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.

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 95^th 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.

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.

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 safety^148,149 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 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.

There were 22 papers with “good” internal validity as rated by our assessment tool^{72–78,80–83,89,160,161,161,163–168,170,171} 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 treatments^82,83

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}

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 outcomes^61,86 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.

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.

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 7^th graders, 8^th graders, and 9^th 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.

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.

Key Considerations, Clinical Identification, and Treatment

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

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