Abstract
To clarify the characteristics of children with attention deficit hyperactivity disorder (ADHD) requiring early drug therapy and changes in ADHD treatment over time, we undertook a clinical survey of ADHD children. We retrospectively classified 168 children with ADHD into groups based on the presence [Group 1, (the early treatment Group A, non-early treatment Group B)] or absence (Group 2) of ADHD drug therapy. The older age at first examination and the frequency of patients born with low birth weight in Group 1 were higher than those in Group 2. The ADHD-Rating Scale (ADHD-RS) scores for total (ADHD-RS-T) and trouble scores (TS) in Group 1 were higher than those in Group 2. All patients requiring early drug medication were diagnosed with ADHD at age 6 or older and showed significantly higher ADHD-RS hyperactivity disorder (ADHD-RS-H) and TS. Guanfacine was the main drug prescribed, being the first-line drug in 45.0% of cases. These results suggest that characteristics of patients requiring early ADHD drug medication include age 6 years or older at first examination and high ADHD-RS-H, ADHD-RS-T and TS. Furthermore, an increase in the frequency of prescriptions for guanfacine was observed as a prescription trend for ADHD medications.
Introduction
Attention deficit hyperactivity disorder (ADHD) is a developmental disorder with a classic triad of symptoms consisting of hyperactivity, impulsivity, and inattention1-6).
Concerning treatments for ADHD in childhood, for patients who do not respond to non-drug treatment and who continue to have difficulty in school and daily life, ADHD drugs are often administered7). In this situation, it is important to clarify the characteristics of the ADHD patients requiring medication, especially those who require early administration, in order to educate and manage these patients. However, in Japan, there are few reports on the characteristics of children who require these early therapies.
On the other hand, in recent years, in addition to the previously available osmotic release oral system methylphenidate hydrochloride (OROS-MPH)and atomoxetine (ATX), guanfacine has been covered by insurance since 2017 and lisdexamfetamine mesylate (LDX) since 2019, increasing the number of drugs available for ADHD patients in Japan to four8). Furthermore, new treatment guidelines for ADHD in Japan were created in 2022, and three drugs, guanfacine, OROS-MPH, and ATX, are currently recommended as first-choice medications for ADHD patients aged 6 years and older8). However, few reports compare the effectiveness of these medications or the changes in treatment selection over time in children with ADHD among Japanese pediatricians and child psychiatrists. The paper is the first to clarify the characteristics of patients requiring early drug treatment, the efficacy of first-choice drugs according to the new treatment guidelines, and changes in drug administration in pediatric patients over time. To clarify these points, we conducted a clinical survey of pediatric patients with ADHD.
Methods
Study setting and design
The Fukushima Rehabilitation Center for Children is the only facility in Fukushima prefecture that combines a child development center and a support center for patients with neurodevelopmental disorders, and treats 300-400 new patients with neurodevelopmental disorders each year. We collected data for 168 patients diagnosed with ADHD in the Department of Pediatrics of the Fukushima Rehabilitation Center for Children between January 2013 and December 2022. Entry criteria included:(1) a diagnosis of ADHD based on the diagnostic criteria of The Japanese versions of Diagnostic and Statistical Manual of Mental Disorders DSM-59,10), with autism spectrum disorder excluded, (2) under 12 years of age as of the start of therapy with follow up for more than one year;and (3) no previous treatment with drugs for ADHD.
The patients were retrospectively divided into two groups based on the presence or absence of drug therapy for ADHD. Group 1 consisted of 111 patients treated with ADHD drugs because behavioral therapy and environmental adjustment were not effective, and Group 2 consisted of 57 patients treated with non-drug therapy. Furthermore, Group 1 was divided into an early treatment group (Group A, 25 patients who started ADHD drug <3 months after diagnosis) and a non-early treatment group (Group B, 86 patients who started ADHD drug ≥3 months after diagnosis).
We investigated patient characteristics, laboratory findings, ADHD Rating Scale IV (ADHD-RS) scores (including scores for attention-deficit and hyperactivity disorder, and total), Intelligence Quotient (IQ), Social Intelligence Quotient (SQ), trouble score (TS), treatment selection (such as the presence or absence of second-line drugs), side effects, and efficacy of treatment for each group.
The protocol for this study has been approved by the auspices of the Committee for Human Experiments at the Fukushima Rehabilitation Center for Children and conforms to the provisions of the Declaration of Helsinki (Institutional Review Board Approval No 2023-05-3). In addition, informed consent was obtained from the patients or their parents for all investigations in this study, and patient anonymity was maintained.
Assessment
The Japanese versions of Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and DSM-5 were used to diagnose ADHD. Patients who were diagnosed with ADHD using the Japanese version of DSM-IV before 2015 were re-diagnosed using the Japanese version of DSM-5, and those who did not qualify were excluded from this study9,10). We classified birth body weight (BBW) into two categories:normal BBW (4,000 g～2,500 g) and low birth weight (LBW <2,500 g). Patients with early treatment with ADHD drugs were defined as those requiring drug therapy within one to 3 months after diagnosis at the time of their first visit and before the next follow-up visit. For evaluation of ADHD traits, the main outcome was the behavioral traits associated with ADHD, consisting of the inattention and hyperactivity domains. To quantify these domains, we used the ADHD-RS based on parental reports to assess the severity of ADHD at the initial consultation. The ADHD-RS comprises 18 items covering the spectrum of inattention (9 items) and hyperactivity/impulsivity domains (9 items). Responses are rated on a 4-point Likert scale ranging from 0 (“never” or “rarely”) to 3 (“very often”)10,11). Similarly, with regard to TS11), the items relating to family, friends, submitting homework, grades, behavioral inhibitions, and self-confidence were halved to a score ranging from 0 (no problem), 1 (slight problem), 2 (some problems), to 3 (severe problems) and the total score was used to evaluate the feeling of distress. The improvement rate was calculated as (difference in score before and after intervention/score before intervention) × 100 (%).
Psychological tests such as the Kyoto scale of Psychological Development 2001, Tanaka-Binet Intelligence Scale12), Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV)13), and Social Intelligence Quotient (SQ) were conducted before diagnosis. The SQ was calculated using the Social Maturity Scale, Third Edition14). The SQ is commonly used as one of the indicators for judging a child’s adaptability in kindergartens and schools and their suitability for inclusion in support classes.
Behavioral therapy and environmental adjustments involve helping parents improve their children’s behavior by teaching them the concepts of behavioral therapy, including parent training, and creating an environment where problematic behavior is avoided by changing the way people around the child, at home and school, interact with the child. The pediatrician in charge provided these instructions in a manner appropriate for each individual patient.
Each patient’s doctor explained the effects and side effects of ADHD drugs to the patient and their parents, and made subsequent decisions regarding oral medications based on the patient’s/family’s wishes.
Statistics
Data are expressed as the mean values ± SD. The statistical analysis was performed using a Macintosh computer with a software package for statistical analysis (Version 4 of Stat View, Abacus Concepts, Berkeley, Calif., USA). Differences in the clinical and laboratory findings between the two groups were assessed using the Mann-Whitney rank sum test or contingency tables (chi-square test). We used analysis of variance with Bonferroni correction for multiple group comparisons, including ADHD RS scores and TS. Correlations were evaluated by Z transformation of Fisher’s r. A value of p<0.05 was considered statistically significant.
Results
Comparison of baseline characteristics, laboratory and clinical findings between Group 1 and Group 2
The age at first examination, the frequency of patients aged 6 years or older at diagnosis, and the frequency of patients born with LBW in Group 1 were higher than those in Group 2 (Table 1). The number of gestational days (GD) in Group 1 was lower than that in Group 2. The ADHD-RS scores for attention-deficit, hyperactivity disorder, total, and TS in Group 1 were higher than those in Group 2. The improvement rates in ADHD-RS scores for hyperactivity disorder and total in Group 1 were higher than those in Group 2. And there were 107 ADHD patients aged 6 years or older and 59 patients under 6 years old in all. Of these, 80 (84.8%) and 35 (59.3%) required medication, respectively, with the proportion of patients requiring medication in ADHD patients aged 6 years and older being higher than in those aged 6 years and younger (p=0.020). The correlation between each ADHD-RS score and the age at first examination is shown in Table 2. There was no correlation between each ADHD-RS score, TS, and the age at first examination.
Comparison of baseline characteristics, laboratory and clinical findings between Group A and Group B
The age at first examination and the frequency of patients aged 6 years or older at first examination in Group A were higher than those in Group B (Table 3). The ADHD-RS scores for hyperactivity disorder, total and TS at diagnosis in Group A were higher than those in Group B. And, there were 25 (23.4%) of 107 ADHD patients aged 6 years or older and 0 (0.0%) of 59 patients under 6 years old required early drugs medication, respectively, with the proportion of patients requiring drugs medication in ADHD patients aged 6 years and older being significantly higher than that in those aged 6 years and younger (p=0.005).
Treatment selection and efficacy among patients treated with ADHD drugs
Figure 1 shows the prescription rates of first-choice drugs. The first-line drugs for patients treated with ADHD drugs were guanfacine in 50 patients (45.0%, guanfacine group), OROS-MPH in 22 patients (19.8%, OROS-MPH group), and ATX in 39 patients (35.1%, ATX group). Central nervous system non-stimulants were also used in 89 patients (80.2%). The prescription rates of ADHD drug medication in patients from 2018-2022 were higher than those in patients from 2013-2017 (Table 4). The prescription rate of ADHD drug medication was 38.9% for OROS-MPH and 61.1% for ATX in 2013-2017, and 10.7% for OROS-MPH, 22.7% for ATX, and 66.7% for guanfacine in 2018-2022. The prescription rates of OROS-MPH and ATX in patients from 2018-2022 were lower than those in patients from 2013-2017, with the prescription rate of OROS-MPH and ATX decreasing over time.
There were no differences in the age at first examination, age at initiation of ADHD medication, the duration from diagnosis to ADHD medication, GD, BBW, IQ, and SQ among groups (Table 5). With regard to the side effects, in the guanfacine group, there was one patient with hypotension, one patient with itching, and three children with sleepiness. In the OROS-MPH group, there were two patients with appetite loss. Further, in the ATX group, there was one patient who complained of a bitter taste, one patient with exanthema, and two patients with digestive symptoms.
Second-line drugs were administered in 26 patients, including 14 patients as mono-therapy and 12 patients as first-line drugs plus ATX, guanfacine, or OROS-MPH (MPH combination therapy) (Figure 2). Conversion to mono-therapy was due to side effects of first-line treatment in 7 cases and ineffectiveness of first-line treatment in 7 cases: guanfacine in 4 cases (28.6%), OROS-MPH in 3 cases (21.4%), ATX in 6 cases (42.9%), and LDX in one case (7.1%). As to the course of treatment for the mono-therapy, 12 patients showed continued efficacy, and treatment was discontinued for two patients due to ineffectiveness. The breakdown of MPH-combination therapy was as follows:before 2016, all four patients were treated with OROS-MPH plus ATX, while after 2017, all eight patients were treated with OROS-MPH plus guanfacine. Regarding the course of treatment for the combination therapy, all patients showed continued efficacy, there were no cases of discontinuation due to side effects.
There were no differences in the improvement rates in ADHD-RS scores for attention-deficit, hyperactivity disorder, total, and TS among the guanfacine mono-therapy group, OROS-MPH mono-therapy group, and ATX mono-therapy group (Table 5).
Discussion
Our study found that patients treated with ADHD drugs had LBW, lower gestational age, higher age at first examination, and higher ADHD-RS total scores and TS compared to patients treated with non-ADHD drugs. The age at first examination, the frequencies of patients aged 6 years or older at diagnosis, the ADHD-RS scores for hyperactivity disorder, total, and TS in the early treatment group were higher than those in the non-early treatment group.
Perinatal factors associated with risk factors for developing ADHD were reported to include environmental factors such as in utero infection, LBW or preterm birth, low Apgar score, and bleeding episodes during pregnancy15-17). Our results showed that the frequency of LBW was higher in patients treated with ADHD drugs than in patients treated with non-drug therapy. This indicates that LBW is associated with the severity of ADHD. Thus, it is necessary to pay attention to the appearance of neurodevelopmental disorders such as ADHD when monitoring the progress of patients with LBW.
In addition, patients treated with ADHD drugs had older age at first examination, higher ADHD-RS scores, and higher TS. Further, all patients requiring early drug medication were diagnosed with ADHD at age 6 or older and showed significantly higher ADHD-RS hyperactivity disorder and TS scores. These results suggest that diagnosis at age 6 or older, hyperactivity/impulsivity symptoms of ADHD (not inattention symptoms), and high TS may be considered risk factors for early treatment, and it is advisable to take into consideration the possibility that early medication may be necessary in patients with these factors.
There are four drugs available for use in Japan: OROS MPH and LDX as central nervous system stimulants, and ATX and guanfacine as non-central nervous system stimulants1,8,18). According to the guidelines, OROS-MPH, guanfacine, and ATX are recommended as first-choice drugs for ADHD patients aged 6 years and older. As to psychiatrists’ reports on drug therapy, in 2021, Sasaki et al. showed that OROS-MPH was used as an ADHD drug in 67% of all patients, ATX in 30.4% of all patients, and Guanfacine in 29.8% of all child and adolescent psychiatric outpatients prescribed multiple ADHD medications in Japan19). In our center, guanfacine has been prescribed since 2018, accounting for approximately 67% of ADHD drug prescriptions, and the prescription rate of guanfacine has been increasing over time.
Guanfacine is a selective α2A adrenoceptor agonist and improves the efficiency of information transmission by activating the postsynaptic α2A receptor among the three types of α2 adrenergic receptors20-22). In our study, guanfacine was the main drug, being the first-line drug prescribed in 45% of cases and the second-line drug in 29% of cases. Of the 50 patients treated with guanfacine, 39 (78%) showed an improvement in symptoms. Guanfacine does not require registration as a central nervous system stimulant and has only minor side effects, suggesting that its use may increase.
ATX was the second-most commonly used ADHD drug, being the first-line drug prescribed in 35% of cases and the second-line drug in 43% of patients with ADHD. Twenty-eight of the 39 patients (71.8%) treated with ATX showed an improvement in symptoms, and treatment was discontinued in 4 patients due to side effects. Since the approval of guanfacine, its use as a non-stimulant has declined.
On the other hand, OROS-MPH is recommended as a first-line drug in ADHD guidelines around the world23-26). In our study, the prescription rate of OROS-MPH decreased from 38% in 2015-2017 to 11% in 2018-2022, and a decrease in the prescription rate of OROS-MPH was observed. Fifteen of the 22 patients (68.2%) treated with OROS-MPH showed an improvement in symptoms, and treatment was discontinued in 2 patients due to side effects. Further, it was used in MPH mono-therapy (15.4%) and MPH-combination therapy (46.2%) as a second-line drug. All four patients before 2016 received OROS-MPH plus ATX, and all eight patients after 2017 received OROS-MPH plus guanfacine. Regarding the course of treatment for the MPH-combination therapy, there were no cases of discontinuation due to side effects, 9 patients showed continued efficacy, and treatment was discontinued for 3 patients whose symptoms improved. MPH combination therapy combines a non-stimulant and a stimulant drug with different mechanisms of action, and may extend the duration of drug action for ADHD more than OROS-MPH mono-therapy27).
Regarding the choice of medication for ADHD patients at our center, each pediatrician decided in consultation with the family, taking into consideration the use of medications that were available during the follow-up period, as well as the differences in side effects and effectiveness of each medication and whether or not there was a drug registration system.
Limitations
The results of this study showed that, contrary to expectations, the use of OROS-MPH as a first-line medication has significantly decreased. The reason for this is that all patients prescribed OROS-MPH must be registered, the number of non-stimulant medications that do not require registration has increased, and the patients at our center are scheduled, which may be due to the fact that their symptoms are more stable. In addition, this study may have been affected by factors such as the fact that it was a retrospective study, there were inconsistencies in the timing of assessment of ADHD-RS scores and TS during follow-up, there was no protocol regarding the dosage of drug treatment, non-drugs medication was not uniform as each doctor gave independent advice, and the small number of patients studied. Therefore, the conclusions of the paper may be subject to potential confounding factors. In the future, we would like to conduct a prospective study including multiple centers to compensate for the effects of these confounding factors.
Conclusion
These results suggest that characteristics of patients requiring early ADHD medication include age 6 years or older at first examination and high ADHD-RS scores for hyperactivity disorder, total and TS. Furthermore, an increase in the frequency of prescriptions for guanfacine was observed as a prescription trend for ADHD medications.
Acknowledgments
We wish to thank all of the patients and their families for their cooperation in this study. In addition, we would like to thank the Fukushima Rehabilitation Center for Children staff who cooperated in the examination implementation.
Conflict Of Interest Statement
The authors declare no conflict of interest.
Author Contributions
YK was responsible for designing the study, conducting the study, and analyzing the data. YS, NS, and KM were responsible for guiding the study design. YK, YS, AK, MH, HM, and HG reviewed the manuscript and finalized the submitted version.
Data Availability Statement
N/A.
Ethics Approval Statement
The protocol for this study has been approved by the auspices of the Committee for Human Experiments at the Fukushima Rehabilitation Center for Children and conforms to the provisions of the Declaration of Helsinki (Institutional Review Board Approval No 2023-05-3). In addition, informed consent was obtained from the patients or their parents for all investigations in this study, and patient anonymity was maintained.
Patient Consent Statement
Parents gave informed written consent for their children’s participation.
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