Special Considerations in Diagnosing and Treating ADHD

Part 1: Preschool-Age Children

Sharon Wigal, PhD
Clinical Professor of Pediatrics, University of California, Irvine

Timothy Wigal, PhD
Associate Clinical Professor of Pediatrics, University of California, Irvine

This is the first in a 3-part Psychiatry Weekly CME series on special considerations in diagnosing and treating ADHD. Parts 2 and 3 in this CME series will focus on the adolescent and adult populations respectively.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)^TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices.

This activity has been peer reviewed and approved by Eric Hollander, MD, Professor of Psychiatry and Chair at Mount Sinai School of Medicine. Review Date: March 28, 2007.

Statement of Need

An estimated 6%–9% of children are affected by attention-deficit/hyperactivity disorder (ADHD). The diagnosis of ADHD involves clinical evaluation of inattentive, impulsive, and hyperactive symptoms. Diagnosis of preschool age children presents a number of unique difficulties hinging around distinguishing symptoms from natural childhood exuberance and inattention.

Treatment in this patient population has not been well-researched. Amphetamines are the only agents approved by the FDA for the treatment of ADHD in children between the ages of 3 and 6 years at this time, but off-label methylphenidate is the most commonly prescribed psychotropic medication for this population. Behavioral interventions have also shown promise.

An important educational need exists to refine the diagnostic and treatment strategies of clinicians in order to more safely and effectively treat preschool-age children with ADHD. Early, accurate diagnosis is paramount, and clinicians must remain aware of the newest information on treatment options, both pharmacotherapeutic and behavioral, available to treat this patient population.

Learning Objectives

• Describe the importance of early and accurate diagnosis of preschool-age patients with ADHD and how comorbidity may result in misdiagnosis.
• Assess available treatments, both off- and on-label, for safety and efficacy in preschool-age children with ADHD.
• Explain the latest information on the genetics and etiology of ADHD in preschool-age children and understand how this affects treatment response and side effect profiles.

Target Audience 

This activity will benefit psychiatrists, hospital staff physicians, and office-based “attending” physicians from the community.

Funding/Support

This activity is supported by an educational grant from Shire.

Faculty Disclosures

Sharon Wigal, PhD, has disclosed that she has received research support from Cephalon, Eli Lilly, McNeil, New Rivers, NIH, and Shire; has served as an advisor or consultant to Cephalon, McNeil, New Rivers, Novartis, Shire, and UCB; and has served on the speaker’s bureau for McNeil, Shire, and UCB.

Timothy Wigal, PhD, has disclosed that he has received research support from Cephalon, Eli Lilly, McNeil, New Rivers, NIH, Novartis, and Shire; has served as a consultant or advisor to McNeil, Novartis, and Shire; and has served on the speaker’s bureau of McNeil and Shire.

Peer Reviewers

Eric Hollander, MD, reports no affiliation with or financial interest in any organization that may pose a conflict of interest
Daniel Stewart, MD, PhD, reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

To Receive Credit for this  Activity

Read this poster, reflect on the information presented, and then complete the CME quiz found in the accompanying brochure or online (www.mssmtv.org/psychweekly). To obtain credit you should score 70% or better. The estimated time to complete this activity is 1 hour.

Release Date: April 23, 2007

Termination Date: April 23, 2009

Introduction

While the literature on ADHD in preschool-age children is limited, and the validity of the diagnosis in children this age is contested, current prevalence estimates for this population range between two and five percent.¹ In addition, there is substantial evidence linking ADHD symptoms in preschool-age children with significant concomitant functional impairment and behavioral problems in later childhood.^2-8 Treatments utilized by clinicians for this population include psychosocial treatment and the prescription of stimulants. While methylphenidate (MPH) is the most widely used stimulant medication for treating preschool children, MPH is not FDA-approved for use in children under the age of 6, and few studies have examined stimulants in this population.^9-10 In addition, a relatively recent study reported a 49% increase in their prescription to children under the age of 5.⁹ The tentatively favorable findings of one large NIMH-funded study on the safety and efficacy of MPH—the Preschool ADHD Treatment Study (PATS)—were recently published in the Journal of the American Academy of Child & Adolescent Psychiatry (2006), but the authors noted that follow-up research was imperative.

The lack of literature on ADHD in preschool-age children in combination with the confusion surrounding reliable diagnosis, apparent prevalence of the disorder, and the associated significant impairments indicate a clear and pressing need for increased study of ADHD and ADHD-like behaviors in young children and merits a revisiting of current best understanding and practice.

Diagnosis

A diagnosis of ADHD by DSM-IV criteria may be classified in three ways: predominately inattentive, predominately hyperactive-impulsive, and combined-type (both inattentive and hyperactive-impulsive).

The application of these criteria to young children poses problems particular to the age group; not only is it difficult to identify inattentiveness inconsistent with age level in preschoolers—who are, in general, far more inattentive than older children—but it is equally difficult to identify hyperactivity-impulsivity inconsistent with age level in this population. In essence, a certain degree of inattentiveness and hyperactivity are the developmental standard for young children. The key is in assessing whether the symptoms are maladaptive. However, identifying maladaptive inattentiveness in preschool-age children is further complicated by the fact that young children are seldom in situations where they are asked to sustain attention. Indeed, a lack of sustained attention is seldom maladaptive for this population—impairment is most likely to be associated with hyperactivity.

Because ADHD is more likely to negatively affect functioning at school, teachers are often the first to notice a problem. The shift in preschool away from, essentially, group daycare toward a more structured learning environment has likely contributed to the identification of maladaptive hyperactivity, due to its disruptive nature in a classroom setting, as well as, to a lesser extent, maladaptive inattentiveness (again, if one is not asking a child to attend, inattentiveness will tend to go unnoticed). Conversely, evidence suggests that parents with a child who does meet criteria for ADHD are significantly more likely to consider hyperactivity and inattentiveness as developmentally standard in comparison to parents whose children do not meet criteria for ADHD.¹¹

In assessing a child who may have ADHD, a clinician needs to first rule out alternative explanations for the ADHD-like symptoms. These can include, but are by no means limited to significant life change (eg, parents’ divorce), learning disability, a mood or anxiety disorder, and/or seizures and other medical disorders that affect brain functioning. (NIMH ADHD site) A thorough history, including school and medical records, and an examination of the home and classroom environment should be the foundation of an ADHD diagnosis. The child’s teachers can be an invaluable source of information—although generally not trained mental health professionals, their access to comparator children (as generally opposed to a parent’s access to same) lends significant credence to their (ie, the teachers’) subjective measures of a child’s behavior.

Due to the natural hyperactivity and inattentiveness of young children, a clinician must be confident that these symptoms cause impairment to make an ADHD diagnosis in this population.

Etiology

Over the years, many theories regarding the cause of ADHD have been advanced, some with more credence than others. Two views that have not withstood scientific scrutiny are the theories that poor parenting or exposure to certain food additives cause the disorder. Little evidence for either has been found, although diet restriction may have a positive effect on ADHD symptoms in some young children with food allergies.¹² A positive correlation has been found between alcohol and cigarette use during pregnancy. (NIMH ADHD site)

There is strong evidence for a genetic element to ADHD from both family and twin studies.^13-14 ADHD has been found to be five times more common in the close relatives of those with ADHD than in the general population. Research has identified genes involved in dopamine regulation, but ADHD does not appear to be a “one-gene” disorder. Variants in the dopamine D₄ receptor gene, the dopamine DRD5 gene, and a dopamine transporter gene have all been linked with susceptibility to ADHD.^15-17

A number of other genes have been associated with the developmental course of the disorder, including the DRD4 7-repeat risk allele (influences persistence and antisocial behavior), a functional variant in the gene encoding COMT (associated with antisocial behavior in ADHD), and a variant in MAOA (associated with antisocial behavior in ADHD).^18-21

Common Comorbidities

Comorbidities are highly prevalent in ADHD (up to 50% of children with ADHD have at least one comorbid disorder).²² Comorbidities are more commonly identified in older children and adults with ADHD than in preschool children; this may be due, in part, to later emergence of certain psychiatric disorders, but is likely also partly accounted for by the difficulty of diagnosing psychiatric disorders in young children.

20%–30% of children with ADHD have a specific learning disability.²³ Conduct disorders, particularly oppositional defiant disorder, are also common comorbidities (they’re present in up to 50% of children with ADHD, though oppositional defiant disorder predominately presents in boys). Anxiety and depression also co-present with ADHD. Some suspect bipolar disorder is also a common comorbidity, but there are no agreed-upon prevalence rates. In part, this is because bipolar disorder is difficult to diagnose in children. However, the picture is further complicated in that bipolar disorder appears to present in children as a chronic mood dysregulation (without the cycling so important to an adult diagnosis), making the symptoms very similar to those of ADHD. Elated mood and grandiosity, however, are particular to children with bipolar disorder, and can form the basis for a distinction.²⁴

In very young children, ADHD also shares a similar symptom cluster with autism. The similarity of ADHD symptoms and the symptoms of other psychiatric disorders in very young children, coupled with the difficulty of diagnosing preschool-age children, has likely led to instances of both under and over-diagnosis of ADHD in this patient population.

Treatment

Amphetamines (ie, dextroamphetamine and mixed amphetamine salts) are the only agents approved by the FDA for the treatment of ADHD in children between the ages of 3 and 6 years at this time. Although MPH is not approved for children under 6 years of age, it is the most commonly prescribed psychotropic medication for ADHD patients in this population. In response to increased off-label prescription of stimulants for preschool-age children, the National Institute of Health Consensus Development Conference on the Diagnosis and Treatment of ADHD (1998) found a need for further study on the safety and efficacy of stimulant medications in young children with ADHD. Specifically, researchers stressed the need for a better understanding of age-related effects on drug absorption and metabolism, dose-response characteristics, and side effects of using stimulants in preschool-age children.

The Preschool ADHD Treatment Study (PATS) (2006) was designed to answer this call for further study. A small handful of previous studies had produced conflicting results on MPH in preschool-age children, with two identifying no difference in response to placebo and MPH^25-26 and one indicating increased adverse events in younger children taking MPH as opposed to older children on MPH.²⁷ These studies were subject to methodological differences, particularly in relation to inclusion/exclusion criteria. The PATS was a large, multi-site trial with rigorous criteria for inclusion and exclusion. Prior to admittance to the study, prospective subjects underwent extensive assessment, and all cases required a consensus agreement of acceptability from a cross-site panel of clinicians prior to admittance.

The study found significant evidence for the efficacy of MPH in preschool-age children when administered 2.5, 5, and 7.5 mg TID. No significant improvement was found for children receiving 1.25 mg TID. The optimal dose for the preschoolers was 14.2±8.1 mg/day. Significantly higher doses were required for maintenance of response during the 10-month treatment period.

Despite the reduction of ADHD symptoms in the PATS subjects taking MPH, effect sizes were significantly lower than those recorded in prior studies of older children. The authors suggest this could be due to age-specific differences in treatment response, differences in study design between PATS and prior large studies of MPH response in older children, or a combination thereof.

Safety and Tolerability of MPH

The 5 most common adverse events (AEs) in the PATS were decreased appetite, difficulty sleeping, repetitive behaviors, emotional outbursts, and irritability. Parent-rated AEs for MPH that were significantly greater than those for placebo were appetite decrease, trouble sleeping, and weight loss. No significant differences in AEs were recorded between different dose sizes of MPH. No cardiovascular AEs were observed.

The PATS uncovered notable differences between AEs in preschool-age children on MPH and older children on MPH. Discontinuation rates were higher in PATS (11%) than in the large, MTA Cooperative Study Group (1999) examination of MPH in school-age children (<1%). Furthermore, preschool-age children demonstrated a different profile of moderate to severe AEs than that found in school-age children. The latter were subject to decreased appetite, delay of sleep onset, headaches, and stomach aches.

The MPH-related AEs in preschool-age children with ADHD, although more aversive than in their older counterparts, appeared, on the whole, manageable. The authors of the PATS noted, however, that a much larger study (N>1,500) is required to meet regulatory guidelines for establishing side-effect profile.

Evidence also suggests²⁸ that persistent treatment with a stimulant can significantly lower the growth rate in young children; however, this possibility needs to be balanced against the likely benefit of treatment on a case-by-case basis.

The related finding that preschool-age children require higher concentrations of MPH in their blood to achieve the same behavioral effects as those seen in school-age children is somewhat surprising.²⁹ Medication absorption and clearance is likely affected not just by weight, but by differences in physiology (as relating to either structure or particular enzymes) between younger and older children. Further analysis of these relationships is critical to properly inform dosing. It seems evident that size and weight are not the only salient factors.³⁰

Psychosocial Treatment

The MTA study of school-age children with ADHD found that, while medication treatment as delivered in the study was highly effective, behavioral treatment was equally effective to the medication treatment delivered in the community, and combination therapy was most effective of all. However, these differences disappeared at follow-up. The PATS did not examine behavioral treatments in preschool-age children, but rather, parent training prior to initiation of medication treatment. Prior work demonstrated that parent training produced clinically significant symptom improvement in preschool-age children with ADHD (as well as increasing ratings of maternal well-being).³¹

The success of psychosocial treatment in older children, preliminary evidence for the efficacy of behavioral treatments in preschool-age children, the side-effect profile of stimulants in young children, and issues surrounding parent resistance to medicating their children all warrant further study of psychosocial intervention and combination therapy in young children with ADHD. While some parents turn to alternative treatments—eg, natural supplements—there is currently no evidence supporting their efficacy.

In summary, both medication and behavioral treatments appear to alleviate the symptoms of ADHD. Most evidence suggests that discontinuation of treatment leads to the reemergence of the condition. ADHD is a chronic problem. At the present time, efforts are continuing towards understanding the genetic underpinnings of ADHD. Early identification and treatment of symptoms of ADHD preschool-age children may contribute to more positive outcomes.

To take the free, online CME post-test, go to www.mssmtv.org/psychweekly

References

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To take the free, online CME post-test, go to www.mssmtv.org/psychweekly