INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children, with core symptoms including age-mismatched inattention, impulsivity, and hyperactivity. It typically commences during the formative years of school-age children, manifesting distinct symptoms by this period, and in some cases, continuing into adulthood [1]. The etiology of ADHD is still unclear, which may be related to genetic causes, adverse environmental factors, differences in the brain, and so on [2]. The latest meta-analysis shows that the global prevalence of ADHD in children and adolescents is 8.0% [3], and the prevalence of ADHD in China is 6.26% [4]. Among them are studies reporting higher rates of disease among rural children, which can reach 7.5% [5]. Empirical research indicates that children with ADHD exhibit not only deficits in executive functioning [6-8] but also substantial emotional disturbances [9]. The disease will continue to affect children’s cognitive, executive function, and emotional states. In severe cases, physical and mental disorders and social dysfunction will occur which will significantly reduce the quality of life of children and cause a huge economic burden to families and even society.
Extensive scholarly inquiry and clinical experience have amassed evidence to substantiate that pharmacological intervention represents the optimal treatment modality for ADHD. At present, methylphenidate and atomoxetine are the first-line drugs for the treatment of ADHD in China. Many researchers from around the world have conducted thorough clinical studies using a variety of analytical approaches. When it comes to safety, it has been observed in multiple countries that both treatments have a relatively positive safety record [10-12]. However, there are differing opinions in the scholarly community regarding their clinical effectiveness. Analyses of clinical symptom enhancement have yielded diametric views. Gilbert’s study [13] demonstrated that both treatments are equally effective. Afterward, Li and Zhou [14] also corroborated their similar efficacy. In a systematic review and meta-analysis, Rezaei et al. [15] reaffirmed that methylphenidate and atomoxetine are equipotent in the treatment of ADHD in children and adolescents; however, sustained-release methylphenidate is more effective than atomoxetine. In contrast, proponents like Kemner et al. [16] contend that methylphenidate demonstrates a superior efficacy in alleviating ADHD symptoms relative to atomoxetine. Bédard’s study [17] focused on the evaluation of attention, revealing that methylphenidate has greater effects than atomoxetine on Conners’ Continuous Performance Test of sustained attention in youth with ADHD. At the same time, multiple meta-analyses of ADHD medications have substantiated the efficacy of both methylphenidate and atomoxetine in the treatment of ADHD, indicating that methylphenidate is superior in terms of improving ADHD symptoms [18-21]. Dissimilarities also persist in the interpretations of executive function restoration. Investigations led by Wu et al. [22], Yang et al. [23], and Ni et al. [24] have shown that both methylphenidate and atomoxetine can bolster executive function in children with ADHD. Wu et al. [22] emphasized that patients who were given methylphenidate showed greater improvements in response selection and inhibitory control in executive function compared to those given atomoxetine. Yang et al. [23] pointed out that methylphenidate could significantly enhance children’s abilities to normal levels, as demonstrated by linguistic fluency tests. On the other hand, Ni et al. [24] highlighted that atomoxetine improved spatial planning significantly more than methylphenidate. In a recent meta-analysis, Isfandnia and others concurred that methylphenidate and atomoxetine exhibited analogous efficacy in enhancing executive function in individuals with ADHD [25]. Concerning a comprehensive assessment of clinical symptom amelioration and executive function restoration, the research conducted by Taş Torun et al. [26] and Ince Tasdelen et al. [27] suggested that the therapeutic efficacy of atomoxetine and methylphenidate in clinical symptom recovery and executive function augmentation is essentially equivalent. However, Yildiz et al. [28] believed methylphenidate is better for treating clinical symptoms and executive function. Additionally, Bymaster et al. [29] praised the therapeutic benefits of atomoxetine, she suggested that by blocking the reuptake of norepinephrine in the brain, atomoxetine could help alleviate the coexisting symptoms of depression and anxiety caused by increased norepinephrine neurotransmission.
Having said all of the above, these two drugs’ efficacy is still controversial. This study was conducted from three perspectives: core symptoms, executive function, and emotional problems, to clarify the efficacy and difference between methylphenidate and atomoxetine, aiming to provide some clinical basis for clinicians to choose the first choice of drugs.
METHODS
This was a 12-week, open-label, head-to-head clinical trial with a sample size of 60 cases.
Inclusion criteria
The study population was composed of children who met the diagnostic criteria of ADHD in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) [30]. They visited the Child Healthcare Department of Tangshan Maternal and Child Health Hospital during the period between 2023 and 2024. This demographic spanned an age bracket of 6 to 14 years of all genders. Furthermore, subjects must have an intelligence quotient (IQ) of 70 or above, as assessed by the Wechsler Intelligence Scale, and should not have taken medication for ADHD in the past.
Exclusion criteria
Patients with a history of psychotic disorder, pervasive developmental disorder, autism spectrum disorder, tic disorder, epilepsy, organic disease of the nervous system, and severe digestive system disease should be excluded from cases. Also, patients with contraindications against methylphenidate and atomoxetine should be excluded.
A consent form had been executed by both the patients and their legal guardians authorizing their inclusion in the clinical trial. This study has been approved by the Medical Ethics Committee of the hospital (NO.2024-052-01).
Design and procedures
The subjects were randomized into two cohorts utilizing a random number table. One cohort was administered methylphenidate hydrochloride sustained-release tablets, while the other received atomoxetine hydrochloride capsules. Within the methylphenidate group, the starting dose was set at 18 mg/day, with the target dose being adjusted based on the age and weight of the patients throughout 1 to 4 weeks, ensuring the maximum daily dose did not exceed 54 mg. Conversely, the atomoxetine group initiated treatment with an initial dose of 12.5 mg/day, subsequently adjusting the dosage to reach the target of 1.2 mg/kg/day throughout 1 to 4 weeks.
Assessments
Assessments were conducted before the initiation of treatment and again at the 12-week follow-up post-treatment. The main criteria for the assessment of core symptoms is the Parent Swanson, Nolan, and Pelham, Version IV Scale (SNAP-IV) ratings, developed by Swanson based on the diagnostic criteria for ADHD outlined in DSM, and it exhibits high reliability and validity [31]. The secondary criteria for the assessment of core symptoms is the Integrated Visual and Auditory Continuous Performance Test (IVA-CPT), which provides objective and directly quantifiable results, serving as an indicator of patient severity with considerable credibility [32]. Conners Parent Symptom Questionnaire (PSQ) was employed to gauge behavioral and emotional problems in children, with its validity aligning closely with that of other pertinent scales [33]. A higher PSQ score indicated a more profound severity of issues. Wisconsin Card Sorting Test (WCST) and the Digit Span Test (DST) were utilized to evaluate executive function. WCST, originally devised by Berg for the assessment of normal individuals’ abstract cognitive abilities [34], was later discovered by Milner in 1963 to be instrumental in gauging frontal lobe dysfunction in patients sustaining brain injuries [35], particularly sensitive to damage in the dorsolateral frontal lobe. Consequently, WCST has become a prevalent metric for executive function assessment. The variant utilized in this study is WCST-64. DST, a component of the fourth edition Wechsler Intelligence Scale for children, evaluates numerical working memory and is frequently applied in the context of executive function assessment [36]. DST is made up of two components: the forward digit span, which necessitates participants to recall a sequence of numbers verbally presented by an examiner, and the backward digit span, which pertains to an executive function process [37], necessitating participants to recall a sequence of numbers in reverse order for a brief duration.
Therapeutic effect evaluation
According to the change in clinical symptoms and the evaluation criteria of ADHD efficacy in the 2010 edition of Clinical Therapeutics of Attention Deficit Hyperactivity Disorder in Children [38]. Clinical cure: when the clinical symptoms have disappeared and the SNAP-IV total scores have decreased by more than 90% compared with before treatment. Markedly effective: when the clinical symptoms have significantly improved, and the total score of SNAP-IV decreased by 60% to 89% than before. Effective: when the clinical symptoms have improved, and the total score of SNAP-IV decreased by 30% to 59% than before. Ineffective: when the clinical symptoms have not improved, and the total score of SNAP-IV decreased by less than 30% from pre-treatment. Mean effective rate=(clinical cure+markedly effective+effective) cases/total cases ×100%. Then, the two groups were compared before and after treatment from three aspects of core symptoms, executive function, and behavioral and emotional problems to evaluate the difference in efficacy.
Statistical analysis
All data were statistically analyzed by SPSS 26.0 software (IBM Corp.). Measurement data conforming to normal distribution were described by mean and standard deviation. Paired sample t-test was used to analyze the changes in each evaluation index in the group, and an independent sample t-test was used to analyze the difference in efficacy between the two groups. Wilcoxon signed-rank tests were used for the analysis of nonparametric data. The statistical significance was p<0.05 (two-tailed).
RESULTS
Clinical characteristics data
The clinical characteristics data of the study objects are shown in Table 1. There were no statistical differences between the methylphenidate and atomoxetine groups in terms of mean age, sex, IQ, and type of ADHD (p>0.05).
Comparison of clinical efficacy
At week 12, 7 cases were ineffective, 13 cases were effective, and 10 cases were markedly effective in the methylphenidate group, while 11 cases were ineffective, 15 cases were effective, and 4 cases were markedly effective in the atomoxetine group, and there was no significant difference between the two groups (p>0.05). The mean efficacy rate for the methylphenidate group was 76.67%, whereas for the atomoxetine group was 63.33%, with a difference in meaninglessness(p>0.05), as shown in Table 2.
Comparison of core symptoms
As shown in Table 3, no significant discrepancy in SNAP-IV scores was observed between the two groups before treatment (p>0.05). Following 12 weeks of treatment, both the SNAPI-V scores exhibited a marked decrease when compared to the pre-treatment levels, with these differences achieving statistical significance (p<0.05). Notably, a statistically significant disparity was identified between the two groups in the inattention, hyperactivity/impulsivity, and total score of SNAP-IV (p<0.05), albeit no statistically significant difference was observed in the oppositional defiant scores (p>0.05). In essence, the methylphenidate group elicited a more substantial improvement in the inattention and hyperactivity/impulsivity scores among children with ADHD.
Similarly, there was no significant difference in IVA-CPT scores between the two groups before treatment (p>0.05). Following 12 weeks of treatment, there was a substantial decrease in IVA-CPT scores for both groups when compared to the pre-treatment scores (p<0.05). Moreover, a comparison between the groups revealed a statistically significant difference in IVA-CPT scores (p<0.05), indicating that the methylphenidate group exhibited a more pronounced effect on enhancing attention and control in ADHD children.
Comparison of behavioral and emotional problems
At baseline, no significant variation in PSQ scores was detected between the methylphenidate and atomoxetine groups as illustrated in Table 4 (p>0.05). However, after 12 weeks of treatment, a significant reduction in PSQ scores was noted for both groups relative to the pretreatment values (p<0.05). When the groups were contrasted, significant differences were found in the scores about psychosomatic disorders, anxiety, and hyperactivity/impulsivity (p<0.05), whereas no statistically significant disparities were observed in the scores for hyperactivity index, conduct, and learning problems (p>0.05). This suggests that the methylphenidate group was more effective in alleviating hyperactivity/impulsivity symptoms in ADHD children, whereas the atomoxetine group demonstrated a more significant impact on alleviating psychosomatic disorders and anxiety symptoms among ADHD children.
Comparison of executive function
Pre-treatment, there were no significant variations in the forward digit span and backward digit span scores between the two groups as delineated in Table 5 (p>0.05). However, significant disparities were observed in the forward and backward digit span scores between the two groups both before treatment and at the 12-week follow-up (p<0.05), yet no significant differences were noted between the groups posttreatment (p>0.05), indicating that methylphenidate and atomoxetine exerted equivalent effects on enhancing the working memory capabilities of children with ADHD.
Similarly, before treatment, no significant differences were detected in WCST scores between the groups (p>0.05). WCST scores decreased for both groups when contrasted with their pre-treatment levels, and this reduction was statistically significant after 12 weeks of treatment (p<0.05). Additionally, the differences between the two groups in terms of the number of response errors and perseverative errors were statistically significant (p<0.05), whereas the disparity in the score for the number of completed categories was not statistically significant (p>0.05). That is to say, methylphenidate is more effective than atomoxetine in enhancing the cognitive transfer abilities and frontal lobe function of children with ADHD.
DISCUSSION
In this study, the analysis of the enhancement in core symptoms revealed that the methylphenidate group achieved a mean effective rate of 76.67%, in contrast to the atomoxetine group’s rate of 63.33%, suggesting comparable clinical efficacy between the two groups. However, there were noticeable differences in the scores for inattention and hyperactivity-impulsivity as measured by the Parent SNAP-IV ratings after treatment, indicating a significant improvement in ADHD symptoms with methylphenidate, consistent with previous research [19]. Moreover, most evaluations of ADHD’s core symptoms were primarily conducted by parents or educators. In this study, children were allowed to complete the IVA-CPT on their own. The results showed that every measure of attention and executive functioning in both the methylphenidate and atomoxetine groups significantly improved compared to their pre-treatment levels, with statistically significant differences between the two conditions after treatment. This supports the superior effectiveness of methylphenidate in reducing ADHD symptoms. So, methylphenidate is more effective in improving the core symptoms of ADHD compared to atomoxetine. This is supported by both parental reports and self-reported measures by the children.
Further analysis of the enhancement in behavioral and emotional problems indicates that all factors of PSQ in the methylphenidate and atomoxetine groups were improved compared with those before treatment, among which the atomoxetine group had better improvement in psychosomatic disorders and anxiety scores, while the methylphenidate group had greater improvement in conduct problems, learning problems, impulsive-hyperactivity, and hyperactivity index factors. In the early stages of the research, Cheng et al. [39] suggested that atomoxetine could have a significant impact on comorbid anxiety in children with ADHD. Subsequently, the study conducted by Chen et al. [40] elucidated the impact of methylphenidate and atomoxetine on the treatment of ADHD-comorbid anxiety in children, revealing that atomoxetine was superior in ameliorating the symptoms of ADHD-associated anxiety, a finding corroborated by Khoodoruth et al. [41] Shih et al. [42] explored the therapeutic impact of methylphenidate and atomoxetine on various emotional and behavioral challenges faced by ADHD adolescents, concluding that the methylphenidate group exhibited greater mitigation of aggressive behavior, physical discomfort, and behavioral issues compared to the atomoxetine group. Additionally, a nationwide investigation indicated that long-term methylphenidate use may be associated with a decreased risk of conduct problems and oppositional defiant behavior [43]. It is manifest that methylphenidate and atomoxetine impart distinct therapeutic benefits in the management of behavioral and emotional disorders. Although our findings do not entirely align with prior research outcomes, this discrepancy primarily stems from inconsistencies in the evaluation scales employed within the study methodology. Nevertheless, we can still find that atomoxetine may emerge as the preferred option for the management of ADHD coexisting with anxiety. At the same time, methylphenidate constitutes the front-line choice for ADHD accompanied by conduct problems or diverse behavioral challenges. This discrepancy may offer valuable insights for the pharmacological intervention selection in ADHD treatment strategies.
As to executive function, herein reveals that both the DST and WCST scores decreased significantly post-treatment for both groups, with statistical significance in the WCST scores for the number of false responses and perseverative errors between the groups, while there was no significant difference in the DST scores, indicating that the two groups had a similar degree of improvement in working memory ability. However, the methylphenidate group can better improve the cognitive transfer ability and frontal lobe function of ADHD children. According to Wu et al. [22], there was no significant difference in the improvement of working memory between methylphenidate and atomoxetine.
In a word, the study highlights a substantial disparity in the therapeutic efficacy of methylphenidate and atomoxetine for pediatric patients with ADHD, potentially attributable to their distinct mechanisms of action. Numerous studies have indicated that the pathogenesis of ADHD is associated with the dysregulation of various neurotransmitters, primarily dopamine, norepinephrine, serotonin, γ-aminobutyric acid, glutamate, and steroid hormones [44-48]. The international consortium known as the ADHD gene project has performed whole-genome sequencing and conducted association studies on 51 candidate genes, identifying several genes implicated in ADHD, most of which are involved in the dopamine, norepinephrine, and serotonin pathways [49]. It is concluded that the dysregulation of dopamine and norepinephrine secretion is a pivotal factor in the pathogenesis of ADHD. Methylphenidate acts by modulating both dopamine and norepinephrine pathways. It inhibits the reuptake of dopamine and norepinephrine by presynaptic neurons, thereby enhancing the transmission from dopaminergic and norepinephrine neurons. The main mechanism of action of atomoxetine is to selectively inhibit the demethylation in the brain Adrenaline reuptake. González-Martínez et al. [50] has highlighted the correlation between dopamine levels and traits such as aggression, hyperactivity, and impulsivity, suggesting that methylphenidate is more efficacious in the therapeutic intervention of these symptoms. Additionally, Kowalczyk et al. [51] observed therapeutic benefits by examining anatomical changes in children undergoing magnetic resonance therapy of the brain, noting that both methylphenidate and atomoxetine exhibit a normalizing effect on spinothalamic-parietal dysfunction in ADHD, but methylphenidate was found to specifically up-regulate the dysfunction of the ventral frontotemporal region in ADHD patients, which is primarily associated with executive functions, indicating an advantage of methylphenidate in the recovery of frontal lobe function. This study reveals that the number of response errors and perseverative errors in the methylphenidate group post-intervention surpasses that observed in the atomoxetine group, thereby affirming that methylphenidate is a more efficacious agent for enhancing the cognitive transference and frontal lobe functionality in children with ADHD.
Conclusion
In summary, although both methylphenidate and atomoxetine are capable of effectively ameliorating ADHD, methylphenidate demonstrates a superior ability to improve the core symptoms of ADHD, as well as address conduct problems, cognitive transfer abilities, and frontal lobe function in pediatric patients. Conversely, atomoxetine is the best choice for cases comorbid with anxiety.
Strengths and limitations
This study assessed the effectiveness of methylphenidate and atomoxetine from various angles, such as ADHD core symptoms, emotional and behavioral issues, and executive function. This approach allows for a more comprehensive understanding of the differences in efficacy between the two groups and enhances the credibility of the results. At the same time, for the assessment of ADHD symptoms, we used Parents SNAP-IV ratings and children’s IVA-CPT to understand the effects of drug treatment from the perspective of themselves and bystanders, which further enhanced the reliability of experimental results. However, this study also has some limitations, because our cases were collected from the Maternal and Child Health Hospital and followed up, the age of our patients was limited to less than 15 years old, so the age width of the sample in this study was 6-14 years old. In addition, the sample size of the study was relatively small, and the follow-up time was only 12 weeks, which may affect our research results to some extent. Therefore, we plan to expand the sample size in future to ensure the credibility of the results.
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