Differential Response to Methylphenidate in Inattentive and Combined Subtype ADHD

Abstract

Objective: To examine response to methylphenidate (MPH) assessed by direct observation of ecologically valid behaviors in boys with ADHD with high hyperactivity-impulsivity (HI) and those with predominantly inattentive symptoms (ADHD/I). Method: Sixty-three boys ages 7 to 13 participated in an ADHD Summer Treatment Program and received a double-blind placebo-controlled assessment of .3 mg/kg of MPH on problem behaviors and individualized behavior goals. Medication effect sizes were calculated for each child for each behavior. Results: Children with ADHD/HI (n = 21) displayed larger MPH effect sizes for interrupting, verbal abuse, and compliance, and marginally greater response for teasing and counselor-directed goals. Children with ADHD/I (n = 21) displayed small medication effect sizes (ds < .20) for many behaviors often identified as primary deficits in this group (e.g., attention to activities, peer interaction, class work completion, and accuracy). Conclusion: Systematic medication assessment for ADHD/I that quantifies response in ecologically valid areas of functional impairment is essential.

Keywords

ADHD subtypes methylphenidate medication treatment

There has been increasing evidence that children with ADHD who display primary symptoms of both hyperactivity and impulsivity (Diagnostic and Statistical Manual of Mental Disorders, 4th ed.; DSM-IV, American Psychiatric Association [APA], 1994; ADHD Combined Type [ADHD/C] and the less common Hyperactive-Impulsive Type) differ on many important characteristics from those who experience inattention symptoms in the absence of significant hyperactivity and impulsivity (e.g., Barkley, DuPaul, & McMurray, 1991; Diamond, 2005; Lahey & Willcutt, 2010; Milich, Balentine, & Lynam, 2001). Whether these two groups represent conceptually meaningful extremes of the ADHD continuum, distinct subtypes of ADHD, or categorically different disorders requiring separate nomenclature is the subject of continued investigation (e.g., Lahey & Willcutt, 2010; Nigg, Tannock, & Rhode, 2010). Lahey and Willcutt (2010) have proposed that a global ADHD diagnosis be maintained but symptom counts for both inattention (I) and hyperactivity-impulsivity (HI) be included as “modifiers.” A number of investigators have suggested that differentiating children with ADHD with primary symptoms of I but low HI from those with high levels of HI may promote “cleaner” research samples and more precisely targeted treatment interventions (Barkley et al., 1991; Lahey & Willcutt, 2010; Milich et al., 2001).

Evidence supporting differences between ADHD subtypes in family history, associated characteristics, laboratory findings, and prognosis has been comprehensively summarized elsewhere (e.g., Diamond, 2005; Lahey et al., 1994; Lahey & Willcutt, 2010; Milich et al., 2001). Interestingly, relatively few studies (Barkley et al., 1991; Solanto et al., 2009; Stein et al., 2003) have examined differences between ADHD subtypes’ response to pharmacological treatment. These studies have primarily assessed response to methylphenidate (MPH) using parent and teacher rating scales, laboratory measures, and Clinical Global Impressions of Severity (CGI).

Pelham and Milich (1991) and Barkley et al. (1991) have emphasized the importance of examining the degree of medication response on an individual basis for each child rather than relying solely on comparisons of aggregate group differences between medicated and unmedicated behavior. Barkley et al. (1991) found that when group averages across a variety of parent and teacher rating scales, laboratory tests, and behavioral observations during a 15-min academic task were examined, both Hyperactive and Inattentive ADHD groups displayed significant improvement on MPH compared with placebo. However, when the magnitude of each child’s medication response on each measure was examined to make conclusions regarding his or her overall degree of improvement and recommendations regarding continued medication treatment, significantly more of the children with inattentive symptoms (ADHD/I) were judged to be medication nonresponders (24%, compared with 5% of hyperactive children) or showed optimal improvement with the lowest dose of MPH (5 mg bid; 35%). Importantly, a moderate to high dose of MPH (10 mg or 15 mg bid) did not produce significant benefit over the low dose for children with ADHD/I. The treatment recommendation for a remarkable 59% of the children with ADHD/I was either no continued medication or 5 mg bid. Almost all of the ADHD+H children displayed a positive response to MPH, and ongoing treatment with a moderate or high dose of MPH was recommended for 71% of these children. Remarkably similar findings were reported by Stein et al. (2003) for long-acting OROS® MPH on parent and teacher rating scales. Sixty percent of ADHD-Predominantly Inattentive (ADHD-PI) children responded optimally to the lowest dose while 66% to 75% of ADHD-Combined Type (ADHD-CT) participants responded best to higher doses. These authors stressed the importance of examining medication response separately for each subtype as well as for different domains of cognitive and behavioral difficulties. In contrast, Solanto et al.’s (2009) research found that both subgroups improved on MPH and showed similar linear dose-response profiles. These results may be due to smaller sample size, other participant characteristics, the possible presence of subthreshold children with ADHD/C included in their ADHD/PI group, or their use of parent and teacher rating scales, CGIs, and laboratory measures (Continuous Performance Test; CPT and Stroop test) as dependent variables. Pelham and Milich (1991) found low correlations between MPH response measured by teacher rating scales, the CPT, and a learning task. Even when combined, positive MPH response on these measures failed to reliably predict positive response on academic or social behaviors in a more natural setting. These authors strongly cautioned against generalizing conclusions about medication improvement based on rating scales and laboratory or learning tasks to assumptions about a child’s response in his or her most problematic everyday behaviors. Medication response was so varied that MPH sometimes improved CPT performance while having no effect or even an adverse effect on natural behaviors.

Hypotheses

Despite renewed interest in the extent to which ADHD subtypes differ in clinically meaningful ways in underlying deficits, associated symptoms, and impairment, the important question of potentially different response to treatment remains. The current study responds to the call for further research examining the possibility that ADHD subtypes (or children with ADHD differentiated by number of I and HI symptoms) may display meaningful differences in response to pharmacological treatment (Lahey & Willcutt, 2010; Milich et al., 2001). We extend Barkley et al.’s (1991) and Stein et al.’s (2003) work by using well-validated observational procedures that have been extensively studied in a natural setting (Pelham & Hoza, 1987) to explore each groups’ response to MPH on ecologically valid behaviors often identified as primary areas of impairment for both groups (negative behaviors, deficits in adaptive behaviors, peer interactions, and classroom behavior and work).

Specifically, we hypothesized that children with ADHD with high levels of HI would display larger MPH effect sizes on most problem behaviors compared with children with ADHD/I (low HI). Examination of the degree to which MPH improved deficits in adaptive behaviors commonly problematic for children with ADHD/I (e.g., attention to ongoing activities, academic productivity and accuracy, and peer interactions) was also of particular interest. Group differences in the types and severity of behavior difficulties on placebo days were also examined for the purpose of obtaining descriptive information that might shed light on specific treatment needs that may differentiate the two groups.

Method

Participants

Participants were 63 boys between 7 and 13 years of age (M = 9.7 years, SD = 1.3) who participated in an ADHD Summer Treatment Program (STP; Pelham & Hoza, 1996). All participants had a Wechsler Intelligence Scale for Children–Revised (WISC-R) Full Scale IQ of at least 79 (M = 103.9, SD = 13.9, range = 79-141). There were no differences in age or Verbal, Performance, or Full Scale IQ scores between the two groups. The sample was predominantly Caucasian (87%; 10% African American; 3% biracial) and of middle-class socioeconomic status (median household income = US$34,000).

Participants met Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; DSM-III-R; APA, 1987) criteria for ADHD based on a structured parent interview conducted by a PhD-level clinician, and a number of standardized parent and teacher rating scales (Disruptive Behavior Disorder Rating Scale [DBD III-R] and DSM-IV field trial items, Pelham, Gnagy, Greenslade, & Milich, 1992; IOWA Conners, Loney & Milich, 1982; Child Behavior Checklist [CBCL], Achenbach & Edelbrock, 1983; and Swanson, Nolan, and Pelham (SNAP) checklist, Pelham, Atkins, & Murphy, 1981) in addition to meeting the age of onset and duration criteria. Rating scales were completed prior to the program by the child’s parent and the schoolteacher most familiar with the child, on a day on which the child was unmedicated (for the 35 children taking medication prior to the program). A primary diagnosis of ADHD was required, although comorbid diagnoses of Oppositional Defiant Disorder (43 participants), Conduct Disorder (1 participant), Anxiety (11 participants), Enuresis, or Encopresis were permitted. Participants comorbid for any other disorder or with a history of seizures or neurological problems were excluded from the study. Parent consent for both the STP treatment and the medication assessment was obtained for all participants.

Procedures

Brief overview of STP

The STP is a comprehensive, evidence-based treatment intervention for children with ADHD that includes intensive behavior modification, academic intervention, and medication assessment (as needed) in a naturalistic recreational setting. The specific components of the STP have been described in detail elsewhere (e.g., Pelham & Hoza, 1996) and are only briefly summarized here. Participants attended the treatment program 9 hr a day (7:30 a.m. to 5:00 p.m.), 5 days a week for 8 weeks. The behavior modification intervention included reward (points) and response cost (loss of points) for 24 operationally defined behavior categories. Each occurrence of every behavior was recorded by undergraduate and graduate-level counselors (who were blind to subgroup membership) continuously throughout all activities. Point system behaviors and the daily report card and classroom measures described below all have well-established reliability (e.g., Pelham & Hoza, 1987). Each week, counselors were quizzed on point system operational definitions and directly observed by a treatment fidelity monitor, thus ensuring a high level of interrater reliability and treatment integrity.

In addition to the point system behaviors, individualized behavior goals addressing classroom rule following, classroom performance (assignment completion and accuracy), and individually selected difficulties in the areas of peer and counselor interactions were included on each child’s STP-home daily behavior report card (DRC). Behaviors judged by counselors to be the most problematic for each child were placed on his DRC. Thus, DRC targets addressed each child’s specific, primary difficulties in four important, ecologically valid domains of functioning. Counselors tallied the frequency of each child’s target behaviors and rated each DRC goal “yes” (attained) or “no” (failed to attain) at the completion of the program each day and parents provided home-based rewards (see Pelham & Hoza, 1996).

Medication assessment procedures

The procedure for the STP medication assessment is also described elsewhere (Pelham & Hoza, 1987; Pelham & Milich, 1991). Parental consent was obtained, and a double-blind, placebo-controlled, daily crossover assessment of the effects of .3 mg/kg of MPH (bid) on the 24 point system behaviors and four DRC categories was conducted with all participants. Medication condition (placebo or .3 mg/kg MPH, typically 8-10 mg bid) was determined randomly for each child independently. Medication (or placebo) was administered by STP staff twice daily (7:30 a.m. and noon), ensuring 100% fidelity of administration. Medication response was obtained by averaging each child’s frequency count for each behavior category over 12 MPH days and comparing with his behavior frequencies averaged across 12 placebo days, thus providing a highly stable measure which included 12 days (108 hr) of behavior observations in each condition. Comparing the average percentage of days a child received a positive rating in each of the four DRC categories on placebo versus MPH provided an ecologically valid measure of whether MPH was effective in improving class work completion and accuracy and the specific adult and peer interaction difficulties judged to be most problematic for each child.

Measures

HI and I

Similar to the method used by Barkley et al. (1991), impulsivity, hyperactivity, and inattention constructs for this study were derived from the standardized rating scales administered. Items measuring impulsivity, hyperactivity, and inattention were selected from each of the rating scales, and reflected DSM-III-R and DSM-IV ADHD criteria. The Impulsivity scale had 10 items, the Hyperactivity scale had 11 items, and the Inattention scale had 14 items. The individual items comprising each of the three scales are available from the first author. For each child, a score on each of these three scales was obtained by summing the reported severity of each item and dividing by the number of items in the scale. The child’s score on each dimension was calculated separately for parent and teacher report.

High internal consistencies were obtained for the derived Impulsivity, Hyperactivity, and Inattention subscales for both parent and teacher report (Cronbach’s α ranged from .85-.93). The correlations among impulsivity, hyperactivity, and inattention were all significant but of moderate magnitude, ranging from .32 to .48 (p < .0001) for parent report and .49 to .67 (p < .0001) for teacher report. Parents and teachers showed low agreement (rs between .15, ns, and .31; p < .01), which is consistent with correlations reported elsewhere (e.g., Achenbach, McConaughly, & Howell, 1987).

Due to factor analytic studies identifying a Hyperactive-Impulsive factor and DSM-IV criteria which specify HI and C subtypes (APA, 1994), hyperactivity and impulsivity scores were combined into indices of parent-rated and teacher-rated HI. The variances of parent- and teacher-rated impulsivity and hyperactivity were similar, thus the unstandardized scores were combined to form the HI indices. The internal consistencies of the combined HI scales were excellent (parent-rated HI α = .91; teacher-rated HI α = .94). Parent- and teacher-rated HI were then combined and divided by 2 to form an overall summary index of HI. Combining information from both informants is consistent with Achenbach et al.’s (1987) conclusion that both parents and teachers contribute unique information and that utilizing ratings from both informants is optimal. Summary HI scores ranged from 0.50 to 2.66 on a 4-point scale (0 = not at all to 3 = very much). Participants were then divided into extremes on HI. The bottom third of the sample was classified as low on HI (n = 21) and had summary HI scores of 1.51 or less (average ratings of “not at all” to “just a little”). This low HI group is comparable with the ADHD/I subtype, given that they met ADHD criteria but displayed low levels of HI. For ease of communication, this group will be referred to as ADHD/I. The top third was defined as high on HI (n = 21), and had HI scores of 1.98 or greater (average symptom ratings of “pretty much” to “very much”). This approach is compatible with Lahey and Willcutt’s (2010) suggestion that counts of I and HI symptoms be used as “continuous modifiers” in conjunction with an overall ADHD diagnosis. The participants in the middle third on the summary HI index were excluded from analyses to select children at the upper and lower extremes of HI and ensure that children with subthreshold ADHD/C were not inadvertently included in the inattentive group, as cautioned by Milich et al. (2001).

Dependent Measures

Point system behaviors

To limit the number of analyses, the current study examined 7 of the 24 point system behaviors and each of the four DRC categories. Most participants exhibited low rates of some prosocial behavior categories such as “sharing with a peer” and “helping a peer”; therefore, these behaviors were excluded from analyses due to the likelihood of floor effects. The 7 behaviors and 4 DRC goals examined had good variability and were judged important for successful real-world functioning in children with ADHD. Point system behaviors have been well studied and validated in previous research (e.g., Pelham & Hoza, 1987, 1996).

Individual medication response

The primary outcome variables in this study included response to MPH for the seven point system behaviors (negative behaviors and adaptive behaviors) and DRC targets, including class behavior, class work completion and accuracy, and counselor and peer interactions. A medication effect size (the difference between the child’s frequency of each behavior averaged across 12 MPH days and across 12 placebo days, divided by the standard deviation of the participant’s behavior on placebo days) was calculated for each participant for each behavior of interest (Pelham et al., 1993, Pelham & Hoza, 1987). These effect sizes provided a standardized index of each child’s response to MPH separately for each behavior that took into account the variability in the child’s behavior across placebo days. Programs were written so that a positive value indicated a positive response to MPH.

Behavioral intervention

It should be noted that as behavior management interventions (i.e., the point system) were utilized at all times throughout the program, response to MPH in this study is actually a measure of response to MPH over and above the response to an intensive behavioral intervention. Frequencies of the point system behaviors and percentage of DRC targets obtained on placebo days are reported in Table 1 and represent each group’s severity of problem behaviors in the presence of an intensive behavior modification intervention. There was not a “no behavior management condition” in the current study, thus individual effect sizes for response to behavior management on each dependent variable could not be calculated.

Table 1.

Mean Placebo Frequency (per day) and Multivariate Analyses of Variance Results for Each Dependent Variable by Subtype.

	ADHD/I		ADHD/HI
Variable	M	SD	M	SD	F
Overall MANOVA					3.66†
Univariate F tests (1, 39)
Interruption	2.21	2.57	11.80	10.90	14.00†
Teasing	0.83	1.24	6.45	6.71	12.91†
Rule violations	9.25	10.29	19.65	15.36	6.27***
Conduct problems	0.34	0.68	1.31	1.48	6.89***
Verbal abuse	1.72	6.49	5.36	7.79	2.58
Overall MANOVA					8.90†
Univariate F tests (1, 39)
% compliance	0.97	0.03	0.93	0.04	13.86†
% attention questions correct	0.78	0.09	0.80	0.09	0.54
Overall MANOVA					3.49**
Univariate F tests (1, 39)
DRC counselors	68.09	26.10	48.26	33.41	4.38**
DRC peers	64.14	24.09	47.38	26.51	4.43**
Overall MANOVA					5.02***
Univariate F tests (1, 40)
DRC class behavior	91.51	13.18	72.34	24.11	9.52†
DRC class performance	63.51	26.62	50.70	26.19	2.40

Note. ADHD/I = ADHD Inattentive; ADHD/HI = ADHD Hyperactivity-Impulsivity; DRC = daily behavior report card %.

p < .05. ***p < .025. †p < .01.

Statistical Analyses

Subtype (ADHD HI and ADHD/I) differences in behavior frequencies on placebo days were examined using 4 separate MANOVAs due to the intercorrelation between these outcome variables. MPH effect sizes across different point system behaviors were generally uncorrelated; therefore one-way ANOVAs were used to examine the relationship between ADHD subtype and response to MPH on the point system behaviors and DRC categories (Huberty & Morris, 1980).

Results

Response to MPH

Across all dependent variables, MPH effect sizes ranged from −1.71 (indicating a strong adverse response to MPH) to +3.18. Approximately 30% of the sample displayed negative medication effect sizes in the domains of attention questions correctly answered, DRC peer and counselor-directed behavior goals, and classroom performance, indicating that their behavior and individualized goal attainment was actually worse on MPH than it was on placebo days.

Separate one-way ANOVAs were used to examine group differences in MPH effect size for each of the outcome measures (see Table 2). The high HI group displayed a more dramatic response to MPH and large average effect sizes (ds ≥ .60) for behaviors including interruption, F(1, 39) = 8.16, p = .007; verbal abuse, F(1, 31) = 6.81, p = .015; and compliance with adult requests, F(1, 37) = 6.16, p < .02; and marginally greater effect sizes for teasing and DRC counselor-directed behavior goals, F(1, 36) = 3.63; F(1, 28) = 3.99, respectively, ps < .065.

Table 2.

Means, Standard Deviations, and One-Way ANOVA Results for Hyperactivity-Impulsivity for Each Dependent Variable (MPH Effect Sizes).

	ADHD/I		ADHD/HI
Variable	M	SD	M	SD	F	df
Interruption ES	.47	.39	.84	.44	8.16††	1, 39
Verbal abuse ES	.30	.33	.63	.35	6.81****	1, 31
Teasing ES	.49	.42	.76	.44	3.63*	1, 36
Rule violations ES	.74	.46	.94	.48	1.67	1, 39
Compliance ES	.22	.49	.60	.47	6.16****	1, 37
Attention questions ES	.19	.36	.25	.44	.18	1, 39
DRC counselors ES	.11	.62	.53	.52	3.99*	1, 28
DRC peers ES	.12	.48	.40	.63	2.21	1, 35
DRC class performance ES	.15	.51	.36	.50	1.48	1, 32
DRC class behavior ES	.53	.13	.67	.34	.97	1, 20

Note. MPH = methylphenidate; ADHD/I = ADHD Inattentive; ADHD/HI = ADHD Hyperactivity-Impulsivity; ES = effect size; DRC = daily behavior report card.

p < .065. ****p < .02. ††p < .007.

Inattentive children generally displayed small MPH effect sizes (average effect sizes on 8 of the 10 dependent variables were below .50; many were .30 or below). It is especially noteworthy that these children displayed negligible MPH effect sizes in four of the five domains in which they continued to display difficulty even with the intensive behavioral intervention (attention questions correctly answered, DRC classroom performance, and DRC peer and counselor-directed behavior, ds all .19 or lower, see Table 2).

The children with ADHD/I displayed their greatest MPH response in the area of rule violations (average MPH effect size d = .74), suggesting that MPH may be beneficial in improving this group’s ability to follow rules including “be responsible for belongings” and “stay in assigned area or position.” It is important to note that for the other three behaviors for which this group displayed moderate medication effect sizes (interruption, teasing, and DRC classroom behavior, ds between .47 and .53), children with ADHD/I exhibited low levels of these negative behaviors (suggesting questionable clinical significance) in the presence of the intensive behavioral intervention alone (i.e., on placebo days; see Table 1).

Inspecting the individual distribution of effect sizes (see Table 3), only 2 to 3 of the 21 children with ADHD/I (9% to 14%) showed large MPH effect sizes in the areas typically problematic for this group. Five to 8 out of the 21 (24% to 38%) of the children with high HI displayed large MPH effect sizes for these point system behaviors.

Table 3.

Number of Participants With Small and Large MPH Effect Sizes for Behaviors and DRC Categories Problematic for ADHD/I.

	ADHD/I	ADHD/HI
Attention questions correct MPH ES
Small or negative ES	9	13
Large ES	2	5
DRC class performance MPH ES
Small or negative ES	11	10
Large ES	2	5
DRC counselor interactions MPH ES
Small or negative ES	11	4
Large ES	3	8
DRC peer interactions MPH ES
Small or negative ES	10	10
Large ES	2	7

Note. MPH = methylphenidate; DRC = daily behavior report card; ADHD/I = ADHD Inattentive; ADHD/HI = ADHD Hyperactivity-Impulsivity; ES = effect size. Small effect size = .35 or less; large effect size = .66 or greater.

Exploring Behavior With Intensive Behavioral Intervention

Four separate MANOVAs using high and low HI as the independent variable and placebo levels of the five negative point system behaviors, two positive point system behaviors, and four DRC categories as the dependent variables were conducted to examine whether children with ADHD/I displayed less impaired behavior with behavior management alone and to examine any domains in which this group continued to have difficulty even in the presence of the intensive behavioral intervention. The Inattentive group displayed lower frequencies of virtually all problem behaviors, including interruption, teasing, rule violations, and conduct problems, overall F(1, 39) = 3.66, p < .01; greater compliance with adult requests, F(1, 39) = 13.86, p < .01; and higher attainment of DRC classroom rule following, F(1, 40) = 9.52, p < .01; and individualized peer and counselor-directed DRC goals, overall F(1, 39) = 3.49, p < .05.

It is noteworthy that even though less impaired than the HI group, even in the presence of the intensive behavioral intervention, the ADHD/I group displayed difficulty with rule following (M number of rule violations per day = 9.25), percentage of “attention questions” correctly answered about the ongoing activity (78% correct), DRC classroom performance (assignment completion and accuracy), and individualized peer and counselor interaction goals (average attainment of these target behaviors = 63% to 68%; see Table 1).

Discussion

This study supports and extends previous research by finding that boys with ADHD with high levels of HI and those with low HI (comparable with ADHD/I) display differential response to MPH on important, ecologically valid behaviors assessed by direct observation in a natural setting over an extended period of time.

Consistent with Barkley et al.’s (1991) and Stein et al.’s (2003) findings, the majority of children with ADHD/HI displayed moderate to large MPH effect sizes in most areas (including problem behaviors, adaptive behaviors, and individualized DRC goals) with the exception of attention questions correctly answered and classroom work completion and accuracy. MPH (compared with placebo) was associated with especially dramatic reductions in the frequency of negative behaviors such as teasing, interruptions, and rule violations for these children. Compared with the children with ADHD/I (low HI), boys with ADHD/HI displayed significantly larger MPH effect sizes for interruptions, verbal abuse to adults, and compliance with adult directives, and marginally greater effect sizes for teasing and individualized counselor-directed DRC goals. ADHD/I children’s lower MPH response for compliance to adult requests and counselor-directed behavior goals is especially noteworthy as following directions, completing tasks, and initiating interactions with others are frequently identified areas of difficulty for these children. Differences in MPH response between groups for all other behavior categories were in the predicted direction but did not reach significance.

Children with ADHD/I generally showed small MPH effect sizes and minimal difference in their behavior with an intensive behavioral intervention alone and when MPH was added. With the presence of an intensive behavior management system alone, children with ADHD/I displayed fewer difficulties than children with ADHD/HI, and low levels of problem behavior in many areas (interruption, verbal abuse, teasing, noncompliance, conduct problems, and DRC classroom behavior). While this may suggest that children with ADHD/I are highly responsive to behavioral intervention, it more likely reflects this group’s low levels of baseline behavior problems in these domains. Even in the presence of an intensive behavior management intervention, children with ADHD/I continued to display rule violations and deficits in adaptive behaviors, including the ability to correctly answer “attention questions” assessing attention to the ongoing activity, individualized DRC goals related to class work (completion and accuracy), and interactions with peers and counselors (many of the ADHD/I children’s DRC goals for peer and counselor interactions related to their low assertiveness and social withdrawal, for example, “greets his counselor in the morning,” “initiates three conversations with peers,” etc.). It is especially noteworthy that in four of these five domains in which children with ADHD/I continued to experience difficulty even with an intensive behavior management system, this group displayed very small medication effect sizes, indicating that MPH did not add clinically significant benefit over behavior management. The addition of MPH to the behavioral intervention produced clinically meaningful improvement only in rule following behavior. This suggests that MPH does not improve inattentive children’s functional impairment in many desired adaptive behaviors.

For ADHD/I, MPH produced no meaningful improvement in many behavior areas assessed in this study, or any improvement was of negligible clinical significance when added to the effects of the existing behavioral intervention. Of particular concern was the finding that approximately 30% of the sample displayed negative medication effect sizes on positive/adaptive behaviors, including attention questions correctly answered, DRC peer and counselor-directed behavior goals, and classroom performance, indicating that their behavior and goal attainment was actually worse on MPH than it was on placebo days. A total of 40% to 60% of participants displayed negative MPH effect sizes or minimal effects in these areas. This suggests that prescribing MPH to children with ADHD/I without carefully evaluating behavior-specific medication response may actually further impair their performance in these important areas. These results highlight Pelham and Milich’s (1991) caveat that MPH response in primary presenting problems and externally valid behaviors must be evaluated, and Barkley et al.’s (1991) findings that the baseline frequency of problem behaviors and medication effect size must both be considered when making conclusions about the need for and effectiveness of medication. The importance of examining individual, domain-specific medication response and not relying solely on findings of aggregate group averages is emphasized; otherwise strong medication responders mask the significant number of children who display negligible or adverse medication response.

Limitations

A limitation of the current study is that only boys were included and one dose (.3 mg/kg; 8-10 mg bid for most participants) of MPH was examined. However, a few studies have demonstrated that there is generally little incremental clinical benefit for children with ADHD/I when MPH dosages are increased from .3 to .6 mg/kg. Given Stein et al.’s (2003), Barkley et al.’s (1991), and Fabiano et al.’s (2007) findings, it is unlikely that increasing the medication dosage would have produced meaningful improvement in most participants with ADHD/I. The possibility that our weak findings for MPH in children with ADHD/I may have represented a floor effect due to the behavioral intervention leaving little room for further improvement remains. The fact that our ADHD/I participants continued to experience difficulty in many important areas on placebo days (i.e., with intensive behavior management alone) suggests that there was room for improvement with MPH and that MPH did not produce this improvement in most ADHD/I participants. Pelham et al. (1993) and Fabiano et al. (2007) note that medication response appears more linear when no behavioral interventions are in place, thus the possibility that children with ADHD/I may show more dramatic improvement to MPH in the absence of an intensive behavior management system exists, although Barkley et al.’s and Stein et al.’s findings seem to argue against this possibility. The possibility that ADHD/I children’s individualized peer, adult, and classroom behavior and productivity goals may improve somewhat with a higher MPH dose and/or if no behavioral intervention is in place should be further explored.

Clinical Implications and Conclusions

The current study addresses some methodological weaknesses of other studies noted by Barkley et al. (1991) and Pelham and Milich (1991). The complete independence of the parent and teacher ratings scales used to classify participants into subgroups and the outcome variables (obtained by direct behavior observation by trained program staff) ensure that our findings were not inflated by method similarity. Selection of ADHD subgroups using the upper and lower third of the sample on HI (and exclusion of participants with middle levels) ensured that participants with subthreshold ADHD/HI were not included in the ADHD/I group, as cautioned by Milich et al. (2001). Our outcome measures included a wide range of both problem behaviors and adaptive behaviors displayed in a natural setting (i.e., the classroom, hallway, and recreational activities) and thus have a higher level of ecological validity than laboratory and learning tasks used in previous studies. Our dependent variables are easily interpretable in terms of real-world impairment and significance, examine functional impairment specific to each child, and include deficits in desired, adaptive behaviors that have been previously unstudied.

Pelham and Milich (1991) have long emphasized the importance of addressing the extent to which any treatment modality improves each child’s unique presenting problems in core domains of adaptive functioning (e.g., interactions with peers and adults, and behavior and performance at school). In all, 30% to 50% of children with ADHD/I failed to show clinically meaningful benefit with MPH in desired, adaptive behaviors and their primary areas of impairment, and a low dose (5 mg bid) appeared sufficient for most of the remaining children in this group. Over half of our ADHD/I group displayed an adverse or negligible MPH response in many real-world behaviors that are commonly reported to be core, functional impairments for this group, indicating that a careful, placebo-controlled medication assessment across each ADHD/I child’s specific presenting problems is crucial. These children appear at high risk of being unnecessarily medicated (medication may actually impair their performance) or overmedicated in current practice.

Lahey and Willcutt (2010) found that ADHD children with high levels of inattention are at much greater risk than children with high HI for mathematics difficulty and teacher-rated need for treatment. Subtyping children with ADHD/I (low HI) or ADHD/high HI appears to provide an efficient heuristic for selecting target behaviors and tailoring medication and behavioral and other academic interventions in developing the most effective treatment plan for each child.

Future Directions

Further investigation of the optimal cut point for identifying children with Inattentive/low HI and children with high HI (and using which ratings completed by which informants) is needed. These groups’ differences in associated behaviors, peer difficulties, and academic problems suggest that different outcome behaviors may need to be used when assessing medication response for each group.

If MPH fails to improve or actually impairs ADHD/I children’s level of many adaptive/positive behaviors that are common deficits in this group, identifying effective behavioral and academic interventions for these children becomes essential. Pfiffner et al.’s (2007) work has begun this important step by finding that a combination of instruction, rehearsal, and contingency management produced clinically significant, sustained improvement in difficulties associated with sluggish cognitive tempo and social, organizational, and time management deficits displayed by their participants with ADHD/I. It is noteworthy that their interventions examined the ability to correctly answer “attention questions” similar to those used in the STP (which showed minimal improvement with MPH in this study). The need to further study the effectiveness of behavioral interventions specifically targeted to core domains of functional impairment for children with ADHD/I takes on additional significance given Elkins, Malone, Keyes, Iacono, and McGue’s (2011) recent work suggesting that girls with ADHD/I experience more severe academic and social impairment throughout middle school than boys with ADHD/I do. Our finding that MPH provided negligible benefit for children with ADHD/I in individualized goals targeting classroom productivity and each child’s most problematic peer difficulties emphasizes the importance of developing effective nonpharmacological treatments for children and teens with ADHD/I, perhaps especially girls. Future research to assess Inattentive children’s responsiveness to these types of behavioral interventions (and the possibility of differential response between children with ADHD/I and children with ADHD/HI) is clearly needed.

Footnotes

Acknowledgements

The authors wish to thank Richard Milich for comments on an earlier draft of the manuscript.

Authors’ Note

Dr. Quay is currently professor emeritus at the University of Miami. The first author bears responsibility for any errors in this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: During the conduct of this research, William E. Pelham was supported by National Institute of Mental Health (NIMH; grants MH48157, MH47390, MH45576, and MH50467); National Institute on Drug Abuse Grant DA05605, and National Institute on Alcohol Abuse and Alcoholism Grant AA06267 and AA11873. Data for this study were collected during the 1992 -1993 Summer Treatment Programs, which were conducted under the direction of William E. Pelham by the Attention Deficit Disorder Program at the Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center. We thank the Western Psychiatric Institute and Clinic for its support.

Author Biographies

Susan H. Beery is an Assistant Professor of Psychology at Lycoming College in Williamsport, PA.

Herbert C. Quay is Professor Emeritus, University of Miami, Coral Gables, FL.

William E. Pelham, Jr. is Chair of the Psychology Department, Distinguished Professor of Psychology and Psychiatry, and Director of the Center for Children and Families at Florida International University.

References

Achenbach

T. M.

Edelbrock

(1983). Manual for the Child Behavior Checklist and Revised Child Behavior Profile. Burlington: Department of Psychiatry, University of Vermont.

Achenbach

T. M.

McConaughly

S. H.

Howell

C. T.

(1987). Child/adolescent behavioral and emotional problems: Implications of cross-informant correlations for situational specificity. Psychological Bulletin, 101, 213-232.

American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders (3rd ed., Rev.). Washington, DC: Author.

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author.

Barkley

R. A.

DuPaul

G. J.

McMurray

M. B.

(1991). Attention deficit disorder with and without hyperactivity: Clinical response to three dose levels of methylphenidate. Pediatrics, 87, 519-531.

Diamond

(2005). Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): A neurobiologically and behaviorally distinct disorder from attention-deficit/hyperactivity disorder (with hyperactivity). Developmental Psychopathology, 17, 807-825.

Elkins

I. J.

Malone

Keyes

Iacono

W. G.

McGue

(2011). The impact of attention-deficit/hyperactivity disorder on preadolescent adjustment may be greater for girls than for boys. Journal of Clinical Child & Adolescent Psychology, 40, 532-545.

Fabiano

G. A.

Pelham

W. E.

Gnagy

E. M.

Burrows-MacLean

Coles

E. K.

Chacko

Robb

J. A.

(2007). The single and combined effects of multiple intensities of behavior modification and methylphenidate for children with attention deficit hyperactivity disorder in a classroom setting. School Psychology Review, 36, 195-216.

Huberty

C. J.

Morris

J. D.

(1980). Multivariate analysis versus multiple univariate analyses. Psychological Bulletin, 105, 302-308.

10.

Lahey

B. B.

Appelgate

McBurnett

Biederman

Greenhill

Hynd

G. W.

Richters

(1994). DSM-IV field trials for attention-deficit/hyperactivity disorder in children and adolescents. American Journal of Psychiatry, 151, 1673-1685.

11.

Lahey

B. B.

Willcutt

E. G.

(2010). Predictive validity of a continuous alternative to nominal subtypes of attention-deficit/hyperactivity disorder for DSM V. Journal of Clinical Child & Adolescent Psychology, 39, 761-775. doi:10.1080/ 15374416.2010.517173

12.

Loney

Milich

(1982). Hyperactivity, inattention, and aggression in clinical practice. In Wolraich

Routh

D. K.

(Eds.), Advances in developmental and behavioral pediatrics (Vol. 3, pp. 113-147). Greenwich, CT: JAI.

13.

Milich

Balentine

A. C.

Lynam

D. R.

(2001). ADHD combined type and ADHD predominantly inattentive type are distinct and unrelated disorders. Clinical Psychology: Science and Practice, 8, 463-488.

14.

Nigg

J. T.

Tannock

Rhode

L. A.

(2010). What is to be the fate of ADHD subtypes? An introduction to the special section on research on the ADHD subtypes and implications for DSM-V. Journal of Clinical Child & Adolescent Psychology, 39, 723-725.

15.

Pelham

W. E.

Atkins

M. S.

Murphy

H. A.

(1981). Attention deficit disorder with and without hyperactivity: Definitional issues and correlates. In Pelham

W. E.

(Ed.), DSM III category of attention deficit disorders: Rationale, operationalization, and correlates. Los Angeles, CA: American Psychological Association.

16.

Pelham

W. E.

Carlson

Sams

S. E.

Vallano

Dixon

M. J.

Hoza

(1993). Separate and combined effects of methylphenidate and behavior modification on boys with attention deficit-hyperactivity disorder in the classroom. Journal of Consulting and Clinical Psychology, 61, 506-515.

17.

Pelham

W. E.

Gnagy

E. M.

Greenslade

K. E.

Milich

(1992). Teacher ratings of DSM-III-R symptoms for the disruptive behavior disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 31, 210-218.

18.

Pelham

W. E.

Hoza

(1996). Intensive treatment: A summer treatment program for children with ADHD. In Hibbs

E. D.

Jensen

P. S.

(Eds.), Psychosocial treatments for child and adolescent disorders: Empirically based strategies for clinical practice (pp. 311-340). New York, NY: American Psychological Association.

19.

Pelham

W. E.

Hoza

(1987). Behavioral assessment of psychostimulant effects on ADD children in a summer treatment program. In Prinz

(Ed.), Advances in behavioral assessment of children and families (Vol. 3, pp. 3-33). Greenwich, CT: JAI.

20.

Pelham

W. E.

Milich

(1991). Individual differences in response to Ritalin in class work and social behavior. In Osman

B. P.

Greenhill

(Eds.), Ritalin: Theory and patient management (pp. 203-222). New York, NY: Mary Ann Liebert.

21.

Pfiffner

L. J.

Mikami

A. Y.

Huang-Pollock

Easterlin

Zalecki

McBurnett

K. M.

(2007). A randomized, controlled trial of integrated home-school behavioral treatment for ADHD, predominantly inattentive type. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 1041-1050.

22.

Solanto

Newcorn

Vail

Gilbert

Ivanov

Lara

(2009). Stimulant drug response in the predominantly inattentive and combined subtypes of attention-deficit/hyperactivity disorder. Journal of Child & Adolescent Psychopharmacology, 19, 663-671.

23.

Stein

M. A.

Sarampote

C. S.

Waldman

I. D.

Robb

A. S.

Conlon

Pearl

P. L.

Newcorn

J. H.

(2003). A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics, 112, e404-e413.