older children. For example, in children with elevated levels of externalizing problems at age 3, scores from a battery of neuropsychological assessments significantly predicted ADHD diagnosis at age 6, and taking into account current ADHD symptoms improved the overall predictive power (Breaux et al. 2016). Inhibition and attention deficits in preschool children predicted ADHD symptoms in first grade, whereas only preschool inhibition deficits predicted ADHD symptoms in third grade (von Stauffenberg and Campbell 2007). In children aged 3 to younger than 7 years old diagnosed with ADHD, nonverbal cognitive score, elevated externalizing behaviors, and elevated internalizing behaviors predicted persistent diagnosis over a 7-year follow-up (Law et al. 2014). In children aged 3–4 years, ADHD symptoms in the 90th percentile as assessed by at least two raters (clinical, school, and/or parent) predicted positive diagnosis at 6 years, particularly if one rater was a parent (O'Neill et al. 2014). A deficit in effortful control (a temperament dimension related to self-regulation) at age 3 was associated with ADHD symptoms in adolescence (ages 12–16) (Einziger et al. 2018). In one study, improvement in neuropsychological functioning in 3- to 4-year-olds at risk for ADHD, but not their baseline severity of symptoms, predicted later attenuation of symptoms (Rajendran et al. 2013).

In their 2009 review, Chacko et al. (2009) discussed the applicability of DSM ADHD symptoms to preschool children, noting that many symptoms assessed for diagnosis may be developmentally imprecise, inappropriate, improbable, or impossible when diagnosing preschool children. That is, behaviors or the frequency of behaviors that indicate inattention, impulsiveness, or hyperactivity in older children may be developmentally normal or merely misbehavior in preschool children and therefore imprecise or inappropriate indicators of ADHD in this group (Felt et al. 2014; Ford-Jones 2015). Conversely, symptoms related to activities, in which very young children rarely or never participate, might be “improbable” or “impossible” diagnostic criteria for preschool ADHD. A 3-year-old child may show hyperactive or inattentive symptoms at home, but DSM-5 criteria require symptoms to be “present in 2 or more settings (e.g., at home, school, or work; with friends or relatives; in other activities)” and “interfere with, or reduce the quality of, social, academic, or occupational functioning” (American Psychiatric Association 2013).

Among patients in the PATS study, the majority of DSM-IV symptoms present, with frequencies greater than 90% based on the Revised Conners' Parent Rating Scale and the clinician-completed ADHD checklist, were hyperactive or impulsive symptoms (Posner et al. 2007). Four of six hyperactive symptoms and two of three impulsive symptoms were scored as 2 (“often”) or 3 (“very often”) on the Conners' Parent Rating Scale in over 90% of participants, compared with two of nine inattentive symptoms. The endorsed symptoms, however, were hyperactive behaviors that may not be unexpected in preschool children: fidgets and squirms in seat, often leaves seat, runs about and climbs excessively, often on the go. In contrast, inattentive symptoms that were endorsed at lower rates, such as loses things necessary for activities, forgetful in daily activities, difficulty organizing tasks, and makes careless mistakes, might be considered “inappropriate” or “improbable.”

Given the reported differences in ADHD symptoms in preschool children compared with school-aged children, assessment of preschool children must take into account the developmental and social/functional context of early childhood (Chacko et al. 2009). Using behavioral assessment scales specifically designed for this patient population may allow clinicians to better identify preschool patients with ADHD while excluding those showing developmentally normal behavior (Egger et al. 2006b; Felt et al. 2014). Several behavioral rating scales (RSs) have been validated in children younger than 6 years of age for the assessment of ADHD, including the Conners Parent Rating Scale–Revised (Conners et al. 1998a) and Conners Teacher Rating Scale–Revised (Conners et al. 1998b), the AD/HD Rating Scale–5 parent and teacher versions (DuPaul et al. 2016), the Early Childhood Inventory–4 (Sprafkin et al. 2002), and the Child Behavior Checklist 1½–5 (de la Osa et al. 2016) (Table 2). The Preschool Age Psychiatric Assessment (Egger et al. 2006a) was developed based on the Child and Adolescent Psychiatric Assessment (Angold and Costello 1995) for use in children 2–5 years of age, but no reports of validation in that population have been published to date. The Vanderbilt ADHD Teacher and Parent Rating Scales have been validated in children aged 6–12 years, but are also applicable to preschool children (Wolraich et al. 1998, 2003; American Academy of Pediatrics 2019).

Table 2.

Rating Scales for Assessment of Attention-Deficit/Hyperactivity Disorder Symptoms in Children Younger Than 6 Years of Age

Instrument	Age, years	Type of scale
Preschool Age Psychiatric Assessment, Egger et al. (2006a)	2–5	Psychiatric symptom/function scale incorporating DSM-IV-TR and RDC-PA diagnostic criteria, includes an ADHD module
Conners Parent Rating Scale–Revised, Conners et al. (1998a)	3–17	Validated ADHD-specific rating scale
Conners Teacher Rating Scale–Revised, Conners et al. (1998b)	3–17	Validated ADHD-specific rating scale
AD/HD Rating Scale–5, parent and teacher versions, DuPaul et al. (2016)	5–17	Validated DSM-5–referenced, ADHD-specific rating scale
Early Childhood Inventory–4, Sprafkin et al. (2002)	Preschool-aged (3–6)	Validated DSM-IV–referenced screening instrument, includes subscales for ADHD inattention and hyperactive-impulsive subtypes
Child Behavior Checklist 1½–5, de la Osa et al. (2016)	1.5–5	Validated behavioral symptom checklist, includes attention problems and attention-deficit/hyperactivity problems subscale (including hyperactive-impulsive and inattentive types)
Vanderbilt ADHD Teacher and Parent Rating Scales, Wolraich et al. (1998, 2003) and DuPaul et al. (2016)	6–12	Validated DSM–referenced, ADHD-specific rating scale, includes items related to oppositional-defiant/conduct, and anxiety/depressive disorders; validated in children 6–12 years of age, but applicable to preschoolers
ADD-H Comprehensive Teacher Rating Scale, Ullmann et al. (1984) and Carlini and Parks (1993)	Kindergarten to Grade 8	Validated Likert response scale with Attention, Hyperactivity, Social Skills, and Oppositional Behavior sections

ADHD, attention-deficit/hyperactivity disorder; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revisions; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, fifth edition; RDC-PA, Research Diagnostic Criteria-Preschool Age.

The Conners scales and AD/HD Rating Scale–5 are specific to ADHD behaviors and based on DSM ADHD criteria, whereas the Child Behavior Checklist and Preschool Age Psychiatric Assessment assess a wide range of behaviors and do not reflect criteria for ADHD alone (Conners et al. 1998a, 1998b; Egger et al. 2006a; de la Osa et al. 2016; DuPaul et al. 2016). Both DSM and non-DSM scales are valuable tools for diagnosis and symptom monitoring in preschool children. DSM-based scales are useful for identifying core symptoms of ADHD; scales based on versions preceding DSM-5 remain valid as the core symptoms of ADHD are essentially unchanged from earlier versions (Wolraich et al. 2019). Non-DSM scales are most valuable when an ADHD diagnosis may not be clear-cut. Clinicians may need to remain cautious in making a diagnosis of ADHD in preschool children, monitoring very young children for emergence of symptoms and impairments over time. Non-DSM scales might capture a broader range of symptoms, and alternative diagnoses can be explored (Wolraich et al. 2019).

Pharmacotherapy in preschool patients with ADHD

Behavioral interventions for ADHD patients and/or their caretakers include parent training, classroom management, and peer interventions (Laforett et al. 2008; Wolraich et al. 2019). The AAP treatment guidelines recommend parent- and/or teacher-administered behavior therapy for the treatment of ADHD in preschool children (Wolraich et al. 2019), and parent training demonstrated significant benefit for treating ADHD in preschool-aged patients in individual trials and in a meta-analysis of eight randomized controlled trials (Laforett et al. 2008; Mulqueen et al. 2015). There are few published reports, however, of trials examining the efficacy of medications for ADHD focused on preschool patients.

The most extensive efficacy and safety data on pharmacotherapy for ADHD in preschoolers to date are the PATS findings (Sonnack and Brenneman 2014). PATS was a randomized, double-blind, placebo-controlled trial of MPH IR for treating ADHD in children aged 3.0–5.5 years with open-label and discontinuation phases (Greenhill et al. 2006; Kollins et al. 2006). The study design included multiple phases: a 10-week parent training phase; a 1-week open-label safety lead-in; a 5-week double-blind, placebo-controlled, crossover titration phase; a 4-week double-blind, placebo-controlled, parallel-group phase; a 10-month open-label maintenance phase; and a 6-week randomized, double-blind, placebo-controlled discontinuation phase. Following the initial PATS report outlining rationale, design, and methods (Kollins et al. 2006), a series of articles reporting efficacy and safety findings for preschool patients treated with MPH IR in PATS have been published (Table 3) (Greenhill et al. 2006; Swanson et al. 2006, 2007; Abikoff et al. 2007; Ghuman et al. 2007; Hardy et al. 2007; Murray et al. 2007; Posner et al. 2007; Vitiello et al. 2007, 2015; Wigal et al. 2007, 2008a; Riddle et al. 2013).

Table 3.

Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study, Published Reports

Reference	Focus of report	Findings
Kollins et al. (2006)	Rationale, design, and methods	• Design strengths: rigorous assessment process, parent training component, consistent with practice guidelines, a blinded crossover titration and extended placebo-controlled comparison against optimally titrated doses
Greenhill et al. (2006)	Primary short-term efficacy and safety of MPH IR	• Significant linear dose/response trend
		• Significant improvement in ADHD symptoms for MPH IR vs. placebo
		• Higher rates of emotional lability compared with school-aged children
Swanson et al. (2006)	MPH IR effects on growth rates	• At baseline, stimulant-naïve, preschool-aged children with ADHD were taller and heavier than expected compared with CDC norms
Swanson et al. (2006)	MPH IR effects on growth rates	• After treatment with MPH IR, mean growth rate slowed
Wigal et al. (2006)	Safety and tolerability of MPH IR	• Preschoolers in PATS had a higher rate of discontinuation due to AEs (11%) compared with school-age children in the MTA (Greenhill et al. 2001) study (<1%)
Wigal et al. (2006)	Safety and tolerability of MPH IR	• Profile of moderate to severe AEs with MPH IR differed from that of school-aged children; most common AEs: crabby/irritable, emotional outbursts, difficulty falling asleep, repetitive behaviors and thoughts, and decreased appetite
Abikoff et al. (2007)	MPH IR effects on functional outcomes	• MPH IR improved clinician-rated global severity ratings and teacher-rated social competence compared with placebo
Abikoff et al. (2007)	MPH IR effects on functional outcomes	• Parent-rated functional outcomes did not show improvement with MPH IR
Ghuman et al. (2007)	Effects of baseline characteristics on treatment response	• Children with high comorbidity (3–4 comorbid conditions) had no improvement with MPH IR compared with a significant treatment effect in children with fewer comorbidities
Ghuman et al. (2007)	Effects of baseline characteristics on treatment response	• No other predictors were identified
Hardy et al. (2007)	Factor structure of DSM-IV ADHD symptoms in preschool-age children	• A 2-factor model of inattention and hyperactivity/impulsivity was a marginal fit for preschoolers with ADHD symptoms; no other tested model was a better fit
Hardy et al. (2007)		• DSM-IV-defined symptoms, domains, and subtypes might not adequately describe ADHD in this age group
Murray et al. (2007)	Concordance of parent-teacher ratings of ADHD symptoms	• Overall parent-teacher agreement for individual items, subscale scores, and total number of symptoms was poor
Murray et al. (2007)	Concordance of parent-teacher ratings of ADHD symptoms	• Results reflect variability in presentation of ADHD symptoms across settings
Posner et al. (2007)	Symptom presentation, clinical correlates, and comorbidity	• 70% presented with comorbid diagnoses, including ODD, communication disorders, and anxiety disorders
Posner et al. (2007)	Symptom presentation, clinical correlates, and comorbidity	• ADHD severity was significantly associated with anxiety symptoms
Swanson et al. (2007)	Genotyping success rate for candidate genes associated with ADHD diagnosis	• Genotyping success rate was higher for blood cell samples (venipuncture) compared with buccal cell samples (cheek swab)
Vitiello et al. (2007)	10-month continuation phase efficacy	• Maintenance phase treatment was associated with continued improvement (modest) in global measures of severity
Wigal et al. (2007)	MPH IR pharmacokinetics	• Slower clearance of MPH was observed in the preschool-aged children compared with MPH clearance measured in school-aged children
Wigal et al. (2008a)	Overview of initial findings	• ADHD can be reliably diagnosed in preschool children, and treatment with MPH IR is generally safe and effective in children <6 years of age
		• The rate of discontinuation due to AEs (11%) was substantially higher than reported in older children (∼2%)
		• A higher rate of AEs suggests that “emotionality” was also reported
Riddle et al. (2013)	ADHD stability in a 6-year follow-up	• 80% of preschool children enrolled in PATS continued to be diagnosed with ADHD at a mean age of 10 years
Riddle et al. (2013)	ADHD stability in a 6-year follow-up	• There was a decrease in symptom severity from baseline to study year 3; symptom severity was stable in study years 3–6
Vitiello et al. (2015)	Pharmacotherapy in naturalistic treatment of children who completed PATS	• Course of pharmacotherapy following PATS was varied: at year 6, 27% were receiving no ADHD medication and 40% were receiving stimulant monotherapy
Vitiello et al. (2015)		• 85% of children who received stimulant medication at year 3 continued receiving a stimulant at year 6

ADHD, attention-deficit/hyperactivity disorder; AE, adverse event; CDC, Centers for Disease Control and Prevention; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; IR, immediate release; MPH, methylphenidate; ODD, oppositional defiant disorder; PATS, Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study.

The primary efficacy findings showed significant improvement in ADHD symptoms observed with MPH IR compared with placebo in PATS subjects (Greenhill et al. 2006). The magnitude of effect of MPH IR treatment, however, was smaller than previously has been reported for school-aged children (Greenhill et al. 2001, 2006). A pharmacokinetic analysis comparing plasma MPH concentrations in preschool- versus school-aged children conducted at one of the six PATS study sites found a slower rate of clearance for MPH in the preschool age group, suggesting that there may be differences in MPH absorption, distribution, metabolism, or elimination in very young children with ADHD (Table 4) (Wigal et al. 2007).

Table 4.

Methylphenidate Pharmacokinetics in Preschool- and School-Aged Children with Attention-Deficit/Hyperactivity Disorder

	Preschool children	School-aged children	Difference in effect size	p
N	14	9
Age, years	5.33 ± 0.56	8.00 ± 0.56	4.77	<0.001
Weight, kg	19.2 ± 2.6	28.3 ± 5.8	2.22	<0.001
Dose, mg	5.89 ± 1.9	6.94 ± 3.3	0.42	0.33
Dose/weight, mg/kg	0.311 ± 0.09	0.252 ± 0.13	−0.54	0.20
CL/F, L/h	99.5 ± 44	232.6 ± 75	2.52	<0.001
CL/F/weight, L/(h·kg)	5.12 ± 1.9	7.91 ± 1.6	1.52	0.01
t_1/2, hours	3.82 ± 2.7	2.18 ± 0.3	−0.53	0.32
C_max, ng/mL	10.2 ± 5.0	7.6 ± 4.2	−0.55	0.22
1000 × C_max/D, 1/L	1.72 ± 0.5	1.10 ± 0.3	−1.44	0.003

Adapted with permission from Wigal et al. (2007).

C_max, maximum plasma concentration; CL/F, apparent clearance; D, dose normalized; t_1/2, half-life.

MPH IR was generally well tolerated in preschool children enrolled in PATS (Greenhill et al. 2006), but some differences in the safety and tolerability of MPH IR in preschool- versus school-aged children were reported. The rate of discontinuations due to adverse events (AEs) was higher in PATS compared with studies of MPH for ADHD in school-aged children (Greenhill et al. 2006; Wigal et al. 2006). Higher rates of emotional lability were also observed in PATS compared with studies of school-aged children. The majority of children who discontinued the titration phase due to AEs (9/15) did so due to emotionality or irritability (Greenhill et al. 2006). Based on study findings, the PATS investigators concluded that in preschool-aged children, MPH IR should be started at 2.5 mg bid (Greenhill et al. 2006), which is half the recommended starting dose for children aged 6 years or older (but not the lowest dose used in PATS [1.25 mg bid]) (Ritalin-SR package insert 2017).

Few additional studies assessing ADHD medication effectiveness in preschool children have been published since PATS was conducted (Table 5) (Kratochvil et al. 2007, 2011; Ghuman et al. 2009a, 2009b; Arabgol et al. 2015; Scahill et al. 2015; Safavi et al. 2016). Almost half of those studies (3/7) included MPH IR arms (Ghuman et al. 2009b; Arabgol et al. 2015; Safavi et al. 2016). One study assessed the efficacy of MPH IR for treating symptoms of ADHD in 14 preschool children (aged 3–5 years) with pervasive developmental disorder or intellectual disability (Ghuman et al. 2009b). In a randomized, double-blind, placebo-controlled trial, MPH IR was associated with modest, but statistically significant improvement in ADHD symptoms, as measured by Conners' Parent Rating Scale-Revised ADHD Subscale score. Treatment with risperidone was compared with MPH IR in a randomized crossover trial of children 3–6 years of age with ADHD (N = 38) (Arabgol et al. 2015). Both medications significantly reduced symptoms of ADHD over time based on Parent ADHD Rating Scale scores, but no significant differences between treatments were observed. Rates of discontinuation were similar between treatment groups. In a single-blind, flexible dose study, MPH IR was compared with combined treatment with MPH IR plus risperidone for the treatment of ADHD symptoms in children with ADHD aged 3–6 years (N = 47) (Safavi et al. 2016). Patients who received the combined treatment had similar reductions in ADHD symptoms (Conners' Parent Rating Scale scores) compared with MPH IR alone, but those who received the combined treatment had significantly lower MPH IR doses and lower rates of some common side effects of MPH, such as insomnia.

Table 5.

Recent Efficacy and Safety Studies for Attention-Deficit/Hyperactivity Disorder Medications in Preschool-Aged Children

Reference	Treatment^a	Age, years	Objective	Findings
Ghuman et al. (2009b)	MPH IR	3–5	Short-term efficacy and safety	• Modest but significant reduction in symptoms vs. placebo
Ghuman et al. (2009b)	Placebo	3–5	Short-term efficacy and safety	• Modest but significant reduction in symptoms vs. placebo
Arabgol et al. (2015)	Risperidone	3–6	Short-term efficacy and safety	• No significant treatment effect on ADHD scores
Arabgol et al. (2015)	MPH IR	3–6	Short-term efficacy and safety	• No significant treatment difference in rates of discontinuations due to AEs
Safavi et al. (2016)	MPH IR	3–6	Short-term efficacy and safety	• Significant response in both groups, no treatment difference
	MPH IR+Risperidone
	MPH IR+Risperidone			• No difference in number of AEs; insomnia, agitation, and anorexia were reported in fewer patients in the combined group
Kratochvil et al. (2007)	Atomoxetine	5–6	Open-label effectiveness and tolerability	• Significant improvement from baseline in ADHD symptoms
Kratochvil et al. (2007)	Atomoxetine	5–6	Open-label effectiveness and tolerability	• Mood lability reported in 55% of patients
Ghuman et al. (2009a)	Atomoxetine	3–5	Open-label effectiveness and tolerability, titration	• Significant improvement from baseline in ADHD symptoms
Ghuman et al. (2009a)	Atomoxetine	3–5	Open-label effectiveness and tolerability, titration	• Mood lability reported in 42% of patients
Kratochvil et al. (2011)	Atomoxetine	5–6	Short-term efficacy and tolerability	• Significant reduction in symptoms vs. placebo
	Placebo			• Significant reduction in symptoms vs. placebo
	Placebo			• No discontinuations due to AEs
Scahill et al. (2015)	Guanfacine	5–14	Short-term efficacy with 8-week extension	• Significant improvement in hyperactivity and ADHD scale scores vs. placebo
Scahill et al. (2015)	Guanfacine	5–14	Short-term efficacy with 8-week extension	• Most common AEs leading to dose reduction: drowsiness, fatigue, emotional fragility, tearfulness, irritability

Papers published since the publication of the primary paper for PATS.

Medications included in search terms were MPH, amphetamine, methamphetamine, atomoxetine, clonidine, and guanfacine.

ADHD, attention-deficit/hyperactivity disorder; AE, adverse event; IR, immediate release; MPH, methylphenidate; PATS, Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study.

The remaining identified studies assessed the selective norepinephrine reuptake inhibiter atomoxetine, alone or compared with a placebo control (Kratochvil et al. 2007, 2011; Ghuman et al. 2009a), or the alpha-2 agonist, guanfacine (Scahill et al. 2015). Atomoxetine safety and effectiveness was assessed in two short-term, open-label pilot studies of children with ADHD, aged 3–5 years and 5–6 years, respectively (Kratochvil et al. 2007; Ghuman et al. 2009a). Symptoms of ADHD improved from baseline over the course of each study, but parents reported high rates of AEs consistent with mood lability (55% and 42%, respectively). The final study demonstrated the efficacy of atomoxetine versus placebo for ADHD symptoms in preschool children (Kratochvil et al. 2011). In a double-blind, placebo-controlled trial enrolling 5- and 6-year-old children with ADHD (N = 93), atomoxetine significantly reduced parent ADHD-RS total scores versus placebo, although the authors reported that clinically significant symptoms remained in most patients. Data from these three atomoxetine studies were combined with pooled atomoxetine efficacy and safety data from children 6–7 years of age in the Eli Lilly database to conduct an extrapolation analysis comparing response to atomoxetine in the two age groups (Upadhyaya et al. 2015). Results of that analysis indicate that atomoxetine is effective in younger children, but potentially to a lesser extent and with a greater AE rate in 4- to 5-year-olds compared with 6- and 7-year-olds with a similar baseline severity of ADHD symptoms (mean [SD] ADHD-RS total score for atomoxetine-treated patients: 38.2 [5.40] and 41.4 [8.22], respectively). The efficacy of guanfacine for treating hyperactivity and symptoms of ADHD was assessed in a single trial enrolling patients 5–14 years of age with a primary diagnosis of autistic disorder, Asperger's syndrome, or pervasive developmental disorder and a minimum score of 24 on the parent-rated Aberrant Behavior Checklist hyperactivity subscale (Scahill et al. 2015). Both parent-rated Aberrant Behavior Checklist-hyperactivity subscale and the clinician-rated ADHD-RS scores improved significantly with treatment versus placebo for the overall population; however, young children were not analyzed separately.

No studies of long-acting formulations of MPH (or other stimulant medications) for the treatment of ADHD in preschool children have been published to date. However, based on clinicaltrials.gov listings, a number of phase 2, 3, or 4 clinical trials of ADHD medications in preschool children (enrolling children 3–6 years of age) are planned, ongoing, or recently completed (Table 6). Medications assessed in those trials include MPH, amphetamine, lisdexamfetamine, atomoxetine, and clonidine. Seven of the 13 preschool studies identified include an MPH treatment arm. Two randomized, double-blind trials evaluate the efficacy and safety/tolerability of MPH IR: one compares MPH with parental training and placebo and the other assesses MPH, clonidine, or MPH plus clonidine versus placebo. Notably, five trials of long-acting formulations of MPH for the treatment of ADHD in preschool children are listed on clinicaltrials.gov. Four of those are open-label studies, two assessing short-term safety and effectiveness, one assessing long-term (12-month) safety and tolerability, and one examining single-dose MPH extended release (ER) pharmacokinetics. One randomized, double-blind, placebo-controlled MPH ER study in children under 6 years of age is listed.

Table 6.

Phase 2–4 Interventional Studies Assessing Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder in Preschool-Aged Children Listed on Clinicaltrials.gov

NCT No.	Title	Ages	Design	Treatment groups	Efficacy outcome measures
NCT02807870	Early Interventions in Children With Attention Deficit/Hyperactivity Disorder	3–5 years	Randomized, double-blind, parallel-group	MPH	SNAP, CGI, CGAS
				Placebo
				Parental training
NCT00414921	Preschool Supplement to Clonidine in ADHD (Kiddie-CAT)	4–6 years	Randomized, double-blind, parallel-group	Clonidine	ASQ-T, ASQ-P, CGAS
				MPH
				Placebo
NCT00257725	Long Duration Stimulant Treatment Study of Preschoolers With ADHD-Feasibility Study	4–5 years	Open-label	MPH (Ritalin LA)	Not provided
NCT00754208	Long Acting Stimulant Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Young Children	4–5 years	Open-label	MPH (Ritalin LA)	ADHD-RS-IV-Parent: Inv, CGI-I, CGI-S, CGAS
NCT02677519	A 12-Month Open Label Safety Study of Aptensio XR in Children Ages 4–5 Years Diagnosed With ADHD	4–<6 years	Open-label	MPH (Aptensio XR)	ADHD-RS-IV-Preschool, CGI-S, ConnersEC BEH-P(S)
NCT02470234	Pharmacokinetic Study of Methylphenidate HCl Extended-Release Capsules in Children 4 to Under 6 Years of Age With ADHD	4–<6 years	Open-label	MPH ER Capsules (Aptensio XR)	Not provided
NCT02683265	A Flexible-Dose Titration Study of Aptensio XR in Children Ages 4 to Under 6 Years Diagnosed With ADHD	4–<6 years	Randomized, double-blind, crossover	MPH (Aptensio XR)	ADHD-RS-IV, CGI-I, CGI-S
NCT02683265		4–<6 years	Randomized, double-blind, crossover	Placebo	ADHD-RS-IV, CGI-I, CGI-S
NCT02402166	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of SPD489 in Preschool Children With Attention Deficit/Hyperactivity Disorder	4–5 years	Open-label	Lisdexamfetamine (Vyvanse)	ADHD-RS-IV-Preschool, CGI-I
NCT02466386	Safety and Tolerability Study of SPD489 in Preschool Children Aged 4–5 Years, Diagnosed With Attention-Deficit/Hyperactivity Disorder	4–5 years	Open-label	Lisdexamfetamine (Vyvanse)	CGI-I, ADHD-RS-IV-Preschool
NCT03260205	Safety and Efficacy Study in Preschool Children Aged 4–5 Years With Attention-Deficit/Hyperactivity Disorder (ADHD)	4–5 years	Randomized, double-blind, parallel-group	Lisdexamfetamine (Vyvanse)	ADHD-RS-IV-Preschool, CGI-I
NCT03260205		4–5 years	Randomized, double-blind, parallel-group	Placebo	ADHD-RS-IV-Preschool, CGI-I
NCT03242772	Impact of Combined Medication and Behavioral Treatment for ASD & ADHD	36–84 months	Randomized, double-blind, parallel-group	Amphetamine (Adzenys-XR-ODT)	VABS-3, PCIT, ADHD-RS-IV-Parent, ADHD-RS-IV-Clinician
				Placebo
				P-ESDM
				P-ESDM
NCT00517647	Atomoxetine Pilot Study in Preschool Children With ADHD	3–5 years	Open-label	Atomoxetine	CRS-R-HI
NCT00856063	Autonomic Correlates of Impulsivity for Preschool Children With Attention Deficit Hyperactivity Disorder (ADHD)	48–70 months	Randomized, double-blind, crossover	Atomoxetine	SNAP-IV-HI, CGAS
NCT00856063		48–70 months	Randomized, double-blind, crossover	Placebo	SNAP-IV-HI, CGAS

Unpublished studies last updated within the past 10 years.

ADHD, attention-deficit/hyperactivity disorder; ADHD-RS-IV, ADHD Rating Scale; ADHD-RS-IV-Clinician, ADHD-RS-IV Clinician Version; ADHD-RS-IV-Parent, ADHD-RS-IV Parent Version; ADHD-IV-Parent: Inv, ADHD-RS-IV Parent Version Investigator-Scored; ADHD-RS-IV-Preschool, ADHD-RS-IV Preschool Version; ASD, autism spectrum disorder; ASQ-P, Conners Abbreviated Symptom Questionnaire-Parent; ASQ-T, ASQ-Teachers; CGAS, Children's Global Assessment Scale; CGI, Clinical Global Impressions Scale; CGI-I, CGI-Improvement; CGI-S, CGI-Severity; ConnersEC BEH-P(S), Conners Early Childhood Behavior-Parent Short; CRS-R-HI, Conners Rating Scale-Revised, Hyperactive-Impulsive subscale; ER, extended release; MPH, methylphenidate; ODT, orally disintegrating tablet; P-ESDM, Parent-delivered Early Start Denver Model; PCIT, parent-child interaction task; SNAP, Swanson, Nolan and Pelham scale; SNAP-IV-HI, SNAP Hyperactive-Impulsive subscale; VABS-3, Vineland Adaptive Behavior Scale.

Several additional preschool ADHD studies, for medications other than MPH, are listed on clinicaltrials.gov. Lisdexamfetamine trials include two open-label studies (short-term efficacy, safety, and pharmacokinetics and long-term safety and tolerability) and one 6-week randomized, placebo-controlled trial. A fourth study is designed to examine whether treatment with an ER amphetamine formulation improves the efficacy of behavioral intervention (based on the Early Start Denver model) in preschool children with ADHD and autism spectrum disorder. In addition, atomoxetine was assessed in two studies enrolling children younger than 6 years of age with ADHD that are listed as complete: one open-label pilot study and a randomized, double-blind, placebo-controlled trial designed to explore biobehavioral and autonomic markers of impulsivity during treatment for ADHD.

Discussion

Differences in age-appropriate behaviors and in social and functional settings for activities for preschool- versus school-aged children complicate the diagnosis of ADHD in very young children. Some behaviors that are symptoms of ADHD in school-aged children may be developmentally appropriate in younger children, whereas some DSM criteria may not occur in preschool children simply because they do not regularly perform the kinds of tasks that ADHD disrupts in older children (Chacko et al. 2009). Nonetheless, while symptoms and subtypes may vary over its developmental course (Lahey et al. 2005; Chacko et al. 2009), the diagnosis of ADHD is relatively stable into the school years (Lahey et al. 2004; Riddle et al. 2013). Several symptom scales have been validated for children younger than 6 years of age and can be used to identify ADHD in this population (Conners et al. 1998a, 1998b; Egger et al. 2006a; de la Osa et al. 2016; DuPaul et al. 2016).

Clinical practice guidelines from the AAP stress the importance of also screening for comorbidities during the evaluation of a patient for ADHD (Wolraich et al. 2019). Comorbidities are common in children and adolescents with ADHD; reported rates of comorbidity range from 50% to more than 80% in ADHD patients, with ODD and CD, anxiety disorders, and mood disorders as the most common (Wilens et al. 2002; Ollendick et al. 2008; Jensen and Steinhausen 2015).

Psychiatric comorbidities appear to be similar for school-aged and preschool children with ADHD (Wilens et al. 2002; Egger et al. 2006b). In the PATS study population (N = 303), 70% of enrolled patients had comorbid conditions (ODD, 52%; communication disorder, 22%; anxiety disorders, 8%; specific phobias, 8%) (Greenhill et al. 2006; Posner et al. 2007). Screening for comorbid conditions is critical because symptoms may indicate an alternate diagnosis or may alter the treatment plan for ADHD, either to avoid treatments that could exacerbate a comorbid condition (e.g., stimulant medications and sleep disorders), or to select treatments that may be appropriate for patients with both ADHD and the comorbid condition (e.g., behavioral therapy for comorbid anxiety). Comorbidities have also been shown to affect treatment outcomes in school-aged children and in preschool ADHD patients (The MTA Cooperative Group 1999; Ghuman et al. 2007).

Current treatment guidelines for ADHD recommend behavioral therapy as first-line treatment for preschool children, with pharmacotherapy (e.g., MPH) recommended for preschool patients with moderate-to-severe ADHD when behavioral therapy does not yield significant improvement (Wolraich et al. 2019). However, the U.S. Centers for Disease Control and Prevention (2016) has reported that, based on 2014 insurance claims data, of children aged 2–5 years treated for ADHD, 49% were receiving only ADHD pharmacotherapy, 27% were receiving pharmacotherapy and behavioral therapy combined, and 15% received behavioral interventions alone. Complementary and alternative options for the treatment of ADHD include elimination diets, dietary supplements, and physical therapy such as massage (Ghuman et al. 2008); however, unlike medication and behavioral therapy, alternative options generally have not been systematically evaluated (Ghuman et al. 2008; Charach et al. 2011, 2013), and therefore are not evidence-based treatments either in preschoolers or in other age groups of individuals with ADHD.

Several commonly used medications for the treatment of ADHD, including MPH, do not have an indication in children younger than 6 years of age (Adderall XR, Concerta, Focalin XR, and Quillivant XR) (The ADHD Medication Guide 2019). Indeed, just three medications—amphetamine, mixed amphetamine salts, and dextroamphetamine—have an indication for the treatment of ADHD in children as young as 3 years (Table 1). Therefore, clinicians often prescribe ADHD drugs off-label for their preschool patients, despite limited evidence to inform pharmacotherapy choices in this population (Pliszka 2007; Charach et al. 2013) compared with the large volume of evidence from trials conducted in school-aged children and adolescents (Otasowie et al. 2014; Storebo et al. 2015; Punja et al. 2016). Indeed, the AAP recommends MPH as a first-line pharmacotherapy option in preschool children with moderate-to-severe dysfunction over any of the approved, medications, based on the substantial evidence for its safety and efficacy in this population (Wolraich et al. 2019).

PATS has provided the most comprehensive data on the pharmacological treatment of ADHD in preschool-aged children to date and suggests that stimulant medications may be used with caution in children aged 3.0–5.5 years (Greenhill et al. 2006). A second placebo-controlled trial of MPH IR confirmed its efficacy for treating ADHD in children 3–5 years of age, but with a modest effect size (Ghuman et al. 2009b). Several additional MPH trials enrolling preschool-aged children are planned, ongoing, or recently completed. Atomoxetine also significantly reduced symptoms of ADHD compared with placebo in a randomized, double-blind, crossover trial of 5- and 6-year-old children with ADHD, although atomoxetine-treated patients continued to show clinically significant symptoms (Kratochvil et al. 2011).

The modest effect sizes and potentially reduced tolerability of ADHD medications observed in preschool-aged patients (Ghuman et al. 2009b; Kratochvil et al. 2011) present challenges for the design of future studies in this population. Studies of ADHD medications in school-aged patients have suggested that each patient has their own therapeutic window and optimal dose (Pliszka 2007; Huss et al. 2014). Thus, the inclusion in future studies of a stepwise dose-optimization period, in which each participant's dose is started low and slowly titrated based on individual efficacy and tolerability in line with clinical practice guidelines (Wigal et al. 2018; Wolraich et al. 2019), may be useful in reducing AEs while enhancing any signal for efficacy in preschool study participants. In addition, adaptive trial designs could be useful for preschool ADHD trials. These designs are complicated and come with their own drawbacks, but adaptive approaches might help identify whether particular subgroups of preschoolers (e.g., children with or without certain comorbidities or specific ADHD subtypes) may benefit from a particular treatment or combination treatments.

The small numbers of FDA-approved treatments with an indication for children younger than 6 years of age and of placebo-controlled, efficacy and safety trials for preschool children with ADHD underscores the need for additional pharmacotherapy options for those children. Pharmacotherapy is not a first-line treatment for very young children with ADHD, and parents or guardians are often hesitant to treat their preschool children with medication (Hart et al. 2018; Wolraich et al. 2019). There are important concerns about side effects of stimulant medications, including loss of appetite, sleep difficulties, and potential cardiovascular effects, and long-term treatment safety has not been studied (Ghuman and Ghuman 2013).

The effect of stimulant medications on growth rate in children has received particular attention: in the PATS study population, growth was 20% less than expected for height and 55% less than expected for weight (Swanson et al. 2006). Analyses of growth trajectories in medicated versus nonmedicated children suggest that effects on growth slow longer-term and may reverse in older children (Murray et al. 2008; Vitiello 2008; Schwartz et al. 2014), but growth should be monitored in young children taking stimulant medications. Nonetheless, available evidence suggests that in preschool children for whom behavioral therapy does not provide adequate improvement in ADHD symptoms and functional ability, treatment with a stimulant or nonstimulant medication may be beneficial (Greenhill et al. 2006; Ghuman et al. 2009b; Kratochvil et al. 2011).

Treatment with MPH is recommended for preschool-aged children with ADHD when impairment persists despite behavioral intervention, according to both the AAP guideline and the algorithm of the Preschool Psychopharmacology Working Group (PPWG), a panel of experts in early childhood psychiatric disorders, psychopharmacology, general and behavioral pediatrics, clinical psychology, and neurodevelopmental processes established to develop best practice guidelines for the pharmacological treatment of preschoolers with psychiatric disorders. The PPWG algorithm recommends amphetamine formulations as a next treatment step; the AAP guideline, citing a lack of safety and efficacy data, recommends only against using amphetamine-based medications as an initial medication (Gleason et al. 2007; Wolraich et al. 2019). Additional pharmacotherapy options for preschool-aged patients may be available in the near future, however. The FDA has requested additional pediatric clinical trials evaluating ADHD medication efficacy and safety in children 4–5 years of age and some of those trials, including several for long-acting formulations, are underway (Table 6). Collecting new data on the efficacy and safety of ADHD medications in 4- to 5-year-old children is critical. Diagnostic criteria for ADHD are deemed appropriate for this age group, and AAP guidelines specifically address treatment options for preschool children (Wolraich et al. 2019). However, for most ADHD medications with an indication for treating older patients, the available data are not adequate to support preschool treatment recommendations (Wolraich et al. 2019). Without robust safety and efficacy data to support their use in preschool children, clinicians should be cautious using these medications.

This review of published and forthcoming preschool ADHD studies highlights areas of concern in the conduct of clinical trials in this age group. Published results suggest that the effect size for ADHD medications is modest in studies of preschool-aged children with ADHD compared with trials enrolling older children diagnosed with ADHD. However, inadequate methods for screening and assessing patients in this age group may contribute to the smaller magnitude of effect observed. Given the differences in normative behavior and presentation of ADHD in very young versus school-aged children, better assessments of preschool ADHD behavior and improvement with treatment are needed. As noted (Table 2), there are few available tools that are validated in children younger than 5 years of age, and even those tools are not used regularly (see outcomes in Table 6). Valid assessment tools in this age group are critical for high-quality clinical trials (Wigal et al. 2008b). A series of probes for use in the preschool age group were introduced earlier (Wigal et al. 2008b). They have been further developed to add structure to identify and differentiate behavioral symptoms and to assess whether symptoms improve or are exacerbated in the context of clinical research. These preschool probes and their methodology are copyrighted and considered proprietary and require proper training to administer. Table 7 provides an example of using impulsive symptom probes in preschoolers.

Table 7.

Sample Preschool Probes Distinguishing the Symptoms “Blurts Out” and “Intrudes/Interrupts”

Impulsive symptom	Disambiguation
Blurts out
Does the child speak too soon (before the question is completed or the other person has finished or before being called upon)?	Child is already in a speaking relationship so “content is on topic”
Intrudes/Interrupts
Does child “butt into” conversations? When parent is talking to other adults or on phone?	Child is not part of the conversation or activity
Or intrude into space or activities of others without an invitation?
Does the intrusiveness or interrupting lead to social difficulties (e.g., grabbing a toy so as to ignore the rights of other kids)?

Clinicians should expect changes to the treatment armamentarium for preschool-aged ADHD patients as the results of planned and on-going trials become available. Additional controlled studies, including studies of the effectiveness of combined treatment modalities (i.e., behavioral treatment alone vs. behavioral treatment combined with pharmacotherapy), such as the Multimodal Treatment Study of Children with ADHD in school-aged children, are needed for preschool-aged children. These future studies should be designed and conducted with the specific challenges of diagnosing and assessing very young children, given that both developmentally normal behavior and symptoms of ADHD differ from those in older age groups. The completion, publication, and registration of these studies in this specific age group, and the consolidation of their collected data and findings, should provide the basis for evidence-based diagnosis and treatment guidelines.

More clinical trial data need to be reported, and a consensus must be realized to drive and establish clinical practice guidelines. Until then, clinicians must consider available and emerging evidence—or the lack thereof—regarding therapeutic efficacy and safety of ADHD medications when making treatment decisions for preschool ADHD patients.

Conclusions

Although symptoms and subtypes of ADHD may differ in preschool children (aged 3–5 years) compared with children aged 6 years or older, ADHD is a neurodevelopmental condition that is recognized in children before they reach school age (American Psychiatric Association 2013). The ADHD diagnosis appears to be generally stable across preschool- to school-age development. Few studies have been conducted assessing medications for the treatment of ADHD in preschool-aged children. The lack of data describing pharmacotherapy options for preschool children with ADHD represents an unmet need for which more research is needed and welcomed. Numerous clinical trials designed to address this need are planned or underway.

Clinical Significance

The symptoms and subtypes of ADHD may differ in preschool children (aged 3–5 years) compared with children aged 6 years or older; however, the ADHD diagnosis appears to be generally stable across preschool to school-age development. The PATS remains the most extensive efficacy and safety data on MPH for ADHD in preschoolers and few additional studies assessing medications for the treatment of ADHD in preschool-aged children have been conducted to date. Clinicians should be aware that, although there is currently an unmet need for safety and tolerability data for ADHD medications in preschool-aged children, the treatment landscape may change in the near future, as a number of studies of ADHD medications, including long-acting formulations, are planned or underway in this patient population.

Acknowledgments

The opinions and assertions contained in this article are the private views of the authors and are not to be construed as official or as reflecting the views of the National Institute of Mental Health, the National Institutes of Health, or the Department of Health and Human Services.

Disclosures

S.W. receives or has received research support, acted as a consultant, been an advisory board member, and/or served on a speakers bureau for Addrenex Pharmaceuticals, Akili, Arbor, Eli Lilly and Company, Forest Pharmaceuticals, Ironshore, McNeil Consumer & Specialty Pharmaceuticals, Neos, Neurovance, NextWave Pharmaceuticals, NIMH, NLS, Noven, NuTec Pharma, Otsuka, Pfizer, Purdue, Quintiles, Rho, Rhodes Pharmaceuticals, Shionogi, Shire US, Sunovion, Taisho Pharmaceutical, and Tris Pharma. P.C., D.P., S.L., S.R., and R.A. are employees of Pfizer, Inc. P.C., S.L., and S.R. holds Pfizer stock and stock options.

Footnotes

Acknowledgements

Appendix A1.

Diagnosis of ADHD in Preschool- vs. School-Aged Children: Developmental Aspects in the DSM-5 Diagnostic Criteria (American Psychiatric Association 2013)

The DSM-5 diagnostic criteria for ADHD are not provided for preschool vs school-aged children even though differences between age groups are described or referenced and the diagnostic criteria include language that is specific to developmental context.

The DSM-5 specifies that symptoms should be assessed relative to developmentally appropriate behaviors. Headers for ‘inattention’ and ‘hyperactivity and impulsivity’ symptom lists including that language are shown here (symptoms not listed), with emphasis added:

1. Inattention : Six (or more) of the following symptoms have persisted for at least 6 months to a degree that is inconsistent with developmental level and that negatively impacts directly on social and academic/occupational activities (DSM-5, p59)

2. Hyperactivity and impulsivity: Six (or more) of the following symptoms have persisted for at least 6 months to a degree that is inconsistent with developmental level and that negatively impacts directly on social and academic/occupational activities (DSM-5, p60)

The impact of symptoms on activities in different settings must be considered for the ADHD diagnosis. The range of settings in which children less than 6 years of age participate is likely to be reduced compared with school-aged children. However, that age difference is not reflected in DSM-5 language, as shown below:

C. Several inattentive or hyperactive-impulsive symptoms are present in two or more settings (e.g., at home, school, or work; with friends or relatives; in other activities) (DSM-5, p60)

The DSM-5 does provide a discussion of the developmental course and manifestation of ADHD:

Many parents first observe excessive motor activity when the child is a toddler, but symptoms are difficult to distinguish from highly variable normative behaviors before age 4 years. ADHD is most often identified during elementary school years, and inattention becomes more prominent and impaired. (DSM-5, p62)

In preschool, the main manifestation is hyperactivity. Inattention becomes more prominent during elementary school (DSM-5, p62)

ADHD, attention-deficit/hyperactivity disorder; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, fifth edition.

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