Effects of Methylphenidate and Atomoxetine Treatment on Improvement of Motor Coordination in Children With Attention-Deficit/Hyperactivity Disorder
Article information
Abstract
Objective
To investigate the effects of methylphenidate and atomoxetine treatment on motor coordination in children with attention-deficit/hyperactivity disorder (ADHD).
Methods
In this single-site, open-label, naturalistic follow-up study, 157 children (7.6±1.4 years; 139 males) with ADHD were recruited between March 2015 and May 2020 from the Department of Psychiatry, Asan Medical Center, and treated for 12 weeks with methylphenidate (n=48) or atomoxetine (n=109). Children completed the Advanced Test of Attention (ATA), and caregivers completed the ADHD Rating Scale (ARS) questionnaire and Developmental Coordination Disorder Questionnaire (DCDQ) at baseline and at 12 weeks. Paired t-tests, a mixed-effects model, and linear regression were used to compare treatment groups and assess factors influencing motor coordination changes.
Results
Methylphenidate and atomoxetine resulted in significant improvement in DCDQ fine motor/handwriting, general coordination, and total scores over 12 weeks. Fine motor/handwriting had a significant main effect for time (F1=16.64, p<0.001, η2=0.097); however, the interaction effect between group and time was not significant (F1=0.24, p=0.625, η2=0.002). Changes in parent-reported ARS inattention scores (β=-0.174, p=0.029) and auditory commission errors of ATA (β=0.191, p=0.022) were significantly associated with changes in fine motor/handwriting. Additionally, changes in parent-reported ARS inattention scores (β=-0.177, p=0.034) and rater-reported ARS inattention scores (β=-0.198, p=0.017) were significant predictors of improvements in general coordination in separate models.
Conclusion
Methylphenidate and atomoxetine had a positive effect on motor coordination in children with ADHD. Improvement in motor coordination was associated with ADHD symptom improvement.
INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterized by core symptoms of inattention, hyperactivity, and impulsivity [1]. The prevalence of ADHD in school-age children ranges 5%–8%, which makes it one of the major childhood mental health disorders [2,3]. ADHD is also associated with behavioral problems in children as well as educational and occupational underperformance [3,4].
In addition to the core symptoms of ADHD, motor coordination problems are also frequently reported [5,6]. Children with ADHD have lower levels of performance in activities involving large muscles, such as balance and movement, and small muscles, such as handwriting [6-8]. Furthermore, comorbidities such as depression [9] and anxiety disorders [10] are more common in children with ADHD and decreased motor coordination [11]. Problems with motor coordination and ADHD can lead to poor handwriting, related academic problems, frustration, and reluctance in completing schoolwork. Therefore, children are exposed to a cascade of negative psychosocial consequences, which in turn lead to negative self-appraisals and the exacerbation of depression and anxiety [12,13].
In many children, ADHD and developmental coordination disorder (DCD) coexist, with an estimated overlap between these disorders of approximately 50% [14-16]. Co-occurring ADHD and DCD tends to have more severe consequences than those observed with ADHD or DCD alone [17,18]. In contrast to children with ADHD alone, those with both ADHD and DCD were found to have a lower performance intelligence quotient and exhibit more internal and external behavioral symptoms such as social deficits, depression, and anxiety [19]. Additionally, the combination of ADHD and DCD was associated with a poor psychosocial prognosis for the other symptoms of ADHD, antisocial personality disorder, alcohol abuse, criminal offending, reading disorders, and a low educational level [16,20]. This can be an important factor in determining the child’s development process and subsequent prognosis. In this regard, assessing the child’s motor coordination deficit early is essential for following ADHD diagnosis and providing appropriate therapeutic interventions [19].
In recent years, with increased awareness of ADHD worldwide, including in Korea, an increased focus on the diagnosis and treatment of the condition has been noted. However, motor coordination problems in children with ADHD are relatively unknown, and treatments such as occupational therapy and physical therapy are rarely used in the management of ADHD [21]. Additionally, though many studies have examined the effects of ADHD drug treatment on attention deficit and hyperactivity, which are the core characteristics of ADHD [22-24], few studies have investigated the effects of ADHD drug treatment on motor coordination.
Studies examining the effect of ADHD drug treatment on motor coordination have found that treatment improved postural stability [25], balance [26], and fine motor functions such as qualitative aspects of handwriting [27,28]. However, these studies have predominantly focused on the short-term (4 weeks or less) treatment effects of methylphenidate on motor coordination in children with ADHD. Longer-term research is needed to evaluate the long-term impact of methylphenidate and other medications on motor skills and ADHD symptoms. Our research distinguishes itself by expanding upon previous work, incorporating not only methylphenidate but also atomoxetine into a 12-week treatment period. Additionally, few studies have demonstrated a correlation between improved motor function and symptoms associated with ADHD. Poor motor coordination or motor performance frequently co-occur in children with ADHD, although this co-occurrence has received limited research attention.
The aim of this study was to investigate the effects of 12 weeks of methylphenidate or atomoxetine treatment on motor coordination in children with ADHD. Additionally, we investigated whether the changes in motor coordination were associated with changes in ADHD symptoms. We addressed the following hypotheses: 1) 12 weeks of treatment with either methylphenidate or atomoxetine will lead to improvements in motor coordination in children with ADHD, and 2) these improvements in motor coordination will be associated with improvements in ADHD symptoms.
METHODS
Participants
The participants were recruited between March 2015 and May 2020 from the Department of Psychiatry of Asan Medical Center in South Korea. Inclusion criteria were as follows: 1) age 5–12 years and 2) positive diagnosis of ADHD according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [29] and Kiddie–Schedule for Affective Disorders and Schizophrenia–Present and Lifetime Version (KSADS-PL) [30,31].
Participants were excluded if they met one or more of the following criteria: 1) intelligence quotient (IQ) <70 confirmed by the Korean Wechsler Intelligence Scale for Children– Fourth Edition [32] or the Korean Wechsler Preschool and Primary Scale of Intelligence–Fourth Edition [33]; 2) past and/or current history of schizophrenia, bipolar disorder, psychotic disorder not otherwise specified (NOS), organic mental disorder, or pervasive developmental disorder; 3) occurrence of seizures or presence of other neurologic disorders; 4) past and/or current history of tic disorder, obsessive-compulsive disorder, major depressive disorder, or anxiety disorder requiring medication; 5) history of taking methylphenidate or atomoxetine within the previous 6 months or for a total period of over 3 months regardless of the time of use of the drug; 6) current treatment with alpha-2 adrenergic receptor agonists, antidepressants, antipsychotics, benzodiazepines, modafinil, or anticonvulsants; 7) presence of significant comorbid medical illness; and 8) presence of serious suicidal ideation.
The study was approved by the Institutional Review Board of the Asan Medical Center (IRB number: 2014-0157). Written informed consent was obtained from the parents and written assent was obtained from the participants.
Diagnosis
ADHD and comorbid psychiatric disorders were diagnosed by three board-certified child and adolescent psychiatrists according to the DSM-IV-TR and were confirmed by the K-SADS-PL. Three raters independently rated 20% of the K-SADS-PL tape, and kappa coefficients ranged 0.76–0.90. Discrepancies were resolved through consensus meetings.
Subtypes of ADHD were defined according to the DSM IV-TR criteria. ADHD NOS was operationally defined as the presence of at least three but no more than five inattentive and/ or hyperactive-impulsive symptoms. Participants also had to fulfill the DSM-IV-TR ADHD impairment criteria to qualify for a diagnosis of ADHD NOS.
Medication
This study was a naturalistic, prospective follow-up study. Thus the type of medication was determined based on the medical assessment of the clinician. Medical treatment with standard doses of methylphenidate or atomoxetine was administered according to clinical guidelines [34]. The initial recommended dose of methylphenidate was as follows: methylphenidate-osmotic controlled release oral delivery system (MPH-OROS, Concerta®) 18 mg/d, methylphenidate-controlled delivery (MPH-CD, Metadate CD®) 10–20 mg/d, or methylphenidate-modified release (MPH-MR, Medikinet® Retard) 5–10 mg/d for participants weighing <30 kg. For participants weighing >30 kg, MPH-OROS 18–27 mg/d, MPHCD 10–20 mg/d, or MPH-MR 5–10 mg/d were recommended. The dosage was increased to a maximum of 60–72 mg/d or 1.4 mg/kg/d depending on treatment effect and tolerability. The initial dose of atomoxetine (Strattera®) was recommended as 0.5 mg/kg/d, and the maximum dose was 1.4 mg/kg/d. Changes in the drug dose of methylphenidate or atomoxetine were made on a weekly basis or more.
Clinical and neuropsychological measurements
Participants completed the Developmental Coordination Disorder Questionnaire (DCDQ), ADHD Rating Scale (ARS) checklist, and Advanced Test of Attention (ATA) before commencing treatment. Next, standard dose drug treatment with methylphenidate or atomoxetine was administered for 12 weeks, and the above tests were reperformed at 12 weeks.
DCDQ
The DCDQ is a parent reported questionnaire used to detect motor problems in children aged 5–15 years. It consists of 15 items, divided across three subscales, namely control during movement, fine motor/handwriting, and general coordination. For each item, the parents are asked to compare their child’s performance with that of their peers and rate performance on a 5-point Likert scale with higher scores reflecting a better performance. All items are equally weighted, and a total score is calculated by summing the scores on the three subscales. The DCDQ total score ranges from 15 to 75. Children with DCDQ total scores falling within the ranges of 15– 46 (5–7 years 11 months), 15–55 (8–9 years 11 months), and 15–57 (10–15 years) are interpreted as having an “indication of ” or being “suspect for” DCD, respectively, for each age group. Scores above the cut-off point for each age group are interpreted as “probably not DCD”. Currently, the DCDQ is the only available questionnaire supported by a good level of evidence [35]. The psychometric properties have been studied extensively and the DCDQ has shown to be useful in screening for motor difficulties in clinical samples. The DCDQ has been demonstrated to have high internal consistency (α=0.94) and construct validity (p<0.001) through previous research [36]. The standardization process of the Korean version has also confirmed its reliability and validity [37].
ARS
Parents completed the Korean version of the ARS to assess the severity of ADHD symptoms. The test is composed of two subscales with nine items each, evaluating inattention and hyperactivity/impulsivity. The validity and reliability of the test have been previously reported [38].
ATA
The ATA was used for the neuropsychological assessment of attention. ATA is a computerized continuous performance test (CPT) developed in Korea [39] that records four major variables: 1) omission errors, which measure inattention; 2) commission errors, which measure response inhibition; 3) response time for correct responses, which evaluates task performance speed; 4) the standard deviations of the response time (response time variability), which measure sustained attention. The test was standardized, and reliability and validity of the test have been previously established. For each variable, a Z score was calculated, adjusted for age and sex [39].
Statistical analyses
A chi-square or Fisher’s exact test was used for categorical variables and the paired-t test was used to examine the significance of within-group changes. A mixed effect model was used to analyze the time (baseline vs. 12th weeks) and group (methylphenidate vs atomoxetine) effects, and the time by group interaction. Linear regression analyses were used to assess the predictive power of various psychological assessments and clinical characteristics on changes in the DCDQ subscales. The last observation carried forward (LOCF) imputation was used for patients who did not complete the final assessments.
Statistical significance for all other comparisons was defined as p<0.05; all comparisons were two-tailed. Data analyses were conducted using SPSS for Windows, Version 18 (SPSS Inc., Chicago, IL, USA).
RESULTS
The participants included 157 children with ADHD (age 7.6±1.4 years; 139 males). Of these, 48 and 109 participants were treated with methylphenidate and atomoxetine for 12 weeks, respectively. Demographic characteristics are shown in Table 1. Comparison of participant baseline characteristics did not reveal any significant differences between the two groups for age (p=0.268), sex (p=0.784), full scale intelligent quotient (FSIQ) (p=0.063), ADHD subtype (p=0.114), and comorbid diagnoses (p=0.919). The mean dose of atomoxetine was 26.82±8.64 mg/d (range 10.0–56.49 mg/d) and the mean dose per weight was 0.89±0.22 mg/kg/d (range 0.37– 1.39 mg/kg/d). The mean dose of methylphenidate was 21.36± 7.29 mg/d (range 8.64–39.28 mg/d) and the mean dose per weight was 0.75±0.22 mg/kg/d (range 0.37–1.18 mg/kg/d).
Ten children, two in the methylphenidate group and eight in the atomoxetine group, discontinued treatment before 12 weeks. Specifically, treatment was discontinued for the following reasons: combined antipsychotic medication (two children in the methylphenidate group and two in the atomoxetine group); psychiatric side effects, including irritability, mood swings, and sleep disturbances (four children in the atomoxetine group); nonresponse (one child in the atomoxetine group); loss to follow-up for unknown reasons (one child in the atomoxetine group). No significant difference was noted in the proportion of children lost to follow-up between the two groups (p=0.453). Including data from participants who dropped out, there were overall 41 (26.1%) missing observations for the DCDQ, 39 (24.8%) for the ARS, and 42 (26.8%) for the ATA at the 12-week follow-up assessment. There were no statistically significant differences in the proportions of missing data for the DCDQ, ARS, and ATA between the methylphenidate and atomoxetine groups (p=0.545, p=0.440, and p=0.742, respectively).
Table 2 displays DCDQ score changes over time in the methylphenidate and atomoxetine treatment groups. A significant main effect of treatment was observed for the fine motor/handwriting DCDQ subscale (F1=16.64; p<0.001; η2=0.097). However, the main effect of each group and the treatment× group interaction effect were not significant. A significant main effect of treatment was observed for the general coordination DCDQ subscale (F1=7.82; p=0.006; η2=0.048). However, the main effects of each group and the treatment× group interaction effects were not significant. No significant main effect of treatment, group, or treatment×group interaction was observed for the control during movement of the DCDQ subscale. A significant main effect of treatment was observed for the DCDQ total score (F1=13.2; p<0.001; η2=0.079).
Changes in ARS and ATA scores that were significantly associated with changes in DCDQ subscales in simple linear regression analyses were included as independent variables in multiple linear regression analyses. Age, sex, FSIQ, and medication type were considered as covariates in these analyses. In the simple linear regression analyses, the significant predictors for the change in fine motor/handwriting were parent-reported ARS inattention score (β=-0.179, p=0.025), visual omission errors (β=-0.188, p=0.021), visual response time (β=-0.182, p=0.025), visual response time variability (β=-0.169, p=0.039), and auditory commission errors (β=0.181, p=0.027) of the ATA. The significant predictors for the change in general coordination were parent-reported ARS inattention (β=-0.158, p=0.048) and hyperactivity/impulsivity scores (β=-0.190, p=0.017), as well as rater-reported ARS inattention (β=-0.189, p=0.017) and hyperactivity/impulsivity scores (β=-0.192, p=0.016). No variables were found to be significantly associated with changes in the total score or the control during movement subscale.
Table 3 presents the results of multiple linear regression analyses predicting changes in the fine motor/handwriting subscale of the DCDQ. Model 1 included age, sex, FSIQ, medication type, and parent-reported ARS inattention score. Model 2 additionally incorporated visual omission errors, Model 3 further added visual response time, and Model 4 included visual response time variability scores from the ATA. The final model (Model 5) encompassed all the variables plus auditory commission errors from the ATA.
In Model 1, only the parent-reported ARS inattention score was significantly associated with changes in the fine motor/handwriting subscale of the DCDQ (β=-0.179, p=0.029). The parent-reported ARS inattention score remained a significant predictor across all models (β=-0.171, p=0.035 in Model 2; β=-0.168, p=0.037 in Model 3; β=-0.169, p=0.036 in Model 4; β=-0.174, p=0.029 in Model 5). The visual omission errors score of the ATA was statistically significant in Model 2 (β=-0.163, p=0.046), but not in subsequent models. Similarly, the visual response time of the ATA was significant only in Model 3 (β=-0.172, p=0.034). In the final model (Model 5), both parent-reported ARS inattention score (β=-0.174, p=0.029) and auditory commission errors of the ATA (β=0.191, p=0.022) were significantly associated with changes in the fine motor/handwriting subscale of the DCDQ.
Table 4 presents the results of linear regression analyses predicting changes in the general coordination subscale of the DCDQ. Model 1 included age, sex, FSIQ, medication type, and parent-reported ARS inattention score. Model 2 additionally incorporated the parent-reported ARS hyperactivity/impulsivity score. Model 3 included age, sex, FSIQ, medication type, and rater-reported ARS inattention score, while Model 4 further added the rater-reported ARS hyperactivity/impulsivity score.
In Model 1, only the parent-reported ARS inattention score was significantly associated with changes in the general coordination subscale of the DCDQ (β=-0.177, p=0.034); this association was not observed in Model 2. In Model 3, the raterreported ARS inattention score was significantly associated with changes in the general coordination subscale (β=-0.198, p=0.017), but this association was not significant in Model 4.
DISCUSSION
In this study, we found that ADHD medication had a positive effect on motor coordination in children. Both methylphenidate and atomoxetine resulted in significant improvements in the fine motor/handwriting and general coordination subscales of DCDQ over 12 weeks of treatment. Changes in the fine motor/handwriting subscale of the DCDQ correlated with improvements in the visual omission errors, visual response time, visual response time variability, auditory commission errors scores of the ATA and inattention score of parent-reported ARS. Changes in the general coordination subscale of the DCDQ were significantly associated with im-provement in both parent- and rater-reported inattention and hyperactivity/impulsivity scores of ARS.
In the present study, both methylphenidate and atomoxetine significantly improved fine motor and coordination. The effect of methylphenidate on fine motor function has been well-documented [27,28,40,41]. Flapper et al. [27] suggested that methylphenidate treatment may be effective in improving fine motor skills such as handwriting, particularly in children with both ADHD and DCD. Another study also showed that form, alignment, spacing, legibility, and uniformity of handwriting improved in hyperactive children undergoing methylphenidate treatment [40]. Kaiser et al. [41] found significant improvements in fine motor skills compared with ball skills or balance following methylphenidate treatment. This suggests a close link between motor coordination, particularly fine motor skills, and the effects of medication on ADHD symptoms, particularly methylphenidate.
Previous studies have predominantly focused on the treatment effects of methylphenidate on motor coordination in children with ADHD. Although atomoxetine was reported to improve the core symptoms of ADHD [42-44] as well as quality of life, peer relations, family relationships, emotional lability, learning, cognitive functions and executive functions [45-48]. there is limited evidence on the effect of atomoxetine on fine motor and coordination. With a relatively large proportion of children undergoing atomoxetine treatment (approximately 69%), this study offers valuable insights into how fine motor function changes after atomoxetine treatment. The findings of this study suggest that atomoxetine may improve motor coordination in children with ADHD, with potential clinical implications. However, further research is needed to confirm these findings with larger sample sizes in both methylphenidate and atomoxetine treatment groups, comparing and analyzing the changes in motor coordination before and after treatment in each group.
The mechanisms by which methylphenidate and atomoxetine affect motor coordination in children with ADHD could differ. Functional imaging studies reveal distinct effects of methylphenidate and atomoxetine on brain activity [49]. Atomoxetine decreases dorsoanterior cingulate and dorsolateral prefrontal cortex activation (improving attention), while methylphenidate increases inferior frontal gyrus activation (enhancing response inhibition) [49].
Transcranial magnetic stimulation short-interval intracortical inhibition (TMS-SICI) is a physiological marker associated with motor coordination in children with ADHD [50]. Studies have shown that TMS-SICI values increase before and after methylphenidate treatment [51,52], while TMS-SICI values decrease before and after atomoxetine treatment, even with improved motor coordination [53]. While the mechanisms of action of methylphenidate and atomoxetine in the brain are considered to differ, both may play a role in enhancing motor coordination. Conducting further research to determine the mechanisms underlying the effects of methylphenidate and atomoxetine on motor coordination in children with ADHD is necessary.
A significant improvement was observed in the DCDQ general coordination subscale after drug treatment in our study, and this improvement was associated with the inattention scores of the ARS. General coordination is often used interchangeably with neurological soft signs (NSS). NSS are very common in children with ADHD and include poor coordination, speed, or accuracy of movements of the limbs or the axial plane [54,55]. Previous studies show that methylphenidate significantly improves ADHD symptoms and NSS, suggesting its potential benefit in treating “clumsy child syndrome,” a frequent feature of the complex symptomatology of ADHD [56,57]. We found a stronger association between improvements in general coordination and ADHD symptoms than the association measured by neurocognitive tasks. This implies that general coordination seems to have greater relevance to real-life situations.
Changes in the fine motor/handwriting subscale of the DCDQ were significantly associated with parent-reported ARS inattention scores and auditory commission errors of the ATA. These findings suggest that fine motor functions in children with ADHD are related to various psychological subconstructs, particularly attention and auditory processing. The positive association between auditory commission errors and improvements in fine motor/handwriting skills observed in this study is somewhat unexpected. Further research, including replication studies and investigations with larger sample sizes, is warranted to elucidate this relationship and explore the underlying neurological mechanisms.
Previous studies have suggested a link between fine motor skills and inattention in children with ADHD, implying that improving attention could lead to improved fine motor skills [27,58,59]. However, Tseng et al. [6] proposed that response inhibition, rather than sustained attention, may be more closely associated with fine motor skills in ADHD, suggesting the potential involvement of neuropsychological subconstructs in the relationship between fine motor skills and ADHD. Conversely, our study demonstrated that improvements in both response inhibition and focused and sustained attention were associated with improved fine motor skills. Furthermore, Bart et al. [60] showed that children’s motor improvement was correlated with improvement in omission and commission type errors in the CPT in children with both ADHD and DCD. While these results are inconsistent, they align with the notion that neuropsychological subconstructs may play a role in the relationship between fine motor skills and ADHD, warranting further investigation.
Some limitations should be considered when interpreting our findings. First, the drug treatment evaluation was conducted as an open study, and it is possible that the physicians or parents may have influenced the results. Second, the DCDQ was the sole instrument used for evaluating motor coordination in study participants, relying on subjective parental assessments rather than objective measurements. Third, we did not control for potential effects of nonpharmacological treatments on motor coordination. Fourth, this study evaluated participant motor coordination and ADHD symptoms after only 12 weeks of treatment, which may not be sufficient to draw any conclusions regarding the long-term effects of treatment. Fifth, high dropout rates and the use of LOCF imputation, which does not account for changes after dropout, can lead to biased results and potentially compromise the accuracy and reliability of the study findings. However, our study focused on drug-naive children; therefore, it provides a considerable contribution to the evaluation of drug-related changes on motor coordination in children with ADHD.
To date, limited research has been conducted on the effects of atomoxetine on motor coordination in children with ADHD, both domestically and internationally. Future studies should be conducted with increased numbers of participants to confirm the effect of atomoxetine alone on motor coordination.
In conclusion, these results can be used by health practitioners to systematically assess children with ADHD for motor coordination difficulties and to develop tailored interventions that address the effects of motor coordination deficits on daily activities and performance. Low motor proficiency is closely associated with low self-esteem, increased emotional problems, and poor social functioning in children,61 highlighting the importance of early identification and intervention. By increasing understanding and intervening in motor coordination problems in children with ADHD, we can contribute to improving their health, social adaptability, and ultimately their quality of life.
Notes
Availability of Data and Material
The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.
Conflicts of Interest
The authors have no potential conflicts of interest to disclose.
Author Contributions
Conceptualization: Hyo-Won Kim, Yoo-Sook Joung. Data curation: Hyo-Won Kim, Yoo-Sook Joung, Kee Jeong Park, Taeyeop Lee. Formal analysis: Eunji Jung, Ju Yeon Kim. Funding acquisition: Hyo-Won Kim. Methodology: Hyo-Won Kim. Project administration: Hyo-Won Kim, Yoo-Sook Joung. Resources: Hyo-Won Kim. Software: Ju Yeon Kim. Supervision: Hyo-Won Kim. Validation: Hyo-Won Kim. Writing—original draft: Ju Yeon Kim. Writing—review & editing: Hyo-Won Kim.
Funding Statement
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the South Korea government (Ministry of Science and ICT) (NRF-2020R1A5A8017671).
Acknowledgements
The authors are grateful to all the children and families who participated in this research. This research would not have been possible without their involvement.