Does Stimulant Pretreatment Modify Atomoxetine Effects on Core Symptoms of ADHD in Children Assessed by Quantitative Measurement Technology?

Abstract

Objective: To compare the reduction of ADHD symptoms under atomoxetine (ATX) in patients with and without pretreatment with a stimulant medication using a computer-based Continuous Performance Test (cb-CPT) combined with an infrared motion tracking (MT) device. Method: Double-blind, placebo-controlled study in ADHD patients (6-12 years) treated with ATX (target dose = 1.2 mg/kg per day). The cb-CPT/MT scores were analyzed using ANCOVA (last observation carried forward). Results: Patient data (n = 125) suggested a differential ATX treatment effect between pretreated and stimulant-naïve patients in terms of three cb-CPT/MT parameters. Conclusion: This secondary analysis provided evidence that ATX reduced ADHD symptom severity measured by cb-CPT/MT parameters regardless of stimulant pretreatment. A few differential effects were seen based on the cb-CPT/MT. However, no clear pattern could be identified and, overall, the observed differences have no larger clinical relevance. The ATX effect in this study seemed to be largely independent of any previous exposure to stimulants.

Keywords

ADHD atomoxetine psychometrics

ADHD is a highly prevalent psychiatric disorder characterized by inattention, hyperactivity, and impulsivity (American Psychiatric Association [APA], 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, Becker, Scherag, Franke, & Coghill, 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), resulting in 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).

Most ATX studies have included patients pretreated with stimulants. In these studies, the proportion of stimulant-naïve patients ranged from approximately 50% (Spencer et al., 2002) to 66% (Bangs et al., 2008). In several of these studies, the influence of pretreatment with stimulants versus stimulant-naïve patients on the efficacy of ATX was investigated. These studies suggest that there may be a considerable variability in patient response to ATX. One study showed response to be good in a sample of newly diagnosed, treatment-naïve patients treated with ATX as a first-line medication (Montoya et al., 2009). Two studies that involved stimulant-naïve children and adolescents with ADHD showed good response to ATX in terms of ADHD core symptoms and health-related quality of life, as measured by the Child Health and Illness Profile-Child Edition (CHIP-CE; Escobar et al., 2009; Svanborg et al., 2009a, 2009b). Evidence from a large placebo-controlled, double-blind study showed that stimulant-naïve patients may preferentially respond to ATX versus osmotically released methylphenidate (Newcorn et al., 2008). The same study found medication-naïve children to have a similar beneficial response to ATX as those receiving osmotically released methylphenidate (Newcorn et al., 2008). However, a meta-analysis of six placebo-controlled ATX trials did not show previous stimulant use to be a predictor for response to ATX (Newcorn, Sutton, Weiss, & Sumner, 2009). One study with children and adolescents with ADHD and comorbid oppositional defiant disorder (ODD) showed a greater treatment effect for ATX in those patients who were pretreated with stimulants, although this difference in effect was observed for ODD symptoms only and not for symptoms of ADHD (Dittmann et al., 2011). Taken together, these results underline the importance of investigating the influence of pretreatment with stimulants on response to ATX in patients with ADHD.

We designed this study in children with ADHD with the primary objective to evaluate the efficacy of ATX on ADHD symptoms compared with placebo, assessed as standard variables of a cb-CPT that assesses aspects of attention and impulsivity combined with an infrared motion tracking (MT) device that assesses the level of activity (Wehmeier et al., 2011; Wehmeier et al., in press). As a prespecified secondary objective, we compared the reduction of ADHD symptoms under ATX treatment versus placebo in patients who had been pretreated with a stimulant against medication-naïve patients using the quantitative measurement approach (cb-CPT/MT) described above and using standard clinical rating scales such as the ADHD Rating Scale (ADHD-RS; DuPaul, Power, Anastopoulos, & Reid, 1998; Faries, Yalcin, Harder, & Heiligenstein, 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 in Germany (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 hospital for child and adolescent psychiatry, 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/day for 1 week, followed by 7 weeks on the standard target dose of 1.2 mg/kg/day or placebo (administered in capsules looking identical to the study drug). Medication was given once daily in the morning. The cb-CPT plus MT was carried out in the morning (prior to taking the medication), 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; APA, 2000) criteria (APA, 2000) 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. The exclusion criteria comprised previous treatment with ATX, treatment with psychotropic medication other than the study drug, clinically relevant over- and 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 standard 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 an 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 earlier approaches to measuring ADHD core symptoms, assessing attention, impulsivity, and hyperactivity quantitatively (Halperin, Matier, Bedi, Sharma, & Newcorn, 1992; Heiser et al., 2004; Schechter, & Timmons, 1985; Tabori-Kraft, Sørensen, Kaergaard, Dalsgaard, & Thomsen, 2007; Teicher et al., 2000; Teicher, Ito, Glod, & Barber, 1996; Teicher, Polcari, & McGreenery, 2008), and has been found to reflect ADHD symptoms (Brocki et al., 2010; Oades, Myint, Dauvermann, Schimmelmann, & Schwarz, 2010). The method used in this study has been published in detail elsewhere (Wehmeier et al., 2011, Wehmeier et al., in press).

Further efficacy measures assessed in this study were as follows: (a) ADHD Rating Scale-IV–Parent Version: Investigator-Administered and Scored (ADHD-RS; DuPaul et al., 1998; Faries et al., 2001), (b) Clinical Global Impression–Severity (CGI-S) scale (Guy, 1976; National Institutes of Mental Health, 1985), and (c) Weekly Ratings of Morning and Evening Behavior–Revised–Investigator Rated (WREMB-R-Inv) scale (Carlson et al., 2007; Kelsey et al., 2004; Sutton et al., 2003; Wehmeier, Dittmann, Schacht, Helsberg, & Lehmkuhl, 2009).

Tolerability Assessments

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

Statistical Analyses

As there were no data available from placebo-controlled trials using the cb-CPT/MT when this study was planned, the effect size necessary for the sample size calculation was based on results seen for other endpoints (e.g., the ADHD-RS). Effect sizes of at least 0.5 were seen for treatment with ATX for the ADHD-RS. For a two-sided t test with an alpha level of 5.0%, 128 patients overall were needed to achieve a power of 80.0% given an effect size of 0.5.

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-effect model repeated measure [MMRM]). 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. Further details of the primary analysis together with information on sample size calculation, randomization, and blinding have been published elsewhere (Wehmeier et al., 2011; Wehmeier et al., in press). The analyses within this report extended the LOCF analyses by including fixed effects for pretreatment and the interaction with study treatment as well as the three-way interaction between study treatment, time of day, and pretreatment into the models. The models for the questionnaires did not contain terms for time of day as these were captured only once per visit. These analyses were prespecified in the protocol or the statistical analysis plan before unblinding the study.

All efficacy and tolerability analyses were conducted on the full analysis set (FAS), which, following the intention-to-treat principle, 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 four patients because of low compliance, exposure to medication for less than 7 days, initiation of structured psychotherapy, or taking methylphenidate in addition to ATX. For this per-protocol (PP) 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. AE rates were evaluated descriptively for each treatment arm. Statistical tests used the two-sided level of 5%, and 95% confidence intervals are used. The data analysis for this article was generated using SAS software version 8.2 or higher (© SAS Institute Inc.). SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc., Cary, North Carolina, USA.

Results

Patient Disposition

The first patient entered the study in October 2007, and the last patient completed the study in May 2009. 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 63, placebo 62; FAS). Of these patients, 105 (84.0%) completed the study (Figure 1). The most common reasons for early discontinuation were lack of efficacy (9.6%), followed by AEs (4.0%), patient decision (1.6%), and physician decision (0.8%). The retention rate was slightly lower in the placebo group (82.3%) than in the ATX group (85.7%). There were four patients with protocol violations leading to exclusion from the PP analysis (ATX 1 and placebo 3).

Figure 1.

Patient disposition.

Baseline Characteristics

In the overall sample, the mean age was 9.0 (SD ± 1.79) years and 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 pretreatment with stimulants were compared using t test or χ² test (see Table 2).

Table 1.

Baseline Characteristics by Treatment Group.

	Atomoxetine (n = 63)		Placebo (n = 62)
	M	SD	M	SD
Demographics
Age (years)	9.1	1.93	8.9	1.64
	n	%	n	%
Sex: Male	47	74.6	50	80.6
DSM-IV diagnosis, ADHD subtype
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
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
Previous treatment
Previous stimulant exposure	13	20.6	18	29.0
	M	SD	M	SD
Disease severity
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 hyperactivity/impulsivity 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 q-scores
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 = Diagnostic and Statistical Manual of Mental Disorders (4th edition); ODD = oppositional defiant disorder; CD = Conduct disorder; ADHD-RS = ADHD Rating Scale; CGI-S = Clinical Global Impression–Severity; WREMB-R = Weekly Ratings of Morning and Evening Behavior–Revised; cb-CPT = computer-based Continuous Performance Test.

Table 2.

Baseline Characteristics for Patients With and Without Pretreatment With Stimulants (t test or χ² test).

	Without pretreatment with stimulants n = 94		With pretreatment with stimulants n = 31
	M	SD	M	SD	p value
Demographics
Age (years)	9.0	1.83	9.2	1.67	.4522
	n	%	n	%
Sex: Male	74	78.7	23	74.2	.5999
DSM-IV diagnosis, ADHD subtype
Combined	61	64.9	27	87.1	.0634
Predominantly inattentive	25	26.6	3	9.7
Predominantly hyperactive-impulsive	8	8.5	1	3.2
Disease characteristics
Comorbid ODD/CD	39	41.5	11	35.5	.5539
	M	SD	M	SD
Years since onset of symptoms	4.8	2.04	5.7	1.93	.0345
Disease severity
ADHD-RS total score	35.8	12.19	40.5	8.63	.0205
ADHD-RS inattention subscore	19.3	5.84	20.4	4.99	.3126
ADHD-RS hyperactive/impulsive subscore	16.5	7.47	20.2	5.11	.0034
CGI-S ADHD	5.2	0.99	5.1	0.79	.7203
WREMB-R total score	21.1	8.01	23.2	6.74	.1555
WREMB-R evening subscore	14.5	4.88	16.2	4.15	.0663
WREMB-R morning subscore	5.0	2.92	5.4	2.50	.4297
WREMB-R Item 11 (difficulty falling asleep)	1.6	1.24	1.6	1.26	.9864
CB-CPT q-scores (mean over the day)
Anticipatory	0.2	0.94	0.3	0.87	.4319
Area	1.3	1.44	1.6	1.86	.3641
Commission error rate	−0.8	1.09	−0.9	0.96	.4205
Distance	1.5	1.53	1.9	1.82	.2306
Error rate	0.4	1.28	0.4	1.36	.8370
Microevents	1.0	1.09	1.3	1.38	.1951
Motion simplicity	0.3	0.93	0.3	1.03	.9261
Multiresponse	−0.2	1.01	−0.1	0.82	.9090
Normalized variation	0.7	1.34	1.3	1.30	.0352
Omission error rate	1.2	1.23	1.3	1.27	.7362
Reaction time	2.3	1.57	1.8	1.96	.1653
Reaction time variation	2.6	2.00	2.6	1.88	.9465
Time active	0.7	0.91	0.9	1.15	.3487

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/MT (Table 3). The respective MMRM analyses based on the PPP (excluding tests where the longest period of time “off task” exceeded 45 s) and the supportive ANCOVA analyses using LOCF (data not shown) yielded corresponding results.

Table 3.

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

	FAS			PPP
	ES		Interaction with treatment	ES		Interaction with treatment
	With pretreatment	Without pretreatment	p value	With pretreatment	Without pretreatment	p value
ADHD-RS
Total score	0.75	0.97	.607	—	—	—
Inattention subscore	0.74	0.80	.889	—	—	—
Hyperactive/impulsive subscore	0.69	1.05	.381	—	—	—
CGI-S ADHD	0.46	0.80	.362	—	—	—
WREMB-R
Total score	0.91	0.67	.576	—	—	—
Evening subscore	0.83	0.74	.830	—	—	—
Morning subscore	0.57	0.49	.848	—	—	—
Item 11 (difficulty falling asleep)	1.42	0.30	.010	—	—	—
cb-CPT q-scores
Hyperactivity
Time active	0.84	0.54	.169	1.29	0.70	.114
Distance	1.04	0.76	.305	1.31	0.93	.314
Area	0.92	0.63	.244	1.16	0.77	.271
Microevents	1.13	0.82	.296	1.13	0.72	.219
Motion simplicity	0.54	0.20	.180	1.16	0.22	.019
Inattention
Reaction time variation	0.74	0.34	.126	1.24	0.52	.062
Omission error	0.39	0.33	.793	0.47	0.65	.707
Mean reaction time	0.38	0.19	.396	0.98	0.27	.036
Normal variation time	0.24	0.18	.805	0.72	0.43	.496
Impulsivity
Commission error	0.08	0.47	.096	0.14	0.81	.048
Anticipatory	−0.04	0.16	.266	0.15	0.25	.656
Other
Error rate
Multiresponse	−0.24	0.12	.088	0.00	0.27	.379

Note: LOCF = last observation carried forward; ADHD-RS = ADHD Rating Scale; CGI-S = Clinical Global Impression–Severity; WREMB-R = Weekly Ratings of Morning and Evening Behavior–Revised; cb-CPT = computer-based Continuous Performance Test; FAS = full analysis set; PPP = per-protocol population; ES = Effect Size. No PPP analyses were done for the ratings scales as this affects only four patients, whereas the PPP analyses exclude these four patients as well as the nonvalid tests for the cb-CPT variable.

The results of the ANCOVA adjusting for pretreatment with stimulants are displayed in Figure 2, showing the effect sizes within the subgroups with and without pretreatment with stimulants for the q-scores of the cb-CPT/MT variables (FAS). The corresponding numbers are summarized in Table 3. For all variables, the p value for the interaction with treatment indicates whether the ATX effect differs between patients with and without pretreatment with stimulants.

Figure 2.

Effect size within and across the subgroups with or without pretreatment with stimulants for the q-scores of the cb-CPT variables: (a) FAS, (b) PPP.

Secondary Efficacy Outcomes—ADHD-RS, WREMB-R, and 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 et al., 2011). Sensitivity tests using ANCOVA supported these results (data not shown).

The results of the ANCOVA adjusting for pretreatment with stimulants are displayed in Figure 3, and further details including the p values for the interaction test are summarized in Table 3.

Figure 3.

Effect size within and across the subgroups with or without pretreatment with stimulants for the ADHD-RS, the CGI-S, and the WREMB-R (FAS).

Tolerability

Patients received study treatment for a median of 55 days in both groups, with upper and lower quartiles of 53 and 55 days in the ATX group and quartiles of 52 and 55 days in the placebo group. Treatment-emergent AEs (TEAEs) were reported in 32 (50.8%) patients treated with ATX and in 27 (43.5%) patients receiving placebo. Drug-related TEAEs were observed in 14 (22.2%) and 7 (11.3%) patients, respectively. Two patients treated with ATX discontinued the study due to TEAEs (3.2%). 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%). Two patients treated with ATX discontinued the study due to TEAEs (3.2%). In the placebo group, 3 patients discontinued due to TEAEs (4.8%). No serious AEs were reported. No clinically relevant changes were observed in terms of weight, blood pressure, and heart rate.

Discussion

Although previous studies have largely relied on clinical rating scales to measure improvement of ADHD symptoms, this is the first randomized, placebo-controlled study using a cb-CPT combined with an infrared MT device as an objective approach to measuring parameters related to executive function, inhibitory control, and motor activity in children with ADHD treated with ATX (Wehmeier et al., 2011; Wehmeier et al., in press). This method allows separate assessment of the three core symptoms of ADHD, which is important because hyperactivity cannot be reduced to impulsiveness or inattentiveness (Taylor, 1998). Although hyperactivity is indeed a characteristic of ADHD, it constitutes a distinct component of the disorder and should be analyzed separately (Taylor, 1998).

The baseline characteristics of the patients in this sample (Table 2) are comparable with those of other placebo-controlled ATX studies (Cheng, Chen, Ko, & Ng, 2007). The time since onset of the disorder was 1 year longer for pretreated patients than the stimulant-naïve patients. Furthermore, the mean age of the pretreated patients was higher than the stimulant-naïve patients, but only slightly (Table 2). This could be explained by the pretreated patients having a longer history of ADHD, allowing for a higher number of treatment attempts. Among the pretreated patients, there was a greater proportion with the combined ADHD subtype. In turn, among the stimulant-naïve patients, there were greater proportions of the predominantly inattentive and the predominantly hyperactive/impulsive subtypes. This could be explained by the pretreated patients having a more complex disorder, possibly resulting in an earlier onset of treatment for ADHD. Alternatively, patients with an earlier onset of ADHD symptoms and of the combined subtype may not respond as well to stimulant pretreatment and, hence, may lead to overrepresentation in the pretreated group. Furthermore, the more severely ill patients were found in the pretreated group (based on ADHD total scores at baseline). This difference is best explained by the hyperactive/impulsive subscore rather than by the inattentive subscore on the ADHD-RS. Overrepresentation of patients in the pretreated group who did not respond well to stimulants can also be explained by the pretreated patients being more difficult to treat—at least with stimulants. However, no clear differences were found between the two groups in terms of baseline cb-CPT/MT results. This difference between findings from the rating scale and cb-CPT/MT results might be explained by the fact that the hyperactive/impulsive subscore comprises several items on the ADHD-RS, whereas the cb-CPT/MT variables are assessed separately. In addition, the questionnaires and the cb-CPT/MT results may reflect different aspects of ADHD, with behavioral functionality being weighted more heavily in the clinical questionnaires and executive function being weighted more heavily in the cb-CPT/MT. It might be a topic for future research to combine different variables for the cb-CPT/MT to summarize data and achieve higher power. However, this would require further psychometric analyses that are beyond the scope of this article.

The primary efficacy analysis 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 in all patients as measured by q-scores of 10 primary variables of the cb-CPT/MT (Wehmeier et al., 2011; Wehmeier et al., in press). ADHD symptom severity, as measured by the ADHD-RS, CGI, and WREMB scales, was also reduced to a statistically significantly greater degree. Thus, the clinical rating scale scores (ADHD-RS, CGI-S) corroborate the results of the cb-CPT/MT (Wehmeier et al., 2011; Wehmeier et al., in press).

The postbaseline data showed an improvement in ADHD symptoms as measured by the ADHD-RS, regardless of whether patients had been pretreated with stimulants or were stimulant naïve. Although no influence of pretreatment with stimulants on the ATX effect was found for the cb-CPT/MT q-scores for the FAS, there were differences between patients with and without pretreatment when looking at the PP analysis. The PP sample excludes patients with time “on task” under 95% of the total 15 min cb-CPT/MT test time. As these excluded patients would only have increased the variability, thus lowering the precision, the PP results are necessarily more exact. Thus, the statistical test results in a clearer separation of the two groups.

In this prespecified secondary analysis, there were two significant findings in terms of interaction with treatment among the cb-CPT/MT parameters. In stimulant-naïve patients, the effect of ATX was larger with respect to the commission error rate (CER). In pretreated patients, the effect of ATX was larger regarding the reaction time (RT). The interaction was almost significant also for the RT variation (RTV), pointing in the same direction. Whereas the first result is in line with findings from another study that has shown stimulant-naïve patients to respond better to ATX than pretreated patients (Newcorn et al., 2008), the two latter test results are contradictory to this previous finding. It is of note that CER mostly measures impulsivity, whereas RT and RTV mostly assess inattention. One can speculate whether stimulants and the nonstimulant ATX differ in their effect on such endpoints when measured using a cb-CPT/MT. This could be the case considering stimulants have a predominantly dopaminergic effect that influences goal-directed search, whereas ATX is presumed to have a predominantly noradrenergic effect that influences sustained attention and target discrimination.

The ADHD-RS scores only showed a numerically larger effect of ATX in stimulant-naïve patients. This lack of statistical significance was unexpected because stimulant-naïve patients responded better than pretreated patients in another study (Newcorn et al., 2008). However, in our sample, the naïve patients had less severe symptoms at baseline as captured by the ADHD-RS, possibly leaving less room for improvement in terms of the items on this clinical rating scale.

The one item “difficulty falling asleep” on the WREMB-R showed a significant interaction. The treatment effect of ATX was larger in pretreated patients. This result corroborates the trend to statistical significance seen in the overall WREMB score. This finding may be due to the different AE profiles of stimulants and ATX. Although stimulants may impair sleep, ATX does not have this effect on sleep (Sangal et al., 2006).

ATX was generally well tolerated. No serious AEs were reported throughout the study. 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 observation period. Furthermore, the cb-CPT/MT used in this study is 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. Finally, analyses such as the one used here generally have low power. Nevertheless, these trends should be taken into account because they provide a basis for further research.

Taken together, the results show small differences between the two groups with respect to the ATX effect as measured by the ADHD-RS. A few differential effects were seen in the results based on the cb-CPT/MT. However, no clear pattern could be identified and, overall, the observed differences have no larger clinical relevance. Thus, the ATX effect in this study seemed to be largely independent of any previous exposure to stimulants.

In summary, the data of this prespecified subgroup analysis provided evidence that ATX reduced ADHD symptom severity in patients who had been pretreated with stimulants and in stimulant-naïve patients 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).

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.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The study was designed and planned by Peter M. Wehmeier (PMW), Ralf W. Dittmann (RWD), and Alexander Schacht (AS). Data were analyzed by PSI St. Petersburg, Russia, under the oversight of AS, statistical consultant of Lilly Deutschland GmbH, Bad Homburg, Germany. The manuscript was first drafted by PMW and AS. PMW 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, and the Vitos Hospital for Psychiatry and Psychotherapy, Weilmuenster, Germany. PMW has received speaker honoraria from Eli Lilly and Company. AS is a full-time employee of Lilly Deutschland. RWD 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. All authors reviewed the manuscript for important intellectual content. Tobias Banaschewski (TB) and RWD have received research grants and speaker honoraria from Eli Lilly & Co. and are members of Lilly Advisory Boards. TB has served as an advisor or consultant for Desitin, Lilly, Medice, Novartis, Pfizer, Shire, UCB, Viforpharma. He received conference attendance support and conference support or received speaker’s fees from 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. RWD was involved in clinical trials conducted by Janssen, Lilly, and Shire. AS and RWD own Eli Lilly & Co. shares.

Funding

The author(s) disclosed receipt of the following financial support for the research and/or authorship 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 a Child and Adolescent Psychiatrist. He is Vice Medical Director of the Vitos Hospital for Psychiatry and Psychotherapy, Weilmuenster, Germany. His academic affiliation is with the Central Institute of Mental Health, Mannheim, University of Heidelberg, Germany, where he is Associate Professor of Child and Adolescent Psychiatry.

Ralf W. Dittmann, M.D., Ph.D., is a full 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.

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.

Alexander Schacht, PhD, is a statistician and works as Senior Research Scientist with Global Statistical Sciences, Lilly Deutschland, Bad Homburg, Germany. He has worked in both university and pharmaceutical industry settings and has been involved in several clinical research projects related to Attention- Deficit/Hyperactivity Disorder (ADHD).

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