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Journal of Developmental & Behavioral Pediatrics:
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Preschool Attention Deficit Hyperactivity Disorder: A Review of Prevalence, Diagnosis, Neurobiology, and Stimulant Treatment

CONNOR, DANIEL F. M.D.

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Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts

Address for reprints: Daniel F. Connor, M.D., Department of Psychiatry-7th Floor, Room S7-828, University of Massachusetts Medical School, 55 Lake Avenue, North, Worcester, MA 01655; e-mail: connod01@ummhc.org; fax: 508-856-6426.

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Abstract

ABSTRACT. The clinical use of stimulant medications for 3- to 6-year-old preschool children who meet diagnostic criteria for attention deficit hyperactivity disorder (ADHD) is becoming more common. A systematic computerized literature search extending back to 1970 identified nine controlled studies of stimulant treatment and two controlled trials of stimulant side effects in preschool ADHD children. Treatment benefits are reported for eight of nine (89%) controlled stimulant trials involving a total of 206 preschool subjects. In comparison with school-aged ADHD youth, there may be a greater variability of stimulant response in ADHD preschoolers. Domains assessing cognition, interpersonal interactions, and hyperactive-impulsive behavior are noted to improve on drugs relative to placebos. Side effects in this age range are generally reported as mild. ADHD preschool children may experience slightly more and different types of stimulant-induced side effects compared with older children. High rates of behavior reported as stimulant side effects are found for children receiving a placebo, necessitating a baseline evaluation for medication side effects before stimulants are initiated. Despite the lack of research assessing stimulant effects on the very young and developing brain and the need for more controlled medication trials in this age range, this review of the extant literature finds stimulants to meet evidence based criteria as beneficial and safe for carefully diagnosed ADHD preschool children aged 3 years and older.

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric diagnosis for children presenting with significant problems in the central nervous system (CNS) regulation of attention span, impulsiveness, and motor overactivity. Children with ADHD represent a heterogeneous population and display great variation in the degree of their symptoms and in the situational pervasiveness of their ADHD. 1 Because the DSM-IV 2 requires an early age of onset for a diagnosis, children in the preschool-age range may come to clinical attention for accurate diagnosis and treatment. Indeed, prospective research has identified the peak age of onset of ADHD as occurring between 3 and 4 years of age. 3 In a study assessing 300 consecutive ADHD children referred to a child psychiatric clinic for evaluation, mothers report 202 subjects (67%) as having the onset of ADHD symptoms at age 4 years or younger (Daniel Connor, unpublished data, 2002).

Much less is known about ADHD in 2- to 5-year-old preschool children than is known for older school-aged youngsters. 1,4 Despite this lack of knowledge, ADHD is increasingly recognized in this population and stimulant medication is increasingly being prescribed to treat it. For example, pharmacoepidemiological studies have documented a rise in overall psychoactive medication treatment for preschool children in the last decade, with a three-fold rise in prescription rates specifically for stimulants in this age group since 1990. Methylphenidate (MPH) use accounts for over 90% of stimulant use in the preschool-age range. 5 Pediatric researchers have noted that 57% of 223 Michigan Medicaid enrollees aged younger than 4 years with a diagnosis of ADHD received at least one psychotropic medication treatment for this condition over a 15-month period in 1995 to 1996. Stimulants were one of two drug classes prescribed most often to these preschoolers. 5

The purpose of this article is to (1) review prevalence rates, diagnostic issues, treatment issues, and recent findings from developmental neurobiology relevant to preschool ADHD, and (2) review methodologically controlled studies completed since 1970 assessing the efficacy and side effects of stimulant medication for the symptoms of ADHD in preschool children 2 to 6 years of age. Computerized database searches using PubMed and MedLine were completed using the search words ADHD and stimulants with limits applied to the preschool-age range, humans, and English journals. Searches extended back to 1970. Relevant bibliographies were also searched. This search identified nine controlled stimulant drug trials for ADHD and two controlled trials of stimulant side effects in the relevant age range.

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PREVALENCE OF ATTENTION DEFICIT HYPERACTIVITY DISORDER IN THE PRESCHOOL YEARS

Many more studies investigating the prevalence of attention deficit hyperactivity disorder (ADHD) have been completed in the 6- to 12-year-old age range than reports focusing on prevalence in the 2- to 5-year-old age range. Prevalence has been estimated using both rating scale methodologies (checklists) completed by parents and teachers and also using DSM-IV 2 diagnostic criteria. Checklist studies do not rate the prevalence of ADHD using diagnostic criteria. Instead, rating scales only establish a level of statistical deviance from the normative population. In addition to symptoms, ADHD diagnostic criteria require an early age of onset (less than 7 yr); pervasiveness across home, school, and community settings (two of three settings); impairment in daily functioning; and the exclusion of other medical and psychiatric disorders that may mimic the symptoms of ADHD. Thus, population prevalence rates established by checklist criteria are often far higher than prevalence rates reported for more stringent diagnostic criteria. Prevalence rates for ADHD are also higher in mental health clinic-referred samples than in primary care, community, or population-based samples.

Studies of the prevalence of ADHD in the preschool-age range are only just beginning. Using checklist criteria, a community study of 181 4- to 5-year-old children in Columbia, South America, identified 33 youngsters (18.2%) as having problematic ADHD symptoms. 6 Preschool ADHD prevalence rates of 5.2% in India and 9.6% in Germany were identified by the use of diagnostic criteria. 7,8 In a community sample of 104 low-income preschoolers from the United States, five children (5.7%) were identified as meeting diagnostic criteria for ADHD. 9 In a psychiatric clinic-referred sample of 79 2- to 5-year-old children, 47 preschoolers (59.5%) met diagnostic criteria for ADHD. 10 Finally, a study of the prevalence rate of preschool ADHD involving 510 youngsters from a primary care pediatric sample ascertained in the Chicago metropolitan area identified 2% as meeting diagnostic criteria for ADHD. 11 A low rate of preschool ADHD identified in primary care pediatric samples may be because of pediatrician underidentification of ADHD or less severe (subthreshold) cases presenting to primary care pediatrics in contrast with child mental health settings. 11,12

These studies demonstrate that 2- to 5-year-old children in community samples, psychiatrically referred samples, and primary care pediatric samples can be identified as meeting the diagnostic criteria for ADHD. Preschool ADHD prevalence rates vary by sample ascertainment, from a low of 2% in a primary care office practice to a high of 59% in a child psychiatric clinic.

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CHALLENGES IN THE DIAGNOSIS OF ATTENTION DEFICIT HYPERACTIVITY DISORDER IN THE PRESCHOOL YEARS

The clinical diagnosis of attention deficit hyperactivity disorder (ADHD) in preschool children is challenging. The first problem in diagnosis is the nonspecificity of ADHD symptoms in the 2- to 5-year-old age range. The essential symptoms of ADHD—inattention, impulsivity, and overactivity—are common daily behaviors of most preschool-aged children. Indeed, studies have shown that up to 40% of children by the age of 4 years have sufficient problems with inattention to be of concern to their parents and preschool teachers. 3 Yet studies also show that the vast majority of these concerns are transient in nature and generally remit within 3 to 6 months. 1,13 Even among those children whose symptoms are frequent and severe enough to warrant a diagnosis of ADHD in the preschool years, only 48% will have this same diagnosis by later childhood or adolescence. 1 These findings suggest that the appearance of significantly inattentive or overactive behaviors by age 3 to 4 years, by themselves, are not indicative of a persistent pattern of ADHD into later childhood or adolescence in at least 50% of those preschool children so characterized. 1 A changing pattern of ADHD symptoms with development, with hyperactivity, impulsivity, and aggression emerging early in the preschool years and attention deficits emerging later in the school-aged years, may account for some of these differences. 1 Approximately 5% to 10% of preschoolers with parental or teacher concerns about inattention eventually develop a pattern of persistent inattention consistent with ADHD by the second grade. 3

ADHD has no biological marker that can aid in diagnostic assessment. Clinical criteria are used to make a diagnosis. In assessing preschool youngsters who present with significant attentional or behavioral difficulties, the clinical task is to distinguish between the 5% to 10% who will develop persistent ADHD and the 90% to 95% who have developmentally appropriate and transient symptoms or ADHD-like symptoms from other causes. Severity of symptoms is important. Children who develop an early pattern of hyperactive, impulsive, and/or inattentive symptoms that are clearly greater than that expected for age or developmental level are at risk. Persistent ADHD symptoms that go beyond a transient adjustment to stress or environmental change is another useful criterion. Symptoms that are evident outside of the home and are also present in the community or at school are important. That the child displays ADHD behaviors with different people other than the child’s parents is relevant. Symptoms that are severe enough to cause the child impairment in social, academic, and/or family domains are clinically significant. 1,4 Thus, the degree of ADHD symptoms, their pervasiveness across settings, and their duration determine which children with early-onset difficulties are likely to show a chronic course of their ADHD symptoms throughout development. 1

Other problems in accurate diagnosis include clinician underrecognition or overdiagnosis of ADHD. Many other psychiatric diagnoses in addition to ADHD present clinically with attentional or concentration problems and motor restlessness or agitation, including depression, bipolar disorder, anxiety disorders, learning disabilities, family stressors such as aggression, violence, or parental psychopathology in the home, parent-child problems, and opposition defiance disorder (ODD), which is highly prevalent in the preschool population. 14,15 To assign a diagnosis of ADHD when one of these other problems is clinically most important may be to overdiagnose ADHD. To not recognize ADHD in the context of these other problems may result in underdiagnosis and undertreatment of ADHD. In addition, many children with ADHD have one or more other psychiatric disorders that may contribute to dysfunction and require clinical identification and assessment. 15 Recognizing comorbid conditions that occur along with ADHD is important for psychoeducational treatment planning. Distinguishing the clinical symptoms of ADHD from the symptoms of other psychiatric disorders or recognizing psychiatric comorbidity in the preschool child is difficult and may require referral to a child psychiatrist, child psychologist, or developmental pediatrician.

Another problem is the lack of appropriate psychometric measures to determine developmentally inappropriate levels of defiance, motor overactivity, impulsivity, and inattention in the preschool child. Although there currently are a vast number of reliable and valid rating scales and psychological tests of inattention and impulsivity, these are mostly validated for school-aged children. 1 The absence of developmentally appropriate assessment protocols has contributed to an understandable reluctance to diagnose ADHD in preschoolers and to recommend a full-treatment regimen for those diagnosed, which may include pharmacological treatment. 16

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NEUROBIOLOGY OF ATTENTION DEFICIT HYPERACTIVITY DISORDER

Despite the absence of a biological gold standard as a marker of illness, it is increasingly clear that the etiology of attention deficit hyperactivity disorder (ADHD) is firmly grounded in neurobiological changes in the central nervous system (CNS). The increasing sophistication of modern research tools for genetics, molecular biology, molecular neuropharmacology, and CNS neuroimaging have significantly advanced understanding of the neurobiology of ADHD. Because ADHD is a heterogeneous condition, it most likely has multiple psychosocial and biological causes, and a single neurobiological etiology will probably not be identified. Indeed, the extant neurobiological and neuropharmacological data do not yet clarify causal issues as to whether the behavioral, emotional, and cognitive dysregulation in ADHD is primary or secondary to experiential effects. However, the present research data base clearly identifies ADHD as a neurobiological disorder.

Research supporting the neurobiological basis for ADHD rests on data from neuropharmacological studies, family-genetic studies, molecular genetics studies, and CNS neuroimaging studies. The neuropharmacological data support a central dopamine/norepinephrine dysregulation hypothesis of ADHD. 17 One model to explain the effects of dopamine/noradrenergic medications in ADHD proposes dysregulation in the inhibitory influences of prefrontal cortical activity, predominantly noradrenergic, on subcortical CNS structures that are predominately under dopaminergic control. 18 Medications that have CNS dopamine and/or noradrenergic actions such as stimulants, 19 guanfacine, 20 clonidine, 21 bupropion, 22 and tomoxetine 23 are effective in ADHD. The net result is enhanced CNS dopamine and noradrenergic neurotransmission, which appears to be correlated with clinical treatment effects in ADHD.

For over a decade it has been well known that rigorously diagnosed ADHD appears to be highly heritable. High heritability rates have been shown in both family, adoption, and twin studies of ADHD. 14,24,25 Heritability rates from twin studies range from 0.60 to 0.95. 26–28 These numbers mean that approximately 60% to 95% of the variance in ADHD phenotype can be attributed to genetic rather than environmental factors. However, heritability rates for ADHD are always estimated at less than 1.0. This means that the disorder cannot entirely be explained by genetic factors. Environmental factors and/or gene-environmental interactions are important in the etiology of ADHD. These interactions yield substantial variability in the ADHD phenotype across populations and between individuals. ADHD thus exists on a spectrum of severity largely determined by the interaction of genetic and environmental factors.

High heritability rates have fueled research investigating specific candidate genes in the etiology of ADHD. Research has focused on the presynaptic dopamine transporter protein (DAT1) and the post-synaptic dopamine D4 receptor (DRD4) because it is well known that these are sites of stimulant pharmacological action. A statistical association is found for polymorphisms in both the DAT1 and DRD4 candidate genes and the clinical expression of ADHD. 29–32 These two genes are both intimately involved in CNS dopamine neurotransmission and are highly present in brain regions where neuroimaging studies have suggested abnormalities in brain structure or functioning among children or adults with ADHD. 33

Using structural and functional magnetic resonance imaging (MRI), a number of studies have examined the prefrontal cortex, basal ganglia, and the cerebellum in children with ADHD. Across anatomic neuroimaging studies, results indicate that in ADHD there is a loss of the normal brain asymmetry as well as small brain volumes of specific structures. 33 The prefrontal cortex, basal ganglia, and cerebellar vermis in children with ADHD are found to be 5% to 10% smaller than in control children. 34 Functional MRI has shown lower blood flow in the striatum, anterior cingulate, and prefrontal cortex in ADHD children and adults compared with controls. 33 Inasmuch as these CNS structures are also rich in dopamine receptors, these findings support the hypothesis that an underlying dopamine system deficit occurs in children with ADHD. Research on noradrenergic CNS mechanisms in ADHD is not so well advanced. Because a great amount of individual brain variation occurs both in normal controls and in subjects with ADHD, these imaging techniques are not useful for diagnostic purposes. At present, they remain tools for research.

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STIMULANT THERAPY AND ISSUES IN CENTRAL NERVOUS SYSTEM DEVELOPMENT

The subject of brain development is important for any discussion of treatment of attention deficit hyperactivity disorder (ADHD) preschool children with sympathomimetic medications. Central nervous system (CNS) development raises the issue of why age may be important to the timing of treating ADHD preschool children with stimulant medication.

The CNS structures believed to be important in the regulation of attention span and motor activity include the prefrontal cortex, thalamus, basal ganglia, and cerebellum. 33,35 The relevant neurotransmitter systems include dopamine and norepinephrine. 17,35 From an embryological perspective, the primary events that establish brain morphology occur by the first 20 weeks of intrauterine life. 36 During this time the locus ceruleus (norepinephrine) and the basal ganglia (dopamine) form. During the first and second trimester of gestation, five broad steps involving brain formation are completed. Induction is the differentiation of the neuroectoderm from the ectoderm. Neurulation is the rolling up of the induced neural plate into the neural tube. Cell migration results in the segmentation of the brain early in ontogeny. Finally, cell proliferation and programmed cell death (apoptosis) all cause the neural tube to achieve its final gyrated form. 37 The structures and neurotransmitter systems relevant to ADHD are all formed by the end of the second trimester. 38

Postnatally, the dopamine and noradrenergic systems undergo further modification. There is a period of exuberant synaptic growth in which more synapses are formed than are necessary. A period of preprogrammed synaptic pruning then occurs that causes neurotransmitters to gradually decline to adult levels. 36 In the macaque, neurotransmitter levels peak between 2 and 4 months of age (prepuberty) and then gradually decline to adult levels in motor, sensory, and association cortex. 39 In addition, CNS myelination is not complete at birth. For example, myelination of the parietal cortex and deep white matter of the prefrontal cortex occurs by postnatal month 8, myelination of the temporal lobe at month 12, and myelination of the corpus callosum only by mid-adolescence in the human. 36,40

That these CNS systems, important in the brain regulation of attention and impulse control, continue to evolve into postnatal life should give rise to caution in the prescribing of stimulant medications to the very young preschooler with ADHD. It remains unclear whether sympathomimetic manipulation of immature monoamine systems as they are still evolving may alter dopamine or adrenergic neurotransmission in a “use-dependent” fashion either by receptor up-regulation or down-regulation. As such, clinical caution in medicating the very young (<3 yr of age) ADHD child is indicated until more is known about the developmental psychopharmacology of stimulants.

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STIMULANT TREATMENT FOR PRESCHOOL ATTENTION DEFICIT HYPERACTIVIY DISORDER

The efficacy of stimulants for attention deficit hyperactivity disorder (ADHD) has been exhaustively studied and represents the most thoroughly researched medication treatment in all of child psychiatry. However, the vast majority of well-controlled studies of stimulant efficacy in ADHD have been completed in school-aged children 6 to 12 years old. Far less stimulant research for ADHD has been conducted in the preschool- or adolescent-age ranges.

Over 200 controlled trials of stimulants in school-aged children have been completed. Only nine controlled stimulant trials in the preschool-age range and only eight controlled stimulant studies in the adolescent-age range have been reported to date. 19 Overall, the extant literature for stimulant treatment of ADHD in 6- to 12-year-old children demonstrates a consistent 70% to 96% response rate. 1,19,41–44 The placebo response rate is approximately 11% for this condition. 43 Approximately 23% to 30% of school-aged youngsters with ADHD do not respond to the first stimulant prescribed, although a higher percentage respond when another stimulant is tried in those who fail to respond to the first medication. 19

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Indications for Stimulant Treatment of the Attention Deficit Hyperactivity Disorder Preschooler

Parent-management behavioral methods using a compliance training model meet criteria for evidenced-based treatment for child ADHD, disruptive behavior, noncompliance, and opposition-defiance behavior in the preschool years. 1,45,46 Outcome measures of parent-mediated behavioral treatment of preschoolers with problematic externalizing behaviors have included parental report, preschool teacher report, and objective observations. Significant gains have been demonstrated in domains assessing preschool-child noncompliance, child hyperactivity, and parent-child interactional difficulties, and increases are seen in positive parent-child interactions. 1,46 Behavior management strategies have also been shown effective in the preschool classroom. 1 However, not all studies have found that classroom behavioral management is effective for preschool children with disruptive behaviors compared with controls. 47 Treatment effects of parent-management training on preschool noncompliant and oppositional behavior are robust and inversely correlated with the age of the child. 1 Indeed, stimulants are not a necessary component of effective treatment for many children with preschool ADHD, and behavioral management strategies are always indicated at home and preschool as a first line of treatment in this age group. 48

However, there are also problems with parent-management training techniques. Results often fail to generalize outside of the clinic to home or to the preschool environment. 45,46 Generalization to nontargeted preschool child behaviors sometimes does not occur, limiting overall treatment effects for the identified child. 1 Because ADHD may be highly familial and associated with other psychopathology in first-degree relatives, parents may be too disorganized or impaired to engage in behavioral treatment plans. Finally, the preschool ADHD child may have severe enough symptoms that parent-management training is ineffective. For these reasons, psychopharmacological treatment of the preschool child with severe ADHD may be clinically indicated.

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Review of Stimulant Studies for Attention Deficit Hyperactivity Disorder in Preschoolers

Since 1975, nine double-blind placebo-controlled studies have assessed the efficacy of stimulants for ADHD in preschool children 1.8 to 6 years of age. These studies are outlined in Table 1.

Table 1
Table 1
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All studies assess ADHD children on methylphenidate (MPH). Seven studies (78%) have a random assignment of subjects to group. These nine studies assess 206 preschool ADHD children receiving stimulant therapy. No other type of stimulant (e.g., Adderall™, Concerta™, dextroamphetamine, or pemoline) has been assessed under controlled conditions in the preschool-age range. Duration of treatment averages 4.5 ± 2.5 weeks (range 3–20 wk). The daily MPH dose ranges between 2.5 to 30 mg per day, generally given in two divided doses. Weight-adjusted daily doses range between 0.15 to 1.0 mg/kg/day, which is slightly less than daily dose ranges used for school-aged children.

Studies have assessed ADHD outcome using parental reports, nursery school personnel reports, and caregiver reports. Only one controlled study has assessed outcome using laboratory psychological tests in this age group. 16 The two neuropsychological domains assessed in MPH drug studies of preschool ADHD children include cognition and attention span. Behavioral domains assessed include interpersonal interactions and hyperactivity/impulsivity. Eight of nine controlled studies (89%) report overall efficacy of MPH on symptoms of ADHD in preschool children. 16,50–56 Three studies report improvement across all domains, including cognitive, interpersonal, and behavioral functioning. 16,51,55 Improvement is reported in two studies specifically assessing behavioral domains, 50,54 and in two studies investigating interpersonal interactions in ADHD preschoolers. 52,53

Stimulants are increasingly used for ADHD symptoms in developmentally delayed preschool children. 57 One study investigated ADHD response to MPH in preschoolers with developmental delay (average IQ = 60.0 ± 11.6). 56 Based on a minimum 40% decrease in rating scale scores assessing ADHD symptoms between placebo and an on-drug condition, eight of 11 developmentally delayed children responded. Side effects, including social withdrawal, irritability, and crying, were found in 45% of the preschoolers at higher doses (0.6 mg/kg/d), prompting the authors to support lower doses of MPH (0.3 mg/kg/d) as appropriate in developmentally delayed young ADHD children (Table 1). 56

Studies reporting outcome variability by MPH dose have generally concluded that preschool ADHD children require 0.3 to 0.5 mg/kg/dose given twice daily to achieve superiority over placebo. Only one study investigating ADHD preschoolers in a simulated classroom reported significant treatment effects at a low dose of 0.15 mg/kg/dose compared with placebo. 51 In contrast, other studies using more ecologically valid parent- and teacher-rating scales report no treatment effects for preschool ADHD children at low doses of 0.15 mg/kg/dose given twice daily. 53 Studies generally suggest linear MPH treatment effects with higher doses achieving more efficacy (but also more side effects) in this age range. The relationship between dose and side effects may especially be true for developmentally delayed ADHD preschoolers. 56

Not all studies of MPH report benefits for ADHD children in the 3- to 6-year-old age range. One methodologically controlled study found mixed findings with many reported side effects using MPH in preschool ADHD children. 49 An open study with random assignment to either MPH, cognitive behavioral therapy, or no treatment was unable to document treatment benefits of either MPH or behavioral therapy relative to no treatment for 24 ADHD preschool children. 58 Another controlled study, although reporting positive effects of drugs on ADHD symptoms in preschoolers, noted a large variability in individual responses in this age range. 50

Although not all studies are in agreement, these methodologically controlled studies largely suggest that MPH in the preschool-age range is beneficial in the treatment of ADHD symptoms. There is a great need for, as well as an increasing focus on, evidence-based treatments in pediatric psychopharmacology. 59,60 Characteristics of studies that define evidence-based treatment include randomized controlled trials, well-described and replicable treatments, tests with clinical samples, tests of clinical significance, and broad-based outcome assessments based on real-world functioning. 59–61 Stimulant medication treatment in preschool children with ADHD largely meets criteria for being defined as evidence-based treatment.

However, there are serious limitations in the research literature that need to be noted. The first limitation is the insufficient number of methodologically controlled studies (nine) and the small sample sizes of extant studies assessing stimulant efficacy for ADHD in the preschool years. Of the 5768 children, adolescents, and adults studied under controlled conditions in stimulant drug trials for ADHD, 44 only 206 subjects are in the preschool-age range. Before firm conclusions about the safety and efficacy of stimulants for preschool ADHD children can be made, much more controlled research is necessary.

Next, the short duration of MPH drug trials in the preschool years is noted. The average length of MPH therapy in these studies is only slightly longer than 4 weeks. Given the fact that ADHD is a generally chronic neuropsychiatric condition that may last many years for an individual child, and that preschool ADHD children may be treated with stimulants for many years, studies assessing long-term stimulant treatment safety and efficacy are needed when stimulant therapy for ADHD is initiated early in development.

Finally, given the rapid advances in ADHD pharmacological treatment with the introduction of many new stimulant preparations expected in the next several years, stimulant drug trials in the preschool-age range should be expanded to assess drugs other than MPH. It is interesting to note that the Food and Drug Administration (FDA) approves product labeling for amphetamine preparations for ADHD down to age 3 years and for MPH only down to age 6 years. Earlier drug studies (before 1970) often used different diagnostic labels including minimal brain dysfunction or hyperkinesis. These studies often used amphetamine and some did study preschoolers. 62 This led to early FDA approval for amphetamine in ADHD, including in the preschool-age range. However, all of the more recent ADHD drug studies in preschoolers have been conducted with MPH and not with amphetamine.

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STIMULANT SIDE EFFECTS IN THE PRESCHOOL CHILD WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER

As the diagnosis of attention deficit hyperactivity disorder (ADHD) and the use of stimulant medication become more prevalent in the preschool years, concern has been voiced about the possible side effects of treating very young children with these medications. Based on studies completed in the 1970s showing many side effects in ADHD preschoolers treated with methylphenidate (MPH), the general clinical opinion has been that very young ADHD children experience more frequent and possibly more severe side effects of stimulant medications than older ADHD elementary-school children. 49,50 However, earlier studies did not systematically evaluate ADHD children for stimulant side effects and many of these early reports did not mention side effects at all. 63

More recently, investigators have begun to systematically evaluate side effects of stimulant drug treatment in ADHD youth in rigorous methodologically controlled designs. Two such studies are presently available. Interestingly, these two studies completed by independent investigators 8 years apart at different institutions used the same side-effects rating scales, MPH dosing, and methodological design. 63,64 One study assessed MPH side effects on a reliable and valid 17-item rating scale in school-aged children 5 to 13 years old (mean age 8.2 ± 2.2 yr). 63 The other study investigated MPH on the same 17-item rating scale in preschool children 4 to 6 years of age (mean age 4.1 ± 0.5 yr) using the same methodology. 64 Doses of MPH used in both studies were placebo, 0.3 mg/kg/dose and 0.5 mg/kg/dose given twice daily. Both studies used a blinded, placebo-controlled crossover design in which children were randomized to each drug condition for 7 to 10 days before crossing over into the next drug condition (drug efficacy is not reported in these studies). The similarity of methodological design in these two investigations allows for direct comparison of MPH side effects in the younger ADHD preschool-age range and the older ADHD elementary school-age range.

Firestone et al 64 assessed MPH side effects in 32 preschool children (27 boys and 5 girls) in a randomized, double-blind, placebo-controlled crossover design using the MPH dose schedule noted above (Fig. 1, top). Parents rated 17 MPH side effects on a 0 to 9 Likert-type scale where 0 indicates the absence of the side effect and 9 indicates great severity and/or frequency of the side effect. Ratings greater than 7 are considered severe side effects on this scale. This scale has been validated by Barkley and colleagues. 63

Figure 1
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Results in preschool ADHD children with a mean age of 4.1 years showed that many behaviors reported as medication side effects occurred when children were receiving placebo. Indeed, 97% of these 4- to 6-year-old ADHD preschoolers exhibited behaviors described as medication side effects while receiving placebo. Side effects reported on placebo were equivalent to side effects reported on the 0.3 mg/kg/dose of MPH given twice daily. Side effects were only statistically different from placebo at the higher 0.5 mg/kg/dose of MPH b.i.d. Irritability, anxiety, and insomnia, which were reported as MPH side effects, actually improved on the drug relative to the placebo. Most parent-reported MPH side effects were rated as mild and less than 10% were considered severe, with approximately as many reports of severe effects on placebo as on low and high MPH doses. 64 This study reported a high rate of behaviors described as medication side effects in these ADHD preschoolers while receiving placebo. Six statistically significant side effects all demonstrate linear effects with increasing MPH dose in the preschool-age range (Fig. 1, top). 64

Barkley et al 63 assessed MPH side effects in 83 elementary school-aged children (71 boys and 12 girls) in a randomized, triple-blind, placebo-controlled crossover design using the MPH dose schedule noted above (Fig. 1, bottom). Results in school-aged children with a mean age of 8.2 years showed that 72% exhibited behaviors described as medication side effects while receiving placebo. In the older age range no drug side effects were reported significantly better on the drug relative to the placebo. Side effects were different in the older children compared with preschoolers with the exception of appetite suppression noted in both age groups. Figure 1 (bottom) illustrates the four side effects significantly different from placebo in school-aged children.

Only appetite suppression and insomnia demonstrate linear effects with MPH in this older age range. Less than 50% of school-aged subjects experienced MPH side effects, generally reported by parents as mild. Only three children (3.6%) had severe side effects necessitating MPH discontinuation. 63

A comparison of these two studies (Fig. 1, top and bottom) reveals several points about MPH side effects. First, many of the behavioral side effects attributable to MPH are found in ADHD children receiving placebo. This may especially be true of younger preschool ADHD children. Second, MPH side effects in preschool- and school-aged children are generally described as mild. Third, this comparison of two studies suggests the possibility that MPH side effects reported as severe by parents may be slightly increased in preschool ADHD children as compared with older ADHD children (i.e., <10 vs 3.6%). Fourth, behaviors reported as side effects may actually improve on drug treatment (e.g., insomnia, anxiety, and irritability in ADHD preschoolers). Finally, with the exception of appetite suppression, side effects reported as significant in younger ADHD children are not the same as side effects reported as significant for older school-aged ADHD children. This suggests the possibility that the type, frequency, and/or severity of MPH induced side effects may change with age and development. For example, insomnia appears to be a MPH side effect when assessed in school-aged children and demonstrates a linear relationship to MPH dose. However, in the younger preschool ADHD child, insomnia actually improves on the drug relative to the placebo.

Before firm conclusions can be drawn, much more research needs to accrue comparing safety and efficacy of stimulants across development. Clinically, these studies demonstrate the need to assess side effects before stimulant treatment begins at baseline to obtain a clearer picture of what is truly a medication-induced side effect in treated patients.

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CONCLUSIONS AND UNRESOLVED QUESTIONS

This review of stimulant use for the treatment of attention deficit hyperactivity disorder (ADHD) in the preschool-age range suggests that preschool children with ADHD can be reliably identified in community, primary care, and psychiatric clinic settings. Indeed, the average age of onset of the diagnosis in clinical settings generally occurs at the age of 4 years or younger. Although behavioral therapy in the form of individual or group parent-management training remains the most common treatment to date, this review suggests that stimulant therapy should not be withheld from the carefully diagnosed ADHD preschool child aged 3 years or older who has not responded to behavioral therapy, has a family that is too dysfunctional for a trial of behavioral therapy, and/or has great severity of ADHD symptoms that endanger the child or cause serious developmental derailment.

Unresolved questions involve the long-term safety of stimulant medications, particularly in light of earlier ages of initiation in the preschool years and longer duration of treatment over the developing years. Although research studies have not found stimulant-related problems in very young ADHD preschoolers, the possibility of adverse effects on the developing brain needs much further investigation. Current methodologically controlled studies demonstrate that stimulant therapy for ADHD in preschool children meets criteria for evidence-based treatment. In conclusion, this review of the extant literature supports the cautious use of stimulants for ADHD in the preschool years in carefully diagnosed children ages 3 years and older. Preschoolers meeting diagnostic criteria for ADHD less than 3 years of age should not presently be considered for stimulant therapy because of a paucity of research on safety and efficacy in the very young.

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Index terms: stimulants; preschoolers; attention deficit hyperactivity disorder; developmental neurobiology

© 2002 Lippincott Williams & Wilkins, Inc.

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