Does Comorbid Disruptive Behavior Modify the Effects of Atomoxetine on ADHD Symptoms as Measured by a Continuous Performance Test and a Motion Tracking Device?

Abstract

Objective: To compare the reduction of ADHD symptoms under atomoxetine in patients with and without comorbid oppositional defiant disorder (ODD) or conduct disorder (CD) using a computer-based continuous performance test (cb-CPT) combined with an infrared motion tracking (MT) device. Method: Secondary analysis of a placebo-controlled study in ADHD patients (6-12 years old) treated with atomoxetine (target dose: 1.2 mg/kg per day). Cb-CPT/MT scores were analyzed using ANCOVA (last observation carried forward [LOCF]). Results: The data (N = 125) suggested a more pronounced atomoxetine effect in the group with comorbid ODD/CD as measured by all cb-CPT/MT parameters except for “normalized variation of reaction time” (nVRT). Conclusion: The results showed that atomoxetine reduced ADHD severity as measured by cb-CPT and MT parameters regardless of whether comorbid ODD/CD was present. The treatment effect of atomoxetine on hyperactivity appears to be more pronounced in the subgroup of patients with comorbid ODD/CD than in the subgroup without this comorbidity.

Keywords

ADHD ODD/CD atomoxetine quantitative behavioral measurement

Introduction

ADHD is a highly prevalent psychiatric disorder characterized by inattention, hyperactivity, and impulsivity (American Psychiatric Association, 2000). Genetic and imaging studies have linked the symptoms of ADHD to abnormalities of the dopaminergic and noradrenergic transmitter systems, leading to impaired neurotransmission (Arnsten, 2009; Banaschewski et al., 2010; Biederman & Faraone, 2005). Results from animal and human studies implicate a dysregulation of frontal-subcortical-cerebellar catecholaminergic circuits (Biederman & Faraone, 2005; di Michele, Princhep, John, & Chabot, 2005). ADHD is associated with impaired executive function and inhibitory control (Arnsten, 2009; Doyle, 2006).

A number of pharmacologic treatments for ADHD have shown effectiveness on executive function, including long- and short-acting psychostimulants (e.g., methylphenidate; Epstein et al., 2006; Levy & Hobbes, 1997), and nonstimulants such as the selective norepinephrine reuptake inhibitor atomoxetine (ATX; Maziade et al., 2009). The effects of ATX on executive function and inhibitory control in patients with ADHD have been assessed by means of various questionnaires (Maziade et al., 2009) and also in imaging studies (Chamberlain et al., 2009), but the clinical effect has not been measured objectively using a computer-based continuous performance test (cb-CPT). However, as continuous performance tests (CPTs) have demonstrated sensitivity to executive dysfunction (Riccio, Reynolds, Lowe, & Moore, 2002), they are a good method for studying executive function and inhibitory control. CPTs can be coupled with a motion tracking (MT) device to assess the level of activity in specific situations (Taylor, 1998; Teicher et al., 1996).

There is a high degree of correlation between symptoms of ADHD and oppositional defiant disorder (ODD; Spencer, 2009). Persistence of ADHD and ODD into adolescence is associated with an increased risk of delinquent behavior, substance dependence, anxiety, depression, and possibly bipolar disorder (Hazell, 2010). Up to 20% of patients with ADHD may meet criteria for conduct disorder (CD), and an even higher proportion of patients will show aggressiveness or other symptoms of CD without meeting full diagnostic criteria (McBurnett & Pfiffner, 2009). ATX has been shown to be effective in treating comorbid symptoms of ODD in children with ADHD in several studies (Bangs et al., 2008; Biederman, et al., 2007; Dell’Agnello et al., 2009; Dittmann et al., 2011; Hazell et al., 2006, 2010), but in two earlier studies, the effect of ATX on the severity of ODD symptoms was inconclusive (Bangs et al., 2008; Kaplan et al., 2004). In the study by Newcorn, Spencer, Biederman, Milton, and Michelson (2005), ATX improved ADHD and ODD symptoms in children and adolescents with ADHD and comorbid ODD, although individuals with comorbid ODD seemed to require higher doses. Finally, the study by Dittmann et al. (2011) showed that treatment of children and adolescents with ADHD and comorbid ODD or CD with ATX resulted in reduced symptoms of ADHD, ODD, and CD. Taken together, these findings suggest that children and adolescents with ADHD and comorbid ODD or CD may benefit to a greater extent from treatment with ATX.

However, the extent to which the presence of ODD and/or CD influences the effect of ATX on ADHD symptoms is unclear (van Wyk et al., 2012). Thus, the aim of this secondary analysis, which was pre-specified in the study protocol, was to investigate whether the presence of ODD and/or CD modifies the effect of ATX on ADHD symptoms.

We designed this study in children with ADHD with the primary objective of evaluating the efficacy of ATX on ADHD symptoms compared with placebo (Wehmeier, Schacht, Ulberstad, et al., in press). The primary endpoints were based on standard variables of a cb-CPT that captures aspects of attention and impulsivity combined with an infrared MT device that records the level of activity. This method allows the separate assessment of the three core symptoms of ADHD. Although hyperactivity is one characteristic of ADHD, it constitutes a separate component of the disorder and should hence be analyzed separately from inattention and impulsivity (Taylor, 1998).

As secondary objectives, we compared the reduction of ADHD symptoms under ATX treatment versus placebo in patients with and without comorbid ODD or CD using the objective measurement approach (cb-CPT plus MT) described above and using standard clinical rating scales such as the ADHD Rating Scale (ADHD-RS; DuPaul, Power, Anastopoulos, & Reid, 1998; Faries et al., 2001).

Method

Study Design

This randomized, double-blind, placebo-controlled, two-arm, multicenter study was approved by an ethical review board (University of Cologne) and conducted (Clinical Trial Registry Number: NCT00546910, www.clinicaltrials.gov) according to the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guideline. The 16 study sites were located all over Germany and included 3 university departments for child and adolescent psychiatry, 1 nonuniversity child and adolescent psychiatry hospital, and 12 office-based practices for child and adolescent psychiatry and/or pediatrics. Informed consent was obtained from the legal representatives and informed assent from the child. Eligible patients were randomized to 8 weeks of treatment with ATX starting at 0.5 mg/kg per day for 1 week, followed by 7 weeks on the standard target dose of 1.2 mg/kg per day or placebo. The cb-CPT plus MT (Knagenhjelm & Ulberstad, 2010) was carried out in the morning, at noon, and in the late afternoon/early evening on visit days. Rating scales were scored only once per visit day at any time during the day. Efficacy and tolerability assessments were performed at baseline and after 1, 2, 4, 6, and 8 weeks.

Patients

Girls and boys aged 6 to 12 years with a diagnosis of ADHD according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) criteria were eligible. The diagnosis was confirmed using the Diagnose-Checkliste Hyperkinetische Störungen (Diagnostic Checklist for Hyperkinetic Disorders [DCL-HKS]), a structured instrument that is routinely used for the diagnostic assessment of ADHD in Germany (Döpfner & Lehmkuhl, 2000). The items of this instrument correspond to those of the ADHD-RS (DuPaul et al., 1998; Faries et al., 2001). The presence of comorbid disorders frequently associated with ADHD was not exclusionary. Therefore, patients with and without ODD or CD were allowed to participate in the study. The ODD/CD diagnosis was established clinically based on the DSM-IV-TR criteria (American Psychiatric Association, 2000). Exclusion criteria comprised previous treatment with ATX, treatment with psychotropic medication other than the study drug, clinically relevantly over- or underweight, a history of bipolar disorder, psychosis, pervasive developmental disorder, seizure disorder (other than febrile seizures), serious suicidal risk, and other relevant acute or unstable medical conditions. Psychotherapy initiated prior to the study was acceptable.

Efficacy Measures

The primary efficacy measures were the q-scores of the cb-CPT combined with an infrared MT device (QbTest, provided by Qbtech, Gothenburg, Sweden, www.qbtech.se). This test simultaneously tracks and quantifies body movement using the infrared MT device during a go/no-go task (Knagenhjelm & Ulberstad, 2010). This method (referred to as “cb-CPT/MT” below) was developed on the basis of an earlier approach to measuring ADHD core symptoms, assessing attention, impulsivity, and hyperactivity objectively (Halperin, Matier, Bedi, Sharma, & Newcorn, 1992; Heiser et al., 2004; Schechter & Timmons, 1985; Teicher et al., 1996; Teicher et al., 2000) and has been found to reflect various ADHD symptoms (Brocki et al., 2010; Oades et al., 2010). The test was shown to have ecological validity in that it correlated well with clinical response (Tabori-Kraft et al., 2007) and was useful in identifying the medication dose which produced the best overall clinical results (Teicher et al., 2008). The method used in this study has been published in detail elsewhere (Wehmeier, Schacht, Ulberstad, et al., in press; Wehmeier, Schacht, Wolff, et al., 2011).

Further efficacy measures assessed in this study were (a) ADHD Rating Scale-IV-Parent Version: Investigator-Administered and Scored (DuPaul et al., 1998; Faries et al. 2001), (b) Clinical Global Impression–Severity (CGI-S) scale (Guy, 1976; National Institutes of Mental Health [NIMH], 1985), and (c) Weekly Ratings of Evening and Morning Behavior–Revised–Investigator Rated (WREMB-R-Inv) scale (Carlson et al., 2007; Kelsey et al., 2004; Sutton et al., 2003; Wehmeier et al., 2009). Beyond clinically establishing the diagnosis at baseline according to DSM-IV-TR criteria (American Psychiatric Association, 2000), ODD and CD symptom severity was not assessed in this study.

Tolerability Assessments

Tolerability was assessed by open-ended questioning for adverse events (AEs) and the assessment of vital signs and body weight.

Statistical Analyses

The 10 primary endpoint variables were tested hierarchically to control for multiplicity. The primary efficacy analysis was a repeated measures analysis based on the restricted maximum likelihood method assuming an unstructured covariance matrix (Mixed Model Repeated Measures; MMRM). Further details of the primary analysis have been published elsewhere (Wehmeier, Schacht, Ulberstad, et al., in press). ANCOVA was performed for sensitivity analyses for the primary analyses based on last observation carried forward (LOCF). These included fixed effects for the respective baseline scores, treatment, time of day, and treatment–time of day interaction.

Two factors (presence of ODD or CD and pre-treatment with stimulants) were pre-specified in the protocol as potential treatment effect modifiers. This report focuses on the prespecified analyses regarding ODD/CD. ANCOVA using LOCF with fixed effects for baseline, treatment, ODD/CD, and treatment–ODD/CD interaction was done for questionnaire scores. The analyses of the cb-CPT/MT variables contained additional terms for time of day, time of day–treatment interaction, and time of day–treatment–ODD/CD interaction. The baseline characteristics for patients with and without comorbid ODD/CD were compared using t test or χ² test. All statistical tests were done using a two-sided level of 5%; 95% confidence intervals are reported. No adjustments for multiple comparisons were done as these were secondary analyses, whereas the primary analyses were adjusted for multiplicity as described above.

All efficacy and tolerability analyses were conducted on the full analysis set (FAS), which included all randomized patients who took at least one dose of study medication (ATX or placebo). A further sensitivity check was done based on a per-protocol population (PPP), which excluded patients with low compliance (one patient), exposure to study medication of less than 7 days (one patient), starting structured psychotherapy (one patient), or receiving stimulants during the study (one patient). For this per-protocol analysis, a reduced set of cb-CPT/MT tests was used, excluding tests where the longest continuous period of time without any response (“off task”) exceeded 45 s (which corresponds to 5% of the total test time of 15 min). By this approach, the analysis was restricted to those tests where patients were on task 95% of the time. Under certain rare and extreme circumstances, calculation of q-scores can lead to unreasonably high values. Therefore, q-scores > 100 were set to missing for all analyses.

Details on sample size calculation, randomization, and blinding have been published elsewhere (Wehmeier, Schacht, Ulberstad, et al., in press; Wehmeier, Schacht, Wolff, et al., 2011). AE rates were evaluated descriptively for each treatment arm. The data analysis for this article was generated using SAS software version 8.2 or higher (SAS Institute Inc., Cary, NC, USA).

Results

Patient Disposition

Of 135 patients initially assessed, 128 patients were randomly assigned to treatment. Of these, 125 patients received at least one dose of study drug (ATX n = 63, placebo n = 62; FAS). Of these patients, 105 (84.0%) completed the study (Figure 1). The retention rate was slightly lower in the placebo group (82.3%) than in the ATX group (85.7%). The first patient entered the study in October 2007, and the last patient completed the study in May 2009.

Figure 1.

Patient disposition.

Baseline Characteristics

In the overall sample, the mean age was 9.0 (SD ± 1.79) years; 77.6% of patients were male. The two treatment groups were comparable in terms of baseline characteristics and baseline ADHD severity as measured by the ADHD-RS (Table 1). The baseline characteristics for patients with and without comorbid ODD/CD are shown in Table 2. We found a trend for a family history of ADHD being more common in the group of patients with comorbid ODD/CD. Also, the ADHD-RS total and inattention scores at baseline were found to be significantly higher in the group with comorbid ODD/CD. No differences such as in the ADHD-RS were found in any of the cb-CPT/MT test parameters at baseline.

Table 1.

Baseline Characteristics by Treatment Group.

	Atomoxetine (n = 63)		Placebo (n = 62)
Demographics	M	SD	M	SD
Age (years)	9.1	1.93	8.9	1.64
	n	%	N	%
Sex: male	47	74.6	50	80.6
DSM-IV-TR diagnosis, ADHD subtype	n	%	n	%
Combined	40	63.5	48	77.4
Predominantly inattentive	17	27.0	11	17.7
Predominantly hyperactive-impulsive	6	9.5	3	4.8
Psychiatric comorbidity	n	%	n	%
At least one psychiatric comorbidity	25	39.7	25	40.3
ODD	20	31.7	19	30.6
CD	9	14.3	12	19.4
ODD or CD	25	39.7	25	40.3
Further disease characteristics	n	%	n	%
Previous stimulant exposure	13	20.6	18	29.0
At least one relative with ADHD	36	57.1	35	56.5
Disease severity	M	SD	M	SD
ADHD-RS total score	37.30	10.62	36.68	12.53
ADHD-RS, inattention subscore	19.98	5.22	19.13	6.05
ADHD-RS, hyperactive/impulsive subscore	17.32	6.77	17.55	7.51
CGI-S ADHD	5.11	1.02	5.05	1.11
WREMB-R total score	21.70	7.64	21.58	7.91
WREMB-R evening subscore	14.54	4.76	15.39	4.74
WREMB-R morning subscore	5.56	2.66	4.63	2.92
WREMB-R item 11 (difficulty falling asleep)	1.60	1.23	1.56	1.26
cb-CPT/MT q-scores	M	SD	M	SD
Anticipatory	0.32	1.03	0.10	0.77
Area	1.19	1.63	1.48	1.48
Commission error rate	−0.71	1.16	−0.87	0.93
Distance	1.48	1.69	1.66	1.55
Error rate	0.41	1.42	0.37	1.13
Microevents	0.96	1.31	1.15	1.05
Motion simplicity	0.23	1.04	0.35	0.82
Multiresponse	0.00	1.08	−0.31	0.78
Normalized variation	0.98	1.46	0.82	1.20
Omission error rate	1.20	1.26	1.25	1.22
Reaction time	2.40	1.86	1.94	1.42
Reaction time variation	2.87	2.14	2.41	1.72
Time active	0.64	1.19	0.82	0.73

Note: DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.); ODD = oppositional defiant disorder; CD = conduct disorder; ADHD-RS = ADHD Rating Scale; CGI-S = Clinical Global Impression–Severity; WREMB-R = Weekly Ratings of Evening and Morning Behavior–Revised; cb-CPT/MT = computer-based continuous performance test combined with an infrared motion tracking device.

Table 2.

Baseline Characteristics for Patients With and Without Comorbid ODD/CD (t Test or χ² Test).

	Without ODD/CD (n = 75)		With ODD/CD (n = 50)
Demographics	M	SD	M	SD	p value
Age (years)	9.1	1.66	8.9	1.97	.7199
	n	%	n	%
Sex: male	59	78.7	38	76.0	.7261
DSM-IV-TR diagnosis, ADHD subtype	n	%	n	%
Combined	50	66.7	38	76.0	.4126
Predominantly inattentive	18	24.0	10	20.0
Predominantly hyperactive-impulsive	7	9.3	2	4.0
Further disease characteristics	n	%	n	%
Previous stimulant exposure	20	26.7	11	22.0	.5539
At least one relative with ADHD	38	50.7	33	66.0	.0900
Disease severity	M	SD	M	SD
ADHD-RS total score	35.2	12.33	39.6	9.84	.0297
ADHD-RS, inattention subscore	18.7	6.11	20.9	4.58	.0195
ADHD-RS, hyperactive/impulsive subscore	16.6	7.63	18.7	6.13	.0898
CGI-S ADHD	5.1	0.90	5.2	1.00	.3640
WREMB-R total score	20.9	8.08	22.7	7.16	.2109
WREMB-R evening subscore	14.5	4.91	15.6	4.46	.2260
WREMB-R morning subscore	4.9	2.99	5.4	2.54	.3112
WREMB-R item 11 (difficulty falling asleep)	1.5	1.25	1.7	1.23	.3943
cb-CPT/MT q-scores (mean over the day)	M	SD	M	SD
Anticipatory	0.2	0.90	0.2	0.96	.7621
Area	1.4	1.62	1.4	1.46	.9558
Commission error rate	−0.9	0.98	−0.7	1.17	.4693
Distance	1.6	1.64	1.6	1.57	.8888
Error rate	0.2	1.2	0.6	1.30	.0949
Microevents	1.1	1.19	1.0	1.15	.6421
Motion simplicity	0.4	0.94	0.2	0.95	.1697
Multiresponse	−0.2	0.99	−0.1	0.93	.7780
Normalized variation	0.9	1.32	0.9	1.40	.9844
Omission error rate	1.1	1.24	1.4	1.21	.1211
Reaction time	2.2	1.45	2.2	1.99	.9523
Reaction time variation	2.7	1.95	2.6	2.00	.7211
Time active	0.8	0.96	0.6	1.01	.4097

Note: DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.); ADHD-RS = ADHD Rating Scale; CGI-S = Clinical Global Impression–Severity; WREMB-R = Weekly Ratings of Evening and Morning Behavior–Revised; cb-CPT/MT = computer-based continuous performance test combined with an infrared motion tracking device.

Primary Efficacy Outcome—cb-CPT/MT Scores

The primary efficacy analysis (MMRM) showed that treatment with ATX once daily over a period of 8 weeks (target dose 1.2 mg/kg/day) was significantly superior to placebo in reducing hyperactivity, inattention, and impulsivity as measured by q-scores of 10 primary variables of the cb-CPT (Wehmeier, Schacht, Ulberstad, et al., in press). The respective MMRM analyses based on the PPP (excluding tests where the longest period of time “off task” exceeded 45 s) and the supportive ANCOVAs using LOCF (data not shown) yielded corresponding results.

The results of the ANCOVA differentiating for comorbidity are displayed in Figure 2. It shows the effect sizes (ES) within the subgroups with and without ODD/CD for the q-scores of the cb-CPT variables (FAS). The corresponding ES findings for the clinical scale scores are summarized in Figure 3. The p value for the interaction between treatment and comorbidity indicates whether the ATX effect differs between patients with and without ODD/CD (Table 3).

Table 3.

ANCOVA (LOCF) for the ADHD-RS, the CGI-S ADHD, WREMB-R, cb-CPT/MT q-Scores (FAS and PPP).

	Effect size (FAS)			Effect size (PPP)
	Without ODD/CD	With ODD/CD	p value*	Without ODD/CD	With ODD/CD	p value*
Rating scales
ADHD-RS
Total score	0.76	1.16	.274	—	—	—
Inattention subscore	0.75	0.84	.824	—	—	—
Hyperactive/impulsive subscore	0.72	1.37	.074	—	—	—
CGI-S ADHD	0.61	1.00	.248	—	—	—
WREMB-R
Total score	0.60	0.93	.370	—	—	—
Evening subscore	0.65	0.96	.399	—	—	—
Morning subscore	0.36	0.75	.300	—	—	—
Item 11 (difficulty falling asleep)	0.57	0.58	.972	—	—	—
cb-CPT/MT q-scores
Hyperactivity
Time active	0.52	0.77	.170	0.65	1.04	.161
Distance	0.75	1.00	.292	0.81	1.32	.076
Area	0.62	0.85	.264	0.73	1.04	.241
Microevents	0.80	1.07	.276	0.94	1.44	.158
Motion simplicity	0.29	0.28	.971	0.43	0.32	.730
Inattention
Reaction time variation	0.55	0.31	.267	0.71	0.58	.668
Omission error	0.39	0.35	.844	0.50	0.33	.493
Mean reaction time	0.28	0.19	.652	0.38	0.46	.757
Normalized reaction time variation	0.35	0.02	.078	0.67	0.18	.135
Impulsivity
Commission error	0.44	0.26	.376	0.74	0.70	.870
Anticipatory	0.15	0.06	.552	0.22	0.27	.787
Other
Error rate	0.53	0.48	.806	0.69	0.61	.768
Multiresponse	0.10	−0.06	.394	0.33	0.02	.197

Note: LOCF = last observation carried forward; ADHD-RS = ADHD Rating Scale; CGI-S = Clinical Global Impression–Severity; WREMB-R = Weekly Ratings of Evening and Morning Behavior–Revised; cb-CPT/MT = computer-based continuous performance test combined with an infrared motion tracking device; FAS = full analysis set; PPP = per-protocol population; ODD/CD = oppositional defiant disorder/conduct disorder. No PPP analyses were done for the ratings scales as this effects only four patients, whereas the PPP analyses excludes these four patients as well as the nonvalid tests for the cb-CPT variable.

p value for the interaction between treatment and comorbidity.

Figure 2.

Effect sizes within and across the subgroups with/without ODD/CD for the q-scores of the cb-CPT/MT variables (FAS).

Figure 3.

Effect sizes within and across the subgroups with/without ODD/CD for the ADHD-RS, the CGI-S, and the WREMB-R (FAS).

We found a trend for an interaction for the normalized variation of the reaction time (nVRT), with a higher ES seen in the group without comorbid ODD/CD. Four of the five cb-CPT/MT parameters related to hyperactivity (time active [TA], distance [DIS], area [AR], and microevents [ME]) suggested a common pattern that point toward a more pronounced ATX treatment effect in the group with comorbid ODD/CD, except for motion simplicity (MS). However, none of the individual tests reached statistical significance.

Secondary Efficacy Outcomes—ADHD-RS, WREMB-R, CGI-S-ADHD

ATX was significantly superior to placebo in reducing ADHD symptom severity as measured by ADHD-RS and CGI-S scores. The WREMB-R total score and the subscores also showed statistically significant differences between the treatment groups by Week 8 (Wehmeier, Schacht, Wolff, et al., 2011). Sensitivity tests using ANCOVA supported these results (data not shown). The effect size (ES) results of the ANCOVA differentiating for comorbidity are displayed in Figure 3, and further details including the p values for the interaction test are summarized in Table 3. We found a trend (p = .074) for an interaction for the ADHD-RS hyperactive/impulsive subscore, with a higher effect size (ES) seen in the group with comorbid ODD/CD (ES = 1.37 vs. ES = 0.72). No such signals were seen for the inattention subscore or for the total score of the ADHD-RS, as well as for the CGI-S and the WREMB-R scores.

Tolerability

Patients received study treatment for a median of 55 days in both groups. Treatment-emergent adverse events (TEAEs) were reported in 32 (50.8%) patients treated with ATX and in 27 (43.5%) patients receiving placebo. Two patients treated with ATX discontinued the study due to TEAEs (3.2%); in the placebo group, three patients discontinued due to TEAEs (4.8%). The three most commonly reported TEAEs (>5%) were abdominal pain (ATX: 11.1%; placebo: 3.2%), nausea (ATX: 9.5%; placebo: 3.2%), and fatigue (ATX: 6.3%; placebo: 1.6%). No serious AEs were reported. More detailed tolerability results have been published elsewhere (Wehmeier, Schacht, Ulberstad, et al., in press; Wehmeier, Schacht, Wolff, et al., 2011).

Discussion

Findings from previous studies have suggested that children and adolescents with ADHD and comorbid ODD or CD may benefit from treatment with ATX (Bangs et al., 2008; Biederman et al., 2007; Dell’Agnello et al., 2009; Dittmann et al., 2011; Hazell et al., 2006; Kaplan et al., 2004; Newcorn et al., 2005; Newcorn, Sutton, Weiss, & Sumner, 2009). However, the extent to which the presence of ODD and/or CD influences the effect of ATX in children with ADHD is unclear (van Wyk et al., 2012). Hence, the aim of this prespecified analysis was to address this question.

The baseline characteristics of the patients in this sample (Table 2) are comparable to those of other placebo-controlled ATX studies (Cheng, Chen, Ko, & Ng, 2007). One difference between the groups of patients with and without comorbid ODD/CD at baseline was a trend for a family history of ADHD being more common in the group of patients with comorbid ODD/CD. This finding could be related to the fact that ADHD and ODD/CD share genetic influences (Dick, Viken, Kaprio, Pulkkinen, & Rose, 2005; Martin, Levy, Peka, & Hay, 2006).

ADHD-RS baseline total and inattention scores were found to be significantly higher in the group with comorbid ODD/CD. This finding may be explained by symptom overlap between ADHD and ODD/CD. Such overlap has been shown to be related to the symptom domains of hyperactivity and/or impulsivity rather than to inattention (Taylor, 1998). However, an alternative explanation for this finding could be that the group with ODD/CD may have had higher ADHD scores because they had more severe ADHD. The analyses regarding the treatment effect of ATX were adjusted for baseline differences in ADHD symptom severity.

No baseline differences were found in any of the cb-CPT/MT parameters, in contrast to ADHD-RS scores. One could speculate whether this might indicate a more clear-cut distinction between ADHD and ODD/CD symptoms as measured by the cb-CPT/MT, and a less clear-cut distinction between ADHD and ODD/CD symptoms measured by the rating scale. This could be caused by ADHD-RS items correlating well with ODD/CD symptoms, while the cb-CPT parameters reflect ODD/CD symptoms to a lower degree. This could involve a kind of “rater bias” in terms of the rater perceiving the patient in a more general way and including ODD/CD symptoms in his rating. Hence, the ODD/CD symptoms may have indirectly influenced the rating on the ADHD-RS. In contrast, the cb-CPT may be expected to measure ADHD symptoms more specifically. However, other explanations could be just as valid.

No other differences were seen in terms of demographic variables or characteristics of the disorder. This suggests that any differences in terms of treatment effects between patients with and without comorbid ODD/CD are likely to be driven by the comorbid ODD/CD rather than by other factors.

The postbaseline data showed a trend for an interaction for the ADHD-RS hyperactive/impulsive subscore, with a higher effect size (ES) seen in the group with comorbid ODD/CD. As the analysis was adjusted/corrected for ADHD-RS baseline scores, this finding was not driven by the differences at baseline. Such interactions were found neither for the inattention subscore nor for the total score of the ADHD-RS. Thus, this finding can be considered a sign that patients with comorbid ODD/CD may benefit from treatment with ATX to a greater extent than patients without these comorbid disorders, at least in terms of hyperactive/impulsive symptoms as assessed by the ADHD-RS.

In terms of the cb-CPT/MT parameters, there was a trend for an interaction for the nVRT, with a higher ES seen in the group without comorbid ODD/CD. Here, a significant treatment effect of ATX could only be detected within the group without comorbid ODD/CD but not in the group with comorbid ODD/CD. In contrast to this finding for nVRT, which is considered a parameter reflecting inattention, all cb-CPT/MT hyperactivity parameters suggested a pattern that points toward a more pronounced ATX treatment effect in the group with comorbid ODD/CD, except for MS. This finding corresponded to the ADHD-RS hyperactive/impulsive subscores. However, for both impulsivity cb-CPT/MT parameters (“commission error rate,” “anticipatory”), the pattern pointed in the opposite direction. Although the ADHD-RS assesses hyperactivity and impulsivity together (in one subscore), these two core symptoms of ADHD can be assessed separately using the cb-CPT combined with the infrared MT device. This is one advantage of an objective approach, as clinical rating scales may not distinguish clearly between hyperactivity and impulsivity (Taylor, 1998).

As a similar pattern regarding ATX treatment effects in patients with and without comorbid ODD/CD was observed for the four hyperactivity variables TA, DIS, AR, and ME, these variables could be combined to form a hyperactivity summary score to achieve higher power and summarize data. This topic merits future psychometric analyses to assess the differential validity of these variables. MS showed smaller effect sizes and hence appeared to be less sensitive to treatment. Thus, MS should be considered separately from the other four hyperactivity variables assessed by this particular MT device. Otherwise, there was no difference between the groups with or without comorbid ODD/CD.

The observed tolerability profile was consistent with the findings from previous ATX studies and reflects the tolerability profile described in the summary of product characteristics.

The limitations of this study include the relatively short duration of the observation period. Furthermore, the cb-CPT used in this study is still not a standard tool for assessing ADHD symptoms in clinical practice. Another limitation could be the close oversight of the patient by the physician (3 times a day on visit days), which may have had an influence on clinical rating scale scores. This may have resulted in better differentiation between nonresponders in the placebo group and responders in the ATX group. This effect might have been reinforced by information available to the physician through the cb-CPT test report as the investigators were not blinded to the cb-CPT test results. However, not blinding the investigators to the cb-CPT test results more closely reflects clinical settings where this test is used as opposed to a more experimental approach with investigators being blinded toward the cb-CPT test results. A further limitation of this study is given by the fact that it focused on ADHD symptoms and did not investigate ODD/CD symptom severity over time. Therefore, it is not possible to determine whether an improvement in ADHD symptoms is associated with an improvement in the ODD/CD symptoms as suggested by another ATX study in children and adolescents with ADHD and comorbid ODD/CD (Dittmann et al., 2011). Furthermore, the ODD/CD diagnosis was established clinically by the investigator based on the DSM-IV-TR criteria (American Psychiatric Association, 2000) and was not validated with a standardized diagnostic interview or questionnaire. Finally, analyses on interactions, as used here, generally have low statistical power because the power is determined for overall sample and not for subgroups. As a result, trends should nevertheless be taken into account because they provide a basis for further research.

In summary, this study demonstrated that ATX reduced ADHD symptom severity in patients with and without comorbid ODD or CD as measured by various clinical rating scales. This study also showed the positive effect of ATX on core symptoms of ADHD as reflected by the objective measurement method (cb-CPT/MT). Interestingly, both approaches to assessing ADHD symptom severity showed a reduction of symptom severity regardless of whether comorbid ODD/CD was present or not.

Furthermore, the data of this subanalysis suggest that the treatment effect of ATX on hyperactivity may be more pronounced in the subgroup of patients with comorbid ODD/CD than in the subgroup of patients without comorbid ODD/CD. This improvement seemed to be greater in terms of hyperactivity (as assessed both with the ADHD-RS and the cb-CPT) and smaller in terms of inattention (as assessed by the cb-CPT). Taken together, these findings support the hypothesis that presence of comorbid ODD and/or CD may enhance the effect of ATX on ADHD symptoms in children with ADHD.

Footnotes

Acknowledgements

We would like to thank Dr. Alfred (Munich), Dr. Behre (Kehl), Dr. Busse (Berlin), Dr. Dieffenbach (Datteln), Dr. Fischbach (Solingen), Dr. Geraets (Düsseldorf), Dr. Kühle (Giessen), Prof. Lehmkuhl (Cologne), Dr. Meyers (Dorsten), Dr. Niemeyer (Hannover), Dr. Otto (Fulda), Dr. Peters-Pasztor (Eberswalde), Dr. Schiekirka (Wolfenbüttel), Prof. Schulz (Freiburg), and Dr. Wolff (Hagen) for participating in the study. We would like to thank Petter Knagenhjelm and Fredrik Ulberstad (Qbtech, Gothenburg, Sweden) for their outstanding technical support.

Authors’ Note

Peter M. Wehmeier and Laura Kipp contributed equally to the first authorship, and Ralf W. Dittmann and Alexander Schacht contributed equally to the last authorship.

Declaration of Conflicting Interests

Data were analyzed by PSI St. Petersburg, Russia, under the oversight of Alexander Schacht (A.S.), statistical consultant of Lilly Deutschland GmbH, Bad Homburg, Germany. The manuscript was drafted by Peter M. Wehmeier (P.M.W.), Laura Kipp (L.K.), and A.S. P.M.W. is a former full-time employee of Lilly Deutschland and is now associated with the Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany. L.K. has no conflict of interest to disclose. Tobias Banaschewski (T.B.) has served as an advisor or consultant for Desitin, Lilly, Medice, Novartis, Pfizer, Shire, UCB, and Viforpharma. He received conference attendance support and conference support or received speaker’s fee by Lilly, Janssen, McNeil, Medice, Novartis, Shire, UCB. He is involved in clinical trials conducted by Lilly, Shire, and a study on ADHD care management conducted by Novartis. Ralf W. Dittmann (R.W.D.) is a former full-time employee of Lilly Deutschland and now holds the Eli Lilly Endowed Chair of Pediatric Psychopharmacology, Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany. A.S. is a full-time employee of Lilly Deutschland. All authors reviewed the manuscript for important intellectual content. T.B. and R.W.D. have received research grants and speaker honoraria from Eli Lilly & Co. and are members of Lilly Advisory Boards. R.W.D. was involved in clinical trials conducted by Janssen, Lilly, and Shire. R.W.D. and A.S. own Eli Lilly & Co. shares.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by Lilly Deutschland, the German affiliate of Eli Lilly and Company.

Author Biographies

Peter M. Wehmeier, MD, is Associate Professor of Child and Adolescent Psychiatry at the Medical Faculty Mannheim of the University of Heidelberg, Germany. He is also Vice Medical Director of the Vitos Hospital for Psychiatry and Psychotherapy, Weilmuenster, Germany.

Laura Kipp graduated this year from Charité Universitätsmedizin Berlin, Germany, with a medical degree. Currently she is a doctoral student at the Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany.

Tobias Banaschewski, MD, PhD, is Professor of Child and Adolescent Psychiatry at the Medical Faculty Mannheim of the University of Heidelberg and Medical Director of the Department of Child and Adolescent Psychiatry of the Central Institute of Mental Health in Mannheim, Germany.

Ralf W. Dittmann, MD, PhD, is Professor of Child and Adolescent Psychiatry and the Eli Lilly Endowed Chair of Pediatric Psychopharmacology at the Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany.

Alexander Schacht, PhD, is a statistician and biometrician. He is Senior Research Scientist with Global Statistical Sciences, Lilly Deutschland, Bad Homburg, Germany.

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