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Background: The aim of this study was to evaluate stimulant medication response following a single dose of methylphenidate (MPH) in children and young people with hyperkinetic disorder using infrared motion analysis combined with a continuous performance task (QbTest system) as objective measures. The hypothesis was put forward that a moderate testdose of stimulant medication could determine a robust treatment response, partial response and non-response in relation to activity, attention and impulse control measures.
Methods: The study included 44 children and young people between the ages of 7–18 years with a diagnosis of hyperkinetic disorder (F90 & F90.1). A single dose-protocol incorporated the time course effects of both immediate release MPH and extended-release MPH (Concerta XL, Equasym XL) to determine comparable peak efficacy periods post intake.
Results: A robust treatment response with objective measures reverting to the population mean was found in 37 participants (84%). Three participants (7%) demonstrated a partial response to MPH and four participants (9%) were determined as non-responders due to deteriorating activity measures together with no improvements in attention and impulse control measures.
Conclusion: Objective measures provide early into prescribing the opportunity to measure treatment response and monitor adverse reactions to stimulant medication. Most treatment responders demonstrated an effective response to MPH on a moderate testdose facilitating a swift and more optimal titration process.
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This study used as its objective measurements a QbTest system which consists of an infrared motion camera combined with a continuous performance test (CPT).
CPT provides neuropsychological testing measuring a person’s sustained and selective attention and to a lesser degree impulsivity. CPT’s are generally characterised by a rapid presentation of continuously changing stimuli among which there is a designated ‘target’ stimulus or target pattern. The duration of the task varies but the task is intended to be of sufficient length to measure sustained attention. The CPT is reported to be the most popular clinic based measure of sustained attention and vigilance and it has been described as the most sensitive measure for monitoring medication effects (Riccio, et al., 2001).
The assessment of motoric activity during CPT is undertaken by analysing the complexity of the child’s head movement pattern. Infrared motion analysis is an effective means of quantifying hyperactivity and was found to correlate significantly with commonly used teacher rating scales for children with ADHD (Teicher et al., 1996).
The work of Teicher et al. (2003, 2008) demonstrated that objective measures of primarily activity and secondarily attention performance show patterns of response to different doses of methylphenidate (MPH) and placebo that are in good agreement with blind placebo-controlled parental ratings of efficacy thus providing preliminary evidence that this office-based assessment of the therapeutic response to stimulants has ecological validity, which is defined as the degree to which the results of a laboratory measure represents the actual behaviours of interest as they occur in natural settings (Barkley, 1991).
Teicher et al. (2003) also found that both moderate and high doses of MPH produced rate-dependant alterations in activity. Consistent with the other neuropsychological studies, MPH exerted a stronger effect on the hyperactive-distracted state than on the hyperactive-impulsive state. Similarly Hale et al. (2005), concentrating on the level of neuropsychological impairment amongst children with ADHD, found that those who showed dramatic medication effects were more likely to be diagnosed with the combined type ADHD and children who required higher dose response levels presented with more externalising and hyperactive/impulsive behaviours.
The hypothesis put forward in this study was that initiating treatment with a moderate test dose of stimulant medication allows for the early identification of treatment response (robust, partial and adverse treatment response) using objective measures of activity, attention and impulse control in children and young people diagnosed with hyperkinetic disorder who were referred to a generic child and adolescent mental health service (CAMHS) clinic.
This study represents a clinical audit on ongoing clinical work.
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Statistically significant effects were present for all activity and attention parameters as well as for the impulse control parameter commission error (all p’s < .05; see Table 2). Children and adolescents receiving medication had lower activity measures and reduced errors of omission and commission. The reaction times were shorter with reduced reaction time variation and normalised variation.
Table 2. Objective measures of activity, attention and impulse control at baseline and after repetition of the test on a moderate test dose of methylphenidate (MPH) in both children (Qbtest) and adolescents (QbTest-Plus)
|Measures||QbTest (6–12 y)||QbTest-Plus (13–18 y)|
|Baseline (SD)||MPH (SD)||t-value||p||Baseline (SD)||MPH (SD)||t-value||p|
|Time Active (%)||71.7 (19.3)||40.8 (27.5)||6.2||<.001||43.5 (23.2)||23.2 (25.7)||3.3||.004|
|Distance (m)||42 (20.1)||24.1 (48.8)||2.1||.048||22.9 (16.4)||11.4 (14.4)||2.5||.024|
|Area (cm2)||144.8 (54)||66 (61.9)||6.1||<.001||90 (56.7)||38.3 (37.6)||3.7||.001|
|Microevents||18258.3 (5510.5)||9962.5 (7692.7)||5.5||<.001||10875 (5641.7)||6330 (7062)||2.5||.024|
|Reaction time (ms)||532.3 (103.7)||462.7 (98)||4.1||<.001||551.5 (116.4)||489.8 (151.2)||2.5||.022|
|Reaction time variation (ms)||314.2 (113.9)||209.8 (112.5)||4.5||<.001||214.1 (62.5)||159.4 (62.7)||3.3||.003|
|Normalised variation (%)||58.2 (16.8)||44.3 (20)||4.3||<.001||39.3 (10.6)||32.55 (7.7)||2.9||.008|
|Omission error (%)||21.2 (17.7)||9.6 (14.9)||5.4||<.001||23.5 (23)||6.6 (13.3)||2.9||.009|
|Commission error (%)||31.4 (16.3)||19.8 (17.2)||5||<.001||5.7 (6.4)||3 (5.2)||2.3||.032|
|Anticipatory (%)||10.8 (14)||7 (13)||1.2||0.252||1.8 (4.6)||1.4 (4.2)||0.4||0.688|
|Error rate (%)||37.1 (20.5)||21.8 (22.7)||4.2||<.001||10.6 (9.2)||4.2 (5.6)||3||.007|
Multivariate analysis demonstrated a highly significant difference between baseline and post-MPH tests for both the QbTest group (F = 45, p < 0.001) and the QbTest-Plus group (F = 23, p < 0.001). A two way analysis of variance did not illustrate a significant difference in response to MPH between the QbTest and QbTest-Plus group (F(1,39) =0.57, p = 0.46). Equally no differences were found between drug naïve and non-naïve responders (F(7,35)=1.67, p = .25).
The mean scores for the anticipatory parameter were lower post medication for both children and adolescents, however the difference was not statistically significant. In the Qbtest group (ages 7–12 y) the scores did not reach statistical significance as a result of a partial response to medication in three cases (7%). These participants showed reduced activity measures but persisted with a high level of response to both targets and non-targets suggestive of a random or impulsive response profile on CPT (Teicher et al. 2004). As they were less hyperactive following the testdose their degree of disengagement or impulsivity is likely to have been measured for a prolonged period of time during CPT with increases in their anticipatory scores in contrast to children who were robust treatment responders. Anticipatory errors in the older QbTest-Plus group (ages 13–18 y) were generally infrequent (see table 2) thus causing the data to be too weak to reach statistical significance.
The unusually raised but still statistically significant p-value for distance in the QbTest group (see Table 2) was related to one participant presenting with the highest distance measure at baseline (89 m) and whose activity measures post medication paradoxically rose to an unusually high score of 250 m, a six fold of the mean group baseline score. Equally the distance p-value in the QbTest-Plus group was affected by two out of the twenty participants showing an overall increase in their activity measures.
In comparison with the normative data, all activity scores on MPH demonstrated a return to the population mean (SD <1). This effect was less pronounced in the QbTest-Plus group. The difference between the two groups is most likely associated with age developmental alterations in the density distribution of the degree of activity. Furthermore the number of non-drug naïve patients in the QbTest-Plus group (85%) was noticeably higher compared to the QbTest Group (17%) suggesting a possible association to long-term MPH exposure. However, as described above, no significant difference in response to MPH between the QbTest and QbTest-Plus group was found.
Attention and impulse control measures on MPH also reverted to the population mean with the exception of reaction time variation and normalised variation measures in the QbTest group, once again as a result of a partial or non-response to MPH in some of the participants.
Table 3 shows the correlation analysis of association between activity, attention and impulse control measures. There was a large and significant correlation between the four activity measures: time active, distance, area and microevents (r = 0.83–0.96, n = 44, p < .001).
Table 3. Comparison of correlation coefficients between activity measures as well as correlations between activity, attention (omission error, normalised variation) and impulsivity (commission error) measures
|Measure||p (2-tailed)||Pearson Correlation|
|Norm. Var./Time Active||.03||0.34|
The correlation between activity and attention measures was significant with a large correlation between activity measures and omission error (r = 0.53–0.57, n = 44, p < .001) and a moderate correlation between activity measures and normalised variation (r = 0.34-0.49, n = 44, p = .03-.001). There was a moderate and significant correlation between activity measures and commission error (r = 0.36-0.47, n = 44, p = .01-.001).
No correlation was observed between the attention parameters omission error and normalised variation (r = 0.15, n = 44, p = .3). A significant correlation was reached between omission and commission error (r = 0.51, n = 44, p < .001).
A total of four participants (9%) had increased distance measures following MPH as illustrated in the scatter plot in figure 1. One participant’s scores could not be captured in the plot because his measures were too high and outside the graph. The same participant presented with abnormal attention and impulse control measures. Another participant with increased activity measures post MPH was drug non-naïve and his baseline scores for activity, attention and impulse control unexpectedly showed to be within the normal range. In addition to the increased activity scores his attention measures also deteriorated on MPH. Of the remaining two cases who demonstrated an increase in their activity scores post MPH, one presented with a moderately hyperactive/impulsive profile and the other participant with an inattentive type profile.
Figure 1. Increased and decreased total amount of activity between baseline and retesting on a moderate dose of methylphenidate. Distance Q-score and Distance Q-score2 indicate deviations from the population mean at baseline and at retesting on MPH. The cases below the diagonal line represent participants responding with decreased distance measures on MPH. The cases above the diagonal line represent participants responding with increased distance measures on MPH. Gender 1 = male; Gender 2 = female
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In this study measuring the effects of a single moderate testdose of MPH using infrared motion analysis combined with CPT demonstrated statistically significant medication changes. These results fall in line with other studies measuring treatment response to MPH with the help of infrared motion analysis and CPT (Teicher et al. 2003, Heiser et al. 2004, Tabori-Kraft et al. 2007). Of note is the consistency of the medication effect when adjusting the CPT task to the developmental age of the participant. Hence no difference was found in the response to the medication between the younger age group (7–12 years) undertaking a CPT X-type and the older age group (13–18 years) switching to a CPT:IP-type. As a result infrared motion analysis can be used with CPT for a broader age range adequately covering the age range of child and adolescent mental health services.
Since this study included patients established on MPH medication as well as drug naïve patients, the lack of difference in treatment response to the same dose of MPH between naïve and non-naïve participants illustrates the possible absence of a noticeable tolerance effect bearing in mind that both sides presented with comparable baseline scores. Similarly, Martins et al. (2004) reported no changes in the efficacy of MPH between children on weekend drug holidays during MPH administration and children receiving 7 days a week MPH.
By implementing a single dose protocol with a range of standard test conditions into clinical practice, a large, significant correlation between changes in activity and errors of omission was obtained. This result is consistent with the findings of Teicher et al. (2004). However, the correlation between activity changes and normalised reaction time variation, another attention parameter associated with a strong and reliable relationship to actual ADHD symptomatology (Epstein et al. 2003, Teicher et al.1996), was only moderate in our study. This result is likely to have been affected by those participants demonstrating a partial response or no response to a moderate dose of MPH.
Similarly a significant but only moderate correlation between changes in activity and errors of commission was found suggesting that in some cases the capacity to inhibit rapid responses may still be impaired despite reduced hyperactivity. This partial response to MPH formed a minority (7%) of cases with the majority of participants (84%) manifesting a robust treatment response on a moderate dose of MPH. Since a partial response is associated with an impulsive response profile (Teicher et al. 2004) this finding supports the suggestion of Hale et al. (2005) that children with more hyperactive/impulsive behaviours require a higher dose of MPH to establish a restoration of their neuropsychological impairment. However other factors, such as rapid metabolism may also be related to a partial response and further studies are required to evaluate the clinical effects of rapid metabolism on the response to MPH.
Elevated activity levels post MPH, in particular an increase in the distance value, has shown in this study to be a predictor for atypical responses to MPH possibly due to greater MPH sensitivity in cases with normal and borderline objective measures at baseline, cases of a predominantly inattentive type (Hale et. al., 2005) and an idiosyncratic response to psychotropic medication seen in children especially when co-morbid learning disabilities and behavioural disorders are present (Hale et al., 1998).
Study limitations and clinical implications
The normative data provided by QbTest/QbTest-Plus is based on 466 Swedish children and adolescents and is not referenced to a UK population. Therefore environmental, ethnical and cultural differences are not accounted for.
In comparison to CPT as a “stand alone” measure of attention deficits, the combined application of infrared motion analysis with CPT has demonstrated a significant and stronger correlation with common behavioural rating scales for ADHD completed by parents and professionals. According to Hale et al. (2005) most medication management strategies typically rely on behavioural observations and ratings in the classroom and at home to determine treatment effects and little attention is paid to the effects of medication on cognition when cognitive and behavioural domains can be affected differentially by medications even at the same dose (Hale et al 1998, Hoeppner et al 1997). Adding motion analysis/CPT into daily clinical practice provides valuable information in relation to both behavioural and neuropsychological medication responses with the capacity to detect partial as well as idiosyncratic responses to psychotropic medication. Further studies are required to assess how informed dose titration and dose monitoring through behavioural and objective neuropsychological evaluation will affect treatment outcomes more comprehensively bearing in mind that so far there is little evidence that the behavioural effects of MPH translate into academic gains (Purdie, Hattie & Carroll, 2002).