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Charach A, Dashti B, Carson P, et al. Attention Deficit Hyperactivity Disorder: Effectiveness of Treatment in At-Risk Preschoolers; Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Oct. (Comparative Effectiveness Reviews, No. 44.)

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Attention Deficit Hyperactivity Disorder: Effectiveness of Treatment in At-Risk Preschoolers; Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment [Internet].

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Results

Figure 2 details the flow of studies and the final subset for review of KQ1 and KQ2. The search for reports for the treatment questions addressing preschool children and addressing long-term treatment or outcomes, yielded 3 6,888 unique citations. During two levels of title and abstract screening, 35,541 articles were excluded. A total of 1,347 citations proceeded to full text screening. After the final eligibility screening, 129 publications were eligible for data extraction.

Figure 2 shows a flow diagram of studies and the final subset for review of KQ1 and KQ2. The search for reports for the treatment questions addressing preschool children and addressing long-term treatment or outcomes, yielded 36,888 unique citations. During two levels of title and abstract screening, 35,541 articles were excluded. A total of 1,347 citations proceeded to full text screening. After the final eligibility screening, 129 publications were eligible for data extraction.

Figure 2

Flow of studies through review (KQ1 and KQ2).

Figure 3 outlines the flow of studies and the final subset for review of KQ3. A separate search was performed for prevalence reports (KQ3). The initial yield of papers was 8,502 of which 5,964 were excluded at the title and abstract screening level 1, with an additional 1,918 excluded at level 2. Of the remaining 620 papers, an additional 132 were excluded at full text screening. Having applied the methodology of systematic review to reduce the volume of papers, the authors then addressed KQ3 using data from 94 of the 485 reports selected as a result of a scan of abstracts and then augmented with other supporting methodological and epidemiological studies which informed discussion of issues surrounding estimates of prevalence.

Figure 3 shows a flow diagram of studies and the final subset for review of KQ3. A separate search was performed for prevalence reports (KQ3). The initial yield of papers was 8,502 of which 5,964 were excluded at the title and abstract screening level 1, with an additional 1,918 excluded at level 2. Of the remaining 620 papers, an additional 132 were excluded at full text screening. Having applied the methodology of systematic review to reduce the volume of papers, the authors then addressed KQ3 using data from 94 of the 485 reports selected as a result of a scan of abstracts and then augmented with other supporting methodological and epidemiological studies which informed discussion of issues surrounding estimates of prevalence.

Figure 3

KQ 3. Flow of studies through review for prevalence question.

Key Question 1. Among children less than 6 years of age with Attention Deficit Hyperactivity Disorder or Disruptive Behavior Disorder, what are the effectiveness and adverse event outcomes following treatment?

Introduction

The systematic search results for comparative clinical trials of psychosocial, behavioral, or pharmacologic interventions for preschoolers with Disruptive Behavior Disorders (DBD) are organized by type of intervention. The first section describes parent behavior training (PBT), with a summary of efficacy trials addressing child disruptive behavior problems and parents’ sense of competence. Three of these trials investigated PBT specifically for preschoolers identified with Attention Deficit Hyperactivity Disorder (ADHD) symptoms. Ten studies measured hyperactivity/impulsivity among other behavior symptoms. The next section summarizes studies investigating long-term extensions following the clinical trials of PBT. The third and fourth sections report on studies designed to address symptoms of ADHD in preschoolers, as well as other disruptive behavior and school readiness. The third section examines interventions that combine PBT and school or daycare components. The last group of studies examines pharmacological agents, specifically trials of psychostimulants.

Parent Behavior Training Interventions for Preschoolers With Disruptive Behavior Disorders

There are primarily four manualized programs of behavior training interventions for parents of preschoolers with DBD that have been developed by separate research groups in the past 25 years. While each program has its own specific features, the Triple P (Positive Parenting of Preschoolers program),16–22 Incredible Years Parenting Program (IYPP),23–27 Parent-Child Interaction Therapy (PCIT),28–35 and the New Forest Parenting Program (NFPP)36–39 share common therapeutic components and are manualized to ensure intervention integrity with dissemination. These programs are designed to help parents manage their child’s problem behavior with more effective discipline strategies using rewards and non-punitive consequences. An important aspect of each is to promote a positive and caring relationship between parents and their child. Primary outcomes are improved child behavior and improved parenting skills. Each program also includes educational components regarding childhood behavior problems and common developmental issues, and may include coaching or consultation to support the parents’ efforts.

Thirty-one reports of controlled trials of parenting interventions met criteria for review;17–39,132–138 of these, 28 met criteria for “good” or “fair” internal validity and will be the basis of this discussion. Additionally, the 8 studies which met criteria for “good” internal validity were used in the general meta-analysis highlighted in the Strength of Evidence Tables (see Table 21). Tables 2 and 3 provide information on the characteristics of the 31 reports. Most of the studies were randomized controlled trials (RCTs). Most studies examined parent-reported child symptom behavior scores, self-reported parenting skills, and sometimes researcher-rated observations of parent-child interactions. The Eyberg Child Behavior Inventory (ECBI) was the most frequently used child behavior measure, with subscales for frequency and intensity of child disruptive behaviors. Several parenting scales were used, most frequently the Parent Sense of Competence scale (PSOC). Almost all studies compared groups of treatment intervention completers to wait list controls, while one study compared two different interventions,132 and two studies compared variants of an intervention without a treatment control group.20,138

Table 2. KQ1. Characteristics of parenting interventions.

Table 2

KQ1. Characteristics of parenting interventions.

Table 3. KQ1. RCTs of parenting interventions.

Table 3

KQ1. RCTs of parenting interventions.

Eight of the trials conducted examined PCIT.28–35 Two studies evaluated the efficacy of PCIT for preschoolers with symptoms of ADHD.30,31 Results from these studies show that PCIT is efficacious in reducing oppositional symptoms and increasing compliance. In addition, both studies reported a reduction in ADHD symptoms posttreatment. Six additional studies evaluated PCIT in oppositional or aggressive preschoolers and found similar results.28,29,32–35 At postintervention, parents who received treatment reported fewer and less intense child externalizing symptoms, in addition to decreased parenting stress and increased internal locus of control.

Seven studies evaluated the Triple P program or its precursors.16–22 Four studies examined self-directed variants,16–18,21 while two studies examined enhanced and standard variants of the program.19,22 In general, results from these studies show that compared to wait list controls, parents who completed the intervention reported fewer and less intense child behavior problems, less frequent use of dysfunctional discipline strategies, and increased sense of competence in their own parenting skills at post-intervention followup. Bor, et al.,19 did not find the enhanced intervention, which included adjunctive components addressing partner support and coping skills, to be superior to the standard Triple P intervention on any of their outcome measures.

Five of the trials examined the efficacy of the IYPP compared to wait list control.23–27 Results from these studies showed reductions in problem behaviors and clinically significant gains in families that completed the intervention. In addition, one of these studies reported a significant decrease in inattention and hyperactivity symptoms even when controlling for postintervention changes in child deviant behavior.24 Another trial examined the efficacy of Supportive Expressive Therapy – Parent Child (SET-PC), a psychodynamic psychotherapy, as compared to the IYPP.132 Results show that both interventions were efficacious in reducing externalizing behaviors and increasing parents’ psychological functioning, as well as positive interactions between parent and child.

Four of the studies examined the efficacy of the New Forest Parenting Program (NFPP), specifically designed for preschoolers with ADHD.36–39 Results from two studies showed a reduction in ADHD symptoms postintervention,36,39 while reductions in oppositional symptoms were less marked.39 One study, in which PBT was delivered by nonspecialist nurses as part of routine primary care, did not result in any change of ADHD symptoms postintervention.37

Three reports on two RCTs by Pisterman, et al.,135–137 reported support for the efficacy of group parent-mediated behavioral intervention to reduce noncompliant behavior in preschoolers and to reduce parent stress and improve parenting competence.

One RCT evaluated the efficacy of the Help Encourage Affect Regulation (HEAR) for aggressive preschoolers.134

A final RCT evaluated a PBT program offered either to individual families in a clinic setting or to groups of parents in a community location.133 Results showed that parents enrolled in a group and community-based program reported greater improvements of behavior problems at home compared to an individual, clinic-based program and wait list control. Moreover, the community/group program was found to be much more cost-effective than the individual/clinic program.

In summary, these studies show that parent behavioral interventions are an efficacious treatment option for preschoolers with DBD. Compared to wait list controls, children show reduced number and intensity of problem behaviors and clinically significant changes postintervention. In five out of six studies where ADHD symptoms are a focus of treatment, these also improve. Moreover, parents report an increased sense of competence and show improved parenting strategies. Self-directed, group, and individual variants of parenting interventions are generally equally effective, though group therapy may be more cost-effective when compared to individual therapy.

Meta-Analysis of Parent Behavior Training for Disruptive Behavior Disorder in Preschoolers

We performed meta-analyses in order to document the degree of benefit following PBT for DBD in preschoolers. We compared all studies with both “fair” and “good” internal validity, presenting the forest plots both with and without the studies rated as “fair.” The standardized mean difference (SMD) for each study represents the measured change in parent-rated child behavior between intervention and control groups. The studies used differing measures of child disruptive behavior, including reports of ADHD symptoms. Sensitivity analysis was done based on different assumptions on the correlation between baseline and outcome values for individual children, using 0.0, 0.3 and 0.5. A random effects model was used for the meta-analyses. Similar results were obtained in the sense of significant overall treatment effect. In all cases, heterogeneity was within acceptable limits. Figure 4 shows the forest plot using the eight “good” studies, using a correlation factor of 0.3. Figure 5 is a forest plot that uses both studies rated as “good” and as “fair.” These summaries indicate that PBT improves parent rated child behavior in preschoolers.

Figure 4 shows a forest plot using the eight “good” studies, using a correlation factor of 0.3.

Figure 4

Effect of PBT on preschool child behavior outcomes (8 “good” studies)*. * includes RCTs rated as “good” quality (assumes correlation between post- and prescore of 0.3) Note: means are post/pre differences; Std. Mean Difference (more...)

Figure 5 shows a forest plot that uses both studies rated as “good” and as “fair”. These summaries indicate that PBT improves parent rated child behavior in preschoolers.

Figure 5

Effect of PBT on preschool child behavior outcomes (8 “good” and 3 “fair” studies)*. *includes RCTs rated as “good” and “fair” quality (assumes correlation between post- and prescore of 0.3) (more...)

These meta-analyses confirm the efficacy of PBT interventions for preschool DBD, including ADHD. There is a high degree of consistency across studies despite the fact that samples were from different countries, different studies used different instruments, and there are differences among the interventions. It should be noted that only those participants who completed the interventions were included in the treatment groups for the purpose of analysis (not an intention-to-treat analysis). In addition, studies were not blinded. Both are factors that lead to higher estimates of effectiveness.

Long-Term Extensions of Controlled Trials of Parenting Interventions

This section describes results from the extension studies investigating maintenance of behavior benefits for preschoolers following PBT (see Table 4). Eight cohorts of preschoolers were followed for greater than 12 months after enrolment in a clinical trial examining parent interventions for DBD. Long-term effects were examined across 9 studies19,21,26,27,29,33,139–141 and ranged from 1 to 6 years after treatment. Most studies examined parent-report and clinician observation of maintenance of treatment gains; one study examined maintenance of treatment effects in the school environment.33 No extension study included untreated comparison groups, and attrition over the followup period ranged from 24 percent at 18 months26 to 54 percent at 3 to 6 years,21,29 limiting interpretation of the results. In general, these extension studies suggest that post-treatment gains, including improvements in ADHD symptoms, are maintained over time. A recent study examining PBT with and without school-based teacher or child interventions did include a no-treatment control. This study showed maintenance of benefits of PBT at two years.40 Studies do not comment on adverse events related to PBT.

Table 4. KQ1. Long-term extensions of clinical trials of parenting interventions.

Table 4

KQ1. Long-term extensions of clinical trials of parenting interventions.

In summary, parenting interventions are effective in reducing child DBD and improving parenting skills. The benefits appear to be maintained following completion of the treatment, but appropriate comparison groups are not available

Effectiveness of Combinations of Parent Behavior Training and School- or Daycare-Based Interventions for Preschool Children With Disruptive Behavior Disorder or ADHD

Seven articles examining multiple component psychosocial and/or behavioral interventions for Disruptive Behavior Disorder (DBD) in preschool children met criteria for review.27,40,42,122,141–143 This group of studies did not include a focus on pharmacological interventions, but primarily examined combinations of PBT and school- or daycare-based interventions. Of these, four met quality criteria for “good” internal validity,27,40,122,143 and three met criteria for “fair” internal validity (see Table 5).42,141,142

Table 5. KQ1. Summary of studies comparing nonpharmacological combination treatment modalities for preschoolers with ADHD or with DBD.

Table 5

KQ1. Summary of studies comparing nonpharmacological combination treatment modalities for preschoolers with ADHD or with DBD.

Five of these studies27,122,141–143 included a specific focus on effectiveness of interventions for children with ADHD symptoms. A sixth study included ADHD symptoms as part of two composite child symptoms variables, either rated by parents or by teachers.40 The seventh study examined children with Oppositional Defiant Disorder (ODD) as the primary concern, however 49.5 percent of them received medication for ADHD between the time of original intervention and 2-year followup assessment.42 Two studies recruited preschoolers using clinical diagnostic assessments, and examined an intensive multi component intervention (MCI) comprised of PBT plus school or daycare consultation for preschool children with ADHD.122,143 One of these trials compared MCI with diagnostic assessment and community care treatment as usual143 and the second compared MCI to diagnostic assessment and a standardized parent education program.122 These trials enrolled children from primarily middle class, educated families, with three percent on social assistance. Three studies in this group recruited children using high ADHD and DBD symptom ratings on screening measures obtained when parents enrolled children for kindergarten and examined combined PBT and teacher training versus no treatment.27,141,142 Barkley, et al.,142 examined a 1-year intervention which included PBT and a specialized treatment classroom, alone and in combination, compared to a no treatment control group for preschoolers with high levels of parent reported ADHD and other DBD symptoms. Adjustments to group assignments due to feasibility issues interfered with randomization. These children were drawn from low to middle socioeconomic status (SES), predominately European-American families, 39 percent of whom received social assistance. This sample was followed long-term by Shelton, et al.,141 who evaluated these children 2 years postintervention in comparison to a community control. Williford, et al.,27 compared teacher consultation and PBT versus services as usual for preschoolers in Head Start programs.27 These children were from predominantly low SES African-American families whose preschoolers had high levels of ADHD and ODD behaviors on screening measures. The sixth study, Hanisch, et al.,40 examined PBT and teacher training versus waitlist control among German kindergarten children of parents with low education levels over a 10-week intervention, reporting ADHD symptoms as part of a composite behavior measure. Overall, these studies of combined PBT and teacher or classroom interventions for children with ADHD or ADHD and DBD symptoms discovered that parent participation in groups for behavior training could be modest even when transportation and babysitting were provided and sessions occurred at convenient times. In this way, outcomes for these PBT interventions will differ systematically from those in the RCTs described earlier, where PBT intervention outcomes were measured for children whose parents completed the intervention.

The seventh study included in this section, Reid, et al.,42 was a 2-year follow up of 159 children ages 4 to 7 (mean age 5.8 years) who participated in an Incredible Years Training program comparing several treatment components alone and in combination. Children were randomly assigned to receive PBT only, teacher training (TT) only, child training (CT) only, PBT + TT, CT + TT, PBT+ CT, PBT + TT + CT, or wait list control for 8 to 9 months and then received treatment. Of the 133 families who received treatment initially, 121 (91%) completed 2-year posttreatment assessments. Attendance at sessions was high (90 to 95%), and at the second year assessment almost half of the children were receiving medication, two important differences from other studies discussed in this section.

Two studies investigated the effectiveness of a multicomponent intervention (MCI) for preschoolers with ADHD who generally came from families from a middle income background.122,143 Overall, children in the MCI group did not improve significantly more than children whose parents were enrolled in the parent education (PE) program122 or who received community treatment as usual.143 Parents in the MCI group attended a mean of 37 percent of 20 group behavior training sessions and 60 percent of families received a home behavior plan, while school plans were developed for 82 percent of children. Parents in the PE group attended 30 percent of 20 sessions, but received no additional services by protocol.122 Child behavior, social skills, and school readiness improved significantly over 12 months in both groups. In the study where the comparison intervention was community treatment as usual, approximately 20 percent received stimulant medication at some point during the intervention.143 These studies suggest that additional resources for home-based behavior plans, or classroom/daycare-based behavior plans, do not provide substantially increased benefit for preschool children with ADHD, beyond that provided by diagnostic assessment and well-organized parent education programs, or community treatment as usual for children in families of middle income. These studies had few children from low SES background. There were no nontreatment comparison groups in these studies.

In contrast, Barkley, et al.,142 showed that at the end of a school year-long intervention, classroom interventions demonstrated significant positive impact on teacher-reported disruptive behavior and social skills outcomes, compared to PBT alone and to a no-treatment comparison. In the PBT groups, 68 percent of parents attended less than 5 of 14 sessions. Ten children (six% of the sample) received medication, and half were in the classroom interventions, half not. The classroom program included behavior training to improve classroom compliance, social skills training, and self control training, along with an emphasis on early academic skills. Their first grade teachers were provided with information about the children and general suggestions about management, and offered additional consultations over the next three months, but only 10 percent of teachers accepted. Two years later, however, Shelton, et al.,141 found that children who had received the classroom intervention no longer showed improved behavior relative to those who did not receive a classroom intervention (controlling for initial behavior scores), suggesting that the benefits derived from the classroom intervention were not maintained 2 years later. The study did not examine the 2-year maintenance effects of PBT.

Williford, et al.,27 examined school consultation and PBT compared with services as usual, in preschoolers from low SES, primarily African-American families enrolled in Head Start programs. The group receiving combined school and home intervention showed improved child behavior and social skills reported by both teachers and parents; in addition, both teachers and parents showed improved child management skills. The majority of parents (65%) did not attend more than 50 percent of the sessions, but those who did reported increased parenting skills.

The recent German study, by Hanisch, et al.,40 examined dose effect for a number of PBT sessions attended in an intervention that offered combined PBT and teacher behavior training for children with ADHD and/or DBD. In a generally low SES sample, approximately 20 percent of parents attended no sessions despite expressed willingness to do so prior to the study. Intention to treat analysis showed improved child behavior and improved parenting strategies with effect size in the range of 0.25 to 0.30. For those families where parents attended five or more PBT sessions, children showed greater improvement in behavior at school than those children whose parents did not attend PBT, with an effect size of 0.39.

Summary and Limitations

Very few studies offer information about the benefits of psychosocial/behavioral interventions for preschoolers with DBD who also have ADHD or who are at risk for ADHD. The seven studies reviewed examine the question of efficacy or effectiveness in offering PBT combined with school or daycare-based interventions for the combination of ADHD, oppositional and aggressive symptoms and, in some studies, school readiness in children, as well as measures of parenting among parents. The outcome measures examined and the methods of analysis vary widely from study to study, as do the interventions to some extent, precluding meta-analysis. Descriptive comparison of these studies suggests that SES may be an important determinant of outcome. Direct SES comparisons within a single study, utilizing proper control groups, would provide the best information to answer these questions.

One study offers observations that enhance the findings reported earlier regarding PBT because they provide a no-treatment wait list comparison group demonstrating superiority of treatment conditions, including PBT, over a school year, upon a 10-week intervention.41 In addition, Hanisch, et al.,40 show a dose response of additional improvements to five or more sessions of PBT, as not all parents attended all sessions. Predictors regarding full attendance were not addressed. The issue of attendance is important, as studies described above supporting effectiveness of parent behavior programs report results for those children whose parents completed the intervention.

Efficacy and Safety of Psychostimulant Interventions for Preschool Children With ADHD

This section reviews pharmacologic interventions for preschoolers with documented ADHD (Table 6). Fifteen articles representing 11 studies examined efficacy of psychostimulants, primarily immediate release MPH, prescribed two or three times daily in preschool children with documented ADHD.7,43–56 The largest randomized clinical trial, the Preschool ADHD Treatment Study (PATS) was rated as a “good” study and is described in detail below.7,51–54 There was one additional “good” study55 and the remaining nine studies were rated “fair” in internal validity. Except for the PATS, samples were generally small. Study participants were primarily boys from middle SES families, with ADHD Combined type (ADHD-C), or hyperactive impulsive type. Two studies examined children with ADHD and developmental disabilities or pervasive developmental disorders.46,48 Clinical trials were generally of short duration, lasting days to weeks. Almost all of the studies investigated immediate release MPH, in comparison to placebo.44–48,50,55,56 One study compared the most effective and well-tolerated dose of either MPH or mixed amphetamine salts (MAS) to placebo.49 All studies noted clinically significant symptomatic improvements on psychostimulant medication. Those studies which compared adverse events of medication or placebo, noted that behaviors attributed to side effects were present in subjects on placebo as well.46,47,49 For those children who participated in fixed dose titrations, adverse events were more common and of greater intensity at high rather than low dose.47 Poor appetite, social withdrawal, lack of alertness, stomach ache, irritability, and rebound were noted as increased when on stimulants relative to placebo.46,49

Table 6. KQ1. Summary of studies reporting interventions with pharmacological agents for preschoolers with ADHD.

Table 6

KQ1. Summary of studies reporting interventions with pharmacological agents for preschoolers with ADHD.

One study compared combinations of medication and parent intervention. Heriot, et al.,43 randomized 26 preschool children with ADHD to four conditions: a single dose of 0.3mg/kg 2 times daily (b.i.d.), immediate release MPH or placebo in combination with PBT or parent support. Only 12 children (46%), ages 3 to 5, and their parents completed the study. Descriptive comparison of individual pre-post analyses indicated that children in active treatment conditions showed improvement relative to those in nonactive treatments. All children in the combination active MPH plus active PBT condition showed symptomatic improvement in at least one domain, whereas only one child showed improvement in one domain in the non-active interventions condition. Some individual children receiving only one active treatment also benefited. This study suggests efficacy for both MPH and for PBT, with the combination addressing a wider range of needs for a greater number of children. However, the sample is too small to draw conclusions, and most of the participants did not complete the protocol.

Preschool ADHD Treatment Study

The multisite National Institute of Mental Health (NIMH) funded PATS, which offers high quality evidence about efficacy, safety, and effectiveness of immediate release MPH, 3 times daily (t.i.d.), for preschool children 3 to 5 years of age.7,51–54 The study included several stages, and ensured that parents of ADHD children received 10 weeks of PBT prior to the initiation of medication. The sample were 76 percent boys, 63 percent Caucasian, and 76 percent two parent families, of which 97 percent had completed high school. Only 165 children of the 303 enrolled (54%) actually entered the randomized double blind crossover titration trial. Two phases preceded randomization: 10 PBT sessions and a preliminary open-label medication safety lead-in phase. However, overall characteristics of the sample remained essentially the same.

Of the 303 participants who consented and enrolled, 279 entered PBT, and 261 completed the 10 sessions. Following this, 34 (11% of original sample) declined further participation or did not want to use medication. Eighteen families (6%) were satisfied with their child’s improvement, and another 19 children (6%) showed significant improvement. Of the remaining children, 183 enrolled in the open-label safety lead-in phase. One hundred sixty five who tolerated the open-label safety lead-in phase were randomized into the double blind titration trial. The investigation of MPH efficacy consisted of a randomized 5-week double blind crossover titration trial including four different MPH doses (1.25mg, 2.5mg, 5.0mg, 7.5mg) and placebo, given t.i.d. to identify best dose. Best dose was determined from parent and teacher reports of symptom ratings and side effects during the cross-over titration trial. One hundred fourteen children entered and 77 completed the next phase, a four-week double blind RCT comparing best dose to placebo. And finally, 140 entered the 10-month open-label maintenance phase. Between each phase families could opt to discontinue the study or move on to another phase. For example, 61 families opted to move to the open-label maintenance phase prior to completing the 4-week RCT parallel phase.

Eleven of 183 children (6%) enrolled in the open-label lead-in phase had moderate to severe adverse events and were not eligible to enter the titration phase. An additional 21 of 183 (11.5%) children did not tolerate the highest dose, 7.5mg t.i.d., and received a second week at 5.0mg t.i.d. during the titration trial.7 These numbers suggest that a substantial proportion of preschool children experience moderate to severe adverse events with doses of MPH within recommended range of doses. Five additional children did not tolerate the crossover titration or parallel phases, while 12 were placebo responders and 7 were MPH nonresponders. Forty children experienced behavioral deterioration during the parallel RCT.

The PATS study offers good evidence for the efficacy of MPH in improving core ADHD symptoms using several different measures. Symptom improvement was noted during the crossover titration phase comparing placebo with low dose and high dose conditions for MPH (low dose mean optimal dose 0.7 ± 0.4mg/kg/day, and high dose mean optimal total dose of 14.2 ± 8.1mg/kg/day).7 During the 4-week parallel phase, functional outcomes included small positive effect for teacher- but not parent-rated ADHD symptoms and social competence on MPH, no improvement in parental stress, and moderate worsening of parent-rated child mood on MPH; clinicians, on the other hand, rated children as improved with a strong effect size.51 These findings were contrary to expectations. In addition, children noted to have more comorbid conditions at baseline were less likely to benefit from the MPH intervention. Those 15 (9% of 165) who had 3 or 4 comorbid conditions were also more likely to have family adversity.52

It is hard to know what to make of the fact that parent ratings and clinicians ratings do not agree about effectiveness of MPH treatment during the 4-week parallel trial. Parent ratings showed little benefit and some functional worsening for children on best dose MPH compared to those on placebo, while clinician’s global impressions documented improvement. One explanation could be that the parent- and teacher-rated symptom measures reported in this phase of the study are designed to be used as population screening measures and therefore are not sufficiently sensitive to change over time.

Adverse Events

The PATS study provides the best quality evidence regarding adverse events in preschoolers using MPH.54 In the study, adverse event recordings included spontaneous reports by parents to a physician’s general inquiry about their child’s health, as well as parent and teacher reports on research forms. Adverse events were recorded whether or not they could be attributed to the use of MPH. Moderate severity of adverse events was defined as causing some functional impairment and/or requiring medical attention or intervention (e.g., over-the-counter medication for headache). Severe adverse events prevented functioning in a major area of daily life and/or presented a serious medical threat. A serious adverse event had to meet the U.S. Food and Drug Administration (FDA) definition (requiring hospitalization or leading to persistent incapacity).

Physicians also monitored vital signs, height, and weight. Tachycardia was defined as a resting heart rate >120 beats/minute twice at the same visit. Hypertension was defined as blood pressure (BP) above 95th percentile for age and gender on two readings at the same visit. If such a reading was noted then the child’s BP was measured again within 7–14 days. If the BP remained elevated then an adverse event for hypertension was noted. Only severe ratings are reported in the article, defined as having a BP >20mmHg above the limit.

Results show that emotionality/irritability was the most common reason for families to discontinue MPH use in the early stages of medication use. Of the 21 children who discontinued the study because of adverse events, nine discontinued because of emotionality/irritability.54 These observations are concordant with functional outcomes reported above for the parallel phase where parents indicated worsening in child mood in the MPH group.51 Early termination from medication was also related to symptomatic behaviors such as increased talking, restlessness, and “spaciness,” suggesting that poor efficacy may also interfere with adherence. Other adverse events, such as sleep difficulties and appetite loss, were tolerated, and were not associated with termination of the MPH trial.54

While emotional adverse events were reported most frequently during the double blind titration trial, they did not occur more frequently for children while on MPH in any of the dose conditions compared with placebo. By contrast, trouble sleeping, appetite loss, being dull/listless/tired, stomach ache, social withdrawal, and buccal/lingual movements were reported more frequently by parents while children were on MPH than on placebo.54 Changes in vital signs, BP, and pulse occurred in similar frequencies in both active treatment and placebo groups. Eight children exceeded the norms for BP on a single visit; none exceeded the norms on a second visit. Cardiovascular adverse events were therefore of no clinical significance during the titration trial.54

Overall, the study evaluating safety and tolerability of MPH for preschoolers in the PATS confirms that physiological adverse events are common for young children with ADHD (spontaneously reported by 30% of parents), but serious clinically significant adverse events attributable to MPH are rare.54 Eleven percent of children who started medication discontinued treatment due to adverse events.

Growth rates were impacted by the use of MPH.53 While the children enrolled were significantly larger than average for their age at baseline, they also showed significant reductions in rate of growth over the period of the study. On average, the children were 2.0 cm taller and 1.8kg heavier than peers at baseline. For those who remained on MPH, the annual growth rate was 22 percent (1.4cm/yr) less than expected for height and 55 percent (1.3kg/yr) less than expected for weight.53

Please refer to the section following Table 7 for further discussion of adverse events related to pharmacological treatments.

Table 7. KQ2. Summary of studies reporting interventions with pharmacological agents.

Table 7

KQ2. Summary of studies reporting interventions with pharmacological agents.

The PATS study provides useful information about adherence to medication in this age group. While the main message of the PATS is that MPH is generally safe for young children, a secondary message is that parents remain uncertain about using stimulant medications for preschoolers. Even in this select group of families willing to participate in research, 34 of 261 (13%) who completed the 10 session PBT declined further participation or did not want medications, while an additional 18 (7%) were satisfied with the child’s improvement; a further 19 children (7%) showed significant improvement in ADHD symptoms following PBT. Only 183 of the original 303 (60%) children entered the open-label safety lead-in trial and 140 (46%) entered the maintenance phase following the trial. Of these only 95/303 (31%) completed the 10 months, although some may have discontinued the trial in order to switch to long-acting MPH.54

The primary study examining long-term outcomes for preschool children using stimulant medication for ADHD is the PATS study, summarized above, which reported on the 10-month outcomes following an open-label continuation trial.7,53,54 In one additional study, Cohen56 followed 24 preschoolers with hyperactive symptoms for a year following a trial of MPH. Where preschool children remain on medication they appear to maintain symptom benefits, but lack of control for maturational effects interferes with drawing conclusions. Many families withdraw from continued use. Ninety-five of 183 (52%) of those in the PATS who tried medication completed the open-label phase and not all of these experienced adverse events, as adverse events accounted for 11 percent of those who discontinued (21 out of 183).

Summary and Limitations

There are several short-term studies, most with small sample size examining psychostimulant use in preschoolers. Of these, only one small study compares medication directly with PBT and the combination of medication and PBT.43 The medication dose it examines is low compared with doses suggested by other studies. The sample size was very small, perhaps due to attrition (16/26 children completing interventions), precluding the usual statistical analysis for controlled trials examining efficacy. The second trial, the PATS study, offered careful analysis of psychostimulants following 10 sessions of PBT, a format consistent with clinical consensus for treatment of ADHD in preschoolers. It confers information about parent preferences, documents the small proportion of children with ADHD benefiting from a series of 10 PBT groups, and the additional benefits (as well as adverse events) posed by MPH use in preschool children with ADHD. It examines functional as well as symptomatic outcomes, with information from several informants. The study shows that for children with no comorbid conditions, or with only one, MPH is very effective, similar to its effectiveness in samples of older children. As informative as this study is, it deserves replication in other samples, especially in light of the finding that presence of three or more comorbid conditions and psychosocial adversity decreases the effectiveness of psychostimulant medication.

Key Question 2. Among people 6 years of age or older with Attention Deficit Hyperactivity Disorder, what are the effectiveness and adverse event outcomes following 12 months or more of any combination of followup or treatment, Including, but not limited to, 12 months or more of continuous treatment?

Studies examining the long-term effectiveness and safety of pharmacologic interventions are an important focus of this review. With the advent of new technologies and formulations of psychostimulants and the development of non-stimulant agents for use in ADHD, industry-sponsored research has provided several high quality extension studies following participants in clinical trials. As well, researchers have used chart reviews and examinations of clinical database information to learn about the naturalistic patterns and long-term outcomes of stimulant use for children with ADHD.

Long-Term Effectiveness and Safety of Psychostimulants, Atomoxetine, and Guanfacine Extended Release Interventions for ADHD

In all, we found 18 studies representing 16 cohorts, 14 in children and two in adults, that offer details about long-term treatment effectiveness and safety of pharmacologic interventions.57–71,144–146 (Table 7). Seven reports representing six studies were rated as “good”58,61–63,66,67,146 while nine reports57,59,60,64,65,68–71 were of “fair” internal validity and two144,145 were assessed as weak by the quality assessment tool. Only studies rated as having “good” and “fair” internal validity are discussed in this section.

Of these, two cohorts describe psychostimulants without distinguishing between MPH and dextroamphetamine (DEX) agents,57,58,146 while other reports describe amphetamine, MPH immediate release, DEX, MAS, and OROS MPH.58–65 Four reports describe cohorts of participants in trials of the norepinephrine reuptake inhibitor atomoxetine (ATX); one of these is an extension of clinical trials in adults.66–69 Three additional RCTs compare MPH with the combination of MPH and psychosocial and/or behavioral interventions lasting 14 months to 2 years. One of these, the Multimodal Treatment of ADHD Study (the MTA study) also compared medication management of MPH to psychosocial and behavioral intervention alone and to a community control group.72–77 Two reports focus on the safety and continued efficacy of the noradrenergic agonist guanfacine extended release (GXR).70,71 Overall, the pharmacologic agents found to be efficacious and safe in shorter length trials provide continued maintenance of ADHD symptomatic improvement for at least 12 months. Few serious adverse events are noted, although GXR appears to be less well tolerated than other agents examined. Global ratings of impairment also indicate continued benefit. Placebo-controlled discontinuation trials are few; one trial discontinued treatment with amphetamine after 15 months,61 another discontinued MPH following 12 months and compared these with ongoing psychosocial intervention,75 and a third examined relapse in children receiving ATX for 12 months.67 These trials suggest that many, but not all, individuals continue to benefit from medication.

Most participants are children between 6 and 12 years of age at recruitment, primarily boys with ADHD-C. The more recent trials recruit few children with comorbid conditions except ODD. Attrition over time occurs for a variety of reasons, including adverse events and ineffectiveness. Retention of participants on active treatment at 12 months varies across studies and agents, from a high of 98 percent for immediate release MPH,58 75 percent for amphetamines,61 63 percent for OROS MPH,60 58 percent MAS XR,63 56 percent for ATX,67 and 43 percent for GXR.71 In general, those who remain on medications show continued benefit and report few adverse events. Over half of these studies were funded all or in part by industry, possibly leading to enhanced representations of effectiveness and safety.147

The following sections are organized by the agent under investigation.

Psychostimulants

Barbaresi, et al.,59 was a population-based birth cohort study with details from school records as well as medical records. They identified 379 children with “research identified ADHD,” of which 295 received stimulant treatment, 66 percent treated with MPH and 30 percent treated with DEX. The children were followed until a median age of 17.6 years for those who received stimulants, and a median age 18.6 for those who did not. The pattern of use was marked by interruptions and changes of stimulant type, with a median of three treatment episodes (defined as initiating or changing dose, or changing agent) per child. Boys were 1.8 times (95% CI, 1.1 to 3.1, p = 0.025) more likely to receive stimulants than girls. The median age of onset for the start of treatment was 9.8 years; those with ADHD inattentive type (ADHD-I) were slightly older at 12.7 years, and children with ADHD-C were 9.2 years of age. The median duration of treatment was 33.8 months, somewhat less for those with ADHD-I (19.1 months) than for those with ADHD-C (40.6 months). Nearly three-fourths of treatment episodes with either MPH or DEX resulted in a favorable response; boys were more likely than girls to experience a positive response with DEX (OR 3.4, 95% CI, 1.5 to 7.54, p = 0.002). However, DSM-IV subtype (i.e., ADHD-C or ADHD-I) was not differentially associated with a favorable response to either MPH or DEX. Eight percent of episodes were associated with a documented side effect; DEX was more likely than MPH to be associated with a side effect (OR 1.8, 95% CI, 1.1 to 3.0, p = 0.034). More side effects were noted among younger children and older adolescents.

Charach, et al.,57 followed 91 children who had been participants in a 12 month RCT of MPH and parent groups (see also Law and Schachar58). They were seen annually in a naturalistic followup. They noted that patterns of adherence varied considerably, with some children continuing to use medications, some discontinuing, and some using intermittently over 5 years. High baseline symptom scores were associated with longer adherence to psychostimulant medication (any type) and greater treatment response. However, children with high levels of symptoms remained symptomatic at year five, despite stimulant treatment. Children receiving medication also showed high levels of clinically significant side effects, compared to children off medication. The most common side effect was loss of appetite.

Gillberg, et al.,61 examined amphetamine response in 62 children 6 to 11 years old with ADHD, 10 percent of whom had pervasive developmental disorder, and 16 percent of whom had mild developmental delay (IQ 51 to 72). The study was initiated with single blind amphetamine treatment where all children improved in Conners parent and teacher ratings, followed by a 12-month double blind placebo randomized discontinuation trial of amphetamine. The primary outcome measured was time to discontinuation of double blind treatment; 71 percent of those randomized to placebo and 29 percent of those randomized to amphetamine stopped treatment or went on to open-label treatment (p <0.001). A final single blind discontinuation of amphetamine to placebo at month 15 for those still on amphetamine led to some statistically insignificant deterioration in teacher symptom scores but not parent scores. Other changes over time included improved IQ for children treated with amphetamine for 9 months or more compared with children treated with placebo for 6 months. Adverse events discussed included poor sleep, which occurred less frequently on single blind amphetamine than at baseline, and 33 of 59 children reported poor appetite following 3 months of single blind amphetamine. Abdominal pain and tics occurred at baseline and in both amphetamine and placebo conditions. Tics were also noted for children at baseline and on amphetamine and on placebo. Of greater concern, hallucinations were noted for four children, three on amphetamine and one on placebo; dose reduction or discontinuation remedied the hallucinations quickly. Weight gain on amphetamine was less than expected over 15 months, while height was not clearly affected.

Three studies specifically addressed the question of worsening of tics with psychostimulants, examining the development of tics while on active treatment and on placebo. Gadow, et al.,62 examined tics in 34 children, ages 6 to 12 years, with ADHD and chronic multiple tic disorder. There was no statistically significant worsening of tics, and there was a maintenance of benefit for ADHD symptoms over 2 years. Nolan, et al.,146 discontinued psychostimulant treatment after long-term use by 19 children with ADHD and chronic multiple tic disorders. Abrupt withdrawal neither improved nor worsened tics. Law and Schachar58 examined 91 children with ADHD but without diagnosable tic disorder at baseline. Nearly 20 percent of the children on active treatment and 17 percent of those on placebo developed clinically significant tics (risk ratio (RR) 1.17, 95% CI, 0.31 to 4.40) while deterioration of tics occurred for 33 percent of those with pre-existing mild tics on both active and placebo interventions (RR 1.0, 95% CI, 0.4 to 1.85). Therefore it appears that tics do not worsen on psychostimulants. All reports concluded by noting that for individual children dose adjustment or discontinuation may be required as some children may be individually susceptible to this adverse event.

Hoare, et al.,60 examined OROS MPH in 105 children, who had been stabilized on immediate release (IR) MPH. Following a 3-week open trial of once daily MPH at doses of 18mg, 36mg, or 54mg, 88 percent of families wished to enter the 12-month extension trial and 63 percent completed it. Effectiveness was rated higher among children aged 10 to 16 years, those taking either 36mg or 54 mg daily, and for children with ADHD-I. Of the participants who discontinued use, 24 percent were for lack of efficacy and 12 percent for adverse events (insomnia (N = 4), abdominal pain (N = 2), and other (N = 2)). Four children (4%) experienced serious adverse events. Adverse events reported in more than 5 percent of children were headache (9.5%) and tics (7.6%), and were not dose related.

McGough, et al.,63 examined once daily mixed amphetamine salts extended release (MAS XR) in 568 children, 6 to 12 years of age, 78 percent male, and 92 percent with ADHD-C, who had previously participated in one of two randomized placebo controlled trials without experiencing clinically relevant adverse events. The participants started the 24-month extension trial as one of three subgroups based on their previous trial, those on MAS XR, placebo, or no active treatment. All started a 12-month extension at 10mg MAS XR daily for 1 week, followed by weekly titration in 10mg increments as required, to a maximum dose of 30mg daily. Participants had an option to remain in the study for an additional 12 months, for a total of a 24-month extension. For those who were on no active treatment or on placebo, the parent report Conners global index scores improved by >30 percent following the initiation of the extension trial and this improvement was maintained over 24 months. The symptom scores were similar to those of the group who had remained on active treatment between the RCT and extension study. Fifty-eight percent of children remained on MAS XR for at least 12 months and 48 percent for 24 months. The majority of children received 20mg daily. Adverse events caused 15 percent of children to withdraw. The adverse events most commonly associated with subsequent treatment withdrawal were weight loss (N = 27), decreased appetite (N = 22), insomnia (N = 11), depression (N = 7), and emotional lability (N = 4). Serious adverse events were reported in 18 children (3%). Adverse events were more frequent with increasing dose; of those reported in the first 6 months at rates of more than 5 percent were loss of appetite (37%), headache (27%), insomnia (26%), abdominal pain (18%), nervousness (17%), weight loss (17%), and emotional lability (14%). Mean blood pressure measures increased by 3.5mm Hg, diastolic blood pressure by 3.5mm Hg, and mean pulse rate by 3.4 beats per minute.

Two studies, Findling, et al.,64 and Weisler, et al.,65 examined cardiovascular adverse events of MAS XR in 24-month open-label extension studies of clinical trials. In 568 children64 ages 6 to 12 and taking 10 to 30mg MAS XR daily and in adults65 taking 20 to 60mg daily, modest increases in blood pressure and pulse rate, and small changes in QT intervals on ECG were noted, all findings judged to be of minimal clinical significance. Four children discontinued due to cardiac events, one for tachycardia, two for intermittent chest pain (one child with premature ventricular contractions, and the other with sinus bradycardia), and one for hypertension.64 Seven adults were withdrawn from the study because of cardiovascular adverse events, two because of palpitations and/or tachycardia and five because of hypertension. 65

Summary of Psychostimulant Reports

Psychostimulants continue to provide control of ADHD symptoms and are well tolerated for months to years at a time. MPH improved ADHD symptoms and overall functioning alone or in combination with psychosocial/behavioral interventions for 14 months74 and up to 24 months.73,76 Concerns about exacerbation of tics with stimulants appear to be unfounded, although sample sizes remain small and may result in type II error. Some of the research summarizes information based on short-acting formulations of psychostimulants, requiring multiple doses daily. For instance, Barbaresi, et al.,59 reports that MPH is better tolerated than DEX. However, direct comparison of once-daily agents, such as OROS MPH and MAS XR is difficult, as Hoare, et al.,60 included adolescents and those with ADHD inattentive type, whereas the McGough, et al.,63 study sample had more than 90 percent with ADHD-C. Comparison might suggest that OROS MPH is better tolerated than MAS XR, but both studies had 15 percent of participants withdraw because of adverse events. Also, the methods for collecting adverse events may have been more sensitive in McGough, et al.,63 as they were collected by both spontaneous reports and by investigator inquiry. It is also possible that participants in the Hoare, et al.,60 study were offered relatively less efficacious doses, thereby diminishing the likelihood of adverse events. Currently, in the United States, MAS is approved for use in children 3 years of age and above, while in Canada it is approved for children 6 years and older.

Effectiveness or tolerability of psychostimulants based on sample characteristics, such as sex, age, DSM-IV subtype or comorbid disorders, show few differences. Barbaresi, et al.,59 found that DEX may be somewhat less well tolerated than MPH, that boys are more likely to show a positive response to DEX than girls, and that young children and adolescents tolerate stimulants less well than children in the middle of the age group examined. Overall, the benefits and safety of MPH for symptom control and general functioning are clearly documented, primarily for boys, ages 7 to 9 years at initiation with ADHD-C. The similarities between MPH immediate release as examined and other preparations of psychostimulants are many, both in terms of efficacy and side effect profile. Therefore, many researchers and clinicians assume that all psychostimulants are effective and safe for extended periods of time. The documentation for this assertion is not yet robust and there continue to be too few studies of long-term outcomes of psychostimulants to make direct comparisons of effectiveness and tolerability among them.

Atomoxetine (ATX)

ATX is a non-stimulant agent, a norepinephrine reuptake inhibitor that is approved for use in the treatment of ADHD. Two studies report on a double blind placebo controlled relapse prevention trial following a 12-week open-label titration trial.66,67 Six hundred and four children, ages 6 to 15 years, 90 percent boys and 74 percent ADHD-C, discontinued any previous medications prior to entering the titration trial. ATX was titrated up to 1.2mg/kg per day in twice daily doses, with further increases to 1.8mg/kg/day if indicated. Four hundred and sixteen patients whose symptoms decreased by more than 25 percent from baseline entered a 9-month randomized relapse prevention trial and after 12 months, 292 on ATX were re-randomized into a second double blind 6-month relapse prevention trial. Michelson et al66 examined the outcomes following the initial 12 months on ATX and noted that fewer children relapsed in the active treatment group (21%) than placebo group (37%), p <0.001. There were no significant treatment interactions with diagnostic subtype, treatment history, age, or site. Discontinuation due to adverse events occurred in nine out of 292 participants (3%) in the ATX group, and one of 124 participants (0.8%) in the placebo group. Adverse events reported by more than 5 percent of participants and statistically different between ATX and placebo groups include gastroenteritis and pharyngitis for ATX and weight gain for placebo. Both weight gain and height gain were slower in the ATX group. There were no clinically meaningful differences in laboratory values, vital signs, or cardiac QT intervals. Adverse events were similar to those reported during acute trials, specifically increases in heart rate and blood pressure.

Buitelaar, et al.,67 examined relapse rates during the second relapse prevention trial begun at 12 months and also showed that fewer in the ATX group (2.5%) relapsed than in the placebo group (12%) with RR for relapse 5.6 (95% CI, 1.2 to 25.6). Comparison of the two relapse prevention trials suggests that the relapse rate on placebo following a full year of active treatment was lower than the relapse rate on placebo following 12 weeks of treatment. The rates of adverse events were similar between ATX and placebo conditions for those who remained in the trial after 12 months of treatment.

Adler, et al.,68 reported on 385 (72%) of 536 adults with ADHD (mean age 42 years, 64% men) who entered an open-label continuation trial (up to 97 weeks) of ATX following initial 10-week RCTs. They had discontinued ATX following the trials, or remained on placebo, and therefore were symptomatic at initiation of the open-label trial. ADHD symptoms showed improvement of 33 percent on rating scales for total ADHD symptoms during the initial phase of the open-label extension; similar improvements occurred for total disability scores. Adverse events were similar to those noted in acute trials, primarily the expected noradrenergic effects, and included increased heart rate (mean change 5.1 beats per minute) increased systolic and diastolic blood pressure (mean change <2.0mm Hg) and mean decrease in weight of 1.3kg. Discontinuation due to adverse events was 11 percent. No clinically relevant changes in laboratory measures or QTc intervals on EKG were noted. Adverse events noted ≥10 percent were dry mouth (24%), headache (21%), insomnia (18%), erectile dysfunction (16%), nausea (15%), and constipation (14%).

Wernicke, et al.,69 reported on cardiovascular effects of ATX noted in an open-label 12-month extension trial following clinical trials for 169 children and adolescents. Initial doses varied from 0.5mg/kg to 2mg/kg/day in divided doses. For children, mean pulse rate and blood pressure increased during the initial few weeks and blood pressure increased over the first few months with increasing dose. Vital signs tended to stabilize at slightly higher levels over time, and subside upon discontinuation of ATX. Mean increases were small and not clinically meaningful. Likewise, no clinically significant changes were noted in ECG.

Summary of Atomoxetine Reports

ATX appears to be effective for continued control of ADHD symptoms and is well tolerated over 12 months. The research examining its use considers global functional assessments as well as ADHD symptom change. The measured threshold for effectiveness was a decrease in ADHD symptoms of more than 25 percent from baseline, and threshold for relapse was considered a return to more than 90 percent of baseline and increase in clinician rated CGI score of two or more points above the score following initial treatment trial. Relative to studies of other agents, these trials offer direct comparison with placebo for examination of relapse prevention, offering strong evidence of ongoing effectiveness and safety in children and teens for up to 18 months, although the thresholds may appear to be set to enhance measured effectiveness. Adler, et al.,68 offer a study of pharmacologic intervention over an extended time period in adults with ADHD.

Guanfacine Extended Release (GXR)

GXR is a nonstimulant noradrenergic agonist with selective effects on cortical alpha 2A adrenoreceptors. Similar to clonidine (another alpha 2 adrenoreceptor agonist which has been shown to be effective in improving some but not all domains for children with ADHD), guanfacine immediate release has been shown to be effective in reducing symptoms in ADHD in short-term RCTs. Two industry-sponsored studies examine long-term safety and efficacy of extended release formulations (GXR) in open-label extension studies of earlier clinical trials.70,71 These multisite studies were similar, enrolling children ages 6 to 17 years, approximately 75 percent boys, and 73 percent ADHD-C. Biederman, et al.,70 enrolled 240 (70%) of participants in previous trials, and administered GXR in 2 to 4mg doses daily. Sallee, et al.,71 studied a sample of 259 children given 1 to 4mg GXR daily, 53 of whom received co-administered psychostimulants. Results were similar in both studies. Reductions in ADHD symptom scores from the baseline of the preceding trial, and improvement in parent-rated global impressions were maintained throughout the extension studies; 57 percent and 60 percent were very much improved or much improved from baseline.

Eighty two percent (N = 198) of participants withdrew from the Biederman, et al., study by 12 months.70 Of these, 52 (22%) withdrew for adverse events and 25 (10%) for lack of efficacy; the most common reason for discontinuation was withdrawal of consent by 67 participants (34%). Somnolence, weight increase, and fatigue were the most common adverse events for discontinuation, with somnolence or sedation, but not fatigue, appearing dose–related. Reports of somnolence, sedation, and fatigue diminished over time, with 40 percent of participants reporting these symptoms at month one, and about 10 percent of those remaining in the trial at month eight reporting these adverse events. Of 11 serious adverse events reported, three were considered possibly or probably related to the study drug: one event of orthostatic hypotension and two events of syncope. Adverse events reported by more than 10 percent of participants were somnolence (30%), headache (26%), fatigue (14%), sedation (13%), cough (12%), abdominal pain (11%), upper respiratory infection (10%), and pharyngitis (10%). Mild reductions in blood pressure and pulse rates were common and returned to baseline upon tapering GXR. Three children had abnormal ECGs judged clinically significant, two with bradycardia and one had junctional escape complexes. Overall hypotension was reported in seven (3%) children, and bradycardia in five (2%). Two children were discontinued due to treatment emergent abnormal ECGs, worsening of a sinus arrhythmia and asymptomatic bradycardia of 46 bpm, two discontinued for hypotension and two for orthostatic hypotension, one discontinued for syncope, all of which were resolved on discontinuation. There were no changes in clinical laboratory analyses and no unexpected changes in height or weight noted.

Sallee, et al.,71 report 77 percent (N = 202) of children withdrew from the study prior to 24 months, 82 percent of those in the monotherapy GXR group and 57 percent of those in the group co-adminstered stimulants, suggesting the combination of GXR and psychostimulants was better tolerated than GXR alone. Overall, 10 percent stopped for lack of efficacy and 12 percent for adverse events. Adverse events reported in ≥10 percent of monotherapy group were somnolence (38%), headache (25%), upper respiratory infection (16%), nasopharyngitis (14%), fatigue (15%), abdominal pain (12%), and sedation (12%). In the GXR plus stimulants group, no somnolence, fatigue, or sedation were noted. Adverse events that occurred included headache (23%), upper respiratory infection (25%), nasopharyngitis (15%), abdominal pain (15%), pharyngitis (11%), decreased appetite (13%), and irritability (13%). As in Biederman, et al.,70 reports of somnolence, sedation, and fatigue decreased over time, from 35 percent early in the extension trial to below 15 percent among those who remained in the trial over 7 months. Patterns in vital signs suggested no clear trends in blood pressure or pulse. Heart rates less than 50 bpm were noted in 15 children (6% of the sample) and rates ≥100 were noted in nine (3%). While 28 children (14%) had new abnormal ECGs at end point, only two were considered clinically significant. One of these showed atrioventricular block, and was noted to have shown intraventricular delay on baseline ECGs; this child subsequently discontinued treatment. The other clinically significant finding was a child who showed significant but asymptomatic bradycardia in month three, at 45 bpm. This child had a baseline pulse rate of 63 bpm and an end of study rate of 76 bpm. For the entire sample, weight and height gains were as expected with only six children (2.3%) showing weight gain possibly related to the medication.

In summary, the extension trials of GXR suggest it is an effective treatment for ADHD and that it is reasonably well tolerated. However, it does not appear to be as well accepted a treatment for long-term treatment of ADHD in children as either psychostimulants or ATX. Unlike the reports discussed in earlier sections, the published reports for GXR did not identify how many children were in the original clinical trials from which the extension studies recruited participants. Eighty-two percent of recruited participants on GXR monotherapy discontinued prior to 12 months and 18 percent completed 12 months, compared to 58 percent of children on MAS XR,63 63 percent of children on OROS MPH,60 and 56 percent who entered the next phase of research following 12 months on ATX.67 While parents report benefit with GXR, in reduced ADHD symptoms and global improvement for a substantial number of children and teens with ADHD, high rates of somnolence, headache, and fatigue likely interfere with its use. Tolerance appears to be improved with concurrent administration of psychostimulants.71 The profile of adverse cardiovascular events with GXR suggests monitoring of cardiac status may be indicated, as there are reports of significant bradycardia, junctional escape complexes, and intraventricular delay.70 ECG changes judged clinically significant occurred in one percent of participants. Three percent of participants (seven of 198) discontinued because of cardiovascular events in the GXR trial, compared with less than one percent of participants (four of 568) in the MAS XR trial, and 0 participants (of 169) in the ATX trial.

Adverse Events: Cardiovascular Events, Cerebrovascular Events, and Rates of Growth

Due to the special interest in literature about adverse events for persons using medication for ADHD, two areas of inquiry required adjustments in inclusion criteria for this review: articles about potentially life-threatening events and articles about changes in growth rates. Research about life-threatening events requires large population-based samples; however, it is noteworthy that we found no case-control studies of these rare events. Therefore, for the review of life-threatening events, we included population-based cohort studies of people with ADHD. Three studies were identified, two about cardiac safety148,149 and one regarding cerebrovascular events.150 Recent studies examining growth rates for children using medication have often used age- and gender-adjusted population norms for comparison (see Tables 8 and 9).

Table 8. KQ2. Medication and adverse events—long-term effectiveness and safety.

Table 8

KQ2. Medication and adverse events—long-term effectiveness and safety.

Table 9. KQ2. Summary of studies reporting on medication and growth rate.

Table 9

KQ2. Summary of studies reporting on medication and growth rate.

Cardiac events: population-based studies. Two recent studies examine population rates of cardiac events among children and youth, ages 3 to 20, with recent diagnoses of ADHD, and compared those using stimulant medications to those no longer using stimulants.148,149 Rates of hospital admission for cardiac reasons are similar to rates in the general population. Rates of emergency department use for cardiac reasons were 20 percent higher for those with ADHD who use stimulant medication compared to those who do not.148 Rates were comparable among those using MPH and amphetamines. Use of concurrent bronchodilators, antidepressants, or antipsychotics, ages 15 to 20 years, and a history of cardiac problems were associated with increased use of the emergency department (ED).149

Cerebrovascular events: population-based study. Holick, et al.,150 used a health insurance database to examine adults with ADHD who initiated either psychostimulant medications or ATX and compared rates of cerebrovascular accidents (CVAs) or Transient Ischemic Attacks (TIAs). These groups were matched to each other using propensity scores and compared with a contemporaneous general population control, age and sex matched to the treatment groups. The groups were followed for a mean of 1.5 years, during which time 44 CVAs and 21 TIAs were confirmed among the three cohorts using medical record data. There was no difference in the rate of incidents between the ATX or stimulant treated groups. However, the combined ADHD medication cohort exhibited a higher hazard ratio (HR) (3.44, 95% CI, 1.13 to 10.60) for TIAs compared with the general population after adjusting for baseline risk factors. A similar pattern was not observed for CVAs. These results do not support an increased risk of CVA events for users of ATX over psychostimulants. However, users of ADHD medications may be at higher risk of TIAs than the general population.

Rates of growth. Studies examining the effects of psychostimulant treatment on growth rates for children with ADHD are listed in Table 9. Of these, six compared the height and weight to population norms by converting to age and sex population norms using z scores.152–157 Two studies compare adult or adolescent height to parent or sibling height or community control groups.154,158 Two studies compare growth rates to both population norms and community controls.53,78 Overall, the studies rated as “good” and “fair” identify somewhat diminished rates of growth, for both weight and height in children receiving MPH, DEX, or MAS. Two well designed clinical trials of psychostimulants, the PATS and the MTA study, both examined the question of growth in children with ADHD who received, and those who did not receive, psychostimulants. The PATS study53 is described in the MPH section of KQ1, and the MTA study78 in the combined interventions section of KQ2. Both studies document decreased growth rates for children receiving MPH over 12 months to 3 years.53,78 These studies note that clinical samples of children with ADHD are taller and heavier than the average for their sex and age. The research overall suggests that there may be an association with cumulative dose.152 Some, but not all studies suggest that catch up weight gain may occur when children take breaks from medication.

Spencer, et al.,159 examined growth in 61 children who had received ATX for 5 years. Both weight and height showed diminished rates of growth at the 12- to 15-month time points relative to population norms, but returned to baseline z scores over time.

In summary, medications used for ADHD appear to have a small but distinct dose–related impact on rates of growth for children with ADHD. Limitations in the studies include small sample size, many use population norms as comparison, and relatively short duration of studies, which interfere with clarification regarding final adult height following years of medication use.

Medication Versus Combination

Medication Plus Behavioral/Psychosocial Interventions. A total of 26 papers which compared medication management against multi-modal treatment (combined medication plus psychosocial/behavioral interventions) were identified (see Table 10). There were two large multicentre RCTs conducted in North America which had “good” internal validity: National Institute of Mental Health’s Multimodal Treatment Study of ADHD (MTA) study, with 14-month intervention and 8-year followup, for which 19 papers are included in this review,72–74,78,80–84,160–169 and the second study led by Abikoff, Hechtman, and Klein, with 2-year intervention, of which we include 5 papers.75,76,89,170,171 There was a small 6-month intervention RCT with 18-month followup in a Chinese population, which had “fair” internal validity.77 Another small study compared MPH, EEG biofeedback, and parenting style in a 1-year multimodal outpatient program that included MPH, parent counseling, and academic support at school. EEG biofeedback therapy was provided for 51 of the 100 subjects.172 These RCTs involved predominantly male children ages 7 to 9 with ADHD-C who have an IQ above 80.

Table 10. KQ2. Summary of long-term controlled studies comparing different treatment modalities for children/adolescents with ADHD.

Table 10

KQ2. Summary of long-term controlled studies comparing different treatment modalities for children/adolescents with ADHD.

There were 22 papers with “good” internal validity as rated by our assessment tool72–78,80–83,89,160,161,161,163–168,170,171 and two papers with “fair” rating.84,169 The following organizes the discussion by focusing on each study in turn, in order of its overall quality.

MTA study. The MTA study compared medication management, intensive behavioral treatment (PBT, child-focused treatment, and a school-based intervention), combined medication management and intensive behavioral treatment, and usual community care. The mean age of the participants at study entry was 8.5 years. The medication strategy in the MTA study was intensive and involved a systematic effort to fully suppress ADHD symptoms using MPH in divided doses.166 Children receiving combined treatment ended maintenance on a lower dose (31.1 ± 11.7mg/day) than the medication only group (38.1 ± 14.2mg/day). Two-thirds of the children in the community care group received medication, mainly MPH (mean dose 18.7mg/day); their visit duration and frequency were shorter than the MTA-medicated subjects (30 min. vs. 18 min. and 8.8 vs. 2.3 visits/year respectively).164

Primary outcomes analyzed included parent- and teacher-rated ADHD and ODD symptoms, comorbid conditions, reading achievement scores, social skills and functional impairment.74 Children in the combined treatment and medication groups showed significantly greater improvement in ADHD symptoms than the behavioral treatment and community care groups. Combined treatment was superior to behavioral treatment and/or community care in improving oppositional/aggressive symptoms, internalizing symptoms, teacher-rated social skills, parent-child relations, and reading achievement. Conners, et al.,72 utilized a single composite measure of treatment outcome by combining standardized parent and teacher measures, covering internal problems, external problems, and social skills, and found combination therapy to be significantly better than all other treatments, with effect sizes ranging from small (0.28) versus medication, moderate (0.58) versus behavioral treatment, to moderately large (0.70) versus community care. Medication management was significantly superior to behavioral treatment and community care, with small effect sizes (0.26 and 0.35 respectively). Behavioral treatment and community care were comparable. Swanson, et al.,165 utilized a categorical outcome based on the average rating by the parent and teacher of ADHD and ODD symptoms on the Swanson, Nolan, and Pelham, version IV (SNAP-IV) scale. The analysis gave the MTA medication algorithm a large effect size (0.59), with combined treatment incrementally superior to medication (effect size of 0.26). Across all treatment groups, rates of Conduct Disorder and anxiety disorders were reduced, and rates of mood and learning disorders remained the same at 14 months, with no difference between the treatment groups.168

The MTA 24-month outcome reported persisting superiority for both combined and medication groups, but with reduced effect size for both ADHD and ODD symptoms.73 The greater deterioration for the combination and medication groups compared to the behavioral and community care groups from the 14- to 24-month time points was related to patients stopping medication in the two former groups and starting medication in the latter two groups.160 By 3 years, Jensen, et al.,81 did not find any significant difference between treatment groups although each treatment group showed substantial improvements from baseline. There was significant reduction in rates of ODD/CD, anxiety, and depressive disorders, but no effect of treatment assignment was seen. Medication use declined for medication and combined treatment groups from >90 percent over the first 14 months to 71 percent, increased from 14 percent to 45 percent for the behavioral treatment group, and remained stable at 62 percent for the community care group. By 8 years, Molina, et al.,82 found that among those followed up (70.1% of original cohort), 32.5 percent of those who were medicated at 14 months were medicated in the past year. There were also no significant differences in medication use among the four treatment groups. They found no significant differences in the primary outcomes or additional outcomes including grades earned in school, arrests, psychiatric hospitalizations, and other clinically relevant outcomes between treatment groups. Overall, the ADHD symptom trajectories noted in the first 3 years appeared to continue in similar patterns through 6 and at 8 years.

Additional post-hoc analyses of the study’s 14-month results are discussed here. Jensen, et al.,80 reported that children with ADHD and a single comorbidity of anxiety disorders responded equally well to medication management and psychosocial/behavioral interventions for 14 months. Children with ADHD-only or ADHD with ODD/CD responded better to medication and combined treatment, while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined treatment. Wells, et al.,161 found that all three MTA treatments decreased self-reported negative parenting more than community care treatment, with no significant effect of treatment on positive parenting. Using more objective measurement by assessing parent-child interactions in a laboratory setting for 89.9 percent of the families in the MTA study, Wells, et al.,162 found significantly greater improvements in parents’ use of proactive parenting strategies in the combined treatment group than the community care group (Cohen’s d = 0.49) and the medication management group (Cohen’s d = 0.38). Hinshaw, et al.,163 found that reductions in negative and ineffective parenting practices at home could be related to improved teacher-reported outcomes in the combination group. Arnold, et al.,167 analyzed ethnicity as a moderator and found that combined treatment produced better outcome than medication management (effect size = 0.36) for the pooled minorities, but not for Caucasians. Hoza, et al,169 found that all groups remained significantly impaired on peer-assessed outcomes with no significant difference between treatment groups. Despite the use of an objective outcome, the study’s validity was affected by the ‘drop out’ of half of the original cohort.

A series of analyses using the 36-month data were conducted. It was hypothesized that the loss of relative superiority of the combined treatment and medication management groups could be due to selective treatment of the most severe cases, but Swanson, et al.,78 did not find evidence for this self-selection hypothesis. This analysis found decreased growth rates when initiating treatment in stimulant-naive children; this may be present for up to 3 years of treatment and accumulate to result in a difference of about 2.0cm in height and 2.0kg in weight. Molina, et al.,83 could not establish a clear benefit of medication treatment on subsequent delinquency and recommended re-evaluation at older ages. When controlled for baseline delinquency, the psychosocial/behavioral treatment group had a lower rate of substance use at 24 months. The published results at 36 months suggested that this benefit no longer held.83 While Molina has presented a different analysis adjusting for developmental stage, and showing continued benefit of psychosocial/behavior intervention for delaying substance use, this has not been published. Between 24 and 36 months, medication use was a marker for deterioration, and Swanson, et al.,84 did not find evidence that “self-selection,” the hypothesis that families with more impaired children are more likely to use medication, accounted for this.

Multimodal Study. The study by Abikoff, et al.,72,73 Hechtman, et al.,75,76,89,170,171 and Klein, et al.,171 randomized 103 children with ADHD ages 7 to 9 years who were free of conduct and learning disorders, and who had responded to short-term MPH, to receive MPH alone, MPH plus multimodal psychosocial treatment (PBT, behavior management training, family therapy, and child social skills training), or MPH plus attention control treatment (parental support and education) over a 2-year period. They reported that all subjects ‘relapsed’ when they received placebo substitution at the end of 1 year, suggesting that combination therapy did not attenuate symptom relapse following medication discontinuation.75 Significant improvement occurred across all treatments and continued over 2 years, and combination therapy was not superior.89 There were no differences among treatment groups for rates of diagnoses of persistent ADHD, ODD, CD, or psychosocial functioning at 24 months.76 In stimulant-responsive children with ADHD, the authors concluded that there is no support for adding an ambitious long-term psychosocial intervention to improve ADHD and ODD symptoms. There was also no difference in the social functioning variables examined between groups, which led the authors to conclude that there is no support for clinic-based social skills training as part of a long-term psychosocial intervention to improve social behavior. These conclusions may not apply for young children who do not show an early favorable response to stimulant treatment or who have comorbidities, especially conduct problems. Hechtman, et al.,170 examined the impact of treatment on parental practices. Psychosocial treatment did not enhance parenting practices, as rated by parents and children. Significant improvement in mothers’ negative parenting occurred across all treatments and was maintained.

Other studies. The smaller study of So, et al.,77 involved 90 ethnic Chinese children, 7 to 10 years old, randomized to receive either MPH or MPH with behavioral treatment for 6 months. The mean dose of medication was 13.6 to 16.8mg/day. Although the combined treatment group improved significantly more than the medication management group in ADHD symptoms at the end of the six month treatment period, there was no difference at 12 or 18 months. However, ODD symptoms improved significantly more in the combined group at 12 and 18 months; there was no noticeable improvement in the medication management group in terms of ODD symptoms. Over 18 months, there was faster rate of improvement in ADHD and ODD symptoms in the combined group, and all gains made were sustained in both groups. However, the study is limited by the relatively small sample size, high dropout rate in the medication-only group, and more significant ODD symptoms among those remaining in the trial.

The EEG biofeedback study of Monastra, et al.,172 reported post-treatment assessments with and without MPH. Significant improvement was noted on the Test of Variables of Attention and the Attention Deficit Disorders Evaluation Scale when participants were tested while using MPH. However, only those who had received EEG biofeedback sustained these gains when tested without MPH.

Summary

Overall, the results from these three cohorts indicate both medication and combined medication and behavioral treatment are effective in treating ADHD plus ODD symptoms in children, primarily boys ages 7 to 9 years of normal intelligence with combined type of ADHD, especially during the first 2 years of treatment. Overall, secondary analyses of the MTA study suggests that combined therapy may have a slight advantage over medication management during the first 14 months (effect size 0.26 to 0.28),72,165 especially for children with multiple comorbidities.80 However, if the child is free of conduct and learning problems and shows an early favorable response to stimulant medication, then medication alone is equivalent to combined treatment in controlling ADHD and ODD symptoms for the first 2 years.75,76 The MTA study also suggests that these two strategies are superior to psychosocial/behavioral treatment alone or community care during the first 2 years,73,74,160,169 with the exception that children with ADHD and anxiety disorder as their single comorbidity benefit equally from medication management and behavioral interventions for 14 months.80 It appears that psychosocial/behavioral treatment reduces the risk for substance use for 10 months following intervention, 24 months after baseline. Initial analyses suggest that this protective effect disappears by 22 months,83 while subsequent analysis adjusting for age, suggests that benefit is maintained through 22 months post-intervention (3 years after baseline). These results have not appeared in a peer-reviewed publication, although formally presented (Molina, October 2010). No treatment strategy is clearly superior in reducing other comorbid psychiatric disorders at 14 months or 3 years.81,168 The trajectories for outcomes identified at the 3-year assessment point are generally maintained at 6 and 8 years with the majority of youth (including those in community care), maintaining benefit relative to baseline, but not improving to the degree of a nonclinical comparison group of children not referred for assessment or treatment. A small proportion (14% of cases) of youth deteriorated by the 3-year assessment after formal interventions ceased.83 Continuity of care following the end of a research study has not been investigated as a potential factor contributing to deterioration. Clearly, participants accessed a complex mix of interventions after following the protocol treatments82,83

Combining medication with behavioral/psychosocial treatment reduces the dose of psychostimulant medication required to maintain behavioral effects and may retain patients in treatment, at least among Chinese families.77 In So’s study involving Asian children, the overall mean daily dose of stimulant medication was less than half that used in the MTA study, although cultural and genetic factors may contribute to this observation.77 From Abikoff’s 2004 study, it may be more cost-effective to treat stimulant-responsive children free of learning and conduct problems with medication alone.75,76 Treatment with medication, intensive behavioral treatment, or a combination of the two can reduce negative parenting, but combined treatment may be the most effective in improving positive parenting.89,161–163,170

Behavioral/Psychosocial Treatment Compared With No Treatment

The literature describing behavioral treatments commonly focuses on these interventions for outcomes of disruptive behavior, not ADHD symptoms, even though these are commonly comorbid conditions. Therefore, few long-term extension studies lasting 12 or more months are available. One paper investigated a behavioral/psychosocial treatment program for parents of children with ADHD. The efficacy of a 9-week parent stress management training program for reducing parenting stress and improving parenting style was compared to a wait list control group, and they were followed up at one year. The study by Treacy, et al.,173 of “fair” internal validity, involved 63 parents from 42 families with at least one child (ages 6 to 15 years) diagnosed with DSM-IV ADHD. They were randomized to either the intervention group or control wait list for 9 weeks. The controls received similar intervention thereafter, and all participants were followed up for one year. The intervention was more effective for mothers than fathers, who reported less stress and less negative parenting. These improvements were maintained at one-year followup.

Long-Term Academic Achievement and School Outcomes Following Interventions for ADHD

While children with ADHD have impairments in many areas of functioning, a common primary focus of concern is academic achievement. This section describes 13 studies reporting on academic achievement outcomes, broadly defined as improvements in standardized test scores and report card grades, and decreases in absenteeism and grade retention following interventions for ADHD (see Table 11). The majority of studies reporting on academic functioning included academic measures as one of several secondary outcomes. Academic outcomes following medication intervention were examined in four studies with “fair” and “good” quality ratings.61,85,86,174 There were five reports looking at academic effects of multimodal interventions in two cohorts; these are reported in publications describing the randomized clinical trials with “good” internal validity.74,89 Four publications of “good” quality describe extensions of the MTA study, reporting on assessments at different time points up to 8 years of followup.73,81,82,90 Three reports on two cohorts examined academic achievement as the primary outcome following classroom-based interventions. These studies were rated as having “fair” internal validity.91,92,175 Overall results indicate that there are improvements in academic functioning with medication, especially in reading skills. There is no added benefit with combining behavioral or psychosocial components to the medication interventions. In contrast, classroom-based programs to enhance academic skills are effective in improving achievement scores in multiple domains, but the benefits are sustained only as long as the intervention is implemented.

Table 11. KQ2. Summary of studies reporting academic outcomes.

Table 11

KQ2. Summary of studies reporting academic outcomes.

Following are the results of the studies reporting on academic outcomes, organized by the type of intervention.

Medication Interventions

The medication interventions were primarily psychostimulants. Powers, et al.,174 followed a group of 90 ADHD children for the average duration of 9 years and the average duration of receiving psychostimulants was 5 years. They found that adolescents diagnosed with ADHD at childhood who had received stimulants for at least 1 year, compared to those who had not, had higher scores on three measures of academic achievement, word reading, pseudo-word reading, and numerical operations. They also showed higher secondary school grade point average (GPA). However, the medicated group did not reach the level of academic function of their non-ADHD peers. The study provides evidence of a modest positive effect of stimulant medication on long-term academic function. In spite of controlling for IQ, the participants were not matched on comorbidity of learning disability, potentially interfering with the conclusions.

Barbaresi, et al.,85 also investigated the benefits of long-term stimulant medication use on academic outcomes in a retrospective birth cohort, including 370 ADHD children. The mean duration of treatment for cases that had a history of receiving medication was nearly 3 years. The participants were followed to a median age of 18 years. There was no difference with regard to mental retardation and learning disability between the two groups. Overall, the authors found a positive correlation between cumulative stimulant dose and last documented achievement skills at a median age of almost 13 years. School absenteeism was significantly lower in the treatment group; any treatment and duration of treatment with stimulants were both negatively associated with the percentage of days absent. Stimulant-treated children were nearly two times less likely to be held back a grade. In contrast, one area of academic skills, the average reading score at the time of the last assessment, was similar between the cases that were treated and those not treated. Biederman, et al., 200986 followed 140 boys with ADHD, 6 to 17 years of age at diagnosis, 73 percent had received stimulants, with a mean duration of treatment of 6 years. Those using medication were less likely to repeat a grade.

Other studies reporting on academic outcomes61,86 found that children treated with stimulants experienced improvements in measured IQ and less grade retention.

In summary, it seems that extended use of psychostimulant medications may enhance some dimensions of academic functioning. However, the outcomes reported are diverse and suggest that more investigation of this question is required.

Combination Interventions

MTA studies are described comprehensively earlier in this report. Following is the description of MTA results in academic and school performance. At the 14-month endpoint of the RCT, combined treatment was superior to intensive behavioral treatment and community care in improving reading achievement. At the 24-month assessment, nine months following discontinuation of the interventions, the differential between groups was no longer present.73,160 At the 36-month assessment, the intention to treat analysis of the study also showed no significant difference between the treatment groups on reading achievement scores, similar to the other symptomatic and functional outcomes reported.81 However, all treatment groups showed substantial improvement from baseline in all domains, although the relative effect size for reading achievement was small compared to other areas (reading 0.1 to 0.2, ADHD symptoms 1.6 to 1.7, functional impairment 0.9 to 1, and social skills 0.8–0.9). After 8 years, intention to treat analyses again showed that originally randomized treatment groups did not differ significantly on academic assessments and grades earned at school.82 Looking at the trajectory of symptoms, impairment and academic achievement, there was convergence of treatment groups from 36 months to 8 years and maintenance of improved overall functioning relative to the baseline, with a somewhat different pattern for mathematics achievement. Examination of math achievement showed a positive association between past year medication use and improved scores at 36 months, 6 years, and 8 years. In contrast, past year medication use was associated with worse hyperactivity impulsivity, ODD symptoms, and functional impairment. Past year medication use was interpreted by the authors as suggesting continued rather than new onset use, and therefore may represent longer duration of use.

The other study reporting academic outcomes following extended use of combination psychostimulants and multimodal psychosocial intervention was a 24-month RCT, described earlier in this report.89 It included 103 participants, ages 7 to 9 years, with ADHD (excluding those with documented learning disabilities or CDs), who received either MPH alone, MPH combined with multimodal psychosocial and academic remediation treatment, or MPH combined with an attention control intervention. Significant improvement in academic functioning was observed with all three interventions at 24 months. There was no advantage on any measure of academic performance with the combination treatment over MPH alone.

In summary, the results of studies investigating combined medication and psychosocial/behavioral interventions indicate improvement from baseline in academic outcomes, with no difference in effect between combined interventions and medication alone. Results from the MTA study suggest that there may be different outcome trajectories for reading and mathematics achievement.

Classroom-Based Interventions

The study by Evans, et al.,175 is a controlled clinical trial of the Challenging Horizon Program and consultation (CHP-C) versus a community care control group over the intervention period of 3 years and a followup after 6 years. CHP-C was an intervention targeting academic skills such as assignment tracking, note taking, and organization skills in addition to social skills training, conversation skills, and problem solving. The beneficial results of treatment on ADHD symptoms were few during the first year of intervention but emerged after 2.5 years. However, neither teacher nor parent rating of academic functioning showed any significant academic benefit. Similarly, no long-term effect was found in student GPA.

The study by Jitendra, et al.,91 consisted of a 15-month RCT of the Intensive Data-based Academic Intervention (IDAI) versus the Traditional Data-based Academic Intervention (TDAI). Volpe, et al.,92 reported the results of this study after a 1-year followup. The assessments at 3, 12, and 15 months of the intervention indicated that both consultation groups demonstrated improvement in reading and mathematics skills on curriculum-based measurement (CBM) and in report card grades, although grades improved more for reading than for mathematics. The followup study at 1 year after discontinuation of interventions revealed that while students in both groups maintained the previous achievements, continued growth in skills was significant only for reading fluency.

While there are few comparative classroom-based intervention studies lasting 12 months or more, information from the ones available is mixed. Some programs are clearly beneficial and lead to improvement in academic skills for children with ADHD, but only as long as they continue to receive them.

Summary

The review of the academic outcomes with long-term followup of treatment interventions revealed benefits with medication interventions in some limited domains, such as very specific skills related to reading and arithmetic. Combining psycho-behavioral and academic skills interventions with medication offers no additional gains over and above that of medication alone for children with ADHD without comorbid learning disabilities. The psychosocial/behavioral intervention in the MTA study included a home and school focus on homework which successfully improved homework completion for up to two years.90 Interventions for academic skills in classroom-based programs enhance both academic achievement and grades, but the findings support the need for sustained intervention to provide continued improvement in academic skills and functioning over time.

Long-Term Studies (5 or More Years) Examining Stimulant Medication Treatment

The studies reviewed in this section examine outcomes which were five or more years after initiation of the intervention (see Table 12). All the studies identified compared those who had been treated with stimulant medication against those who had not. The 6 to 8 year outcome of the MTA study, which compared medication, behavioral, and multimodal interventions, has been discussed in an earlier section.82

Table 12. KQ2. Summary of controlled studies reporting very long-term (>5 years) outcomes of ADHD treatment.

Table 12

KQ2. Summary of controlled studies reporting very long-term (>5 years) outcomes of ADHD treatment.

There were 15 papers identified. Two studies were rated with “good” internal validity,82,176 nine studies had “fair” internal validity,57,86–88,177–181 and four were weak,151,182–184 according to the quality assessment tool used. Twelve papers57,86–88,151,176–182 reported on prospective followup studies of one or more cohorts of ADHD youth, while two were retrospective studies.183,184 As these papers reported on a variety of outcomes, they are summarized according to the outcomes studied. Only studies meeting criteria for at least “fair” internal validity are discussed below.

Psychiatric Disorders

Biederman, et al.86 conducted a 10-year prospective cohort followup study involving 140 Caucasian male children with ADHD, ages 6 to 17 years at baseline, which controlled for parental psychopathology. Out of the 112 participants assessed, 73 percent had lifetime treatment with stimulant medication, starting at a mean age of 8.8 years for a mean duration of 6 years. Those who were treated with stimulants were significantly less likely to subsequently develop ODD, CD, depressive, and anxiety disorders, and were less likely to repeat a grade.86 There was no significant difference for Bipolar Disorder between groups.

Substance Use Disorders

Katusic, et al.,87 reported on 379 research-identified ADHD children from a birth cohort (74.9% boys) and followed them up for a mean duration of 17 years. While 295 received stimulant medication (alone or in combination, median average daily dose of 21.4 MPH-equivalent units, median duration 34 months, median age at treatment 10 years), 84 did not receive treatment. The study found stimulant treatment to be associated with reduced risk for later substance abuse among boys, but not among girls. Mannuzza, et al.,88 followed 176 MPH-treated Caucasian male children, ages 6 to 12 years, with DSM-II hyperkinetic reaction but without CD, into adulthood (mean age 25 years, retention rate 85%), and overall found no association between use of stimulants and substance use outcomes. However the early-treated subjects (age 6 to 7 years) had lower lifetime rates of substance use disorders compared with those treated at older age. Age at stimulant treatment initiation was also significantly and positively related to the later development of antisocial personality disorder, but was unrelated to mood and anxiety disorders. The study by Biederman, et al.,86 which was described at the beginning of this section, also examined substance use disorders as an outcome. The analysis of 56 medicated and 19 non-medicated boys who were over the age of 15 (54% of original cohort of ADHD children) at the 4-year followup, revealed that those who were medicated were at a at lower risk for substance use disorders.179,182 However, when they reassessed 112 young men (80%) after 10 years (mean age at followup was 22 years), they found no associations between stimulant treatment (including age and duration of treatment) and alcohol, drug, or nicotine use disorders.179 The report by Wilens, et al.,181 on the 5-year outcomes of the same cohort of girls as previously studied by Biederman, et al.,185 assessed 114 (mean age at followup 16 years, 95% Caucasian, 67% treated with stimulants) of the original 140 English-speaking females ages 6 to 18 years with ADHD. They found stimulant treatment to reduce the risk of development of any substance use disorder and cigarette smoking, even after controlling for CD. Huss, et al.,180 performed a multi-site retrospective study on a nonrandomized cohort of 215 ADHD children. One hundred and six received treatment with short-acting MPH (mean duration of treatment was 2.3 years) while 109 did not. The medicated group was significantly delayed in their age of onset of regular smoking, by a time period of approximately 2 years. Monuteaux, et al.,176 followed up on 99 subjects (70% male, 80% Caucasian, with a mean age of 13 years) with ADHD involved in an initial year-long placebo-controlled RCT of bupropion treatment (mean dose 3.2mg/kg at week 52) for up to 6.5 years (the mean duration of followup was 12 months). Twenty-nine study subjects received concurrent stimulant treatment (mean maximum dose 1.0mg/kg). They found bupropion not to be effective in the prevention of smoking, but stimulant treatment was associated with statistically significant lower risk of smoking initiation (p = 0.03) as well as a lower risk of continued smoking (hazard ratio (HR) = 0.3, p = 0.02).

Several of the above studies suggest that stimulant treatment may protect against early onset of adolescent substance use, however, most of the studies were cohorts where families self-select into treatment conditions rather than being randomized. Therefore, the apparent benefits of stimulant treatment may result from other nonspecific protective factors associated with this choice. For example, the level of detail reported in most studies did not include potential co-interventions such as PBT, or school interventions.

Other Functional Outcomes

In their 30-year prospective longitudinal study, Satterfield, et al.,178 followed 179 Caucasian patients diagnosed as ‘hyperactive’ between ages 6 to 12 years, whom they reported would have met DSM-IV-TR criteria for ADHD (78% had parent-reported conduct problems), and studied their official arrest records later in adulthood. There was no statistically significant difference in the criminality rates studied between those who had received drug treatment only (N = 103) and those who had received combined treatment (the behavioral component included PBT, individual or group therapy for the child, family therapy, and educational therapy). Even the ‘most-treated’ subgroup, who received 2 to 3 years of combined treatment, did not differ in the rate of arrest from those who received medication management only. The rates of anti-social behavior were no greater in ADHD individuals without concomitant conduct problems as children (7.8%) than in the community control group (8.0%).178

Treatment-Adherent Versus Treatment-Non-Adherent Groups

Charach, et al.,57 followed up 79 of 91 participants (81% males with no comorbid anxiety or mood disorder) of a 12-month randomized controlled trial comparing MPH and parent groups. Those who were adherent to medication showed better teacher-reported outcomes at years two and five, but by year five, only 16 treatment-adherent and 14 nontreatment-adherent patients remained. For those who continued to use medication, stimulants continued to be effective with few side effects. The study sample size was small and adherents tended to have more severe baseline ADHD symptoms. Youth who no longer found medications effective or who experienced adverse effects may have discontinued.

Summary

The outcomes and time frames varied across studies. Except for Biederman179 and the Wilens181 group, which studied an exclusively female cohort, all others studied an exclusively or predominantly male sample. Stimulant medication might protect against psychiatric disorders (e.g., ODD, CD, depression, or anxiety disorder) in the long-term (at 10 years). Some studies suggest that stimulant medication reduces substance use disorders in late adolescence,87,181 while another reported no benefit by young adulthood.179 Two studies suggested stimulant medication may protect against nicotine use.176,181 Treatment with stimulant medication, especially at an earlier age, may delay onset of smoking and reduce substance use disorder.88,177,180 However, these benefits may disappear by adulthood.88,179

Satterfield found no clear effect of childhood intervention on arrest rates in adulthood.178

Key Question 3. How do (a) underlying prevalence of Attention Deficit Hyperactivity Disorder, and (b) rates of diagnosis (clinical identification) and treatment for Attention Deficit Hyperactivity Disorder vary by geography, time period, provider type, and sociodemographic characteristics?

The introduction to Key Question 3 (KQ3) underlines the complexity of addressing issues of ADHD prevalence in the population, compared with prevalence of clinical identification and of treatment. The literature obtained to address the issues was largely based on epidemiological surveys and administrative data sources in the United States. From this body of research, it appears that clinical identification in the United States exceeds estimates of population prevalence worldwide. As a corollary, ADHD medication use is higher than expected for per capita GDP. Variability exists among regions of the United States, with lower rates of identification and medication treatment in the West than in other regions. More boys than girls, and more Caucasians than African-Americans or Hispanics receive diagnoses and treatments. Rates of identification and treatment have increased over the past 20 years, especially among girls and adolescents. While rates of medication use are small compared with school age children, they have been increasing among preschoolers and adults as well. Service provider characteristics and access to insurance are important health systems factors which play influential roles in the receipt of treatment.

Some important limitations were imposed on the review process for KQ3. While the literature was searched using the methodology of a systematic review, selection of papers for inclusion was not subject to the same constraints dictated by the methodology, since it was included as a context piece and choices were made as to which of the over 440 included reports appeared most pertinent to the question asked. With the assistance of peer reviewer feedback, other relevant papers were identified and added to this section.

Underlying Prevalence

As will be evident from Tables 13 through 20, within the ranges of prevalence reported worldwide, from different regions, and even from different studies in the same region, there are nearly as many estimates as published studies.93 The thrust of KQ3 is to identify the background or “endemic” rate of ADHD and compare it with rates of clinical identification and subsequent treatment. The question implies that there is a “true” rate of disorder but, as indicated earlier in this report, and discussed more fully below, historical, cultural, and contextual factors affect the definition of ADHD. Moving into the clinical context, characteristic traits or symptoms alone do not confer the status of disorder, but poor functioning in a particular context, causing distress and concern for the individual and family, is important. Below are comments about methodological and contextual aspects of ADHD that influence the interpretation of results.

Table 13. KQ3. Study design and application to ADHD research.

Table 13

KQ3. Study design and application to ADHD research.

Table 14. Timeline of identification of ADHD and development of treatment—derived from Eisenberg and Mayes.

Table 14

Timeline of identification of ADHD and development of treatment—derived from Eisenberg and Mayes.

Table 15. KQ3. A sample of summary data for clinical diagnostic prevalence of ADHD among children in the United States.

Table 15

KQ3. A sample of summary data for clinical diagnostic prevalence of ADHD among children in the United States.

Table 16. KQ3. A sample of summary data for treatment prevalence for ADHD among children in the United States.

Table 16

KQ3. A sample of summary data for treatment prevalence for ADHD among children in the United States.

Table 17. KQ3. A sample of summary data for provider type for ADHD in the United States.

Table 17

KQ3. A sample of summary data for provider type for ADHD in the United States.

Table 18. KQ3. A sample of summary data for clinical diagnostic prevalence of ADHD among adults in the United States.

Table 18

KQ3. A sample of summary data for clinical diagnostic prevalence of ADHD among adults in the United States.

Table 19. KQ3. A sample of summary data for treatment prevalence of ADHD among adults in the United States.

Table 19

KQ3. A sample of summary data for treatment prevalence of ADHD among adults in the United States.

Table 20. KQ3. A sample of summary prevalence information by region and subgroup.

Table 20

KQ3. A sample of summary prevalence information by region and subgroup.

Methodological Considerations

Additional complexity for identification of community prevalence is introduced by methodological issues regarding identification of the population at risk, individual cases within that population, measurement reliability and validity, and quality of data sources. Once a definition of disorder is chosen (e.g., using specific diagnostic criteria), operationalizing the definition for use in large population-based studies raises issues. The symptoms used for characterizing ADHD, as well as quality of day-to-day functioning, are generally understood to exist on a continuum within a community; the question then becomes how to choose a threshold on that continuum that maximizes accuracy. The choice of measure, its reliability, validity, and the source of informant, are all important. Frequently, the cost, feasibility, and measurement burden on informants influence choice of measures, as well as methods of data collection (e.g., epidemiological survey or use of pre-existing administrative data). Study designs used to answer KQ1 and KQ2, (RCTs and observational cohorts) use volunteer participants and have rigorous diagnostic and intervention specificity. The studies compiled for KQ3 are descriptive and use research designs geared for large community populations. Strengths include generalizability of information to large segments of a community population, while weaknesses include a loss of detailed descriptions of individual cases. Administrative data provide important information about trends in actual clinical practice. Since the data are collected for nonresearch purposes (e.g., insurance claims to justify use of intervention, prescription records of tablets bought), reliability and validity of case identification and characterization of treatment received is comparatively weak. Relative strengths and weaknesses of study designs are described in Table 13.

Definition of ADHD

While there are many, one of the key challenges which obscures definition of ADHD cases and therefore contributes to the difficulty of defining its prevalence, is the difficulty identifying children and adults in a population who display the representative behaviors in the middle range of possibility. The nature of the condition is defined by the context of a situation – with other people, in families, in classrooms, and in play yards. Patients at either end of the spectrum, those having the true condition and those who clearly do not, are quite readily identified; however, there is a large population in the centre for whom the picture is less clear. Rather, the condition is a matter of degree with no startlingly clear boundaries and is often understood as a continuous variable rather than a categorical one. In common with other medical disorders, the use of diagnostic criteria imposes a categorical paradigm, which is subsequently used for decisionmaking regarding recommendations for treatment within the individual clinician-patient relationship, or for describing population health needs.186

Criteria for International Comparison

The history of the identification and inclusion of ADHD and related disorders in disease classifications is also instructive in this regard (see Table 14). Since introduction of Hyperkinesis Syndrome of Childhood in DSM-II (1968) and ICD-9 (1977) and Attention Deficit Disorder (ADD) to the DSM-III (1980), subcategories have burgeoned with variants and subtypes further parsed with each release of updates to the classification systems. This process highlights two additional issues which affect prevalence estimates as well as diagnosis of individuals, the evolution of criteria and how these influence who is diagnosed with the condition over time, and how these criteria are interpreted and operationalized in real life situations rather than within the rigorous setting of research.187 Different prevalence rates have been derived for the same population when the results from questionnaires based on the diagnostic criteria of DSM-III-R and DSM-IV are analysed.188

ADHD has only recently been recognized as persisting among the adult population,190,191 although it is not yet differentiated from formal classification with a childhood disorder. The work on estimating prevalence of ADHD in adult populations is further obscured since, as a result of lack of diagnosis in childhood, retrospective self-report measures are often accepted as a best available proxy for diagnosis of ADHD.192,193

Lower rates of background prevalence are generally cited in Europe and there may be more than one explanation or factor contributing to this discrepancy. The DSM criteria, the use of which is favored in the United States, are generally cited as being more inclusive, such that higher rates are consistently cited in regions where studies use these; in Europe, however, the ICD codes are used preferentially and these are generally agreed to require more stringent interpretation of criteria, resulting in much lower reported rates of ADHD.109,110,194 Santosh, et al.,195 report that only 25 percent of children in the MTA study who were diagnosed as ADHD using DSM criteria would have met criteria for “Hyperkinetic disorder” using the ICD system. Other classification options have also been put forward for consideration, such as the ICF,196 which introduces considerations of function and impairment into the picture of ADHD, the composite international diagnostic interview (CIDI),93 another instrument from the WHO which was used as part of their global mental health survey, the Development and Well-being Assessment (DAWBA), used by the United Kingdom for a national statistics study of child psychiatric morbidity197 and the ADHD Rating Scale, 198 among many others.

Instruments

A vast array of standardized, and not so standardized, measures have been used to assess ADHD children in research and in clinic, and may be applied to situations for which they were not designed so that the resultant data is interpreted in a manner not consistent with their psychometric properties. Even when assessment instruments are validated and applied in a standardized manner, the sheer variety of validity tests makes comparisons difficult. The logistics of finding trained personnel to make rigorous identifications is impractical on a scale large enough to identify the background population prevalence of the disorder and, therefore, clinical research measures have been adjusted to create the simpler and less time-consuming diagnostic screening measures used in epidemiological surveys adminstered by nonprofessionals. How these instruments are collected, interpreted, and applied may be a source of imprecision.199 Lack of standardization across studies can make comparison difficult.23 To date, there has been limited monitoring reported in the literature of fidelity of application, even with the most widely used instruments.

Cultural and Ethnic Observations

Cultural expectations and child-rearing practices may also influence background prevalence rates. Harkness, et al.,200 observes that expectations regarding normal development in infants vary from country to country, as well as beliefs about sleep hygiene, optimal socialization for infants, and different classroom cultures and expectations as to desirability of whether to teach and promote attention and focus, as in the Netherlands - or to ‘stimulate,’ which is valued in the United States186,200 Ethnicity may influence the interpretation of behaviors, as well; Gidwani, et al.,201 find differences in perception and interpretation of hyperactivity in U.S. subpopulations, Stevens202 in regional rates of identification and service provision, while Mattox and Harder203 report similar findings in their review of ADHD in diverse populations, from the perspective of social work.

Point of View

Diagnostic measures of childhood ADHD, whether detailed measures or simpler screening instruments, generally rely on parents or teachers to describe symptoms and impairment. More rigorous studies include both parent and teacher informants, since identification of the clinical disorder should be documented as causing impairment across settings. Teacher reports generally correspond only partially with parent reports.199,204 Similarly, for studies using youth self-report as a key source of information, adolescents and their parents show only partial agreement.204 The child may act differently in different settings and contexts, but the informants may also hold different expectations for child behavior.

Parental understanding of effective parenting strategies may influence interpretation of normal child behavior,205 some of which will resolve with maturity;206,207 Children have a limited repertoire of responses to stress, and can show behaviors which mimic ADHD but which are not. Researchers have observed that family stressors in the forms of poverty,208 trauma, 209 insurance status,210–213 disordered sleep,214 and food insecurity215 contribute to apparent rates of behavioral problems in children of the affected households.

Teachers may exert significant influence in who gets diagnosed since they may be the first to introduce the idea of ADHD to a family as a potential “diagnosis” for their child, and this identification may be influenced by a myriad of social factors, such as teacher perceptions and understanding of the child, the family, and background.216–220 Nevertheless, the more subtle influence of halo221 and rater 222 effects may still be found to influence diagnosis, treatment, and thus expressed prevalence rates. Similarly, the concept of ‘a good student’ is culture-bound, which makes the correct attribution of behaviors and their interpretation as beyond an accepted norm within a particular classroom very unlikely.222

The discrepancy between the reports of parent and teacher informants may also introduce a confounding effect, as noted by Costello, et al.,223 in the U. S., while Rowland, et al.,224 further demonstrate that the weight given to the observation of a particular informant influences the classification into a subtype. Discrepancies between parent and teacher assessments have also been identified in Japan.225

For estimates of adult ADHD, self-report measures are used. However, aspects of the diagnosis depend on a history of having had ADHD as a child. For this information, both clinicians and researchers depend on retrospective reports from adults about their own behavior as children, and it is therefore open to problems with interpretation.

Underlying Population Prevalence of ADHD Compared With Clinical Identification of ADHD and Subsequent Treatment of ADHD

The section above discussed the methodological pitfalls to examining the background population prevalence of ADHD using epidemiological methods that include diagnostic screening measures. Despite the difficulties noted, the screening measures that include symptom scales and measures of impairment most closely approximate a valid and reliable diagnosis for purposes of accurately assessing population prevalence.93 In comparison, an additional level of contextual complexity is added when determining the prevalence of diagnosed or clinically identified ADHD. Clinical identification can be impacted by access to clinical services and by service provider and patient characteristics. The most common way this prevalence has been ascertained in the United States is by including items in epidemiological surveys that ask caregivers, usually mothers, if their child has ever been diagnosed with attention problems or ADHD by a professional.104,219,226,227 Froehlich, et al.,104 examined both background population prevalence and parent-reported clinical identification and treatment in a nationally representative U.S population; approximately half the children identified with ADHD via research measures had a prior clinical identification of ADHD, and a third were treated. In contrast, Barbaresi, et al.,228 examined medical and school records in a population birth cohort in Rochester, Minnesota for documentation of diagnosis. This study of written records noted a continuum of certainty regarding the clinical diagnosis, where definite diagnoses were more likely to result in higher rates of treatment than diagnoses where the record was less certain. Indeed, in the cohort from Rochester, Minnesota, definite diagnoses resulted in 85 percent of children receiving stimulant treatment compared with probable diagnoses resulting in 40 percent of children receiving treatment.228

Characteristics of service provider type as well as system of remuneration have been linked to likelihood of both clinical diagnosis and treatment.2,227,229 These additional sources of potential bias are important in understanding research using administrative databases as sources of information. Recent studies examining trends in identification and prescribing practices using insurance claims and prescription databases offer useful information about geographic and time trends in clinical practice, but pressures to justify treatments shape data reporting and collection. Patient and parent requests also play a role. In a 1999 survey of Canadian physicians drawn from family physicians, developmental and general pediatricians, and child psychiatrists, the top four explanations selected for recent increases in MPH use were “increasing public awareness of ADHD and its treatments,” “pressure from parents and teachers to use medications to treat ADHD,” “acceptance of medication as a treatment for ADHD,” and “few resources for other interventions.”230 Other pressures occur among university age patients. There are societal pressures on university and college campuses to use stimulant medications as “study aids”231 and likely, motivated students can convincingly feign ADHD symptoms,232,233 presumably well enough to acquire prescriptions from harried physicians. Despite these examples, however, analysis of prescription trends in administrative databases can provide insights into service access and provision gaps.127

Geography, Time Period, Provider Type, and/or Sociodemographic Factors in Studies of Population Prevalence

Of the above-mentioned factors, recent studies from a variety of countries primarily address issues of age, gender, and in some cases, SES and ethnicity/race in the ascertainment of ADHD prevalence. In general, epidemiological survey methods are used and include diagnostic screening measures, using either a parent or teacher informant or questions regarding past identification of the disorder from the parent. The bulk of the literature consists of studies of children with ADHD conducted either in North America or Western Europe, with clear gaps in knowledge on the subject of the prevalence of ADHD among adolescents and adults, and in ethnically distinct regions where it has been scarcely researched. The general pattern of results includes higher rates of the disorder among boys than girls, higher rates among primary school age children than among preschoolers or older adolescents, and higher rates of identification among children from lower SES families.

Children and Youth

Examining recent national surveys, the National Health Interview Survey (NHIS) in 2007 estimated that nearly 4.5 million children in the United States between the ages of 3 to 17 years (7%) had ADHD, with a larger proportion of boys (10%) than girls (4%).100 The National Health and Nutrition Examination Survey (NHANES) estimated 2.4 million children ages 8 to 15 years, or 8.7 percent (95% CI, 7.3 to 10.1) met DSM-IV criteria for ADHD between 2001 and 2004.104 Of these, more boys than girls (11. 8% vs. 5.4%) and children in lowest SES group were more likely to meet criteria, as well as those not in minority racial/ethnic groups.104 In Germany, the KiGGs study (The German Health Interview and Examination Survey for Children and Adolescents), a representative cross-sectional health study of 17,461 individuals ages 3 to 17 years, reported an overall lifetime prevalence of ADHD diagnosis of 4.8 percent (95% CI, 4.4 to 5.3), with a significant gender difference (7.8% for boys, 1.8% for girls).234 Significant effects of age and SES were also detected; the prevalence of a parent-reported lifetime diagnosis was 1.5 percent for those of preschool age, 5.3 percent in primary school, and 7.1 percent in secondary school, and was 6.4 percent, 5.0 percent, and 3.2 percent for low, medium, and high SES, respectively.234 Logistic regression results highlighted boys of low SES as having the greatest risk of a diagnosis of ADHD.234 Another report from Germany, the BELLA mental health module of the KiGGS, generally supported these trends, with the exception of a different age effect: they found a decline in prevalence with increasing age (their sample was comprised of 7–17 year olds).110 The latter study used different methods to measure ADHD; namely, the German ADHD rating scale (FBB-HKS/ADHS), which is consistent with other DSM-IV scales and assesses functional impairment.110

The effects of gender and age (that is, a greater prevalence in boys and a negative association between age and prevalence of ADHD) emerge in many studies, though not all. In a Puerto Rican community sample of children ages 4 to 17 years, the 12-month prevalence using the DISC-IV was 7.5 percent (95% CI, 6.1 to 9.3).235 The estimate for males was 10.3 percent ( 95% CI, 8.0 to 13.1) versus 4.7 percent (95% CI, 3.1 to 7.2) for females, with the highest prevalence documented in the 6 to 8 years age group.235 In a randomly selected sample from school registers in Venezuela (N = 1,535 children ages 4 to 12 years), the total prevalence estimate (DISC-IV-P) was 10 percent (95% CI, 7.9 to 13.0), with a greater prevalence in males (7.6% vs. 2.4% in females).236 In addition, a larger proportion of ADHD cases were classified as lower SES than medium or high SES.236 In contrast, in a sample of 300 children ages 6 to 12 years from outpatient pediatric clinics at private hospitals in Buenos Aires, Argentina, 9 percent (95% CI, 6.0 to 12.8) had positive scores on the DuPaul Scale consistent with DSM-III-R ADHD, and no gender differences were found.237 Similarly, in a study of 774 school children ages 6 to 17 years conducted in Salvador, Brazil using a teacher ADHD scale designed to evaluate ADHD behavioral symptoms in a school setting, 6.7 percent were judged highly likely to have the disorder and no trend with respect to gender was observed.238

From other settings for ADHD research, a study of preschoolers in Mumbai (N = 1,250, ages 4 to 6 years) whose Conner’s index questionnaire scores (completed by teachers and parents) were positive for ADHD (>15) reported that in total, 12 percent were diagnosed, with a significant difference between boys and girls (19.0% vs. 5.8%, respectively).239 Having adopted a similar methodological strategy, 12.3 percent (95% CI, 10.3 to 14.2) were given a diagnosis in a randomly selected sample of kindergarten-aged children (N = 1,083) in Mashhad, Iran.240 Another study conducted in nearby Shiraz, in a random sample of 2,000 school-aged children (7 to 12 years), employing a DSM-IV referenced rating scale of ADHD symptoms (the CSI-4) completed by parents, found that approximately 10.1 percent obtained screening cut-off scores for probable ADHD, with 13.6 percent in boys vs. 6.5 percent in girls.241 A gender difference (prevalence ratio of 2:1 across the subtypes of ADHD except hyperactivity/impulsive type which had a ratio of 3.2:1) was also revealed in a study of primary school children ages 6 to 12 years in Nigeria (N = 1,112), assessed by means of rating scales based on DSM-IV ADHD criteria (the Vanderbilt ADHD Teacher Rating Scale (VARTRS) and Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS), with an overall estimated prevalence of 8.7 percent.242

Other relevant, exploratory studies include the following. Among 7 to 10 year-olds in Yemen sampled from school registers (N= 1,210,), the prevalence of various DSM-IV psychiatric disorders, including ADHD, were examined and were reported to be among the least common disorders at 1.3 percent (95% CI, 0.1 to 2.5), with a significantly higher prevalence among boys than girls.243 This was determined in 2 phases, using the SDQ as a screener and both the parent and teacher information included in the Development and Well-Being Assessment (DAWBA) to generate diagnoses in screen positive children. A cross-sectional study of patterns of mental health morbidity in children attending the psychiatry clinic of a tertiary care hospital in Karachi, Pakistan (N= 200, up to age 14 years included) stated a prevalence estimate of 17 percent, occurring most frequently in those between the ages of 5 to 10 years.244 This estimate was ascertained using the P-CHIPS (Child Interview for Psychiatric Syndrome), a structured interview for parents based on DSM-IV criteria.244 From a high school-based panel study carried out in Taiwan between 1995 to 97 of 1,070 students, ages 13 to 15 years, the weighted 3-month prevalence estimates of DSM-IV ADHD were 7.5 percent (95% CI, 5.1 to 10.0), 6.1 percent (95% CI, 4.6 to 7.5), and 3.3 percent (95% CI, 2.2 to 4.4) among 7th graders, 8th graders, and 9th graders, respectively, with higher odds of the diagnoses in boys than in girls.245 Cases were identified using the Chinese K-SADS-E along with the teacher report form of the CBCL.245

Finally, a recent review of all epidemiological studies on ADHD carried out in Arab countries from 1966 to 2008 in various samples reported that the estimate of ADHD symptoms using rating scales in a school setting ranged from 5.1 to 14.9 percent, whereas estimates of an ADHD diagnosis using structured interviews in children and adolescents ranged from 0.5 percent in the school to 0.9 percent in the community.246 It was noted, however, that the limited number of studies conducted in the designated countries and their employment of different methodologies rendered the task of comparing the results difficult.246

Fewer studies have been conducted in the adolescent age group. Some, but not all, of these agree with the gender and age effects proposed in studies of school-aged children. For instance, in a sample of 4,175 Houston youths ages 11 to 17 years from households enrolled in large health maintenance organizations, the DISC-IV prevalence of ADHD (any type) was 2.1 percent (95% CI, 1.59 to 2.54), with lower odds of ADHD noted in females.247 However, a study of the prevalence of ADHD symptoms assessed by teacher reports using the SNAP-IV SDQ scales in 536 adolescents (ages 12 to 17 years) in a community in the European north of Russia found that 8.9 percent of boys and 3.6 percent of girls had positive ratings on the six items in either of the ADHD sub-types.248 The estimate of DSM-IV ADHD in 541 Hong Kong Chinese adolescents (mean age 13.8 years, SD 1.2) from 28 randomly selected high schools was 3.9 percent (95% CI, 2.3 to 5.5).249

Worldwide Pooled Estimate of ADHD in Children and Youth

A recent comprehensive systematic review and meta-regression analysis that encompassed studies from many regions estimates the worldwide pooled prevalence of ADHD among those 18 years of age or younger to be 5.3 percent (95% CI, 5.01 to 5.56).93 Though a significant amount of variability was noted in the comparison of prevalence estimates across world regions, results seemed to indicate that once methodological differences of studies were controlled for, geographic location explained very little of the variability. In fact, after this step, significant differences were only detected between studies carried out in North America, Africa, and the Middle East. The requirement of impairment for the diagnosis, diagnostic criteria used, and source of information (parent or teacher), were the main sources of variability in the pooled prevalence estimate of ADHD. For that reason, a standardized methodological approach has been proposed in order to improve the state of epidemiological research in this domain.93,250

ADHD in Adults

Estimates of the prevalence of DSM-IV adult (18 to 44 years) ADHD in the World Health Organization’s (WHO) World Mental Health Survey Initiative (comprising of Belgium, Colombia, France, Germany, Italy, Lebanon, Mexico, The Netherlands, Spain, and the United States, N = 11,422) were: 3.4 percent (total sample), with a significantly higher estimate in France (7.3%) and lower in Colombia, Lebanon, Mexico, and Spain: 1.9 percent, 1.8 percent, 1.9 percent, and 1.2 percent, respectively.8 A study in the United States reported a prevalence of 2.9 percent for ‘Narrow’ ADHD and 16.4 percent for ‘Broad’ ADHD in a random sample of 966 adults (>18 years) in the community.251 As part of a larger telephone survey, respondents were asked about each DSM-IV symptom of ADHD, with a narrow diagnosis constructed to estimate the prevalence of adult ADHD among those who presented strong evidence of ADHD in both childhood and adulthood and a broader diagnosis serving to estimate the screening prevalence, although this strategy comes with the caveats of telephone survey methodology.251 In terms of sociodemographic correlates, adult ADHD was significantly more prevalent in men and among those with a level of education less than university, though limitations such as imputation and the use of self-report without confirmation were identified.8 Recently, a meta-regression, perhaps the first of its kind to address these issues, cited a pooled prevalence of adult DSM-IV ADHD of 2.5 percent (95% CI, 2.1 to 3.1), while reporting that the proportion of individuals with ADHD seems to decrease with age.9 The question of appropriate diagnostic criteria for use with adults was, however, highlighted as a potentially problematic factor in producing epidemiological estimates in this age group.9 Furthermore, many of the same problems (i.e., methodological and diagnostic differences) that plague ADHD research in children and youth, also appear to be relevant in adult studies.9

Brief Summary

  • The estimated worldwide pooled prevalence of ADHD among those 18 years of age or younger is 5.29 percent (95% CI, 5.01 to 5.56).93
  • Little geographic variability was noted, once methodological variability was taken into account.93
  • ADHD is more common in boys than in girls.
  • ADHD is more common in the age-group 5 to 10 years, than in preschoolers or in adolescents or adults.
  • ADHD is more common among those from a low SES background.
  • ADHD research detailing prevalence in adults is lacking.
  • Key limitations: different sample types (e.g., school, community, clinical) are used, along with different informants/instruments to measure ADHD across geographic areas.

How Do Rates of Diagnosis (Clinical Identification) and Treatment of ADHD Vary by Geography, Time Period, Provider Type, and/or Sociodemographic Characteristics?

Much variation remains in the literature concerning the factors of interest on the receipt of a diagnosis and the use of psychotropic medication by individuals with ADHD, with some of the characteristics more commonly investigated than others. Though these factors have not been fully investigated, they appear to play a role in determining these outcomes and therefore, warrant attention.102 A review of relevant findings follows, organized by geographic region. Details regarding the surveys will also be included to clarify whether the study is based on epidemiological surveys providing parent-reported data about individual children or administrative data providing information about patients through less direct, secondary sources collected for alternative purposes. Overall, the picture that emerges is one of increasing rates of lifetime diagnosis as children enter adolescence, starting as early as preschool years in the United States, with patterns of diagnosis similar to patterns of background population prevalence; that is, more boys than girls, and occurring more frequently among lower SES and non-minority children. However the overlap between clinical identification and underlying prevalence is inexact, with variation in geographic rates, and social, school, and health care system characteristics predicting clinical diagnosis. The picture that emerges regarding treatment for ADHD, most commonly stimulant medication use, varies to some degree from that of clinical diagnosis. Use of educational and health care services is higher among children with ADHD, and most frequent among those from higher SES families. Time trends show clear increases in medication use from the early 1990s to 2005 or later, perhaps due to the increasing size of the pool of individuals identified. Also noted are increasing use of multiple psychotropic medications, often in concert with the assignment of multiple diagnoses. Especially noteworthy are higher rates of diagnosis and medication use among Medicaid supported populations in the United States, a population representing low SES and minority groups. Regional disparity in rates of diagnosis and medication treatment are present, with no statistically significant increases noted in the west relative to other regions of the country. Rates of diagnosis and medication use are higher in the United States than in Europe.

United States

Clinical diagnosis. Regarding the receipt of a clinical diagnosis, it is clear from reports from the National Health and Nutrition Examination Survey (NHANES) that children whose parents report that they have been identified with ADHD overlap with, but are not identical to, those who are identified by DSM-IV diagnostic parent-report measures.104 For approximately half of those who met criteria for ADHD and had received an ADHD diagnosis, predictors of clinical identification were being male, older in age, and having health insurance. One third of those with a diagnosis were likely to have received consistent treatment in the past year, with higher income a significant predictor.104 The National Health Interview Survey (NHIS) shows gradual increases in the clinical identification of ADHD between 1997 and 2006, more in girls than in boys, and primarily among adolescents rather than primary school age children, with prevalence of 8.4 percent among children ages 6 to 17 years. 226 Children with ADHD were more likely to use health care and educational services, and use prescription medication. Hispanic children were less likely to have ADHD.226 Another nationally representative survey of parents, the Medical Expenditure Panel Survey, (MEPS) was used to examine diagnosis and treatment issues for children between the ages of 3 to 18 years. It found that Hispanic-American as well as African-American children were less likely to receive a diagnosis of ADHD compared to Caucasian children.210 Furthermore, once given a diagnosis by a physician, African-American children were found to be less likely to ever receive stimulant medication, compared to Caucasian children.210 Children in the 7 to 12 years age group were most likely to be diagnosed with ADHD and children with ADHD between the ages of 7 to 18 years were more likely to receive at least one stimulant prescription relative to children in the 3 to 6 years age category.210 In 2000–2002, Caucasian children between the ages of 5 to 17 years were found to be approximately twice as likely to use stimulants as either Hispanic or African-American children.252 Differences in individual/family characteristics (i.e., health insurance status, access to care) accounted for about 25 percent of the discrepancy between Caucasians and Hispanics in stimulant use, although the same characteristics cannot account for any of the differences between Caucasian and African-American children, with respect to stimulant use.252 A Centers for Disease Control (CDC) national survey, the 2003 National Survey of Children’s Health (NSCH), identified that nearly 8 percent of children ages 4 to 17 years are diagnosed with ADHD nationally, with geographic variation in both clinical identification and medication treatment.227 Lower rates of identification and medication use occur in the west, and diagnosis rates are higher in the south, with treatment rates higher both in the south and the midwest compared with the west.227,253 Rates of clinical identification and treatment were associated with characteristics of pediatricians within a state, but not with educational policies.227 The NSCH survey was repeated in 2007 and rates of ADHD reported by parents increased from 7.8 percent to 9.5 percent, most dramatically among adolescents ages 15 to 17 years, and in all regions but the West.254 In a study of younger students, the 2002 Early Childhood Longitudinal Study-Kindergarten cohort (ECL-K) sponsored by the U.S. Department of Education, social and school environment factors were identified that influenced rates of ADHD diagnoses.219 Of the children in grade three at the time of the survey, 5.44 percent had received a previous diagnosis of ADHD. Lower rates of diagnosis were reported among girls, African-American children, Hispanic children, and those living with their biological father. School contextual predictors of diagnosis were having an older teacher, and stricter state-level performance accountability laws, but not larger class sizes; lower rates were associated with Caucasian teachers.219

A recent review has suggested that being male, belonging to a family with a high education level, and having a non-Hispanic ethnic background are factors that are most consistently associated with receiving a diagnosis of ADHD.102 Additionally, the use of stimulants by Caucasian males seems disproportionately higher than the use by African-American and Hispanic children.102 Another recent review of the ADHD literature with reference to African-American children arrived at these conclusions: although African-American youths have a tendency to be rated by parents and teachers as having more ADHD symptoms than Caucasian youth, they are only two-thirds as likely to have been diagnosed with the disorder by health professionals as their Caucasian counterparts.101 The authors suggest that that this less frequent receipt of ADHD diagnoses in the former group may be attributable to a lack of information on the part of parents, a lack of access to appropriate health care services, or a lack of willingness to seek out services.101

Medication treatment. While treatments indicated for ADHD include both pharmacological and nonpharmacological interventions, studies examining treatment patterns have primarily focused on the use of psychotropic medications, both because medical care and pharmacy data sources have become available and because concerns exist about the rate of increase of medication use in recent years (see Table 16).

According to a study of regional and national databases in the United States, there was a 2.5-fold increase in the prevalence of MPH treatment for youths ages 5 to 18 years with ADHD during the period 1990 to 95.94 These increases appear to have been due to the extended duration of medication use, as well as to more girls and adolescents receiving treatment; in addition, public attitudes had improved regarding pharmacotherapy.94 Another study, also using a national data source of office visits (the NAMCS: National Ambulatory Medical Care Survey), confirmed the trend of an increase in the prevalence of both the diagnosis of ADHD and the prescription of stimulant medication for its treatment during the same time period and in the same age group.95 Analysis of a more recent wave of data (1995 to 2000) from the same source, demonstrated that an ADHD diagnosis and/or stimulant prescription was less likely to be recorded during visits by Hispanic American youths compared to visits by Caucasian youths (ages 3 to 18 years). However, no differences were found between ethnic groups in terms of the likelihood of being given a prescription once a diagnosis was given.202 An additional point was that prescriptions were given more frequently to children with ADHD in the south and west areas of the United States versus the northeast.202 Data from the MEPS showed increased use of stimulants between 1987 and 1996, from approximately one per 100 children to four per 100 children 6 to 12 years old, but suggested that increasing rates in the use of stimulants among children less than 19 years slowed considerably from 1997 to 2002.96 In 2001 to 2002, use among boys was greater than girls (4.0% vs. 1.7%) and Caucasian greater than African-American or Hispanic children (3.6%, 2.2%, 1.4%), although they noted a trend toward increased use among African-American children. Those without insurance had low usage (0.9%) compared with those with public (3.3%) or private (3.0%) insurance. Geographical regions showed little statistically significant variation in 2002 ranging from higher use in the south, (3.4%), than in the west, (2.2%).96 Children whose parents reported functional impairment were more likely to use medication (13.9%) than those without (2.7%). Use in preschoolers appeared to have stabilized from 1997 to 2002 at approximately 0.4 percent (1997) and 0.3 percent (2002).96 In contrast, other data sources suggest that the use of ADHD medications continued to increase during this time period. Data from a large California Health plan identified increases in the prescription of psychostimulants from 1.86 percent of children ages 2 to 18 years in 1996 to 1.93 percent in 2000.256 Approximately one quarter of those receiving stimulants received a single prescription, suggesting primarily short-term or intermittent use, with more prescriptions written by pediatricians than by psychiatrists.256 Another study examined time trends in diagnosis and treatment from 1995/96 to 2003/04.257 Using Medicaid databases, they found increases in both diagnosis of ADHD and treatment with medications among those under the age of 20. Diagnoses of ADHD increased from 3 to 5 percent, and medication use was 5 percent in 2003/04. The most common age to begin medication was 5 to 9 years, more among boys than girls, and more among Caucasians than African-Americans or Hispanics. The largest increase in prevalence was in adolescents ages 15 to 19 years, at 2.5 percent, up from 0.45 percent in 1995/96; persistence of use was variable with only half of new users continuing more than 12 months.257 More recent pharmacy claims data from 2000 to 2005 suggest that use of ADHD medications increased among girls and adults, with the overall rate among children up to age 19 at 4.4 percent, and among adults at 0.8 percent in 2005.258

In 2001, 2.3 percent of preschoolers ages 2 to 4 years identified in seven state Medicaid databases received one or more prescriptions for psychotropic medications.97 Two thirds of the prescriptions were for psychostimulants.97 The overall use of medications for ADHD increased most dramatically in the 1990s, but increases among specific groups and regions appear to be continuing. Rates reported vary based on study methods, participants, and data sources.

An important trend has been an increase in multiple medications, especially for children identified with more than one diagnosis. Data collected between 1993/94 and 1997/98, recorded from visits to doctors offices in the National Ambulatory Medical Care Survey (NAMCS) database, were used to evaluate visits for those under 18 years of age where stimulant medications were prescribed. Authors noted that an increasing proportion of visits also resulted in another psychotropic medication being prescribed, most commonly clonidine or an antidepressant.259 Data from state Medicaid and State Children’s Health Insurance Programs (SCHIP) from 1999 were used to examine medication use among youth less than 20 years of age; 28 to 30 percent of those who received any psychotropic medications received multiple psychotropic medications, primarily stimulants with antidepressants, antipsychotics, or alpha-agonists.260 The children most likely to receive multiple agents were Caucasian, male, ages 10 to 14 years, disabled, or in foster care.260 Data from the NAMCS, and the outpatient component of the National Hospital Ambulatory Medical Care Survey (NHAMCS) were used to examine ATX use in 2003/04, following its approval in 2002.261 Approximately 60 percent of prescriptions for ATX were accompanied by prescriptions of stimulants, with ATX preferred for children ages 10 to 14 years with private insurance.261

A final study has used data from the office visit database, NAMCS, to examine use of multiple types of medications among children and teens with mental health disorders.262 The authors confirm increasing use of co-prescriptions for children and adolescents between 1996 and 2007; a common pairing is ADHD medications and antipsychotic medications.262

Geographic variation in the prevalence of stimulant medication use, evaluated using a prescription claim database (restricted to activity in 1999), was observed even after controlling for age and gender—specifically, relative to children living in the western region of the United States, children living in the midwest and south were significantly more likely to use stimulant treatment.213 Those living in areas with some proximity to urban areas were also found to be more likely to receive stimulant treatment.213 In support of these findings, the results of a study using National Drug Enforcement Agency Automation of Reports and Consolidated Orders System (ARCOS) data in 2000 looked at variation between counties in terms of their per capita psychostimulant consumption and showed that most variables that were significantly associated with greater percapita use of ADHD medications served as proxies for county affluence ( e.g., higher per capita income, lower unemployment).99 Wide variation in rates of children receiving prescriptions can occur, ranging from 9.6 to 117 per 1000 of 10 and 11 year old boys in 1992, as per Michigan pharmacy data.129 Pediatricians wrote 59 percent of prescriptions for people under 20 years of age; half of which were written by only 5 percent of those pediatricians.129

A final note is how few studies are available regarding interventions that are not pharmacological. In a large county Medicaid program in California, Zima, et al.,254 identified 530 children with ADHD, ages 5 to 11 years, and followed them to examine services received over 18 months during 2004 to 2006. Children seen in primary care were compared with those seen in specialty care. During the study, 34 to 44 percent of children who showed poor functioning received no care, more commonly when followed in primary care settings. The majority (80 to 85%) of children seen in primary care received medication and averaged one to two visits per year, with less than half receiving psychosocial services. All children seen in specialty care services received psychosocial services, averaging five visits per month, and less than half received medication. No differences were found between those children who received care and those who did not in a range of functional areas.

Provider type. Some information is available about differences between provider type and subsequent prescribing patterns (see Table 17). Children diagnosed by psychiatrists are less likely to receive a prescription within the initial 6 months after diagnosis than those identified by primary care physicians, even after adjustment for comorbid conditions.265 Presence of comorbid disorders, especially bipolar disorder, schizophrenia, or autism decreased the use of ADHD drug use, but increased the use of other categories of psychotropics, prescribed primarily by psychiatrists and neurologists.265 Higher rates of prescription of these other psychotropics occur among school-aged males, Caucasians, those in rural areas, and those in foster care.265 Dose titration is associated with a lower initial dose, a higher maximal dose, 3 or more visits in the first 90 days, increased monitoring, and treatment by a psychiatrist.266 Overall, it appears that specialists’ practice patterns are different from those of primary care physicians in regards to ADHD and its pharmacologic treatment. Those who are seen by psychiatrists are more likely to receive a medication titration trial. Specialists are more likely to prescribe a variety of psychotropic medications for combinations of ADHD and comorbid conditions.

Other issues. Other studies point out medication compliance issues, noting that nearly a third of persons prescribed stimulants did not refill their initial prescription and over 60 percent did not use pills for more than 30 days.105 Extended-release preparations of MPH were associated with longer duration of use, compared with immediate-release preparations.106 Increased duration of treatment was associated with use of case management services, but inversely related to a comorbid condition, recent inpatient hospitalization, and managed care.106 Fewer teens compared with younger children, and fewer minority persons compared with Caucasians took stimulants over an extended duration.106 Increased examination of the factors impacting duration is needed. Certainly convenience, efficacy, and safety of agents is important for increased duration of use, but the high rate of non-refill following initial prescription suggests a more nuanced approach to the issues of medication adherence is warranted. Increased rates of discontinuation among minority groups and teens suggests that cultural and social factors may affect use.

Discussion of ADHD prevalence and treatment among U.S. adults. The estimated prevalence for adult ADHD stands at 4.4 percent.109 Overall, levels of symptoms of overactivity and impulsiveness decrease with age; however, the majority of children with ADHD continue to show impairment, especially poor attention, relative to same-age peers throughout adolescence and into adulthood. The estimate of prevalence of ADHD among adults in the United States is 5.2 percent,8 while worldwide it is 2.5 percent (95% CI, 2.1 to 3.1).93 The lack of research addressing adolescents and adults with ADHD presents a major gap in the literature. For estimates of adult ADHD, self-report measures are used; however, aspects of the diagnosis depend on a history of having had ADHD as a child. For this information, both clinicians and researchers depend on retrospective reports from adults about their own behavior as children, and it is therefore open to problems with interpretation.

No clinical studies have been designed to follow children through adolescence and into adulthood, tracking the mix of interventions obtained by participants and their functional outcomes, as well as providing sufficient control comparison. No prospective studies examining non medication interventions have enrolled adolescents or adults identified with ADHD to investigate whether interventions at later stages of development are effective for improving function. As with estimates of diagnostic prevalence, self-report measures of treatment are often used, which will render coordination of observations regarding academic interventions and outcomes particularly challenging.

Use of ADHD medications increased globally by almost 300 percent between 1993 and 2003.98 Like other health care interventions, use of ADHD medications is correlated with per capita Gross Domestic Product (GDP). In 2003, moreover, the United States reported a usage rate approximately four times that expected based on per capita GDP.98 Use of short-acting preparations of stimulants plateaued between 1997 and 2000, and showed a decrease in use through 2003, while use of long-acting preparations increased.98 Numerous factors contribute to these observations, including regulatory restrictions, differences in diagnostic systems, and availability of alternative formulations of ADHD medications around the world.

Brief Summary With Focus on Trends in United States
  • Rates of ADHD medication use have been increasing globally since the early 1990s. Use of pharmacologic interventions is higher in the U.S than in other areas of the world, nearly 4 times that expected by per capita GDP.
  • In the late 1990s, use of short-acting stimulant preparations leveled off in the United States and subsequently decreased while use of long-acting formulations has increased. This pattern may be emerging in other countries. The rate of increase appears to have slowed for primary school age boys, however increasing numbers of girls and adolescents are now treated for ADHD. Geographic variation has been noted, with more affluent areas, access to insurance, and access to specific service providers being contributing factors.
  • The western region of the United States consistently has fewer children with diagnoses and undergoing treatment from the 1990s until the current time.
  • Ethnicity/race predict receipt of a diagnosis and/or treatment, as well as duration of pharmacological treatment Many persons prescribed medication for ADHD do not continue use beyond 1 month.
  • ADHD medications are increasingly combined with other psychotropic medications.
  • Specialists prescribe fewer stimulants than primary care physicians when prescribing patterns are controlled for comorbid conditions, they start with lower initial doses and titrate to optimal levels, and they require more frequent visits.

Key Considerations, Clinical Identification, and Treatment

Geography and Time Trends
  • Clinical identification and treatment vary considerably by geographic area, between nations and between regions within the United States.
  • The U.S. national rate of clinical diagnosis of ADHD is high compared with the pooled worldwide prevalence estimates generated from epidemiological studies.
  • Treatment rates reported generally provide rates of medication use for ADHD, without details regarding use of other interventions, reflecting data sources available for research
  • Based on parent surveys, rates of medication use appear to be lower than those based on administrative or prescription data.
  • Data from epidemiological surveys suggests that many children in the United States with a lifetime diagnosis of ADHD do not take medication.
Age, Sex, SES, and Race/Ethnicity in the United States
  • More boys than girls are diagnosed and treated for ADHD.
  • Increases over time in the diagnosis and treatment of girls and adolescents have occurred.
  • More Caucasian children than African-American or Hispanic children receive medication.
  • Direct comparisons between SES is difficult; however, access to insurance plays a role, as families having either public or private health insurance use medication more than those without insurance.
  • Parent-reported child impairment is associated with increased use of medication.

Provider characteristics. Although few comparisons among service providers are available, it appears that characteristics of the service provider exert strong influence on interventions received.

Canada

Canadian data from cycles of the National Longitudinal Survey of Children and Youth (NLSCY) showed that among children ages 2 to 11 years, the overall prevalence of MPH use as reported by parents was low (<2% from 1994/95 to 1998/99), noting an increase in use among girls and among those aged 6–11 years.131 Another study using data from cycles 1 (1994/95) and 2 (1996/97) found that boys were 4.6 times more likely than girls across all age categories to use MPH, with the highest prevalence of use among those ages 7 to 9 years.272 However, the overall prevalence of use of MPH was also deemed to be relatively low, ranging from 0.09 percent to 3.89 percent in children ages 2 to 11 years in 1994/95.272

To consider variation by province, a study of patterns of use and prescribing of MPH in youth ages 19 years or less, using linked administrative and health databases in B.C. for the period 1990 to 1996, reported an increase from 1.9 per 1,000 children in 1990 to 11.0 per 1,000 in 1996 as the number of children who had received at least one prescription.127 MPH use was found to be slightly higher (RR 1.17, 95% CI, 1.14 to 1.21) among individuals in the lowest two socioeconomic quintiles (least privileged) relative to the highest three quintiles (most privileged).127 Pediatricians and psychiatrists wrote 23 percent and 21 percent of all prescriptions, respectively, whereas General Practitioners (GPs) wrote 56 percent of all prescriptions, while writing only 41 percent of the initial prescriptions.127 Using computerized administrative records of physician visits and prescriptions, a cohort of 4,787 Manitoba children (up to the age of 19 years) diagnosed with ADHD within a 24-month period (1994 to 1996) or prescribed psychostimulant treatment over a 12-month period (1995 to 1996) was assembled in order to calculate estimates of ADHD diagnosis and use of stimulants at the provincial level.128 Overall, 1.52 percent of Manitoba children were noted to have received a medical diagnosis of ADHD and 0.89 percent, to have received stimulant medication.128 Among those who received a diagnosis, 58.6 percent were treated with medication. On average, the peak age to receive a diagnosis and medication was between 7 to 9 years of age, with males much more likely to be both diagnosed and treated with stimulants in each age group.128 Lastly, these outcomes were found to vary according to physician speciality; children in Manitoba appeared more likely to be diagnosed and treated by a pediatrician than by a GP or psychiatrist.128

A recent publication compared patterns of stimulant use by those less than 19 years of age in the provinces of B.C. and Manitoba, using population-based administrative prescription medication data for the years 1997 to 2003.273 Important differences were detected: though psychostimulant prescription rates were nearly identical in the two provinces in the late 1990s and increased over the next 6 years, the increase in use in Manitoba was more than threefold the increase observed in B.C. children.273 Next, in 2003, psychostimulant use in Manitoba was greatest in the 11 to 14 year age group, whereas in B.C., it was highest among 15 to 18 year olds.273 Use was found to have decreased among children ages 6 to 10 years in B.C. between 1997 and 2003, whereas in Manitoba all three categories (6 to 10, 11 to 14, and 15 to 18 years of age) experienced an increase.273 A suggested explanation of more discriminate diagnosing and prescribing by B.C. physicians was given for these discrepancies.273

Brief Summary
  • There was a relatively low prevalence of MPH use in the early 1990s among those <11 years old, with boys receiving treatment more often than girls.
  • In B.C, more initial prescriptions for psychostimulants were provided by specialists while the majority of prescriptions were provided by primary care physicians.
  • Practice patterns vary from province to province as well as over time. Between 1997 and 2003, there was a much larger increase in treatment of children in Manitoba in contrast to B.C.

Europe

Observing time period trends in the United Kingdom (U.K.), a population-based study conducted to estimate the prevalence of psychotropic drug prescriptions in children and adolescents (<19 years of age) between 1992 and 2001 in primary care settings revealed that stimulant prescriptions (mostly MPH) rose significantly from 0.03 per 1,000 (95% CI, 0.02 to 0.04) in 1992 to 2.9 per 1,000 (2.52 to 3.32) in 2001, a 96-fold increase.274 Of note, 2.4 percent of stimulant prescriptions were made for children less than 6 years of age and a higher proportion of boys received stimulants than girls.274 Next, using the same large, population-based database (General Practice Research Database (GPRD), patients were between 15 to 21 years of age at this point and had had a minimum of one stimulant prescription and 1 year of research data available), the prevalence of prescribing averaged across all age groups of ADHD medications was found to have increased eightfold, from 0.26 per 1,000 patients in 1999 to 2.07 per 1,000 in 2006.275

In the Netherlands, a large increase in the use of psychostimulants during the years 1996 to 2006 was documented in those less than 19 years old using a pharmacy prescription database.276 The use of psychostimulants increased in boys overall, irrespective of age, from 4.5 percent (95% CI, 3.8 to 5.3) in 1996 to 31.1 percent (95% CI, 29.8 to 32.5) in 2006 and for girls, from 0.7 percent (95% CI, 0.5 to 1.1) to 8.1 percent (95% CI, 7.4 to 8.8), in the same years, respectively.276 The group that experienced the largest increase in use was boys ages 10 to 19 years and the male to female prevalence ratio declined from 6.4 in 1996 to 3.8 in 2006.276 It should be pointed out, however, that the U.K. studies used population-based samples, whereas this one used a pharmacy prescription database made up only of individuals who took pharmaceuticals, which may possibly account for the larger estimates in the latter study.

Notable differences in the prevalence of psychotropic medication used in youth 0 to 19 years of age emerged in a cross-national comparison between Germany, the Netherlands, and the United States, using administrative claims data for the year 2000 for insured enrollees in selected large health insurance systems from the three nations.103 The annual prevalence of stimulant medication use in youth was significantly greater in the United States in 2000 (4.29%) than in either Germany or the Netherlands (0.71% and 1.18%, respectively). Keeping provider type factors in mind, GPs prescribe most of the psychotropic drugs in Western Europe whereas in the United States, pediatricians tend to fulfill that role.103 Diagnostic criteria for the disorder and cultural norms regarding child rearing differ. The variety of psychostimulant agents prescribed was greater in the United States. These factors, taken together, may account for differences in prescribing practices.103

Australia

Between the years 1988 and 1993 in Western Australia and New South Wales, a significant increase in the use of stimulants for ADHD in youths up to the age of 16 years was noted, which may have been related to practice patterns.277 In contrast, an analysis of new psychostimulant prescriptions in south Australia during the period 1990 to 2000 for approximately 5,000 youths up to the age of 18 years observed that despite a significant rise in prescriptions up to the year 1995, the rate then declined.278 At the end of the year 2000, the rate of children and adolescents on stimulant medication for ADHD was 11.3 per 1,000 (1.1%) of the population ages 2 to 17 years in New South Wales.279 In terms of sociodemographic profile, the rate of treatment was highest among 10-year olds (19.9 per 1,000 aged 10 years) and the majority of those receiving stimulant treatments were male.279 An examination of treatment with psychostimulants for ADHD in children ages 3 to 17 years during the year 2004 in the Western Australia region using whole population-based administrative pharmacy data, concluded that the prevalence of treatment with stimulants for this cohort was 2.4 percent, with age-specific prevalence as high as 3.5 percent.280 The male to female ratio of stimulant treatment was 4 to 1.280 Prevalence increased rapidly from ages 3 to 8 years, remained high until a peak at 14 years and declined rapidly thereafter, signifying that children between the ages of 8 to 14 years have the highest levels of treatment. Most children (89.3%) received their prescriptions from pediatricians.280

Israel

A longitudinal, population-based investigation of MPH use for the treatment of ADHD among children up to the age of 18 years in Israel from 1998–2004 found a rapidly increasing rate of MPH use among Israeli children during this time frame, with the increase being more pronounced in girls.281 The overall 1-year prevalence estimate of MPH use in the whole group increased from 0.7 percent in 1998 to 2.5 percent in 2004.281

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