Practical clinical guidelines and pharmacological treatment for attention‐deficit hyperactivity disorder in Asia

Abstract

Attention‐deficit hyperactivity disorder (ADHD) is characterized by persistent symptoms of inattention, hyperactivity, and impulsivity. Both, stimulant and nonstimulant medications have been approved for the treatment of this disorder. Several Western guidelines recommend the use of prescribed Food and Drug Administration (FDA)‐approved medications for ADHD along with parental training in behavior management and behavioral classroom intervention. In 2022, new Japanese guidelines for ADHD were issued, which recommended school environment management and psychosocial treatment as the first‐line treatment, with pharmacological treatment added as the second‐line treatment. Although Japanese guidelines, including pharmacological treatments, have been established, the guidelines and utilization of ADHD medications across Asian regions are unclear. Therefore, to appropriately evaluate the strategy of pharmacological treatments for ADHD, we investigated Asian regional guidelines for ADHD medication in children. We also reviewed the guidelines in Malaysia, Singapore, India, and the Republic of Korea and found that these guidelines differ from Western guidelines.

INTRODUCTION

Attention-deficit hyperactivity disorder (ADHD) is characterized by persistent symptoms of inattention, hyperactivity, and impulsivity and is one of the most common psychiatric disorders in childhood.¹ The use of medications to treat this disorder has increased, and two main classes of medications, namely, stimulants, and nonstimulants, have been approved for its treatment.² Pharmacological treatment is crucial because ADHD frequently persists into well into adulthood with negative impacts in many life domains if left untreated.³ The National Institute for Health and Care Excellence (NICE) guidelines identify pharmacological treatment for ADHD as its symptoms still cause persistent significant impairment in at least one domain despite the implementation and review of environmental modifications among children aged 5 years and over and the young population.⁴ The U.S. guidelines developed by the American Academy of Pediatrics (AAP) recommend Food and Drug Administration (FDA) approved medications for ADHD along with parental training in behavior management and behavioral classroom interventions.¹ The most recent Japanese guideline for ADHD was published in 2022, which recommends both, school environment management and psychosocial treatment as the first-line treatment; and pharmacological treatment as the second-line of treatment.⁵ In Western countries, first-line pharmacological treatment mainly includes stimulants; however, the guidelines or utilization of ADHD medication use across Asia remains unclear (Table 1).⁶ Hirota et al. reported that epidemiological studies conducted in Asia have been scarce compared to Europe and North America as per a survey of postgraduate training systems of child and adolescent psychiatrists in the Far East region.⁷

TABLE 1 Food and Drug Administration (FDA)-approved ADHD medications in Children and Adolescents aged 6–17 years old.⁶

	Drug name
Stimulants
MPH short-acting	Focalin, Methylin, Methylin Chewable, Methylin Solution, Ritalin
MPH intermediate-acting	Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR
MPH long-acting	Adhansia XR, Aptensio XR, Concerta, Cotempla XR-ODT, Daytrana patch, Focalin XR, Jornay PM, Quillivant XR, QuilliChew ER
Amphetamine short-acting	Adderall, Desoxyn, Evekeo, ProCentra Oral Solution, Zenzedi
Amphetamine long-acting	Adderall XR, Adzenys ER, Adzenys XR-ODT, Dexedrine Spansule, Dyanavel XR, Evekeo ODT, Mydayis (over 13 years old), Vyvanse, Xelstrym
Nonstimulants
Selective norepinephrine reuptake inhibitor	Strattera
Alpha-adrenergic agonists	Kapvay, Intuniv

In 1996, the Asian Society of Child and Adolescent Psychiatry and Allied Professions (ASCAPAP) was established to develop a regional, culturally sensitive understanding and sharing of expertise.⁸ Japan is one of the founding members of ASCAPAP, and the Japanese clinicians and researchers have been making significant contributions to the science of child psychiatry. Despite recognizing the importance of guidelines to be effective for treating ADHD in children in Asian countries, the presence of an effective set of guidelines for ADHD there was unclear. For the development of ADHD treatment in Asia, the organization of ADHD guidelines in each Asian country and region is, thus, critical. Therefore, this study aimed to investigate ADHD guidelines in many Asian countries and regions.

DATABASE SEARCH STRATEGY

We accessed international articles on guidelines for medication use for ADHD through PubMed, Google Scholar, and Scopus. The articles classified in this review included those published in the year before June 2023. The search terms or keywords used were: “guidelines” AND “ADHD” AND “each country name.” The methods of the search were identifying official guidelines or peer-reviewed articles that mentioned the ADHD guidelines for pharmacological treatment in English.

REGIONAL GUIDELINES AND UTILIZATION OF PHARMACOLOGICAL TREATMENT FOR ADHD IN THE ASIAN REGION

In this study, we investigated guidelines for Malaysia, Singapore, India, the Republic of Korea, China, Taiwan, Indonesia, and Japan as major countries in Asia (Table 2). No articles on ADHD guidelines were found in Thailand, the Philippines, Macao, Nepal, Cambodia, Vietnam, Sri Lanka, Pakistan, Bangladesh, East Timor, Bhutan, Brunei, Myanmar, Maldives, Mongolia, Laos, and North Korea.

TABLE 2 ADHD guidelines in various countries.

Country	Language	Year of publishing	Medication	Maximum dose, mg/day
Japan	Japanese	2022	OROS-MPH 18, 27, 36 mg LDX 20, 30 ATX 5, 10, 25, 40 mg GXR 1, 3 mg	54 70 120a 6
Malaysia	English	2020	MPH-IR 10 mg MPH-ER 18, 27, 36 mg MPH-LA 20, 30, 40 mg ATX 10, 18, 25, 40, 60 mg	60 72 60 100
Singapore	English	2020	MPH-IR MPH-ER ATX	N/A
India	English	2020	MPH-IR 5, 10 mg MPH-ER 10, 18, 20 mg, OROS-MPH 18, 36, 54 mg ATX 10, 18, 25, 40, 60 mg Clonidine 0.1 mg	60 60 72 100 0.2–0.4b
Republic of Korea	Korean	2016	MPH-IR 5, 10 mg MPH-ER 10, 20, 30, 40 mg OROS-MPH 18, 27 mg ATX 10, 18, 25, 40, 60, 80 mg Extended-release clonidine 0.1 mg	60 60 72 1.4 mg/kg 0.4
Indonesia	Bahasa Indonesia	2016	N/A	N/A

MALAYSIA

In Malaysia, the clinical practice guidelines 2020 for ADHD are available in English.⁹ In the Ministry of Health Medicines Formulary, only methylphenidates (MPH) and atomoxetine (ATX) have been approved for the treatment of ADHD in children over 6 years. Here, three types of MPH; immediate-release (IR), extended-release (ER), and long acting (LA) are available (Table 2). Dose titration and timing are also described in each drug in the guidelines. According to these guidelines, medication should be offered to children if their ADHD symptoms are persistent and cause significant impairment in at least one domain despite behavioral and environmental interventions. Furthermore, MPH was recommended to children with ADHD aged over 6 years if medication is indicated, although the type of MPH for the first line is not described.

SINGAPORE

In Singapore, the clinical practice guidelines 2020 for ADHD are available in English.¹⁰ The guidelines recommended several modes of treatments, such as training for parents, training (academic) interventions for children, consultation with teachers who work closely with the child, social skills training, cognitive behavioral therapy, biofeedback, and psychopharmacological treatment. The guidelines also mentioned that physicians have to plan long-term strategies and always discuss them with patients and their families for the management of patients with ADHD. It is found that MPH and ATX are approved for the treatment of ADHD, and the former is recommended as a first-line treatment. Two types of MPH formulations, MPH-IR and MPH-ER, are available in Singapore. According to the guidelines, the use of an MPH-ER instead of an MPH-IR should be considered if there is a concern about medication abuse. Dose titration and timing are not described in the guidelines.

INDIA

Clinical practice guidelines for ADHD are available in English.¹¹ The Indian guidelines for ADHD described that there are differential effects of pharmacological and nonpharmacological intervention, with the former being more efficacious for the core symptoms and nonpharmacological interventions being more effective in improving associated behavioral problems and functioning. Furthermore, the treatment should, as far as possible, be tailored to the individual needs based on the current level of symptom severity and impairment, and improvements, if any gained by the nonpharmacological measures. The MPH, ATX, and Clonidine have all been approved for the treatment of ADHD in children in India. Guanfacine and clonidine extended-release are not available. According to the algorithm for managing ADHD, if patients with severe symptoms show no contraindication to stimulants, stimulants are to be used first. It is considered as no adequate evidence of differences in efficacy or side effects between the different formulations of MPH exist. The starting dose and recommended dose are described in each drug. The guidelines also mention that the drugs should be started at a lower dose, and side effects and improvement must be monitored after each increment.

REPUBLIC OF KOREA

Guidelines for the diagnosis and treatment of ADHD are available only in Korean.¹² Several formulations of MPH, ATX, and Extended-release clonidine are available in the Republic of Korea. According to a nationwide health insurance claims database study for ADHD children in the Republic of Korea, MPH is the most commonly prescribed ADHD drug.¹³

CHINA

To the best of our knowledge, guidelines for ADHD are unavailable in China. Currently, available ADHD drugs in China include MPH and ATX, with MPH being the most frequently prescribed.¹⁴ Clinical practice appears to follow the NICE guidelines in China.⁴

TAIWAN

To the best of our knowledge, guidelines for ADHD are not available in Taiwan. The medications approved for ADHD treatment in Taiwan include MPH and ATX. According to a national survey conducted in Taiwan, MPH-IR, OROS–MPH, and ATX have all been approved for the treatment of ADHD. Since MPH-IR has been designated as the first-line medication in Taiwan for ADHD treatment, it is the most popular drug prescribed for children with ADHD, followed by OROS–MPH and ATX. Within the first year after ADHD diagnosis, less than 1% of patients were prescribed ATX in Taiwan.¹⁵ The low utilization of ATX may be explained by the fact that atomoxetine was reserved as a second-line therapy for patients who could not tolerate the side effects of MPH or who did not respond well to MPH in Taiwan.¹⁶

INDONESIA

The prevalence of ADHD in Indonesian children is 8.09%, which is similar to other countries.¹⁷ To the best of our knowledge, in Indonesia, guidelines for ADHD diagnosis and management were established in 2016 by the Child and Adolescent Psychiatry section of the Indonesian Psychiatric Association.¹⁸ However, this set of guidelines is not available on the internet. Furthermore, journals of pharmacological treatment for ADHD are also unavailable in the country.

JAPAN

In Japan, the guidelines for the diagnosis and treatment of ADHD, 5th edition, are only available in Japanese.⁵ The OROS-MPH and Lisdexamfetamine dimesylate (LDX) are approved as stimulant medication; ATX and Guanfacine extended release (GXR) are approved as nonstimulants for ADHD indication in Japan. According to the Japanese guidelines, the first-line pharmacological treatment is OROS-MPH, ATX, or GXR. If the first choice of pharmacological treatment is ineffective, one of the other two drugs is selected as the second-line treatment. In case the second-line pharmacological treatment is ineffective, LDX is one of the options for third-line treatment. The NICE guidelines recommend switching to LDX in patients who have undergone a six-week trial of methylphenidate at an adequate dose and did not derive enough benefit in terms of reduced ADHD symptoms and associated impairments.⁴ The fact that two non-stimulants (ATX and GXR) are the first choice of treatment in Japan, differs from Europe and the USA. Furthermore, according to a Japanese administrative data survey, the proportion of prescribed non-stimulants is higher in Japan than in other countries.¹⁹ One of the reasons for this is that MPH-IR is not approved for ADHD treatment in Japan because stimulant abuse, mainly of MPH-IR, is a social issue among adults. Due to this, strict control of OROS-MPH and LDX prescriptions by the circulation management committee limits the qualification of prescribers and the prescription period. According to the National Database of Health Insurance Claim Information and Specified Medical Checkups (NDB), the percentage of methylphenidate use among ADHD drug users is much lower in Japan (64%) than in the UK, Norway, and Germany.²⁰ Japanese physicians may prefer ATX or GXR as initial drugs as they have no restrictions.

DISCUSSION

To the best of our knowledge, this is the first study to assess the guidelines for the pharmacological treatment of ADHD in Asia. Although the main focus of this manuscript is on pharmacological treatment, any guidelines recommend nonpharmacological treatment before pharmacological treatment must also be explored. In the Singaporean guideline, a physician should consider nonpharmacological treatment like training the parents of patients with ADHD on behavior management strategies, referring to an appropriate specialist (psychologist, occupational therapist), consultation with teachers who work closely with the child in the process of schooling. It has been found that in the Singapore guideline, pharmacological treatment has high levels of evidence and recommendation grades. However, the guidelines mention controlling the behavior with regard to parents’ understanding and cultural background. In the Malaysian guideline, parents' perceptions of ADHD and its treatment acceptability are the main barriers to medication adherence. Therefore, a physician must discuss any preferences regarding medication with parents and patients with ADHD.

In almost all Asian countries, barring Japan, MPH is the mainstay pharmacological treatment for ADHD. Although the approval status and guidelines recommend MPH and ATX as the first-line pharmacologic treatment in many European countries, the Canadian ADHD Resource Alliance (CADDRA), and NICE guidelines recommend ATX and GXR as second-line treatment.^4,21,22 Pharmacological treatment trends in Asian countries and regions may be based on these highly evaluated clinical practice guidelines. The prevalence of ADHD in school-aged children varies considerably between countries; for example, white individuals have higher rates of ADHD than Asian individuals.²³ Despite concerns about overdiagnosis and inappropriate prescription for ADHD worldwide, many children diagnosed with ADHD may receive insufficient pharmacological treatment in Japan because of caution against the risks compared with the benefits.^24,25 Raman et al. indicated that differences in regional clinical guidelines for ADHD treatment recommendations are related to the differences in prescription prevalence across the world.²⁶ The Japanese guidelines for ADHD are peculiar compared with that of other Asian countries and regions as LDX and GXR can be prescribed while MPH-IR is unavailable. If LDX or GXR is introduced in Asian countries and regions, and the Japanese guidelines for ADHD translated into English, and is made available online, it will be immensely useful.

AUTHOR CONTRIBUTIONS

KK designed the study concept and wrote the first draft of the article. All authors contributed substantially to the interpretation of the clinical data. SU supervised this study.

ACKNOWLEDGMENTS

We thank everyone who participated in this study.

FUNDING INFORMATION

Not applicable.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

ETHICS STATEMENT

Approval of the research protocol by an Institutional Reviewer Board: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: N/A.

Human/animal studies: N/A.

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