Current Pharmaceutical Design, 2010, 16, 000-000
1381-6128/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
What can Actigraphy Add to the Concept of Labschool Design in Clinical Trials?*
Henrik Uebel1,*, Björn Albrecht1, Roumen Kirov2, Alexander Heise1, Manfred Döpfner3, Franz Joseph
Freisleder4, Wolff Dieter Gerber5, Michael Günter6, Frank Hässler7, Claudia Ose8, Fritz Poustka9, Roland
Fischer10, Tobias Banaschewski11 and Aribert Rothenberger1
1Child and Adolescent Psychiatry, University of Göttingen, 2Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia,
Bulgaria, 3Department of Psychiatry and Psychotherapy of Childhood and Adolescence at the University Cologne, 4Heckscher Klinik,
Munich, Germany, 5Institute of Medical Psychology, Christian-Albrechts-University of Kiel, Germany, 6Department of Psychiatry and
Psychotherapy in Childhood and Adolescence, University of Tübingen, Germany, 7Clinic for Child and Adolescent Psychiatry,
University of Rostock, 8Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, 9Department of
Child and Adolescent Psychiatry, J.W. Goethe University Frankfurt/Main, Germany, 10MEDICE Arzneimittel Pütter GmbH & Co.
KG, 11Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany
Abstract: Pharmacological intervention with methylphenidate (MPH) is very common and helpful in the treatment of attention-
deficit/hyperactivity disorder (ADHD). It ameliorates inattention, impulsivity and hyperactivity and improves psychosocial functioning.
The core symptoms of ADHD are problematic mainly in demanding structured situations such as in the classroom. It was argued that
MPH does not only lead to a decrease of hyperactivity in these situations but may also result in a general dampening of motor activity
during non-structured leisure time. Unfortunately, only few clinical trials have investigated this practically important issue and thus it is
still a matter of debate. It follows that many parents hesitate to accept psychotropic drugs for their children. To elucidate this problem in
the current study, not only overall behavioral ratings (half-day blocks) but also day-long actigraphy was applied during an analogue class-
room setting, where structured and non-structured situations alternated over time. Fourty-nine children with ADHD were assessed for
treatment effects of once-daily extended-release and twice daily immediate-release methylphenidate (MPH) as well as placebo.
Both MPH regimes yielded improved behavioral ratings during morning and afternoon, while actigraphy showed reduced motor activity
in structured situations, but not during leisure time. Furthermore, the movement information obtained with actigraphy during structured
situations could be differentiated from the one gained with overall behavioral ratings.
Thus, while behavioral ratings provide a valid estimate of the overall symptomatology, additional information gathered with actigraphy
may help to differentiate the impact of medication on hyperactive movement in different situations during the day. This may reflect a
more valid picture of a child’s real life and improve the quality of clinical trials. Thus, both methods may be regarded as complementary
for the assessment of drug effects in children with ADHD and should be a standard of further laboratory school protocols in clinical trials.
Keywords: Attention-deficit/hyperactivity disorder, ADHD, pharmacology, clinical trials, methylphenidate, MPH, actigraphy, behavioral
Methylphenidate (MPH) is regarded as the medication of first
choice for children with Attention-Deficit/Hyperactivity Disorder
(ADHD) in order to reduce inappropriate levels of inattention,
impulsivity and hyperactivity [1-4].
Reduction of hyperactivity is desired in structured demanding
situations like during school lessons but it should not lead to re-
duced motor activity where higher levels of movement is appropri-
ate, like during leisure time on the playground. Thus, the situation-
related specificity of MPH effects on motor activity is an important
precondition for its helpful effects, but only few studies suggest that
it is met [5, 6]. However, questions remain and the debate lead to
the fact that many parents still hesitate to accept psychotropic drugs
for their children or do not adhere regularly to the prescribed medi-
cation. Hence, there is a need to better clarify the issue, especially
with regard to the meaning of movement control by actigraphy
while planning clinical trials, e.g. in the context of laboratory school
protocols (LSP) which are accepted as a modifiable standardized
measure for psychotropic drug evaluations along the life span (e.g.
extension to guidelines for preschool assessment laboratory (PAL)
*Address correspondence to this author at the Child and Adolescent
Psychiatry, University of Göttingen, von Siebold Strasse 5, 37075
Göttingen, Germany; Tel: ???????????; Fax: ????????????;
*The study was conducted and sponsored by MEDICE Arzneimittel Pütter GmbH &
Co. KG as part of the drug approval process for Medikinet-RetardTM.
and Adult Workplace Environment (AWE); personal information
by B. Wigal (USA) in Oslo 2010).
Actigraphy is an objective method for recording and on- or off-
line analyzation of motor activity by means of small, computerized,
watch-like devices (actigraphs) worn on the body. The actigraphs
detect the acceleration resulting from movements either by ana-
logue systems or by piezo-electric beams detecting movements in
two or three axes from different parts of the body (wrist, hip, ankle
or leg), depending on the purpose. The detected movements or
accelerations are translated to digital counts accumulated across
predesigned epoch intervals (e.g., 30 sec or 1 min) and stored in
internal memory. The method is relatively inexpensive, non-inva-
sive, and well-tolerated. This allows reliable data collection of
general or highly specific motor activities for extended time periods
without major disturbance of the everyday activities, and thus re-
flects the child’s spontaneous behavior [7, 8].
Activity monitoring in medical studies and sleep research has a
long history, and accordingly the medical application of actigraphy
is very promising [8-10]. Actigraphy is currently used extensively
for characterizing sleep parameters and circadian rhythms in many
sleep-related disorders and sleep alterations associated with psychi-
atric conditions and drug therapy [7, 11-14]. One important applica-
tion of actigraphy is the activity monitoring during everyday situa-
tions in psychiatric disorders characterized by excessive or deviant
movement patterns such as ADHD and mood disorders [6, 10, 15-
17], Parkinson’s disease , schizophrenia [19, 20], major depres-
sion , and autistic spectrum disorders . Furthermore, the
2 Current Pharmaceutical Design, 2010, Vol. 16, No. 00 Uebel et al.
daily actigraphy in psychiatric disorders with motor disturbances is
an advantageous tool for the objective assessment of pharmacother-
apy effects on spontaneous behavior [6, 23, 24]. This approach
allows detection of specific patterns of motor activity and their
variation during different daily situations as well as their modula-
tion by drug therapy, which might have been otherwise obscured by
both subjective observations and the awareness of being an object
of examination that structured interviews and clinical settings intro-
duce. While the use of daily actigraphy for research or clinical prac-
tice in psychiatry is still moderate, there is an increasing awareness
of the great potential which this method provides [25, 26].
One psychiatric condition where daily actigraphy can be suc-
cessfully used as a powerful tool for diagnostic and therapeutic pur-
poses is ADHD. Specifically with respect to pharmacotherapy in
ADHD, daily actigraphy may not only be adjuvant but also an
auxiliary investigational approach. A significant body of literature
has documented the behavioral benefits of stimulant therapies, with
the methylphenidate hydrochloride (MPH) being the first line drug
[1, 2, 27]. However, since the majority of these studies have used
subjective behavioral indices such as parent and teacher rating
scales and interviews to document medication effects, objective
evaluations of the core ADHD symptoms in treatment trials are
relatively rare [28, 29]. Especially, the assessment of actigraphy
responses to different delivery formulations of MPH in the ana-
logue classroom setting throughout the course of a usual school day
is lacking. This approach could be useful to provide important
information about the effects of MPH immediate release (MPH-IR)
compared to those of MPH modified release (MPH-MR) on the
movement behavior during a school day in children with ADHD,
probably demonstrating the day-long smoothing effect of extended
release formulations such as MPH-MR according to its pharma-
cokinetic profile .
Two previous studies which have used daily actigraphy in boys
with ADHD and matched controls have addressed essential ques-
tions concerning the situation-by-situation daily variations of hy-
peractivity symptoms, as well as the effects of stimulant medication
on hyperactivity during the day. Firstly, in a situation-by-situation
analysis, it has been shown that, compared to controls, hyperactive
boys consistently have displayed augmented motor activity only
during structured school situations . Secondly, the stimulant
drug dextroamphetamine has been shown to exert a striking bipha-
sic effect on motor activity in the ADHD boys: decreased activity
only during structured classroom situation and a drug-induced
increase in motor activity during physical education . Collec-
tively, the results from these studies suggest that hyperactivity in
ADHD depends on environmental demands, and that stimulant
medication may be associated with a decrease of excessive motor
activity in structured situations. A later study using daily actigraphy
as an objective method for the assessment of hyperactivity symp-
toms in children with ADHD tested the effects of two (immediate
and extended release) MPH formulations. The previous findings
were confirmed, however no differences between MPH-IR and
MPH-MR were found . This study demonstrated situation-depen-
dent MPH effects that were smaller for the playground than for the
classroom settings. It remained open whether this outcome followed
a direct impact of MPH on motor activity, or whether it was a con-
sequence of enhanced focus and attention to the demands of the
structured situations which probably led to a more adequate motor
performance. Thus, both interpretations differ in their view whether
MPH has a primary or a secondary impact, but both support the
view that stimulants have a regulatory effect on motor activity,
depending on the demands of the environment .
In order to broaden the data base and testing this hypothesis, the
present study aimed at further investigating the effects of once-a-
day MPH-MR and twice-a-day MPH-IR, both compared to placebo,
on behavioral rating scales and objectively evaluated motor activity
during three days in children with ADHD. Motor activity during the
course of the days was measured by means of actigraphy in a situa-
tion-by-situation schedule, comprising either analogue structured
classroom settings or leisure periods. The order of the situations in
the course of the days was altered, not only to imitate the usual
school day activities but also to minimize possible ultradian effects.
It is hypothesized that both MPH regimes would lead to im-
provements in behavioral ratings and to a reduction of motor activ-
ity only in structured school-like situations and during lunchtime,
while activities in unstructured leisure time sessions would not be
dampened. Further, it is explored whether behavioral ratings and
actigraphy do provide similar or distinct information on problematic
behavior in ADHD. In the latter case, it would be beneficial to
comprise both methodological approaches in clinical trials.
The data included in the present evaluation is part of a multi-
centre investigational clinical study conducted at seven university
departments of child and adolescent psychiatry in Germany (Frank-
furt, Goettingen, Kiel, Köln, Munic, Rostock and Tuebingen). Prior
publications of other parts of the study can be found in [3, 31, 32].
The study was performed in accordance with Good Clinical Practice
(GCP), national law and the Declaration of Helsinki. Parents and
teachers gave written consent. Children also gave age-appropriate
assent. The Local Ethical Review Boards confirmed the study.
A total of 82 children aged from eight to fifteen years diagnosed
with ADHD according to ICD-10 diagnosis of Hyperkinetic Disor-
der (F90) and DSM-IV criteria as verified by a diagnostic checklist
(DCL-HKS ), participated in the study. All children had at least
a normal total intelligence quotient (IQ range 85 to 135), were
responders to MPH-IR therapy and were carefully titrated. A first
cohort of 6 children was assessed in order to calibrate the actigra-
phy devices. Further datasets were excluded due to incomplete
documentation in two centres (N=23) or technical problems with
the actigraphy devices (N=4). Thus, complete datasets of 49 chil-
dren with a mean age of 10 years that attended regularly to primary
(71%), secondary or other schools were analyzed (see Table 1 for
demographic sample description).
The study was conducted as a double-blind, randomized, pla-
cebo-controlled trial with a cross-over design to examine the effects
of an immediate release Methylphenidate (MPH-IR; Novartis Rita-
lin®) and a modified release preparation (MPH-MR, MEDICE
Medikinet® retard) and placebo on the daily motor activity in a
cohort of children with ADHD in a situation-by-situation schedule.
To ensure a double-blind trial, the double-dummy method with
administration of a once-daily capsule and twice-daily tablets was
After a pre-screening and a run-in phase arranged on a Thurs-
day in order to adapt the children to the protocol, the study was
conducted over two-and-a-half weeks. Each treatment with tablets
and capsules was administered respectively for four consecutive
working days and during the weekend. The analogue classroom
protocol followed the design by Swanson and co-workers [6, 34,
35]. On weekdays, a recreational educational program composed of
a fixed daily routine with alternating analogue classroom sessions
and leisure phases including elements of behavioral therapy or
social skills training (e.g. joint making of a video film or theatre
play) was carried out. See Table 2 for the daily schedule.
Actigraphy was recorded from the dominant ankle using cali-
brated ActiTrac™ devices (Individual Monitoring Systems, Balti-
more, MD, 21286, USA). The device recorded accelerations above
a threshold of 1.25 mG with a sampling rate of 40 Hz and a meas-
urement frequency bandwith of 1 to 10 Hz (3db). The data was
What can Actigraphy Add to the Concept of Labschool Design in Clinical Trials? Current Pharmaceutical Design, 2010, Vol. 16, No. 00 3
Table 1. Descriptives
Gender: N (%)
Age (year): mean ±SD 10.3 ±1.4
Range 8 - 13
Height (cm): mean ±SD 144 ±11
Range 117 - 171
Weight (kg): mean ±SD 36.7 ±10.5
Range 20.4 – 70.0
IQ: mean ±SD 102 ±10
Range 85 - 120
Primary (grade 1 to 4): N (%) 35 (71)
Secondary / Other: N (%) 14 (29)
Combined Type: N (%) 46 (94)
Predominantly Inattentive: N (%) 3 (6)
DSM-IV Comorbidity ODD/CD 33 (47)
MPH Dosage (mg): mean ±SD 22 ±6
Range 10 - 40
averaged for 30 sec intervals, linearly transformed to a reference
scale (full-scale range 250 units, equal to 312.5 mG) and stored
within the device. Offline, activity scores of the respective sessions
(the first five and the last ten minutes were skipped as transition
time) from the four days of data collection of each week were ac-
cumulated and averaged for each treatment.
Behavioral ratings using FBB-HKS (measuring ADHD symp-
toms) were rated by the same respective investigators after the
morning session at 1: 00 pm and after the afternoon session at 4: 45
pm. The FBB-HKS is a component of the Diagnostic System for
Mental Disorders in Childhood and Adolescence (DISYPS-KJ
), based on ICD-10 and DSM-IV. It includes 20 items describ-
ing the symptom criteria of ICD-10 and DSM-IV . Further
details of the study design can be found elsewhere .
Behavioral scores of the FBB-HKS, also subdivided into hyper-
active, impulsive and inattention scales, covering morning and
afternoon sessions were analyzed in a repeated-measure Analyses
of Variance (ANOVA) with factors “Treatment” (Placebo vs. MPH-
IR vs. MPH-MR) and “Session” (morning vs. afternoon). The main
dependent actigraphy scores (mean activity during the scheduled
phases of the four assessment days of each week) were analyzed
separately for the (structured) analogue classroom sessions, during
(structured) lunch and during the (unstructured) leisure sessions in
repeated-measure ANOVAs with factors “Treatment” and “Ses-
sion”. Since the pharmacokinetics of MPH-IR and MPH-MR would
Table 2. Daily Schedule
~ Time Activity
8: 30 Arrival, breakfast, then Dose 1
9: 00 Math tasks / copying
9: 30 Social skills training
11: 00 Math tasks / copying
11: 30 Recess
12: 30 Math tasks / copying
13: 00 Lunch, Dose 2
13: 45 Social skills training
15: 00 Math tasks / copying
15: 30 Recess (computer gaming)
16: 15 Math tasks / copying
16: 45 Dismissal
predict no impact on the first structured school-like situation imme-
diately following administration, this phase was considered as a
baseline and neglected for comparisons between the interventions.
Violations from sphericity were corrected following Greenhouse-
Geisser; ? and adjusted p values are reported along with original
In order to test whether the behavioral ratings provide similar
information as the actigraphy parameters, correlations and a princi-
pal component analysis (PCA) including hyperactive subscales
from morning and afternoon sessions and all actigraphy parameters
were conducted. The reason for this procedure was that variables
with high correlations and loadings on the same component reflect
similar information, while loadings on different orthogonal compo-
nents indicate that these variables reflect different information.
Adjustment for multiple comparisons following Sidak requires for
the ten correlations explored
=.0051 and allows the detection of large effect sizes
(correlations r>.40) with an overall significance level of ?<.05 for
each of the treatments.
a significance level of
1. Does MPH improve Behavioral Ratings of ADHD Symp-
Overall behavioral ratings obtained with FBB-HKS revealed
improvements for ADHD total problem scores as well as all ADHD
subscales during treatment with MPH-IR and MPH-MR as com-
pared to placebo (all Treatment effects: F(2, 96)=24.3, p<.01, part.
?2=.33). No differences between morning and afternoon sessions
(Session: F(1, 48)<2.2, p>.14, part. ?2<.04) and no interactions
(Treatment*Session: F(2, 96)<1.9, p>.16, part. ?2<.04) were found for
total ADHD, ADHD-Impulsivity scores. ADHD-Inattention scores
were generally lower during the morning (Session: F(1, 48)=4.5,
p=.04, part. ?2=.09). ADHD-Hyperactivity scores were under
treatment with MPH-IR higher in the morning, for Placebo higher
in the afternoon and did not differ between sessions for MPH-ER
(Treatment*Session: F(2, 96)=4.8, ?=.99, p=.01, part. ?2=.09). See
Fig. (1) for confidence intervals with p<.05.
4 Current Pharmaceutical Design, 2010, Vol. 16, No. 00 Uebel et al.
2. Does MPH Reduce Motor Activity in Structured Classroom
Assessment of the remaining four classroom sessions revealed
significantly reduced motor activity if patients received MPH-MR
as compared to placebo, while MPH-IR yielded only a tendency
towards reduction (Treatment: F(2, 96)=7.7, ?=.89, p<.01, part.
?2=.14, see Fig. (2), red bars for post-hoc comparison with confi-
dence intervals from each session). Activity during the considered
classroom sessions was generally highest in the 11: 00 until 11: 30
h session (Session: F(3, 144)=8.5, ?=.61, p<.01, part. ?2=.15), and no
interaction was present (Treatment*Session: F(6, 288)=0.4, ?=.59,
p=.91, part. ?2<.01).
Activity levels during lunchtime differed between treatments
(F(2, 96)=3.6, ?=.99, p=.03, part. ?2=.07), and post-hoc tests revealed
improvements for MPH-MR as compared to placebo and (as a
tendency) MPH-IR vs. placebo, while the two MPH preparations
did not differ (Fig. (2), yellow bars).
3. Does MPH Reduce Activity in Unstructured Leisure Ses-
No difference between treatments was found during the four
leisure sessions (Treatment: F(2, 96)=1.1, ?=.99, p=.35, part. ?2=.02,
see Fig. (2), blue bars for confidence intervals). But activity levels
differed between sessions (Session: F(3, 144)=19.3, ?=.72, p<.01, part.
?2=.29) with significantly lower activity in the last leisure session
(computer gaming). The interaction “Treatment*Session” was not
significant (F(6, 288)=0.9, ?=.76, p=.49, part. ?2=.02).
4. Do Behavioral Ratings and Actigraphy Provide Similar
Behavioral ratings obtained from morning and afternoon ses-
sions with FBB-HKS hyperactivity subscales show high significant
intercorrelations for all treatments (r>.9, p<.001), but significant
correlations with actigraphy data was only found for the placebo
condition during unstructured leisure sessions (except computer
gaming 15: 30 - 16: 15) and during lunch (all r>.4, p<.001) No
significant correlations surviving adjustment for multiple compari-
sons were found between behavioral ratings and actigraphy during
school situations for any treatment (see Fig. 3).
This selection of variables is also acceptable for PCA since the
Kaiser-Meyer-Olkin measure of sampling adequacy was equal to
.61 which is regarded as “mediocre”  and the Bartlett test re-
jected sphericity (?2
nents with eigenvalues above 1 were extracted and explained 77.8%
of the total variance. The first component, explaining 27.6% vari-
ance, had high factor loadings above .60 from actigraphy during
structured situations but low loadings from FBB-HKS hyperactivity
(below .20), while the second component explaining 11.5% vari-
ance had high loadings from FBB-HKS hyperactivity (above .40,
and for MPH regimes above .80), but very low loadings from acti-
graphy throughout the day (below .25). The third and fourth com-
ponents explaining around 10 % variance showed more complex
factor loading patterns: the third component was characterised by
high factor loadings of motor activity as measured by actigraphy
immediately after the treatment administration, while the fourth
component has high factor loadings of hyperactivity and impulsiv-
(630)=1929.1, p<.01). Seven orthogonal compo-
Fig. (1). Behavioral Ratings of ADHD symptoms from the morning and afternoon sessions.
Behavioral ratings using FBB-HKS for morning and afternoon sessions. Analyses of confidence intervals revealed that both MPH-IR (dashed) and MPH-MR
(checkerboard) provided improvements as compared to Placebo (solid). Significance with p<.05 is retained if the confidence interval indicated by vertical
black bars does not contain the respective mean in comparison.
What can Actigraphy Add to the Concept of Labschool Design in Clinical Trials? Current Pharmaceutical Design, 2010, Vol. 16, No. 00 5
ity ratings during placebo as well as of motor activity during the
later morning leisure and lunch sessions as well as relatively low
loadings of all school sessions. Fig. (4) shows the component load-
ings of the dependent variables on these Varimax-rotated compo-
Treatment of ADHD with MPH-IR has been found to be effec-
tive in numerous studies, as it led to improvement of hyperactivity,
impulsivity, and inattention based on behavioral assessments and
enhanced academic performance and social functioning accordingly
[2, 38, 39]. However, due to its short half-life, clinical effects are
restricted to about four hours after administration. New galenic
formulations with modified release aim to overcome these difficul-
ties by releasing the agent over a longer period of time. Concerning
side effects of MPH, one still debatable objection is whether MPH
leads to an unspecific dampening of motor activity in all situations,
i.e. not only at school, where it is favourable, but also during unre-
stricted or unstructured leisure times.
Hence, the aim of the current study was twofold. First, the
efficacy of MPH, both in the traditional immediate-release and a
modified-release administration, was compared to placebo. Second,
the data collected for objective measurement of motor activity was
contrasted with the information obtained from behavioral rating
As expected, both kinds of MPH administration reduced ADHD
and ODD/CD symptomatology, which is reflected by lower prob-
lem scores in FBB-HKS and ODD/CD scales which is in line with
previous studies . However, since the FBB ratings cover the
whole morning and afternoon including alternating structured as
well as unstructured sessions, it remains unclear whether the effect
of MPH was specific for the structured situations. This point was
elucidated by day-long actigraphy, which provides an objective
Fig. (2). Activity levels throughout the schedule.
Confidence intervals of actigraphy from the baseline (green), leisure (blue), school (red) and lunch (yellow) sessions under the treatment with placebo (solid),
MPH-IR (dashed) and MPH-MR (checkerboard). Significance with p<.05 is retained if the confidence interval indicated by vertical black bars does not con-
tain the respective mean in comparison.
Fig. (3). Correlations between behavioral ratings of hyperactivity and actigraphy.
For each of the three treatments, hyperactivity ratings from the morning and afternoon session are highly correlated and do show for the placebo condition
correlations with actigraphy during several leisure sessions and lunchtime (r>.4, p<.001). However, no significant correlations with actigraphy during struc-
tured school-situations were found. Correlations r>.40 retain an overall significance level of ?<.05 for each of the treatments.
6 Current Pharmaceutical Design, 2010, Vol. 16, No. 00 Uebel et al.
measure of accelerations during leg movements with sub-minute
time resolution .
As expected, motor activity was generally higher and showed
further higher inter-individual variability during leisure time as
compared to the structured classroom-like activities or during
lunchtime. Therefore, both types of situations were analysed sepa-
rately. It was found that MPH reduces motor activity in the struc-
tured situations during classroom and lunch time sessions. Moreo-
ver, the leisure session from 3: 30 pm to 4: 15 pm was also charac-
terized by generally reduced motor activity by MPH effects. How-
ever, this session consisted of computer gaming, which is leisure
time that is also more or less self-structuring as known from daily
life of children with ADHD. This reduced motor activity is proba-
bly due to the reduction of delay aversion while actively being
involved in a computer game . Thus, it appears that MPH medi-
cation results in lower motor activity also when it is probably fa-
voured by the child in order to reach a high motivated goal. In this
regard, both kinds of MPH administration are effective as compared
Fig. (4). Factorloadings for the four most important components.
The first seven components with eigenvalues above one explained 77.8%, but the first four already explained almost 60% of the total variance and show more
or less distinct factor loading patterns. Please note that behavioral ratings of hyperactivity and actigraphy in structured situations load on different components
(1 vs. 2).
What can Actigraphy Add to the Concept of Labschool Design in Clinical Trials? Current Pharmaceutical Design, 2010, Vol. 16, No. 00 7
to placebo, i.e. the drug supports and increases the movement regu-
latory abilities of the child and thus helps to improve his psychoso-
These observations are in accordance with three previous find-
ings [5, 6, 30], and support the hypothesis of specific stimulant
therapy effects in ADHD depending on environmental demands
, allowing the child with ADHD to have adequate self regula-
tion. A similar pattern of results found for academic performance as
assessed with an age-appropriate math test from the same study
suggests that improvements following MPH administration may
The time-resolution of actigraphy helped to detect a further
benefit of MPH-MR compared to MPH-IR: consideration of confi-
dence intervals revealed that the efficacy of MPH-IR was insuffi-
cient particularly during the lunch session, which took place ap-
proximately three and a half hours after application. This observa-
tion is in line with expectations based on the pharmacokinetics of
twice daily MPH-IR , and confirms the improved day-long
smoothing effect of MPH-MR formulations given once-a-day.
The last question addressed in this study was whether actigra-
phy can provide movement information beyond the one obtained
from questionnaires. Usually, in clinical trials only the latter are
used in order to measure the primary motor outcome of drug ef-
fects, probably neglecting an important part of the problem. The
current study shows systematic correlations between behavioral
ratings of hyperactivity and actigraphy only for the placebo condi-
tion and only for actigraphy during unstructured leisure sessions
and during lunchtime. There were no significant correlations with
actigraphy during the school sessions. This was further differenti-
ated in a principal component analysis (PCA). It revealed a total of
seven components that explained more than 3/4 of total variance of
the data. Since the PCA was used as a tool for exploring the data
and for generating hypotheses, these results need to be taken as
preliminary. Several authors suggest that PCA requires a sample
size of around 150 subjects for accurate solutions, but a Monte
Carlo simulation by Guadagnoli and Velicer suggests that the effec-
tive coherence within the data is more important. Thus, these
authors suggest interpreting a component structure if components
possess four or more eminent factor loadings (or correlations be-
tween the extracted components and the behavioral ratings or acti-
graphy data) above .6, irrespective of sample size .
The two most important factors were consistently characterized
by high factor loadings above this critical magnitude and explained
40% of the total variance. The first component reflected motor
activity in structured situations during the baseline and school
sessions, distinct from actigraphy during unstructured leisure ses-
sions and behavioral ratings of ADHD hyperactivity, while the
second component did reflect FBB hyperactivity ratings almost
unrelated to motor activity. This pattern of results suggests that
particularly actigraphy during structured situations consistently
reflects symptomatology (hyperactivity), which is not included as
such in behavioral ratings using FBB-HKS. The behavioral items
do not seem to be formulated in a clear distinctive manner and
raters may include other behavioral aspects than motor activity in
their ratings, while the actigraph records just movements with a
high temporal resolution which allows the differentiation of specific
events. Clinical trials without actigraphy are missing this potentially
important information of an ADHD core symptom, namely the
situation specific ‘pure’ motor aspect of hyperactivity which is
otherwise (e.g. by questionnaires) blurred and mixed with other
behavior. Since additional and independent behavioral information
can be gained by actigraphy the latter may be recommended as a
standard tool of further laboratory school protocols to measure
ADHD medication outcomes. Hence, considering actigraphy in
clinical trials could advance the understanding and guidance of
ADHD treatment. Also, it could feed back to a better psychometric
evaluation of ADHD rating scales to get a more distinct picture of
hypermotor behaviour in ADHD.
Actigraphy during more complex labschool designs requisite a
proper synchronisation with the protocol. Since the current study
aims to provide event-related actigraphy to distinguish motor activ-
ity during structured school from less structured leisure phases of
the day-long schedule, a detailed schedule protocol is essential and
should be at least as accurate as the intended time resolution of the
applied actigraphy. Consequently, datasets with incomplete docu-
mentation need to be excluded from further analyses. Thus, particu-
larly for group assessments in real life situations, a robust actigra-
phy device that incorporates external triggering and documentation,
preferably by means of videotaping, would be beneficial to control
for technical artefacts. Advanced actigraphy may be used to dis-
cover oscillations in motor activity not accessible with the current
A further limitation of this study is that only ADHD patients
were assessed. As a consequence, the activity level of typically
developing children during the schedule is unknown, and dynamics
within the investigated group probably differ from real school
situations. As developmental effects on situation-specific motor
activity are likely, considering age-matched control subjects would
help to create more representative scenarios and to broaden the
scope of the study considerably.
Finally, the overall behavioral rating was done blockwise
(morning and afternoon session; both including structured as well
as non-structured situations) while actigraphy could clearly disen-
tangle structured vs. non-structured situations and thus be more
precise. It remains to be clarified if similar situation-by-situation
behavioral ratings could also disentangle movement problems from
other behavior usually mixed when half-a-day or a full day of be-
haviour has to be considered.
The current study provides further evidence that MPH is an
effective treatment of ADHD and leads to improved overall symp-
tomatology and reduced motor activity, particularly in structured
situations. Findings from this study suggested that modified-release
formulations of MPH can fine-tune treatment effects (here: move-
ment regulation) throughout the day. Furthermore, actigraphy is
regarded as a useful tool in pharmacological research that provides
objective insights into specific aspects of motor activity. It is dem-
onstrated that these characteristics are not directly accessible with
CONFLICTS OF INTEREST
Research Support: Shire, Schwaabe
Travel Support: Janssen-Cilag
B. Albrecht, Fritz Poustka:
Advisory Board and Speakers Bureau:
Lilly, Shire, Medice, Novartis, Vifor
Research Support: Lilly, Medice, Shire, Vifor, German Research
8 Current Pharmaceutical Design, 2010, Vol. 16, No. 00 Uebel et al.
German Minstry of Health, German Ministry of Education and
Travel Support: Lilly, Medice, Shire,
Educational Grant: Shire, Medice
Consultant: Medice, Lilly, Shire, Vifor
Is sponsor's employee
Advisory Board: Lilly
Research Support: Bayer Vital, Janssen-Cilag, UCB, Medice, No-
Travel Support: Novartis, Janssen-Cilag, Lilly, Bayer Vital, Cy-
beronics, Astra Zeneca
Research support: Medice
Research Support by MEDICE for statistical analysis, monitoring,
data management and project management of this trial
Advisory Board and Consultant: Desitin, Lilly, Medice, Novartis,
Pfizer, Shire, UCB and Viforpharma
Speakers fee and travel support: Lilly, Janssen McNeil, Medice,
Research Support: Lilly, Shire and Novartis
Unrestricted grants for organizing a CME conference by Lilly,
Janssen McNeil, Medice, Novartis, Shire, UCB
Advisory Board and Speakers Bureau: Lilly, Shire, Medice, Novar-
Research Support: Shire, German Research Society, Schwaabe
Travel Support: Shire
Educational Grant: Shire
Consultant: UCB/Shire; Lilly
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Received: April 30, 2010 Accepted: May 19, 2010