1 Introduction
Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by inattention, hyperactivity/impulsivity, or both. Symptoms of ADHD typically first occur in childhood and most children with ADHD will continue to experience symptoms throughout adolescence and sometimes even into adulthood [
1]. ADHD often impacts many aspects of an individual’s well-being, including physical health, emotional development, and academic, social, and occupational performance. Meta-analysis found the worldwide ADHD prevalence to be 7.2% [
2]. In 2022, a prevalence of ADHD among Chinese children and adolescents aged 6–16 years was reported as 6.4% in a large sample study [
3].
Treatment for patients with ADHD can either be pharmacological, non-pharmacological, or both. Pharmacological treatments have been proven to be effective, and a number of medications are available, recommended, and widely used [
4‐
6]. Medications for ADHD are categorized into stimulants and non-stimulants. Stimulants include methylphenidate (MPH) and amphetamine products, while non-stimulant medications include the norepinephrine transporter inhibitor atomoxetine (ATX) and the α2 agonists guanfacine and clonidine. Although international guidelines vary in their recommendations for the treatment of ADHD, there is a general consensus that first-line pharmacologic treatment has typically involved the use of stimulants [
5]. According to the National Institute for Health and Care Excellence (NICE) guidelines [
7], pharmacological therapy should begin with MPH for children older than 5 years of age and be switched to amphetamine with inadequate response. NICE also suggests that if the response to amphetamine is also poor, the patient should be switched to ATX or guanfacine [
7]. In contrast to NICE guidelines, the Chinese official guidelines list MPH and ATX as the first-line drugs in the treatment of ADHD, and these have become the most prescribed psychotropic medications for ADHD [
8,
9]. Although MPH experienced a downward trend in popularity in the past decade, it is still more frequently prescribed than ATX in clinical practice [
9].
MPH acts as a dopamine-norepinephrine reuptake inhibitor, modulating the patient’s dopamine levels and, to a lesser extent, norepinephrine levels. ATX is classified as a norepinephrine reuptake inhibitor, which increases extracellular synaptic levels of norepinephrine and dopamine by obstructing norepinephrine presynaptic reuptake [
5]. The benefits, tolerability, and safety of the two ADHD medications are of significant concern to clinicians, patients, and their families. Although a large number of studies and meta-analyses have confirmed the effectiveness of both medications, inconsistencies were found in their response rates and safety profiles, and there is wide variability between studies [
6,
10‐
15]. The most common adverse events (AEs) of MPH include decreased appetite, insomnia, abdominal pain, and headaches [
16‐
18]. ATX has a longer list of AEs, including decreased appetite, headaches, somnolence, abdominal pain, nausea, vomiting, constipation, dizziness, irritability, and mood swings [
8,
16,
19,
20]. We do not yet have a sufficient understanding of the neurobiology of ADHD to accurately inform medication choice. Currently, medications are selected on a trial-and-error basis, meaning that if one medication does not work well, it is replaced with another medication [
5]. It is important for clinicians and patients to facilitate risk assessments in clinical practice to more accurately estimate the frequency of known medication adverse effects and efficacy. Despite the fact that MPH and ATX are the most common medications used to treat ADHD in China, there is still a paucity of studies comparing their efficacy and safety, particularly for different subgroups.
To address these issues, we conducted a real-world, head-to-head, prospective cohort study to examine the efficacy and safety of MPH and ATX in previously medication-naive children with ADHD, and to analyze correlations associated with age, sex, and different ADHD presentation.
4 Discussion
The present study reported the results of a real-world comparison of the efficacy and safety of OROS MPH and ATX in a large sample of Chinese children and adolescents with ADHD. To our knowledge, this is the largest prospective cohort of children with ADHD undergoing pharmacologic treatment in a real-world clinical setting. We studied a total of 1021 previously medication treatment-naive patients with ADHD, for a period of 26 weeks. We not only compared the efficacy and safety of the two drugs as a whole but also analyzed the different subgroups.
In this study, the response rates of MPH and ATX were 84.6% and 63.6%, respectively. Due to differences in the definitions of ‘response’ and heterogeneity in study populations, there are certain differences in ‘response rates’ between different studies [
12].
Many previous studies have found that compared with ATX, MPH showed a higher response rate and had greater improvement in improving ADHD symptoms [
11,
12,
22‐
25]. The results of our study were in agreement with these researches. We found that, overall, MPH was more effective than ATX. In particular, we compared the differences in the subgroups (sex, age, and ADHD presentation) and found that the treatment effect of MPH over ATX was consistent across subgroups except in girls and children with hyperactive/impulsive presentation. It is worth noting that the sample size of the girls and children with hyperactive/impulsive presentation was significantly smaller compared with the other subgroups, and due to the smaller sample size, it may be difficult to detect statistically significant differences between them and other subgroups.
With regard to AEs, a meta-analysis reported that the overall AE rate during MPH treatment was 66% [
26], and a Chinese study reported 42.3% of patients receiving MPH treatment had AEs [
27]. In a meta-analysis, the AE rate in ATX-treated children was reported to be 70.4% [
11]. However, in a real-world study, only 28.0% of ATX-treated children and 25.9% of MPH-treated children were reported to experience AEs [
28]. In the present study, the rates of AEs were 47.8% and 56.8% in MPH-treated and ATX-treated subjects, respectively. The incidence of AEs reported here is slightly lower than in many studies from other countries [
11,
22,
26], which may be related to differences in age, sex, race, or other demographic characteristics of study subjects. It was reported that AEs were significantly more frequent in ATX-treated participants than in MPH-treated participants [
28], with this study showing the same result; compared with ATX, MPH treatment resulted in a low frequency of AEs. For MPH-treated subjects, no statistical difference was found between the different sexes or ADHD presentations, and similar findings were found in the ATX-treated group. It is noteworthy that the incidence of AEs in the MPH-treated group was higher in young children and lower in children over 10 years of age; however, this age-related difference was not found in the ATX-treated group.
The specific AEs observed in our study are consistent with previous literature; however, the proportion of AEs varies between studies. Decreased appetite was the most common AE in our study, in both MPH- and ATX-treated children, and occurred in approximately one-third of subjects. This rate is in agreement with several previous studies and slightly higher than reported in other studies [
26,
29]. During the 26-week follow-up period, 3.8% of the MPH-treated children and 3.9% of the ATX-treated children experienced weight loss as a result of decreased appetite. To manage decreased appetite and weight loss, guidelines suggest administering medication after meals, rather than before, as well as encouraging the consumption of high-calorific snacks and late-evening meals [
29].
In addition to decreased appetite, sleep disturbances, somnolence, and psychiatric AEs were also common. Twelve percent of subjects treated with MPH experienced sleep disturbances, which was higher than the rate in subjects receiving ATX treatment. This may suggest that children with ADHD who experience comorbid sleep disturbances should choose ATX treatment over MPH. Conversely, somnolence was more common in ATX-treated children (12.5%) than MPH-treated children. If ATX-treated children experience serious somnolence, it is recommended administering the medication once daily, in the evening [
29]. Previous studies have reported that some psychiatric problems were seen in MPH- or ATX-treated children, such as irritability, anxiety, depression, sadness, crying, nervousness, emotional lability, aggression, tension, etc. [
11,
28,
30‐
32]. In this study, psychiatric AEs associated with MPH treatment consisted of irritability, aggression, and emotional instability. ATX-treated subjects also experienced these as well as several other AEs, including depression, crying, anxiety, and sadness. The risk of psychiatric AEs associated with ATX treatment was higher than that with MPH, and MPH has a better safety profile for psychiatric symptoms.
Tics are common in childhood and approximately 20% of children with ADHD go on to develop a chronic tic disorder [
33]. When ADHD and tics co-occur in an individual, the onset of ADHD typically precedes that of tic symptoms [
34]. Therefore, it is difficult to determine the relationship between the two—whether the tics are an adverse effect of pharmacological treatment or they would likely occur anyway. Although there is no statistically significant relationship between stimulant use and the onset or worsening of tics in children with ADHD, stimulants may nonetheless exacerbate tics in individual cases [
33,
35]. The notion that MPH may aggravate tics is still unexplored, and this is a key area for future research. In the present study, we observed that 3.8% and 1.4% of subjects developed tics or worsening tic symptoms during MPH and ATX treatments, respectively. Overall, MPH-treated children had a higher incidence of tics than ATX-treated children.
Rare AEs such as eyebrow alopecia, eyelash pulling, hair pulling, urinary hesitancy, frequent micturition, enuresis, tinnitus, earache, fever, rash, skin itch, oral ulcer, lip cracking, and hand trembling may also occur to a lesser extent during ATX and MPH treatment. During the follow-up period, we excluded other factors that could cause such adverse effects and found that these AEs were related to ATX or MPH treatment. These AEs are usually transient and disappear soon after medication withdrawal. It is perhaps worthwhile to mention that there were more rare adverse reactions (including quantity and type) during ATX treatment than during MPH treatment (Table
3). We found that these rare adverse reactions mainly involved skin mucosa and the urinary system. Eyebrow alopecia, hair loss, oral ulcer, and lip cracking occurred in the skin and mucous membranes. Frequent micturition, enuresis and urinary hesitancy was related to urinary system. The mechanism of these adverse effects may be related to excessive extracellular or synaptic dopamine and norepinephrine, which can regulate the sympathetic and parasympathetic pathways [
36]. Although these AEs are rare and have only been reported as individual cases in previous literature [
37‐
41], clinicians should be aware and pay attention to these adverse reactions.
A few limitations of this study should be considered. First, although the use of an instrument such as the Swanson, Nolan and Pelham version IV (SNAP-IV) scale or the ADHD Rating Scale (ADHD-RS) to assess the improvement of ADHD symptoms would have resulted in greater accuracy and objectivity, we did not use any of these scales. We developed a simpler clinical questionnaire to investigate the efficacy of the two drugs. The ‘response’-related items include whether the core symptoms of ADHD (inattention, hyperactivity, and impulsivity) were significantly improved because of medication, i.e. concentrates better on schoolwork, is less easily distracted, and interrupt others less often, whether the improvement occurred in either the school or home setting. Second, in this study, if symptoms had not improved after 6 weeks of medication, this was categorized as a ‘no response’; however, a small number of patients may not respond to ATX during the 6-week treatment period. The reason why we chose 6 weeks as the treatment period is because in a real-world clinical setting, 6 weeks is the length of a conventional course of treatment. Thus, in the event a 6-week treatment period yielded no appreciable effect, treatment with the drug in question was halted and the patient was transferred to another treatment. Throughout our research, in most cases of unresponsiveness to medication, a change of medication was accepted, i.e. ATX to MPH, or MPH to ATX). However, within a practical setting, no washout period was used, a fact that may affect the results. Consequently, the results after a change of dressing were not analyzed. Third, although ADHD medications are known to be associated with statistically significant increases in blood pressure and heart rate, we did not routinely measure these in participants. ECG examinations were only arranged at baseline, around week 26 and when cardiovascular symptoms occurred. Fourth, the present study was a real-world study and not a randomized study. The prescriptions were prescribed by a specialist, mainly based on a patient’s clinical symptoms, the urgency of treatment, parents and patients’ preference, and compliance, which may introduce some bias. However, when we compared the demographic characteristics of the MPH and ATX treatment groups, we found no significant differences in sex, age, IQ, or ADHD presentation. Although the lack of randomization could be viewed as a limitation, our naturalistic study design is also a strength because it allows for an understanding of differences in response rates and AEs in a real-world clinical context. Fifth, AEs are related to drug dose, which is usually determined by body weight in children. Information about dose and body weight was not analyzed in this study, and as a result, the AE incidence was not adjusted by dose or body weight, which is a potential confounder. Sixth, we did not address the issues of comorbidity in both ADHD groups. ADHD is associated with high rates of comorbidities, ranging from 40% to nearly 90% [
8,
42‐
45]. Common comorbidities include learning disorders (LDs), oppositional defiant disorders (ODDs), conduct disorder (CD), sleep disorders, anxiety /depression disorders, and tic disorders [
42‐
44]. Children who have ADHD and who also have psychiatric comorbidities may experience poorer outcomes compared with those without. Additionally, treating these children is generally more challenging [
42,
46]. However, studies showed that ATX plays an important role in the treatment of ADHD patients with various types of comorbidities [
8,
47]. We envisage future work should address these limitations to expand this work.
5 Conclusions
In the present real-world study, MPH was found to be more effective and better tolerated than ATX overall. The incidence of AEs during MPH treatment was higher in young children and lower in those over 10 years of age. Decreased appetite and sleep disturbances were the most frequent AEs in children taking MPH, while decreased appetite, somnolence, and psychiatric problems were the most frequent AEs in ATX-treated children. A higher incidence of tics and sleep disturbances was observed in MPH-treated children than in ATX-treated children. However, ATX-treated children had a higher incidence of psychiatric problems and somnolence than their MPH-treated counterparts. Psychiatric problems mainly included irritability, aggression, emotional instability, depression, crying, anxiety, and sadness. In addition, rare AEs such as eyebrow alopecia, eyelash pulling, hair pulling, urinary hesitancy, frequent micturition, enuresis, tinnitus, earache, fever, rash, skin itch, oral ulcer, lip cracking, etc. may also occur during ATX and MPH treatment, and clinicians and prescribers need to monitor patients for these adverse effects.