To evaluate health-related quality of life (HRQL) and medication satisfaction after switching from a stable dose of oral extended-release methylphenidate (ER-MPH) to methylphenidate transdermal system (MTS) via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD).In a 4-week, multisite, open-label study, 171 children (164 in the intent-to-treat [ITT] population) aged 6-12 years diagnosed with ADHD abruptly switched from a stable dose of oral ER-MPH to MTS nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. Subjects remained on the scheduled dose for the first week, after which the dose was then titrated to an optimal effect. The ADHD Impact Module-Children (AIM-C), a disease-specific validated HRQL survey instrument measuring child and family impact, was used to assess the impact of ADHD symptoms on the lives of children and their families at baseline and study endpoint. Satisfaction with MTS use was assessed via a Medication Satisfaction Survey (MSS) at study endpoint. Both the AIM-C and MSS were completed by a caregiver . Tolerability was monitored by spontaneous adverse event (AE) reporting.AIM-C child and family HRQL mean scores were above the median possible score at baseline and were further improved at endpoint across all MTS doses. Similar improvements were noted for behavior, missed doses, worry, and economic impact AIM-C item scores. Overall, 93.8% of caregivers indicated a high level of satisfaction with their child's use of the study medication. The majority of treatment-emergent AEs (> 98%) were mild to moderate in intensity, and the most commonly reported AEs included headache, decreased appetite, insomnia, and abdominal pain. Seven subjects discontinued the study due to intolerable AEs (n = 3) and application site reactions (n = 4).This study demonstrates that MTS, when carefully titrated to optimal dose, may further improve child and family HRQL, as well as behavioral, medication worry, and economic impact item scores, as measured by the AIM-C in subjects switching to MTS from a stable dose of routinely prescribed oral ER-MPH after a short treatment period. Furthermore, following the abrupt conversion from oral ER-MPH to MTS, the majority of caregivers reported being highly satisfied with MTS as a treatment option for their children with ADHD.NCT00151983 Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder of childhood, affecting an estimated 7-10% of school-aged children  and ofte® ), an alternative to oral MPH formulation, is approved by the US Food and Drug Administration (FDA) as part of a comprehensive treatment for ADHD in children aged 6-12 years ) was 68.2 (23.3). Family HRQL mean (SD) score at end of study was 78.4 (21.7), reflective of a mean absolute change from baseline of 10.2 and a mean percent improvement of 15.0% in family HRQL.Subgroup analyses by prior treatment revealed similar changes in mean from baseline scores for Concerta (9.7), Ritalin LA (9.2), and Metadate CD (13.0). For subjects aged 6-9 years, the change in mean family HRQL scores from baseline to end of study (14.4) was more than double that demonstrated by subjects aged 10-12 years (6.1), reflective of a 23.5% improvement in family HRQL after 4 weeks of MTS treatment. Gender analysis revealed a greater improvement in child HRQL mean scores from baseline to end of study for girls (11.8) versus boys (9.5).AIM-C items regarding behavioral issues were generally improved over the course of the study. From baseline to endpoint, percentages of caregivers agreeing that their child's behavior "stayed the same"  increased (35.4-73.3%), those agreeing that their child's behavior tended to be up and down at different times throughout the day decreased (64.0-24.8%), and those agreeing that their child's behavior became more problematic at night decreased (68.3-39.1%). At study endpoint the majority of caregivers (85.1%) reported that handling changes in their child's behavior was not very difficult or a little difficult, and 63.8% reported that they were "very often" or "fairly often" successful in getting their child to focus or regain self-control.Subgroup analyses based on prior treatment, age, and gender demonstrated similar trends in these AIM-C behavioral items.Overall improvements from baseline to endpoint were seen in the Medication Tension/Worry Scale and School/Missed-Doses Worry Scale. On the Medication Tension/Worry Scale, the mean (SD) score at baseline was 68.0 (24.95). At endpoint, the mean (SD) score was 85.4 (17.4), indicative of a change in mean from baseline of 17.3 and a percent improvement from baseline of 25.4%.Subgroup analyses revealed that improvement in mean scores from baseline to endpoint with regard to the Medication Tension/Worry Scale scores were similar for all prior treatment groups  as well as for the 6- to 9-year-old and 10- to 12-year-old age groups . Gender analysis demonstrated greater improvement from baseline to endpoint in Medication Tension/Worry Scale scores for girls (22.3) compared with boys (15.4).On the School/Missed-Doses Worry Scale, the mean (SD) score at baseline was 79.1 (17.8). At endpoint, the mean (SD) score was 90.1 (14.1), reflecting a percent improvement in mean scores from baseline of 13.9%. Subjects that were receiving Metadate CD prior to MTS dose transition showed a greater improvement from baseline to endpoint in the School/Missed-Doses Worry Scale score (15.4) compared with those that were receiving Concerta (10.5) or Ritalin LA (8.7), and improvement for girls (16.3) was nearly double the improvement noted for boys (8.9). No apparent difference was noted between age groups.The percentage of subjects with missed doses was reduced at study endpoint (23.6%) compared with baseline (28.6%), indicating a slight improvement in compliance. This trend was also noted for prior treatment, age, and gender subgroups as well.Overall, there were improvements from baseline to endpoint in all economic impact items. From baseline to endpoint, the percentage of subjects missing school days decreased from 14.9-7.5%. The percentage of subjects requiring no extra hours of tutoring, nursing, home healthcare, or other services increased from 60.2% at baseline to 77.6% at endpoint. Furthermore, from baseline to endpoint, the percentage of caregivers reporting no missed days of work to manage ADHD-related issues increased from 78.3-86.3%. The percentage of subjects with emergency room visits related to their ADHD symptoms was unchanged between baseline and endpoint at 1.9%. Prior treatment, age, and gender subgroup analyses for all AIM-C economic impact items revealed similar results.Ratings on the MSS are displayed in Table Caregiver satisfaction with the effect of MTS on behavioral symptoms was high (93.8%), reflecting respondents' satisfaction with their child's behavior while he or she received the study medication. The majority of caregivers (82.6%) reported improvements in their child's social interactions since beginning the study medication, and 91.9% were satisfied with the efficacy of the study medication on their child's attention. The majority of caregivers (93.1%) indicated a high level of satisfaction with the duration of effect of the study medication on their child's ADHD symptoms.Regarding medication satisfaction with tolerability of MTS, at study endpoint the majority of caregivers (59.6%) agreed that the study medication decreased their child's appetite. The majority of caregivers (88.1%) disagreed that the study medication made their child feel sleepy during the day, but 34.8% of respondents agreed that MTS treatment made it hard for their child to fall asleep at night. The number of caregivers reporting concerns about their child's falling asleep at night appeared to be dose related: 5 (33.3%) for subjects receiving MTS 15 mg, 15 (37.5%) for subjects receiving MTS 20 mg, and 38 (34.8%) for subjects receiving MTS 30 mg.Prior treatment, age, and gender subgroup analyses produced similar results for all 11 MSS items.A total of 201 treatment-emergent AEs (TEAEs) were reported by 97 subjects (57%) in the safety population during the 4-week study. Most TEAEs (> 98%) were considered to be mild to moderate in intensity and the most common included headache (5.1%), decreased appetite (4.7%), insomnia (3.5%), and upper abdominal pain (2.7%).A total of 7 subjects discontinued the study due to intolerable effects. Four subjects withdrew from the study because of reactions at the application site that ranged from definite erythema with severe itching to normal appearance at the patch application site with moderate itching. None of these 4 subjects reported continuing AEs at follow-up. Three subjects reported AEs that led to study withdrawal. Two subjects reported 4 serious AEs that at follow up were reported to have resolved. A 7-year-old boy experienced "worsening of ADHD symptoms" and "condition aggravated" after receiving MTS 10 mg for 1 day; both events were considered unrelated to study treatment. A 12-year-old girl experienced "acute depression" and "suicide attempt" while receiving MTS 30 mg for 16 days; both events were considered possibly related to study treatment. The last subject, a 6-year-old girl, continued to experience anger/irritability after MTS study medication was discontinued.No deaths were reported during the study. At follow-up, no subject reported continuing AEs.Overall, AIM-C scores for child and family impact, behavior, worry, missed dose, and economic impact had a tendency to improve with all doses of MTS treatment from baseline to endpoint. Such results are consistent with other published reports of pharmacotherapy impact on HRQL in children with ADHD -46. InteCaregivers of children in the Ritalin LA subgroup, children aged 6-9 years, and girls reported greater improvements from baseline to endpoint in child HRQL when compared to the other subgroups. Children aged 6-9 years and girls experienced greater improvements from baseline to endpoint in family HRQL when compared with children aged 10-12 years and boys. Improvements seen in family HRQL for the prior treatment subgroups  were not very much different from one another.Behavior, as measured by the AIM-C, was also generally improved over the course of the study. At baseline, most caregivers indicated inconsistency in their child's behavior across the day in contrast to endpoint where the majority reported consistency in behavior. Further, at study endpoint the majority of caregivers reported that handling changes in their child's behavior was "not very difficult" or only "a little difficult" and that they were "very often" or "fairly often" successful in getting their child to focus or regain self-control. It may be inferred that improvements in behavior and the ability of the caregiver to manage their child's behavior after treatment with MTS may positively impact the HRQL for children with ADHD and their families.Overall improvements from baseline to endpoint were seen in the Tension/Worry Scale and School/Missed-Doses Worry Scale, with the latter possibly due to a slight reduction in number of missed doses reported by caregivers at study endpoint. Improvement in compliance may reflect increasing capacity to establish a routine of patch administration with time, although noncompliance is often underestimated in any clinical trial.Improvements from baseline were also noted for the AIM-C economic impact items. Although the majority of caregivers reported no missed school days due to ADHD symptoms at both baseline and endpoint, the number of children who missed 1 or more days of school was lower at endpoint compared to baseline. In addition at endpoint, there was a decrease in the number of missed days from work for caregivers and in the number of subjects requiring extra hours for tutoring, nursing, and home healthcare. The number of subject visits to the emergency room due to ADHD remained relatively unchanged from baseline to endpoint. Although an economic evaluation was not performed, the improvements in HRQL observed in children with ADHD coupled with the decreased direct and indirect costs associated with the disorder may lead to MTS being a cost-effective treatment option from a societal perspective.Overall, MSS scores were high across all dose groups. When asked to rate their overall satisfaction, caregivers indicated that they were satisfied with MTS as a treatment for their child's ADHD . Similar percentages of caregivers were satisfied with the behavioral efficacy of MTS as well. Consistent with the commonly reported TEAEs of decreased appetite and insomnia, the majority of caregivers agreed that the medication caused their child to want to eat less, and approximately one-third of caregivers agreed that the medication made it hard for their child to fall asleep at night. A recently published study evaluating MTS wear times of 4 and 6 hours, instead of the 9-hour wear time used in this study, suggests that some late day side effects may be attenuated by early removal of the patch .The current study was open-label, with no control group, and was nonrandomized. The sample was restricted to subjects who were previously taking a stable dose of oral ER-MPH with ADHD symptoms that were within 1.5 SDs above age/sex norms. Thus, these results may not be generalizable to subjects who were not taking a stable dose of oral ER-MPH or who had either a poor or excellent response to oral ER-MPH prior to switching to MTS.All study subjects were abruptly switched to MTS from a stable dose of their previous oral ER-MPH. Motivation for participation in this study may have been prompted by low efficacy, high prevalence of AEs, or low HRQL with subjects' previous medications. These motivations for study participation may have contributed to a bias toward HRQL improvement.HRQL was assessed using the AIM-C, a validated caregiver-completed measure. As noted earlier, the AIM-C consists of a 10-item scale to assess the impact of ADHD on the caregiver and life at home. In addition, the caregiver is also asked to report on how well their child is completing chores/homework, behaving in public, and working to his or her potential. The AIM-C Child Impact Scale also includes items such as how comfortable the child seems with others, how well the child seems to get along with others, and how well he or she handles everyday hassles. Thus, caregiver ratings in these latter areas  provide a more indirect account of the everyday impact of ADHD on the HRQL of the child.During the study, management of subjects involved regular visits, dose adjustments, and careful attention to AEs. This optimal management may also have had a role in improving behavior, HRQL, and satisfaction.Subjects who failed to respond to psychostimulants in the past, and those with conduct disorder, were excluded from the study. Therefore, the results of this study should not be extrapolated to these patient populations.The current study was of a relatively short duration and was designed to evaluate subject response after abrupt conversion from ER-MPH to the MTS dose specified by the dose-transition schedule. Thus, the safety data presented herein should not be considered representative of the long-term safety of MTS or the safety of MTS in treatment-naïve children with ADHD. Also, although a predefined dose-transition schedule was utilized in this current study, because of differences in bioavailability between products, MTS dose should be titrated based on individual response when patients are switched from oral ER-MPH formulations.Despite these limitations, the results of this study imply that MTS may further improve child and family HRQL, as well as behavior, medication worry, and economic impact item scores, as measured by the AIM-C in subjects switching from a stable dose of oral ER-MPH over a short treatment period. Furthermore, following the abrupt conversion from oral ER-MPH to MTS, the majority of caregivers were highly satisfied with MTS as a treatment option for their children with ADHD. Further studies evaluating the long-term impact of MTS on HRQL as well as analysis of probable predictors of HRQL change and/or satisfaction will be important in understanding what elements of stimulant treatment contribute most to improvements in HRQL and satisfaction. These studies will require additional controls on medication administration, including optimal dosing for the compared agents, as well as the use of blinded evaluators, and a validated medication satisfaction instrument.This study demonstrates that MTS was well tolerated and, when carefully titrated, may further improve child and family HRQL, as well as behavioral, medication worry, and economic impact item scores, as measured by the AIM-C in subjects switching to MTS from a stable dose of oral ER-MPH after a short treatment period. Furthermore, following the abrupt conversion from oral ER-MPH to MTS, the majority of caregivers were highly satisfied with MTS as a treatment option for their children with ADHD.OGB receives or has received research support and/or acted as a consultant for Ortho-McNeil Pharmaceuticals, Problem-Based Learning Institute, Quintiles CME, Routledge Press, and Shire Pharmaceuticals. LEA receives or has received research support, acted as a consultant, and/or served on a speaker's bureau for Autism Speaks, Neuropharm, NIMH, Novartis, Organon, Reach Institute, Ackerman Foundation, Shire Pharmaceuticals, and Targacept. PH is an employee of Shire Pharmaceuticals. JML is vice president and chief scientific officer with HealthActCHQ, which owns the intellectual property rights to the AIM-C survey.All authors have made substantial contribution to the conception, design, and/or conduct of the study, have been involved in the drafting and/or critical review of this manuscript, and all authors have given final approval of this manuscript.Thinking about your child's ADHD during the past 2 weeks, how much does each statement describe your child?• My child did well following through with chores and homework on his/her own• My child seemed to get along with kids his/her age• Feedback from teachers and parents about my child with ADHD has been generally positive• My child was able to deal well with everyday hassles and frustrations with friends and siblings• My child behaved well in public places like stores/restaurants• My child seemed comfortable with how things are going with friends and siblings• My child worked to his/her potential• My child adapted well to disruptions or unexpected changes in his/her routineIn general, how closely do each of the following statements describe life for you and your family?• My child's ADHD has added stress to our home life• My child's ADHD limits me from entertaining at home• I avoid going certain places or doing certain things with my child because of problems with his/her ADHD• I feel as if I am "on guard" in public settings because I never know if my child with ADHD will act up• My child's ADHD limits what we can do as a family• I am anxious about my child's future because of the ADHD problems he/she is having• I feel tired and worn out because caring for a child with ADHD requires a lot of my time and energy• I feel my child's ADHD controls my life• I am frustrated that my child's ADHD is unmanageable• I am concerned about the long-term effect my child's ADHD behavior may have on his/her siblingsPlease tell us how long your child has been on the following treatments for his/her ADHD.*(NOTE: not used in the current study but part of the AIM-C)Which of the following statements best describes your child's current ADHD medication status?* *(NOTE: not used in the current study but part of the AIM-C)Are the following statements TRUE or FALSE for your child?• My child's behavior stays about the same throughout the day• My child's behavior seems to be up and down at different times throughout the day• My child's behavior becomes more problematic at night• Is it difficult to handle changes in your child's behavior when the medication wears off?In general, how often are you successful in getting him/her to focus or regain self-control?How would you rate the school's cooperation in each of the following areas?**• Diagnostic/testing process for ADHD• Obtaining additional academic services• Developing a classroom behavior management plan• Designing a homework "plan of action"• Giving your child his/her ADHD medicine• Ongoing support in managing your child's ADHDPlease answer each of the following questions:• How much tension is there between you and your child about taking his/her ADHD medication?• How much do you worry about your child missing a dose of ADHD medication at school or when you are not around?• How bothered are you by having to monitor your child's ADHD medication everyday?• How embarrassed do you think your child is about taking ADHD medication at school?• How much does your child resist taking medication at school?• How often does your child's dose at school get missed or forgotten?• How often has your child had problems because of a missed dose at school?During the last 7 days, how many scheduled doses of your child's ADHD medication have been missed?How strongly do you agree or disagree with the following statements?**(NOTE: Not used on this study but included in the AIM-C)• ADHD can be helped by drugs alone• ADHD can be helped by behavioral interventions and therapy/counseling WITHOUT medication• ADHD can be helped by behavioral interventions and therapy/counseling with medication• ADHD can't really be helped. It's something my child will "outgrow"During the past 6 months, has your child missed days from school due to problems with his/her ADHD?During the past 6 months, have you, your spouse or partner missed days from work due to problems with your child's ADHD?During the past 6 months, has your child required any hours of extra tutoring, nursing, home healthcare, or other services as a result of his/her ADHD?During the past 6 months, has your child visited an emergency room due to an accident or incident that you believe was related to his/her ADHD?© Copyright 2006-2008. All rights reserved.][Reproduced with permission from HealthActCHQ Inc.


The impact of once daily atomoxetine treatment on symptoms in children and adolescents with ADHD may vary over the day. In order to capture such variations, two studies were undertaken in children and adolescents with ADHD using two instruments that capture morning and evening behavior and ADHD-related difficulties over the day. This secondary measure analysis builds on two primary analyses that were conducted separately for children and adolescents and also published separately.In two open-label studies, ADHD patients aged 6–17 years (n = 421), received atomoxetine in the morning (target-dose 0.5–1.2 mg/kg/day) for up to 24 weeks. Morning and evening behavior was assessed using the investigator-rated Weekly Rating of Evening and Morning Behavior (WREMB-R) scale. ADHD-related difficulties at various times of the day  were assessed using the Global Impression of Perceived Difficulties (GIPD) scale, rated by patients, parents and physicians. Data from both studies were combined for this secondary measure analysis.Both WREMB-R subscores decreased significantly over time, the evening subscore from 13.7  at baseline to 8.0  at week 2, the morning subscore from 4.3  to 2.4 . Scores then remained stable until week 24. All GIPD items improved correspondingly. At all times of the day, patients rated ADHD-related difficulties as less severe than parents and physicians.These findings from two open-label studies suggest that morning and evening behavior and ADHD-related difficulties in the mornings and evenings improve over time with once daily atomoxetine treatment. Attention-deficit/hyperactivity disorder (ADHD) affects 3–7% of school-age children and is characterized by inattention, impulsivity, and hyperactivity . ADHD isPsychostimulants and behavioral therapy are known to be effective in the treatment of ADHD, as reported in the MTA study . Since tThe non-stimulant atomoxetine is one of several long-acting treatment options for ADHD . In contThe GIPD and WREMB-R were used in two almost identical atomoxetine studies that were designed to investigate the degree of ADHD-related difficulties, as perceived by patients, parents and physicians, in patients with ADHD treated with atomoxetine. These two instruments enabled us to assess ADHD-related difficulties a various times of the day, most importantly the evenings and the following mornings. This report is based on a secondary measure analysis of data from the two atomoxetine studies. The secondary measure analysis builds on two analyses for the primary endpoint (GIPD) based on two studies that were conducted separately for children and adolescents.The two primary analyses have been published elsewhere ,40. The Patients were recruited from child and adolescent psychiatric and pediatric practices and outpatient clinics throughout Germany. Patients aged 6–17 years with ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) . The iteFollowing a wash-out period, baseline assessments were carried out with all instruments used. During the first week of treatment, patients received atomoxetine at a dose of approximately 0.5 mg/kg body weight (BW) per day. During the following 7 weeks, the recommended target dose was 1.2 mg/kg BW per day. This dose could be adjusted within a range of 0.5–1.4 mg/kg BW per day, depending on effectiveness and tolerability. Medication was given once a day in the morning. Assessments were carried out weekly during the first two weeks of treatment and every two weeks thereafter. After the 8-week treatment period, the physicians decided together with the patients and their parents whether the patient was to continue treatment for additional 16 weeks. Those who participated in this extension period continued on the same atomoxetine dose. Again, this dose could be adjusted within a range of 0.5–1.4 mg/kg BW per day as considered appropriate by the physician. During the extension period, three assessments were carried out: at 12, 16, and 24 weeks after baseline.The following instruments were used: Weekly Rating of Evening and Morning Behavior – Revised (WREMB-R), Global Impression of Perceived Difficulties (GIPD), Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS), and the Clinical Global Impression-Severity (CGI-S) scale. The data from both studies were combined and analyzed together.The WREMB-R-Inv scale is based on the Daily Rating of Evening and Morning Behavior – Revised (DPREMB-R) scale . The DPRThe Global Impression of Perceived Difficulties (GIPD) instrument is a five-item rating of ADHD-related difficulties that assesses difficulties in the morning, during school, during homework, in the evening, and overall difficulties over the entire day and the night ,40. EachThe GIPD total score was calculated for each rater as the mean of the item scores ranging from 1 to 7. If one item was missing, the total score was also considered to be missing. The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored (ADHD-RS) is an 18-item scale, with one item for each of the 18 ADHD symptoms listed in DSM-IV-TR ,31. TherThe Clinical Global Impression-Severity-Attention-Deficit/Hyperactivity Disorder (CGI-S ADHD) scale is a seven point single-item rating scale of the clinician's assessment of the severity of ADHD symptoms ,33.Details on the sample size calculation for the two studies first using the GIPD have been published elsewhere in detail ,40. In sEvaluation was largely descriptive. To present WREMB-R and GIPD scores over time, a last observation carried forward (LOCF) approach was used. Two-sided confidence intervals (CI) were computed using a 95% confidence level. All inferences regarding statistical significance were based on comparisons of the 95% CI. This is equivalent to significance tests with p-values and a two-sided α-level of 5%.The WREMB-R morning and evening subscores were compared with the corresponding GIPD items for morning and evening behavior by calculating Pearson's correlation coefficients with 95% CIs for each perspective, at each time point, and for all time points pooled. To avoid correlations of imputed values, only observed cases (OC) were used for these correlation analyses. There was no imputation of missing values. 95% confidence intervals for the correlation coefficients were computed based on Fisher's z-transformation.Overall, 421 patients (100%) diagnosed with ADHD according to DSM-IV-TR criteria were enrolled in the two studies and treated with atomoxetine ,40. Of tThe baseline characteristics of the patients are shown in Table In boys, a combined subtype of ADHD according to DSM-IV criteria was diagnosed most frequently  followed by the predominantly inattentive subtype . The combined subtype of ADHD according to DSM-IV criteria was diagnosed in 39 girls (47.0%) and the predominantly inattentive subtype in 38 girls (45.8%). The subgroups of patients with "predominantly hyperactive-impulsive subtype" and "ADHD, not otherwise specified" were small .The most frequent pre-existing comorbid conditions in the two study populations were psychiatric comorbidities Table . 349 (82The mean atomoxetine dose given during the first week of treatment was 0.5 mg/kg body weight (BW) per day . Thereafter, the mean dose for the respective visit intervals ranged between 1.17 and 1.18 mg/kg BW per day (range 0.4 – 1.5 mg/kg BW per day).Concomitant medication was taken by 272 (64.6%) of the patients. Cough and cold remedies, analgesics, antibiotics and herbal/complementary medicines were given most frequently. Concomitant behavioral therapy was given to 27 (6.4%) patients, and 20 (4.8%) patients received additional occupational therapy.Evening and morning behavioral symptoms, as reflected by the WREMB-R evening and morning subscores, both decreased significantly over time, as shown by non-overlapping confidence intervals  were 2.5 (2.4 to 2.7) for difficulties in the morning and 2.5 (2.3 to 2.6) for difficulties in the evening. At week 2, both ratings had decreased significantly to 2.0 (1.9 to 2.2) for difficulties in the morning and 1.9 (1.8 to 2.0) for difficulties in the evening. Again, ratings then remained stable until week 24.As shown in Table Treatment emergent adverse events were reported in 331 (78.6%) patients over the entire study period. Adverse events reported in more than 5% of all patients  were: fatigue 106 (25.2%), headache 86 (20.4%), nausea 77 (18.3%), vomiting 52 (12.4%), upper abdominal pain 42 (10.0%), nasopharyngitis 41 (9.7%), decreased appetite 30 (7.1%), diarrhea 27 (6.4%), abdominal pain 24 (5.7%), upper respiratory tract infection 23 (5.5%), cough 21 (5.0%), dizziness 21 (5.0%). In 207 (49.2%) patients the investigator considered the adverse event possibly related to atomoxetine. Adverse events reported in more than 5% of the patients and rated as possibly related to atomoxetine were: fatigue , nausea , headache , upper abdominal pain , reduced appetite , and vomiting . There were 11 (2.6%) patients with serious adverse events: dissociation, fall, fatigue and forearm fracture were reported twice, abdominal injury, abdominal pain, alcohol poisoning, appendicitis, circulatory collapse, depression, disturbance in attention, dizziness, drug abuse, head injury, hypothermia, injury, somnolence, tendon rupture, vasoconstriction, and vomiting were reported once . In two of these 11 patients, the adverse events were considered related to atomoxetine by the physician . Overall, no clinically relevant changes in vital signs were observed for the entire sample.The aim of this secondary measure analysis was to evaluate whether behavioral symptoms and ADHD-related difficulties during treatment with atomoxetine as perceived by patients, parents and physicians, differ at various times of the day. A total of 421 children and adolescents diagnosed with ADHD according to DSM-IV criteria were included in this analysis of data from two open-label studies ,40. The The WREMB-R evening and morning scores decreased over the 24-week observation period Table . This fiAt baseline, the parent- and physician rated GIPD scores over the day  ranged between 3.4 and 4.2 . Parent and physician rated scores were highest during homework, lower during school and in the evening, and lowest in the mornings (Figure Interestingly, the two GIPD items that reflect ADHD-related difficulties in the evening and in the morning improved in a pattern similar to the WREMB-R evening and morning subscores Table . This heCorrelation between the investigator-rated WREMB-R evening and morning subscores and the corresponding GIPD scores for the evening and morning items as rated by parents and physicians was high Table . The corIn the two studies reported here, discontinuation rates were low ,40. The These studies and analyses have several limitations. Most importantly, they did not include a placebo control, so that the degree to which the results reflect drug-specific effects cannot be determined definitively. Due to the open-label design, unspecific factors such as rater bias, expectation effects, and time effects cannot be ruled out. However, this does not automatically compromise the validity of the results . Also, sOverall, findings from this secondary measure analysis of two open-label studies suggest that morning and evening behavior, as reflected by the WREMB-R, and ADHD-related difficulties in the mornings and evenings, as reflected by the GIPD, improve over time with once daily atomoxetine treatment. This effect persisted over a period of up to 24 weeks. This finding applied to all three rater perspectives: patient, parent and physician. The value of using instruments such as the WREMB-R and the GIPD in a clinical context is that they can guide the physician in working towards remission, not only in terms of core symptom response, but also in terms of subjective patient outcome.PMW, AS, and KHE are full-time employees of Lilly Deutschland, RWD is a former employee of Lilly Deutschland and now holds a Eli Lilly Endowed Chair of Pediatric Psychopharmacology. PMW and RWD own Eli Lilly & Co. stock. GL has received research grants and speaker honoraria from Eli Lilly & Co. and is member of a Lilly Advisory Board.PMW, RWD and AS developed the two clinical trials. AS developed the analyses reported in this manuscript. All authors participated in development of the GIPD scale and the interpretation of data. PMW, AS and KHE drafted the manuscript, RWD and GL revised it critically for important intellectual content. All authors read and approved the final manuscript.


The aim of this study was to evaluate the association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children with attention deficit hyperactivity disorder (ADHD) in a continuous performance test (CPT).This study included 72 ADHD children (mean age=9.39±2.05 years) who were recruited from one child psychiatric clinic. The omission errors, commission errors, reaction time and reaction standardization in the CPT were computed. The number of 48-base pairs tandem repeats in the exon III of DRD4 was analyzed in a blind manner.The homozygosity of the 4-repeat allele at DRD4 was significantly associated with fewer commission errors  and standard deviation of reaction time  even after adjusting for age. The results of analyses of CPT measured values among three groups showed that the group with higher frequency of the 4-repeat allele showed a lower mean score of commission errors .These results suggest a protective role of 4-repeat allele of the DRD4 polymorphisms on commission errors in the CPT in children with ADHD. Attention deficit hyperactivity disorder (ADHD) is a disease with principal symptoms of inattention, hyperactivity and impulsivity. The results of various epidemiological studies report a prevalence rate of 8-12%. This disease is one of the representative childhood and adolescent mental disorders occurring most commonly in children aged 4-11 years old,3The meta-analytic results of 1) a multi-ethnicity population-targeted family study, 2) a twin study, and 3) an adoption study indicate that ADHD showed about 76% heritability, and the implication is that hereditary factors play an important role in pathogenesis.The subject group in this study included 72 male children with aged 6 to 15 years old, who visited the Outpatient Clinic of the Department of Pediatric and Adolescent Psychiatry at the Kwandong University College of Medicine Myongji Hospital. The subjects had been diagnosed as having ADHD by a psychiatrist specialized in children and adolescents. Diagnosis of ADHD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria. The subjects were in drug-naïve state. The consent for the study was obtained from children's parents or representatives. Exclusion criteria of subjects were 1) current cases with a convulsive disorder and other neurologic defect including brain damage, 2) schizophrenia and cases with a history of psychosis, 3) cases with developmental problems such as autism and learning disability, and 4) those who did not provide consent to participate in this study. This study was approved by the Institutional Review Board (IRB).Korean Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version is a semi-structured clinical interview designed to assess the present, life-time morbidity state and severity of ADHD of 32 psychiatric diseases of children and adolescence, based on the DSM-IV diagnostic criteria.In order to assess the severity of ADHD symptoms of school-aged children, the Korean ADHD Rating Scale-IV (K-ARS) was designed based on the DSM-IV diagnostic criteria consisting of 18 items.ADHD is known to be associated with disorders of executive and frontal lobe function.17The CPT presents stimuli-target and non-target in a mixture at regular intervals. The CPT is a tool to test task vigilance and distractibility by allowing the subject to react in the presence of a prescribed specific target. Various types of stimuli, such as letters, shapes, numbers and sounds are used. The CPT types are diverse depending on the form of stimuli.18The form of CPT used in this study is a Korean language version developed and standardized by Shin et al.In this study, in the presence of a target stimulus, four indices were as follows:1) Number of cases where a response is missed-namely, omission error, as an indicator of inattention; 2) Number of cases where a response occurs in the presence of non-target-these are commission errors, an indicator of hyperactivity or impulsivity; 3) Mean reaction time that measures the speed of process handling as a hit response time toward target stimuli; and 4) Standard deviation of reaction time that measures vigilance.19The results were converted into values of assessments on the basis of standard computation from the normal group of the same age. The measured values were used for statistical analyses.Blood collected from the peripheral veins of subjects in this study was treated with ethylenediaminetetraacetic acid (EDTA), transferred to a tube, and then stored frozen at -70℃ before the experiment began. A Genomic DNA Extraction Kit  was used to perform genomic DNA extraction from the lymphocytes of 1 mL whole blood. The established Kotler et al.The sequence and detailed analytic method of oligonucleotide primers used to form DRD4 exon III polymorphic region  were as follows:Primers: (5'-ACCACCACCGGCAGGACCCTCATGGCCTTGCGCTC-3' and 5'-CTTCCTACCCTGCCCGCTCATGCTGCTGCTCTACTGG-3') Amplification of polymerase chain reaction (PCR) was carried out in a 20 µL solution containing 100 ng genomic DNA, 10 pmol of each primer, 1 X PFU PCR buffer , 400 µM dATP, dTTP, dCTP, 200 µM GTP , 200 µM 7-Deaza-dGTP (Boehringer Mannheim) and 5% DMSO, 2 U Solgent PFU Taq.With respect to PCR response, denaturation occurred at 98℃ for five minutes, and the three-phase extension process at 98℃ for 45 seconds, 55℃ for 45 seconds and 72℃ for 1 minute and 30 seconds was carried out for 35 cycles. Then, the final extension was performed at 72℃ for 5 minutes. The PTC-100 thermal cycler  was used for thermal cycling, and PCR products were verified by bands seen through the ultraviolet (UV) transilluminator via ethidium bromide staining after carrying out electrophoresis using a 2% agarose gel.With respect to statistical analysis, the target group was divided by the presence or absence of the 4-repeat allele of DRD4, and an independent t-test was used to make comparative analysis of differences in scores of CPT. Also, one-way analysis of variance (ANOVA) was used to analyze the correlation between the 4-repeat allele and CPT measured values by dividing them into 3 groups-Group with no 4-repeat allele, Group with one 4-repeat allele and Group with both 4-repeat allele. The Statistical Package for the Social Science  for Windows was used for all statistical analyses. Values less than 0.05 were defined as being sta-tistically significant.The 72 male ADHD children were assessed (9.39±2.05 years). The average intelligence quotient was 105.12±16.33, and the mean K-ARS score was 33.02±8.19. The distribution of ADHD diagnostic subtypes, diagnosed by K-SADS-PL-K, showed combined type, 48.6%; inattentive type, 41.7%; and hyperactive-impulsive type, 9.7%. Comorbidity shown in 38.9% of the subjects and revealed, in decreasing order, mood disorder, 22.3%; anxiety disorder, 12.5%; tic disorder, 9.7%; and conduct disorder and oppositional defiant disorder, at 2.8% each. Comorbidity of having two or more disorders included a total of 7 cases: 3 cases of mood disorder+anxiety disorder, 1 case of mood disorder+conduct disorder, 1 case of anxiety disorder+oppositional defiant disorder, 1 case of mood disorder+oppositional defiant disorder, and 1 case of mood disorder+anxiety disorder+tic disorder .2=1.13, df=5, p=0.89).Among the 144 chromosomes of 72 samples in this study, the 4-repeat allele (80.5%) showed the highest frequency among exon III 48-bp VNTR polymorphism of DRD4, and the 2-repeat allele (14.6%) showed the next highest frequency. The 5-repeat allele and 6-repeat allele showed distributions of 2.1%, 2.8% each. The 7-repeat allele was not shown. The genetic distribution of exon III VNTR polymorphism of DRD4 coincided with the expected values of the Hardy-Weinberg Equilibrium  out of 72 samples, the 2/4 genotype in 13 (18.1%), the 2/2 and 4/6 genotype in three (4.2%) each. The 4/5 genotype was observed in two (2.8%) and the 2/5 and 2/6 genotype in one (1.4%) each .The results of comparative analyses of scores for commission error and standard deviation of reaction time in CPT, depending on homozygosity of 4-repeat allele of DRD4 genes, identified a significant difference in the mean score of these two groups . The groPerformance on the CPT was analyzed by subdividing into three groups-4/4 genotype group having two 4-repeat alleles; 2/4, 4/5 and 4/6 genotype having only one 4-repeat allele; 2/2, 2/5 and 2/6 genotype having no 4-repeat allele. Subjects having greater instance of the 4-repeat allele showed a significantly lower mean score for commission errors  .The results of the present study identified a significant association between homozygosity for the 4-repeat allele at the DRD4 gene and lower scores of commission errors and standard deviation of reaction time in CPT. These findings suggest that the 4-repeat allele of DRD4 gene plays a protective role against inattention and impulsivity of ADHD symptoms.The limitations of this study are as follows: First, the number of subjects was relatively small. This study involved target patients visiting the outpatient clinic of a university hospital in a specific area and may thus offer limited generalization of the conclusions. Second, comorbidity and psychosocial variables that may affect CPT results have not been controlled. In this study, 28 out of 72 subjects (38.9%) were verified as having comorbid disorders. ADHD has a high frequency of comorbidity of approximately 50% or more, and other psychiatric disorders such as anxiety disorder and mood disorder may also include the symptom of "inattention." Comorbid tic disorder seen concurrently in 40-60% of ADHD cases may largely affect the characteristics of the target group. Hence, future studies should be conducted controlling such an element. Lastly, it is not clear whether or not the CPT used in this study is a sensitive test that to detect inattention of ADHD, hyperactivity and impulsivity. Taken together, previous work demonstrates more commission errors and omission errors as well as differences in the standard deviation of reaction time, sensitivity and reaction time in CPT with ADHD patients as opposed to normal children.However, as mentioned above, with low difficulty of CPT comes to the likelihood that results can vary depending on age and intelligence. In such cases, auditory stimuli may have a higher degree of difficulty as opposed to visual stimuli. It has been reported that, in cases with an old age or with high intelligence, auditory stimulus-incorporated CPT may be more useful in ADHD diagnosis.Notwithstanding such limitations, this investigation offers comparative analysis of CPT measured values depending on the existence of homozygosity of 4-repeat allele of DRD4 targeting on an Asian population, and provides an analysis of correlation of genetic polymorphism and CPT measured values in accordance with number of 4-repeat alleles.In future studies, more samples from various Asian ethnic groups should be collected. Comorbidity and other psychosocial elements that might affect ADHD should be maximally controlled.


In their study of the relationship of blood lead levels (BLLs) in children 4–12 years of age and attention deficit hyperactivity disorder (ADHD), ADHD and other externalizing disorders  are known to have substantial genetic components, and ADHD heritability has been estimated to be 75% . Among cIn their backward stepwise logistic model (their Table 3), Familial transmission of ADHD and its diagnostic forebears has been documented for more than three decades , and sys


Association between polymorphisms in HTR2C and ADHD were reported in a recent study.Attention deficit hyperactivity disorder (ADHD) is a common, childhood-onset neurodevelopmental disorder that is more frequent in males than females. Several genes on the X chromosome have been studied as candidate risk factors for ADHD including the 5-HTP = 0.017). No association was detected between the C-759T polymorphism and ADHD. Haplotype analysis of the two markers revealed no significantly increased transmission of any haplotype to ADHD.In this study we investigated the association between ADHD and two polymorphisms C-759T (rs3813929) and G-697C (rs518147) in the promoter region of the HTR2C gene using a sample of 180 UK ADHD probands and their parents. We have shown that the -697G allele was significantly over-transmitted to affected ADHD probands (The findings provide evidence that the G-allele of the G-697C HTR2C polymorphism may be involved in the development of ADHD. The results replicate one of the findings published recently. Attention deficit hyperactivity disorder (ADHD) is a childhood onset, neurodevelopmental disorder characterized by inattention, hyperactivity and impulsivity. Molecular genetic and pharmacological studies suggest the involvement of the dopaminergic, serotonergic and noradrenergic neurotransmitter systems in the pathogenesis of ADHD. Polymorphic variants in several genes involved in regulation of the dopamine, and related neurotransmitter pathways are reported to be associated with ADHD -3.2C receptor (HTR2C) gene is located on human chromosome Xq24. The previous studies showed that the 5-HT2C receptor is a key contributor to control of central dopamine functions [Serotonin is a neurotransmitter in human brain, and involved in a variety of functions including learning, aggression and cognitive processes ,5. The sunctions ,7 and maunctions ,9. Genesunctions -14.2C receptor could be involved in the promoter activity, as the -759C and -697G allele had less promoter activity than the -759T and -697C allele. One study has investigated association between HTR2C and ADHD in the Han Chinese population [P = 0.891 and P = 0.613, respectively).Yuan et al.  have sugpulation . Two polpulation  also foupulation  analysedTo provide further clarification of the reported association, in this study we examined the two associated polymorphisms previously reported in the Han Chinese population.DNA was collected from 180 DSM-IV ADHD combined subtype probands, from both parents for 116 of the ADHD probands and from the mother alone for 64 of the probands. Cases were recruited from child behaviour clinics in South-East England and referred for assessment if they were thought by experienced clinicians to have a diagnosis of the combined subtype of ADHD under DSM-IV criteria, with no significant Axis I co-morbidity apart from oppositional defiant disorder (ODD) and conduct disorder (CD) and IQ greater than 70. Only those individuals fulfilling the recruitment criteria after completion of research assessments were included in the study. 96% of the sample was male. The age range was 5–15 years at the time of assessment . Parents were interviewed with a modified version of the Child and Adolescent Psychiatric Assessment (CAPA) . The subAciI (New England Biolabs) and the digested PCR products were run on 4% agarose gel containing ethidium bromide. Both the C to T substitution at nucleotide position -759 and the G to C substitution at position -697 abolish an Aci I sites; positions -726 and -645 are also fixed restriction sites for AciI. For the C-759T polymorphism, the C allele is represented by a 126 bp fragment, and the T allele by a 160 bp fragment. For the G-697C polymorphism, the C allele is represented by a 53 bp fragment, and the G allele by a 81 bp fragment.The C-759T (rs3813929) and G-697C (rs518147) polymorphisms were genotyped using the method of PCR and enzyme digestion. Genomic DNA was amplified by using forward primers 5'-ATCTCCACCATGGGTCTCGC-3' (spanning nucleotide positions -885 to -866) and reverse primers 5'-CAATCTAGCCGCTCCAAAGG-3' (spanning nucleotide positions -653 to -634). The reaction was performed according to the protocol described in the previous study . After d. Since HTR2C is X-linked gene, genotype data from fathers was only used in the analysis of female ADHD probands. Genotype information from both parents in female probands, and from mothers alone in male probands was used to analyse linkage disequilibrium (LD). The Bonferroni correction was applied for multiple tests and P < 0.025 was considered to show a statistically significant difference.Family genotype data were analysed using the transmission disequilibrium test (TDT) implemented in UNPHASED program (TDTPHASE) , . Since2 = 5.69, P = 0.017, OR = 1.7). Even after correcting P- values using the Bonferroni method for multiple tests a significant association was still found between the -697G allele and ADHD. Nevertheless, this finding should be treated with caution until further replication studies have been completed, since the significance level falls far below that required to adjust for the number of independent genetic variants across the genome . No difference in the transmission of any alleles of the C-759T SNP to ADHD was found (P = 0.384). Moderate LD was observed between the HTR2C markers (D' = 0.63). Haplotype analysis of the two markers revealed no significantly increased transmission of any haplotype to ADHD .The allele frequency of the two markers was estimated from the probands' mothers. For C-759T polymorphism the C-allele frequency is 76% and the T-allele frequency is 24%. For G-697C polymorphism the frequency of G-allele and C-allele is 48% and 52%, respectively. TDT analysis Table  showed tGenes coding to the X chromosome have been suspected as candidates for ADHD because ADHD is much more frequent in males than females ,9. PreviP = 0.010) and to ADHD-C probands (P = 0.041). We did not observe any association with the C-759T polymorphism and ADHD in our samples, and was thus unable to replicate the finding for this SNP by Li et al [In this study, we carried out further investigation between polymorphisms in HTR2C gene and ADHD in UK samples. We found a significant over-transmission of the -697G allele to ADHD combined subtype cases. Our study replicates a finding conducted by Li et al. , who fouLi et al . HaplotyIn this study we only observed that the -697G allele was associated with ADHD in a UK population. The finding suggested that the -697G allele may be a risk factor in the development of ADHD although this conclusion was not supported in a large multi-site European sample of ADHD . Due to The authors declare that they have no competing interests.XX selected the SNPs, performed genotyping, statistical analysis and drafted the manuscript. KB sorted out the samples. BS and NI participated in the genotyping for the study. PA supervised the study. All authors contributed to the final critical revision of the manuscript.


Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that starts in childhood and frequently persists in adults. Several theories postulate deficits in ADHD that have effects across many executive functions or in more narrowly defined aspects, such as response inhibition. Electrophysiological studies on children, however, indicate that ADHD is not associated with a core deficit of response inhibition, as abnormal inhibitory processing is typically preceded or accompanied by other processing deficits. It is not yet known if this pattern of abnormal processing is evident in adult ADHD.The objective of this paper was to investigate event-related potential indices of preparatory states and subsequent response inhibition processing in adults with ADHD. Two cued continuous performance tasks were presented to 21 adults meeting current criteria for adult ADHD and combined type ADHD in childhood, and 20 controls.The ADHD group exhibited significantly weaker orienting attention to cues, cognitive preparation processes and inhibitory processing. In addition, we observed a strong correlation between the resources allocated to orienting to cues and the strength of the subsequent response strength control processes, suggesting that orienting deficits partly predict and determine response control deficits in ADHD.These findings closely resemble those previously found in children with ADHD, which indicate that there is not a core response inhibition deficit in ADHD. These findings therefore suggest the possibility of developmental stability into adulthood of the underlying abnormal processes in ADHD. Adult ADHD (AD-ADHD) is recognised as a valid and reliable disorder that shares many features with ADHD in childhood -3. PrevaSeveral theories postulate deficits in ADHD that have effects across many executive functions, such as response inhibition, attention or working memory, with some data further suggesting that this may be particularly true for a subgroup of ADHD . A meta-One of the prominent theories of ADHD proposes that a core deficit of response inhibition underlies the development of broader deficits in executive function, which in turn cause the wide range of dysfunctional behaviours in ADHD . AlthougFew ERP studies have been carried out later in development on AD-ADHD. Studies investigating inhibitory processes in relation to the CPT-OX found that inhibitory no-go-P3 activity was attenuated in adults who reported psychopathology related to childhood ADHD  and pareGiven the limited existing ERP data on AD-ADHD, this study aimed to provide a detailed investigation of key ERP indices, previously reported as affected in childhood ADHD, in adults with ADHD, to investigate possible developmental stability in the associated deficits. We used both the standard CPT-OX paradigm -18,30,31In addition, we aimed to investigate the functional significance of the no-go-N2. The N2 is thought to specifically relate to inhibitory processing in adults ,34 but o21 males with ADHD and 20 male controls participated in the study following informed consent. The joint South London and Maudsley and the Institute of Psychiatry NHS Research Ethics Committee approved this study (086/05). All participants were aged 18-40 years, with the ADHD  and control  groups closely matched for age (t(40) = -1.08, p = 0.29). IQ was >79 on the Wechsler Adult Intelligence Scale (WAIS-II) ; mean IQAdults with ADHD were recruited from the National AD-ADHD Clinic at the Maudsley Hospital where they had received the diagnosis from a consultant psychiatrist specialising in AD-ADHD, following in-depth clinical and psychological evaluations. For the purposes of this study, diagnostic criteria for DSM-IV ADHD were applied using clinical interview data for the 18-ADHD symptoms in childhood and adulthood. In addition to the diagnosis from the clinical interview, individuals were only included if either the proband or an informant reported six or more DSM-IV items for both the hyperactive-impulsive and inattentive sub-scales using the Barkley AD-ADHD rating scale for retrospective recall of childhood symptoms ; and in Exclusion criteria, for the ADHD group, included the presence of an Axis I or II co-morbid psychiatric diagnosis, any previous substance abuse or head injury, taking any psychoactive medication other than stimulant medication, which they were free of for at least 48 hours before testing. All participants were right handed, as determined by preferred writing hand, and had normal or corrected-to-normal vision.Age and gender matched controls were selected from a database of volunteers at the Institute of Psychiatry, which includes information on psychiatric and medical history. Controls were selected if they had no major psychiatric conditions, substance abuse or previous head injury, but were unselected for ADHD. Self-report data was collected on current and retrospective ADHD symptoms using the Barkley scales . One conThe cued CPT was identical to that used in previous studies of childhood ADHD -18,30,31The flanker version of the task ,32 was iPrior to EEG data collection, participants' IQ was assessed using four subtests of the Wechsler Adult Intelligence Scale (WAIS-II): block design, vocabulary, picture completion and similarities . The IQ Performance measures in the cued CPT task included target reaction time , within-subject variability in reaction times (SD-RT), and the coefficient of reaction time variability . MRT and SD-RT were calculated across correctly answered target trials. Hits were characterized by target Xs that were detected between 200 and 1500 ms after stimulus onset. False alarms were responses to letters other than target X. Errors were broken down into subcategories .ERPs were recorded with a sample rate of 500 Hz and cut-off frequencies of 0.1-30 Hz via Nihon Kohden Ag/AgCl cup electrodes (impedances kept below 5 kOhm) fixed to the scalp with electrolyte gel at electrode positions, which included the 19 standard electrodes of the 10-20 system, FCz as recording reference, and a ground electrode placed at the forehead using calibrated technical zero baselines and a Neuroscan recording system. Vertical and horizontal electrooculograms (EOGs) were simultaneously recorded from electrodes above and below the left eye and at the outer canthi. The EEG file was analysed using Brainvision Analyzer and was corrected for horizontal and vertical (blinks) eye movements using the Gratton and Coles method . Trials Two ADHD participants were excluded from the ERP analyses due to excessive movements. ERP amplitudes were restricted to leads and time windows for which effects were expected to be largest, based on previous studies ,45. The For the analysis of performance data, the measures of error rates had pronounced heterogeneity of variance and skewed distributions and transformations were unsuccessful ; analyses of these data were therefore performed using GEE models. MRT, SD-RT and CV were analysed using repeated-measures ANOVAs with age as a covariate. Time-on-task effects on RT data were investigated by comparing RT in equal length quartiles over the course of the task in a repeated measures ANOVA. We investigated the relationship between the performance measures using Spearman's rank correlation coefficient.p < 0.05 (two-tailed) was adopted throughout the analyses, with trends (p≤09) also reported for predicted effects. We initially included age as a covariate in all analyses and only report it when it was significant, as we dropped it from the analyses otherwise.Although IQ did not differ between groups, initial analyses were run with IQ as a covariate, which confirmed IQ effects as non-significant. IQ was therefore not included in subsequent analyses. A significance level of All analyses remained stable when the control participants who retrospectively reported high numbers of ADHD symptoms were excluded (data not shown). We additionally re-ran all analyses excluding the ADHD participants who had subthreshold hyperactive-impulsive symptoms in adulthood and again the results did not change (data not shown). Further, these participants were not outliers on any of the ERP or performance variables.Repeated-measures ANCOVA of the reaction time measures indicated no significant effects of age as a covariate, so it was subsequently dropped from analyses,  nor were there group-by-task interactions for MRT , SD-RT  or CV . There were, as predicted, significant group differences on MRT , SD-RT  and CV , with the ADHD group being slower and more variable than the control group  = 7.60, p < 0.01, d = 0.90] with no group by time interaction . For SD-RT in the CPT-OX, no main effect of time on task emerged ; however, there was a time by group interaction, with more variation in levels of SD-RT (increases and decreases) in the ADHD group over the course of the task . For the CPT-OX with flankers, no main effect of time on task emerged for MRT , nor was there a group by time interaction . Similarly, for SD-RT in this task, no main effect of time on task emerged for MRT , nor was there a group by time interaction .GEE analysis indicated no significant interaction between group and task for commission errors , commission errors of the O-not-X type  or omission errors . No significant group differences emerged for commission errors  or commission errors of the O-not-X type ; however, there were very few commission errors  in the ADHD group. Similarly, in the flanker version, lower accuracy was again significantly associated with slower RTs in the ADHD group , but not in the control group .The groups did not differ significantly in their cue-P3 latency  for the CPT-OX, whereas a significant group difference emerged in the flanker version , with the ADHD group activating the preparatory process earlier than the control group (Table ,38 = 0.0For the amplitude of the cue CNV, a significant group-by-task interaction emerged  with the ADHD group decreasing and the control group increasing in amplitude in the flanker version. We obtained a trend in the predicted direction for a difference between the groups in amplitude of the cue CNV in the CPT-OX  and a significant group difference in the flanker version , indicating that cognitive preparation processes are abnormal in the ADHD group for the flanker task. The difference between the groups is particularly visible in Figure The analysis indicated a significant effect of age on the amplitude of the cue-P3  yet no significant group-by-task interaction ; however, as predicted, the groups differed significantly for both tasks . This difference is particularly visible in Figure Spearman's correlations indicated significant association between the cue-P3 and the inhibitory P3 in the control group for the CPT-OX task and in both groups for the flanker version . Additionally, in order to test whether this association was specific to the cue and no-go-P3, Spearman's correlations were calculated between these components and the go-P3. These analyses indicated that there was not a significant relationship between the go and no-go-P3 components except for trend for the ADHD group in the flanker version  and that there was a significant relationship between the cue-P3 and the go-P3 for both groups and both tasks . To further examine the relationship between motor preparation and response execution control, we additionally tested the relationship between the go and no-go P3 components and the CNV. No significant relationships emerged between the CNV and the go P3 component for either task in cases  or controls . Similarly, no significant correlations emerged between the CNV and the no-go-P3 in the CPT-OX for either cases  or controls ; however a significant correlation did emerge in the CPT-OX flanker for cases  and a trend emerged for controls .For the no-go-N2, the group-by-task interaction was not significant  and the groups did not differ significantly in no-go-N2 amplitudes . However, a significant difference emerged between the tasks , with both groups showing an increase in amplitude in the flanker version. The group-by-task interaction was not significant for the go-N2 amplitude , but a group difference indicated a trend  for an attenuation in the ADHD group. The tasks did not differ significantly in the amplitude of the go-N2 . The go and no-go-N2 components were significantly correlated for both groups and both tasks, though with the correlation for controls in the flanker version showing a trend only .In a comparison of 21 male DSM-IV AD-ADHD cases and 20 age and gender matched controls, we identified a similar pattern of altered cognitive-electrophysiological processing to that previously reported in childhood ADHD. This finding suggests persistence of the abnormalities in underlying processes and provides external validation for the diagnostic construct of AD-ADHD.Attenuation of the fronto-central no-go-P3 indicated the presence of abnormal inhibitory processing and confirmed previous ERP findings on AD-ADHD ,25,26 anThe AD-ADHD group also displayed reduced cue-P3 amplitudes, indicating reduced attentional orienting to cue stimuli; and reduced CNV, indicating abnormal anticipation and preparation. This novel finding indicates that, similar to childhood ADHD ,22,24,50Despite a strong positive relationship between the cue-P3 and the go-P3 for both groups in both tasks, there was limited evidence of abnormal processing to stimuli associated with response execution control, as indexed by the go-P3. This is similar to findings in childhood ADHD that used the same task ,17 and mIn additional investigations we did not find abnormal go or no-go-N2 effects in AD-ADHD, which again was identical to previous findings in children with ADHD using this task ,17,30. WIn terms of task performance, there was no evidence of speed-accuracy trade-off differences between the groups and adults with ADHD were slower with more variable RTs than controls. In particular, RT variability across a wide variety of neuropsychological tests was recently reported to be the best discriminator between ADHD cases and controls, with principal components analysis suggesting that RT variability across tasks forms a unitary construct . FurtherTo increase homogeneity of the sample, the study included only males; however a recent study confirmed the findings presented here in females . To maxiIn conclusion, in a detailed combined investigation of ERP indices of response execution, inhibition and preparatory processes in AD-ADHD, we found a similar profile of altered processing deficits as previously identified in children with ADHD. This suggests that the ERP measures represent underlying processes that are developmentally stable. Furthermore, these findings provide external validation of the ADHD diagnosis in adults, which is becoming increasingly recognised as a common psychiatric disorder in adulthood ,8. SinceThe authors declare that they have no competing interests.GM carried out the EEG assessments, performed the data analysis and drafted the manuscript. BA, TB, DB and AR provided training and supervision in EEG analysis. PA and JK conceived of the study, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.


The address given for author affiliation number 5 is incorrect. The correct address is Malaysia Genome Institute, Ministry of Science, Technology and Innovation, UKM-MTDC Technology Centre, UKM Bangi Selangor, Bangi, Selangor, Malaysia.


Differentiating between bipolar spectrum disorder (BD) and attention deficit hyperactivity disorder (ADHD) in childhood and adolescence is difficult because the clinical presentation is influenced by ongoing neural development, causing considerable symptom overlap. Motor problems and neurological soft signs have been associated with ADHD for decades. Little is known about motor skills in BD. Here we assess the diagnostic accuracy of neuromotor deviations in differentiating ADHD from BD in clinical practice. We also investigate if these deviations exist in concurrent ADHD and BD, thus indicating true comorbidity64 patients 6-18 years  fulfilling the diagnostic criteria of BD, ADHD combined subtype (ADHD-C) or comorbid BD and ADHD-C, were compared using an age-standardized neuromotor test; NUBU. Categorical variables were analyzed using cross table with two-tailed chi square test or Fisher's exact test when appropriate. Continuous variables were analyzed by Kruskal-Wallis test and, if significant, Mann-Whitney U test and ROC plots.The ADHD-C group and the comorbid ADHD-C and BD group both showed significantly more neurological soft signs (p less than 0.01) and lower mean static coordination percentile (p less than 0.01) than the BD group. The positive predictive value of NUBU in the diagnosis of ADHD-C with or without concurrent BD was 89% (80-95) for total soft signs and 87% (79-95) for static coordination below the 7.5 percentile.An age-standardized neuromotor test battery may promote diagnostic accuracy in differentiating ADHD from BD in clinical practice, and help evaluating whether symptoms of ADHD in children who have BD reflect symptom overlap or real comorbidity. This may have important implications for everyday diagnostic work. The frequent co-occurrence of BD and ADHD in children has been a matter of much discussion and research . Still, Motor skill problems and neurological soft signs have been associated with inattention and behaviour difficulties for decades. Concurrent developmental coordination disorder (DCD) is reported in about 50% of children with ADHD ,7, mainlThere are few reports on motor problems in BD. In two studies, patients with BD were impaired on sequential motor performance consistent with the frequent reported impaired attention set-shifting in BD ,24. In c1. Investigate if prevalence of motor deviations differs between youths with ADHD and BD. 2. Investigate if these deviations also exist in concurrent ADHD and BD, thus indicating true comorbidity. A priori hypotheses: 1. Neuromotor deviations are a common feature of ADHD but not of BD. 2. Neuromotor deviations occurring in concurrent ADHD and BD are indicative of true comorbidity.Inclusion criteria were ADHD combined subtype (ADHD-C), BD and concurrent ADHD-C and BD (ADHD-C+BD). We included ADHD-C only, because data supporting the validity of other subtypes of ADHD is scarce . Those wMental retardation according to DSM-IV or sequelae of brain injury.Subjects were recruited from a general child and adolescent psychiatry outpatient unit, mainly from one Norwegian community with approximately 25,000 persons <18 years. Inclusion period was December 2004 to April 2008, 1267 subjects  were referred to the unit in this period. In addition ten subjects were referred from other child and adolescent psychiatry units because of this study. Whenever bipolar disorder was suspected (n = 208) by any of the employees, the patients were evaluated for further assessment. Finally 172 subjects were interviewed by the Kiddie-Schedule for Affective Disorders and Schizophrenia Present and Lifetime version (KSADS). CaregivMost of the patients with ADHD-C were recruited from subjects with suspected BD, who fulfilled the ADHD-C criteria only according to the KSADS interview. Ten additional patients with suspected ADHD-C only were selected from patients at the unit to optimize the age, gender and IQ match between the groups. These went through the same diagnostic assessments as the other participants.In addition to diagnoses of ADHD-C and BD, other diagnoses and background information were recorded from KSADS. All subjects completed an IQ-test . Further information was obtained from school , teacheSixty-six subjects were initially included. Two female BP-I patients were later excluded; one because of drug abuse during testing and one because of possible perinatal brain injury. Sixty-four subjects grouped as ADHD-C, ADHD-C+BD or BD were finally included in the study. Six patients with concurrent ADHD-C and BP-NOS symptoms no longer satisfied the criteria for BP-NOS after stimulant medication; these were reclassified as ADHD-C only. One patient with BP-I successfully treated by a mood stabilizer, switched to mania when adding a stimulant to treat concurrent ADHD symptoms, this patient was therefore classified as BP-I only.Twenty-six fulfilled the criteria for ADHD-C only, mean age 13.2 years (S.D. = 3.8 years), mean total IQ 91.4 (S.D. = 10.9), 11 females. Fifteen fulfilled the criteria for both ADHD-C and BD , mean age 14.0 years (S.D. = 3.6 years), mean total IQ 90.1 (S.D. = 14.7), females 7. Twenty-three fulfilled the criteria of BD , mean age 13.8 years (S.D. = 3.8 years), mean total IQ = 95.1 (S.D. = 13.3), females 13. Differences in age and total IQ were non-significant.The Neuromotor examination for children and adolescents 4-16 years (NUBU) was used . It incl1. Total soft signs (summarized test 2-12)2. 20 jumps on one foot (6 years)3. Fingertip touch with open (5 years) and closed eyes (6 years)4. Oculomotor function; coordinated eye movements without head following (7 years)5. Stretch arms forward for 20 seconds without involuntary or abnormal movements (8 years)6. Walking heel-toe on line for 20 paces (8 years)7. Speech; pronunciation and comprehension (8 years)8. Standing on one foot for 20 seconds (8 years)9. Diadochokinesis (8 years)10. Cutting a paper circle (8 years)11. Fog's test: Walking on lateral sides of feet (11-12 years)12. Finger opposition (15-16 years)1. Total motor age 2. Static coordination 3. Hand-eye coordination 4. Dynamic coordination 5. Motor tempo 6. Simultaneous movement (motor coordination and sustained rhythm in simultaneous motion)We used the percentile scores in our group comparisons. The NUBU testing was performed by a psychiatrist trained by the authors of NUBU and by two physiotherapists with special competence in child and adolescent psychiatry, supported by a detailed manual with DVD demonstration of the NUBU tests. Interrater reliability was established by two of the investigators, testing 6 patients together. For motor percentile test, Intraclass Correlation Coefficient range was 0.91-1.00 (single measure). Soft sign tests kappa measure of agreement range was 0.57 - 1.00 (kappa). Inclusion date and test date were not significantly correlated with total soft sign deviations or total motor age.We attempted to do the test in euthymic and drug free patients. This was impossible in a minority of the subjects because of severity of symptoms , these were assessed using mood stabilizers. All other medication was discontinued for a minimum of five times the elimination half-life before testing. We had to retest the first included patients (n = 12) after two years because the NUBU scoring algorithms were slightly changed. Missing data: One did not do the dynamic coordination subtest because of discus prolapse and one did not co-operate in the tempo subtest. There were no missing data in the soft sign tests.The KSADS does not include the diagnostics of DCD, but the introductory part contains questions about motor development and motor difficulties. Answers on these questions were compared with the NUBU findings.Data were analyzed using the Statistical Package for Social Sciences (SPSS), version 16. Analyzed factors were soft sign deviations and motor age percentiles adjusted for possibly confounders (comorbidity and medication). Categorical variables were analyzed using cross table with two-tailed chi square test (with Yates Continuity Correction) or Fisher's exact test when appropriate. Continuous variables were analyzed by Kruskal-Wallis test and if significant, pairwise comparisons using Mann-Whitney U test. ROC curves were used to decide cut off value for presence of ADHD-C diagnosis and corresponding sensitivity, specificity and predictive values. Reported motor problems (from the introductory part of KSADS) were compared with total motor problems and total soft sign deviations by Spearman correlation.The protocol was approved by the Regional Committee for Medical Research Ethics of Southern Norway and the Norwegian Social Science Data Services. All children and their caregivers were given verbal and written information. Caregivers gave formal written consent for all children under age 18 years. Children ≥ 12 years gave formal written consent, younger children gave spoken consent. Data collection was mostly incorporated in routine clinical work. Considering the uncertainty of psychiatric diagnosis in childhood and adolescence, all subjects were offered diagnostic reassessment after 2-3 years and after the age of 18.Soft sign deviations and differences between the groups are shown in Table Median motor age percentiles and differences between the groups are shown in Table When the BP-NOS patients were excluded from the analysis (renaming the BD groups BDx and ADHD-C+BDx), the ADHD-C group performed significantly worse than the BDx group on all tests except tempo and simultaneous movement. Median motor age percentiles remained significantly lower in the ADHD-C+BDx group compared to the BDx group on total motor age and static coordination.There were no significant differences between the ADHD-C and the ADHD-C+BD or ADHD-C+Bx groups.Sensitivity, specificity, and predictive values of soft signs in predicting ADHD-C diagnosis (with or without BD) are shown in Table Using ROC curves we found that a static coordination percentile below or equal to 7.5 was the best motor age predictor for ADHD-C diagnosis (with or without BD). The sensitivity of the other motor tests was too low to be used as signs of ADHD-C Table , althoug2 = 9.14, p = 0.01). These differences persisted when excluding BD-NOS from the analysis  = 6.47, p = 0.037).Because anxiety disorders may be associated with postural instability ,40, we c2 = 17.55, p < 0.000) and finger opposition  = 8.667, p = 0.003). The ADHD-C group performed significantly worse than the ADHD-C/ADD+BD group on total soft signs  = 6.297, p = 0.012), jump on one leg  = 5.790, p = 0.016) and finger opposition  = 3.878, p = 0.049). There was no change in significant differences between the groups on the motor tests.In this study we compared the three groups ADHD-C, BD and comorbid ADHD-C and BD. In the BD group, most subjects reported considerable attention problems; of which ten fulfilled the diagnostic criteria of ADD. Because some studies indicates that motor deficits are particularly prominent in ADD , we moveCaregiver-reported motor problems (from KSADS) and total motor age percentile was only weakly negatively correlated . There were no differences in soft signs between those who reported motor problems and those who did not (44.4% versus 41.3%).Nine subjects in the BD or ADHD-C+BD groups were on eleven mood stabilizers or antipsychotics, although these were not taken on the test day . The medication group had significantly lower total motor age percentile , simultaneous movement percentile  and hand-eye coordination percentile  than the non-medicated BD group. No other significant differences between the medication and the no medication group were found.To our knowledge, this is the first report comparing motor skills and soft neurological signs in subjects with ADHD and BD.Firstly, we found that neuromotor deviations may be used as a possible sign of ADHD-C, thus aiding the differential diagnosis of ADHD-C and BD. Secondly, neuromotor deviations in ADHD-C+BD may be due to ADHD-C and thus indicating that ADHD-C in paediatric BD is a phenotypic copy of ADHD-C in non-BD patients.Including ADD in the ADHD-C+BD group reduced the differences between the ADHD-C/ADD+BD and BD groups, indicating that the attention deficit is associated with BD mainly, and not with concurrent inattentive subtype of ADHD.Caregiver-reported motor problems were only weakly correlated with neuromotor deviations in this study. We therefore assumed that our findings might be due to ADHD-C and not solely to concurrent DCD, whose diagnostic criteria require reduced motor performance relative to age in daily activities.The most prevalent soft sign in ADHD-C was deviations in the complex task finger opposition. This test requires motor timing and inhibition, which are consistently found abnormal in ADHD . AlthougBalance problems in ADHD are confirmed in several studies, but are also common in many other disorders, often associated with cerebellar dysfunction. Cerebellar abnormalities have been reported in several neuroimaging studies of ADHD ,42. In ath percentile on static coordination and in the normal range for soft signs. This may be an expression of the variability of performance reported in the ADHD literature suggesting different pathways involved in the disorder [Some patients with ADHD-C scored above the 7.5disorder .Compared to other studies, we found more motor difficulties in the ADHD group. Firstly, we only included ADHD combined subtype. Secondly; it may be that ADHD patients actually have specific motor deviations, but most test batteries are not specific enough to uncover these. The test battery often used in diagnosing DCD; the Movement Assessment Battery for Children , scores The motor tests in NUBU are time consuming and require special equipment and are therefore cumbersome in everyday clinical work. However, the demonstration of soft signs requires no special equipment and is far less time consuming. Considering the high positive predictive value of total soft signs, their demonstration may add diagnostic accuracy for ADHD.This study is based on a convenient and small sample, limiting a generalization of the findings.Because of uncertain validity of the BD diagnosis in young patients, the findings in BD should be interpreted carefully. Including BD-NOS increases the uncertainty. However, the results mainly remained unchanged when excluding BD-NOS from the analysis. The diagnosis ADD also causes problems; in some cases the symptoms may be due to BD, and in other cases they may be due to the inattentive subtype of ADHD. It is also reasonable to presume that the main investigator improved her proficiency diagnostic assessment during the data collection period. These diagnostic uncertainties will be considered in an ongoing follow up study (diagnostic reassessment after 2-3 years and after the age of 18).A weakness of NUBU is the contribution of subjective judgement in scoring. Thus, the lack of blinding may have contributed to the high prevalence of neuromotor problems among ADHD-C patients in this study. Yet, the highly significant differences between the groups and the high inter-rater reliability between the raters in this study rule out the possibility that bias rating alone explain the results.This study indicates that an age standardized neuromotor test battery may contribute to diagnostic accuracy in differentiating between early onset BD and ADHD-C in clinical practice. It may also contribute in evaluating whether ADHD symptoms in children who have BD reflect symptom overlap or real comorbidity. This may have considerable implications for everyday clinical work, because the soft sign tests can be carried out in any child and adolescent unit or family practice. Specific test batteries should be designed to detect the specific motor problems in ADHD. FurtherADHD: attention deficit hyperactivity disorder; ADHD-C: attention deficit hyperactivity disorder, combined subtype; ADD: attention deficit hyperactivity disorder, inattentive subtype; BD: Bipolar spectrum disorder; BP-I: Bipolar disorder I; BP-II: Bipolar disorder II; BP-NOS: Bipolar spectrum disorder not other specified; BDx: Bipolar Disorder I or Bipolar disorder II; BDr: BD excluding those with concurrent ADD; NUBU: Neuromotor examination for children 4-16 years; DCD: Development coordination disorder; PFC: Prefrontal cortex; KSADS: The Kiddie-Schedule for Affective Disorders and Schizophrenia Present and Lifetime version; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th EditionAll authors except Bente Gjaerum declare that they have no competing interests.Bente Gjaerum is the senior author of NUBU, and thus declares a financial interest.AHU is responsible for conception and design, acquisition of data, analysis and interpretation of the data, drafting, revising and approval of the manuscriptBG, UFM and HL are co-responsible for conception and design, critically revising of the manuscript and have given final approval of the version to be published. BG and UM has also contributed to interpretation of the data.AHP is responsible for statistical analysis and interpretation of the data, critically revising of the manuscript and have given final approval of the version to be published.BG is responsible for training AHU in assessment and interpretation of NUBU, critical revising of the manuscript and final approval of the version to be published.