Lancet. 2020 February 08; 395(10222): 450-462. doi:10.1016/S0140-6736(19)33004-1.
Lancet.2020年02月08日；395(10222): 450-462.doi:10.1016/S0140-6736(19)33004-1。

Attention-deficit hyperactivity disorder (ADHD), like other psychiatric syndromes, has been refined and developed over the past 50 years, from its first contemporary description in the Diagnostic and Statistical Manual of Mental Disorders (second edition; DSM-II) as a
注意力缺失過動症 (ADHD) 和其他精神科症候群一樣，在過去 50 年來不斷改進和發展，從最初在《精神失調診斷與統計手冊》(第二版；DSM-II) 中描述為「注意力缺失過動症」(ADHD)，到現在已發展成為「注意力缺失過動症」(ADHD)。

hyperkinetic reaction of childhood to its current inclusion in DSM-5 ${}^1$${}^1$^(1){ }^{1} as a lifespan neurodevelopmental condition with specific criteria for children and adults, a change reflected in its counterpart, the International Classification of Diseases (11th revision; ICD-11). ${}^2$${}^2$^(2){ }^{2} This process of diagnostic evolution has been the result of periodic review and reformulation shaped by both research and clinical drivers. From a research perspective, the ADHD diagnostic formulation can be considered a part of a larger working hypothesis about the nature and structure of the disorder. ${}^3$${}^3$^(3){ }^{3} As such, this diagnostic formulation is tested against empirical evidence so that it represents an increasingly accurate approximation of nosological reality as reflected in established research findings. Because the primary purpose of diagnostic systems is to provide intuitive and implementable guides for clinical decision making, the threshold for diagnostic innovation is set high and the pace of diagnostic evolution has been incremental in nature. ${}^4$${}^4$^(4){ }^{4} Furthermore, as diagnostic systems in psychiatry have adopted a descriptive or phenomenological approach, considerations of the underlying causes of ADHD have been excluded from this process of re-evaluation and refinement. However, this diagnostic framework might be set to change. Progress in the aetiology and pathophysiology of ADHD challenges our current ways of thinking about the condition, while raising the prospect of new and potentially more effective clinical approaches.
${}^1$${}^1$^(1){ }^{1} ${}^2$${}^2$^(2){ }^{2} 這個診斷的演進過程是由研究和臨床兩方面的因素所形成的定期審查和重新定義的結果。 ${}^2$${}^2$^(2){ }^{2} 這個診斷演進的過程是由研究和臨床驅動因素所形成的定期審查和重新定義的結果。從研究的角度來看，ADHD 的診斷方式可被視為關於失調症本質與結構的大型工作假設的一部分。 ${}^3$${}^3$^(3){ }^{3} 因此，這個診斷表述會根據經驗證據進行測試，使其日益準確地接近已確立的研究結果所反映的病理現實。由於診斷系統的主要目的是為臨床決策提供直觀且可執行的指引，因此診斷創新的門檻設定得很高，而診斷演進的速度也是循序漸進的。 ${}^4$${}^4$^(4){ }^{4} 此外，由於精神病學的診斷系統採用的是描述性或現象學的方法，因此ADHD的根本成因被排除在這個重新評估和改進的過程之外。然而，這種診斷架構可能會有所改變。ADHD的病因學與病理生理學的進展，挑戰了我們目前對於這種疾病的思考方式，同時也提出了新的、可能更有效的臨床方法。

Developing a broader range of more effective clinical approaches for people with ADHD, through the use of scientific discoveries, represents an important goal for the field.
利用科學發現為 ADHD 患者開發更廣泛、更有效的臨床方法，是本領域的重要目標。

ADHD is a prevalent, impairing condition that is frequently comorbid with other psychiatric disorders and creates a substantial burden for the individual, their family, and the community. ${}^5$${}^5$^(5){ }^{5} Medication-based treatment strategies have proven efficacious and costeffective in the short term and a number of compounds are available, recommended, and widely used. ${}^{6,7}$${}^{6,7}$^(6,7){ }^{6,7} However, the long-term effectiveness of these treatments on key educational, vocational, and social outcomes remains uncertain. ${}^{8,9}$${}^{8,9}$^(8,9){ }^{8,9} Furthermore, such effects are compounded by low adherence, especially after extended use in adolescence. ${}^{10}$${}^{10}$^(10){ }^{10} These limitations are probably the result of both biological and psychosocial processes (eg, the build up of medication tolerance, ADHD-related stigma, and social resistance to medication). ${}^{8,11}$${}^{8,11}$^(8,11){ }^{8,11} Clearly, there is a pressing need for better long-term treatments for ADHD. By changing the way the field thinks about the causes of ADHD, scientific progress might help stimulate the development of new strategies for increasing the effectiveness of current treatments or the evolution of new alternatives. This Seminar will explore the issue of longterm treatment in three sections. The first section provides an account of the consensus about the clinical condition of ADHD, its diagnosis, epidemiology, developmental course, and treatment. The second section presents an up-to-date overview of ADHD science, focusing on advancements in aetiology and pathophysiology. The final section briefly explores how some of the most important scientific discoveries are beginning to challenge conceptions of ADHD in specific ways and examines the prospect that they will encourage new clinical perspectives and approaches.
ADHD 是一種常見的損害性疾病，經常與其他精神疾病併發，對個人、家庭和社區造成沉重的負擔。 ${}^5$${}^5$^(5){ }^{5} 以藥物為基礎的治療策略在短期內已證實具有療效和成本效益，而且有許多化合物可供使用、推薦和廣泛使用。 ${}^{6,7}$${}^{6,7}$^(6,7){ }^{6,7} 然而，這些治療對主要教育、職業和社會成果的長期療效仍不確定。 ${}^{8,9}$${}^{8,9}$^(8,9){ }^{8,9} 此外，這些效果會因為依從性低而更形複雜，尤其是在青少年期長期使用之後。 ${}^{10}$${}^{10}$^(10){ }^{10} 這些限制可能是生物和心理社會過程（例如，藥物耐受性的累積、ADHD 相關的標籤，以及社會對藥物的抗拒）造成的結果。 ${}^{8,11}$${}^{8,11}$^(8,11){ }^{8,11} 顯然，我們迫切需要更好的ADHD長期治療方法。透過改變這個領域對ADHD成因的思考方式，科學進步可能有助於刺激新策略的發展，以提高現有治療方法的有效性，或發展新的替代方法。本研討會將分三個部分探討長期治療的問題。第一部分將說明關於ADHD臨床狀況、診斷、流行病學、發展過程和治療的共識。第二節介紹 ADHD 科學的最新概況，重點是病因學和病理生理學的進展。最後一節簡要探討一些最重要的科學發現如何開始以特定方式挑戰 ADHD 的概念，並探討這些發現將鼓勵新的臨床觀點和方法的前景。

ADHD is a clinical diagnosis requiring a detailed evaluation of current and previous symptoms and functional impairment. A full family, gestational, and developmental history should be taken. ${}^{12}$${}^{12}$^(12){ }^{12} The American Psychiatric Association’s DSM-5 defines ADHD in children (younger than age 17 years) as the presence of six or more symptoms in either the inattentive or hyperactive and impulsive domains, or both (panel 1). Fewer symptoms (ie, at least five symptoms in either domain) are required to meet the adult diagnostic criteria. The age of symptom onset was modified from before age 7 years in DSM-IV to before age 12 years in DSM-5 to permit greater flexibility when diagnosing adults. Additionally, whereas DSM-IV divided ADHD into three subtypes on the basis of the predominant symptomatology (inattentive, hyperactive and impulsive, or combined), DSM-5 replaced the term “subtype” with “presentation” to emphasise that symptom clusters can change as patients mature and develop. ${}^{14}$${}^{14}$^(14){ }^{14} The ICD has updated its diagnostic formulation to bring it into line with DSM-5, moving ADHD from the disruptive to the neurodevelopmental disorder domain, exchanging the label hyperkinetic disorder with ADHD, and including inattentive and hyperactive-impulsive presentations of symptoms. ${}^{15}$${}^{15}$^(15){ }^{15} Distinct from DSM-5 and ICD-10, ICD-11 describes the essential features of the disorder, without giving a precise age of onset, duration, or number of symptoms. ${}^{15}$${}^{15}$^(15){ }^{15} We reviewed the diagnostic challenges, common comorbidities, and the role of neuropsychological tests (appendix pp 1-3).
ADHD 是一種臨床診斷，需要詳細評估目前和過去的症狀以及功能障礙。應瞭解完整的家族史、妊娠史和發育史。 ${}^{12}$${}^{12}$^(12){ }^{12} 美國精神醫學會的 DSM-5 將兒童 (17 歲以下) 的 ADHD 定義為在注意力不集中或過度活躍與衝動領域中出現六個或以上症狀，或同時出現這兩個領域 (面板 1)。較少的症狀（即在任一領域中至少有五個症狀）即可符合成人診斷標準。症狀出現的年齡從 DSM-IV 的 7 歲前改為 DSM-5 的 12 歲前，以便在診斷成人時有更大的靈活性。此外，DSM-IV根據主要症狀（注意力不集中、過度活躍和衝動，或綜合症狀）將ADHD分為三個亞型，而DSM-5則以「表現」取代「亞型」一詞，以強調隨著患者的成熟和發育，症狀群組也會發生變化。 ${}^{14}$${}^{14}$^(14){ }^{14} ICD更新了診斷表述，使其與DSM-5一致，將ADHD從破壞性疾病領域移至神經發育障礙領域，將動力過度障礙（hyperkinetic disorder）與ADHD交換標示，並將注意力不集中和多動衝動的症狀表現納入其中。 ${}^{15}$${}^{15}$^(15){ }^{15} 有別於DSM-5和ICD-10，ICD-11描述了障礙的基本特徵，但沒有提供精確的發病年齡、持續時間或症狀數量。 ${}^{15}$${}^{15}$^(15){ }^{15} 我們回顧了診斷上的挑戰、常見的併發症以及神經心理學測試的作用（附錄 pp 1-3）。

Although ADHD is chronic in nature, and treatment is typically provided over several years, the course of the disorder can vary from one patient to the next. Longitudinal studies suggest the possibility of at least four developmental trajectories: early onset (preschool ADHD [3-5 years]), middle childhood (6-14 years) onset with a persistent course, middle childhood onset with adolescent offset, and adolescent or adult onset (16 years and older). ${}^{16-18}$${}^{16-18}$^(16-18){ }^{16-18} Treatment approaches and particular medications overlap substantially across these trajectories (as we discuss later), but prognosis might differ and understanding these disease courses might aid in treatment planning (eg, whether a child with ADHD no longer needs medication when they reach adolescence). Efforts are underway to predict the onset and course of ADHD across the lifespan. For example, on the basis of four longitudinal cohorts, Caye and colleagues ${}^{19}$${}^{19}$^(19){ }^{19} developed a risk calculator of childhood characteristics, such as intelligence quotient (IQ) and childhood maltreatment, that collectively estimates risk for adult ADHD. Establishing of robust predictors of clinical course would aid treatment decisions, informing, for instance, the duration of interventions and periods of elevated risk.
雖然 ADHD 屬於慢性疾病，且治療通常需持續數年，但不同患者的病程可能會有所不同。縱向研究顯示至少有四種發展軌跡的可能性：早期發病（學前 ADHD [3-5歲]）、中童年期（6-14歲）發病且病程持續、中童年期發病且青少年偏移，以及青少年或成人發病（16歲以上）。 ${}^{16-18}$${}^{16-18}$^(16-18){ }^{16-18} 在這些軌跡中，治療方法和特定藥物有許多重疊（如我們稍後討論的），但預後可能會有所不同，瞭解這些疾病的病程可能有助於治療規劃（例如，患有 ADHD 的兒童在進入青春期時是否不再需要藥物治療）。目前正在努力預測 ADHD 在整個生命週期的發病與病程。例如，Caye及其同事在四個縱向群組的基礎上， ${}^{19}$${}^{19}$^(19){ }^{19} 開發了一個兒童特徵風險計算器，例如智商（IQ）和兒童虐待，該計算器可共同估算成人ADHD的風險。建立健全的臨床病程預測指標將有助於治療決策，例如，為干預期和高風險期提供資訊。

Accurately estimating the number of individuals affected by ADHD in a population is essential to health service planning. This estimate allows the burden associated with the disorder to be approximated and then the required investment to be made. Furthermore, accurate epidemiological data across time and countries can help test the validity of the ADHD diagnosis, and might provide indications about its causes and pathophysiology. ${}^{20}$${}^{20}$^(20){ }^{20} Initial studies in the 1970s and 1980s provided a wide range of prevalence estimates, which, when interpreted in the context of the rapidly increasing number of children treated with
準確估計人口中受注意力缺失過動症影響的人數，對於健康服務規劃至關重要。有了這個估計數字，就可以大概估算出與失調症相關的負擔，進而作出所需的投資。此外，跨時間和國家的精確流行病學資料有助於檢驗ADHD診斷的有效性，並可能提供有關其成因和病理生理學的指示。 ${}^{20}$${}^{20}$^(20){ }^{20} 20世紀70年代和80年代的最初研究提供了範圍廣泛的患病率估計值，如果將這些估計值與迅速增加的接受ADHD治療的兒童數量相結合，就可以得出這樣的結果。

medication at the time, raised societal concerns about inconsistent and excessive diagnosis. These studies also created disputes about the validity of the diagnosis. Some suggested the disorder was nothing more than a cultural product of competitive developed societies, its increasing use spurred on by the influence of the pharmaceutical industries trying to build market share. Meta-analytic studies investigating the factors responsible for this variability in prevalence were important in resolving such disputes. Two studies were especially influential and aggregated 102 studies ${}^{21}$${}^{21}$^(21){ }^{21} (and then an additional 41 studies) ${}^{20}$${}^{20}$^(20){ }^{20} involving community samples of children and adolescents from 35 countries in six continents worldwide and estimated the prevalence of ADHD as 5•29% (95% CI 5•01-5•56). ${}^{21}$${}^{21}$^(21){ }^{21} Followup meta-regression analyses indicated that the variability in previously reported ADHD prevalence was, in fact, attributable to methodological differences between studies, specifically in the diagnostic criteria, sources of information, and the requirement of functional impairment for diagnosis factors that varied between regions and countries. ${}^{21,22}$${}^{21,22}$^(21,22){ }^{21,22} Point prevalence from Europe, Oceania, South America, Asia, Africa, and the Middle East did not differ from those from North America, nor did the prevalence change across time from 1985 to 2012. ${}^{21,22}$${}^{21,22}$^(21,22){ }^{21,22} These data suggest that ADHD prevalence worldwide is stable when study methods are consistent. In general, studies done in the same populations with equivalent rating scales do not detect temporal changes in the number or severity of symptoms, ${}^{23}$${}^{23}$^(23){ }^{23} supporting the meta-analytical data, with only some studies pointing to decreasing ${}^{24}$${}^{24}$^(24){ }^{24} and fewer to increasing rates of subthreshold symptoms. ${}^{25}$${}^{25}$^(25){ }^{25}
當時的藥物治療，引起了社會對診斷不一致和過度診斷的關注。這些研究也造成診斷有效性的爭議。有些人認為這種障礙只是競爭激烈的發達社會的文化產物，而製藥業為了擴大市場佔有率，刺激了這種障礙的使用。元分析研究調查導致患病率變化的因素，對於解決這些爭議非常重要。有兩項研究特別具有影響力，它們彙集了 102 項研究 ${}^{21}$${}^{21}$^(21){ }^{21} （之後又增加了 41 項研究） ${}^{20}$${}^{20}$^(20){ }^{20} ，涉及全球六大洲 35 個國家的兒童和青少年社區樣本，估計 ADHD 的患病率為 5-29% (95% CI 5-01-5-56)。 ${}^{21}$${}^{21}$^(21){ }^{21} 後續的元回歸分析顯示，先前報告的 ADHD 流行率的差異性，其實是由於不同研究在方法上的差異所致，特別是在診斷標準、資訊來源，以及診斷因素對功能障礙的要求上，不同地區和國家之間都有差異。 ${}^{21,22}$${}^{21,22}$^(21,22){ }^{21,22} 來自歐洲、大洋洲、南美洲、亞洲、非洲和中東的點數流行率與來自北美洲的點數流行率沒有差異，1985 年到 2012 年間的流行率也沒有改變。 ${}^{21,22}$${}^{21,22}$^(21,22){ }^{21,22} 這些資料顯示，當研究方法一致時，ADHD 在全球的流行率是穩定的。一般而言，在相同人群中使用等效評量量表所做的研究並未發現症狀數量或嚴重程度在時間上的變化， ${}^{23}$${}^{23}$^(23){ }^{23} 支持薈萃分析資料，只有部分研究指出 ${}^{24}$${}^{24}$^(24){ }^{24} 閾值以下症狀的發生率下降，較少研究指出閾值以下症狀的發生率上升。 ${}^{25}$${}^{25}$^(25){ }^{25}

Meta-analyses have estimated the prevalence of ADHD in adults aged 19-45 years at 2.5% (95% CI $2\cdot 1-3\cdot 1$$2\cdot 1-3\cdot 1$2*1-3*12 \cdot 1-3 \cdot 1 ). ${}^{26}$${}^{26}$^(26){ }^{26} Longitudinal studies following clinical samples of children with ADHD document a general decline of symptoms; meta-analytic data estimate that 15% of patients will persist with full diagnostic criteria in adulthood and $40-60\mathrm{\%}$$40-60\mathrm{\%}$40-60%40-60 \% of patients will be classified as partial remitters. ${}^{27}$${}^{27}$^(27){ }^{27} Prevalence in adults is higher than would be expected by the persistence rates from children, suggesting the emergence of new cases during development. In fact, studies of prospectively followed up, representative community samples showed the emergence of ADHD during adolescence and adulthood, indicating a new developmental subtype of the disorder, ${}^{28}$${}^{28}$^(28){ }^{28} a finding discussed further in subsequent sections of this Seminar.
元分析估計，19-45 歲成人的 ADHD 患病率為 2.5% (95% CI $2\cdot 1-3\cdot 1$$2\cdot 1-3\cdot 1$2*1-3*12 \cdot 1-3 \cdot 1 )。 ${}^{26}$${}^{26}$^(26){ }^{26} 對ADHD兒童臨床樣本進行的縱向研究記錄了症狀的普遍下降；薈萃分析數據估計，15%的患者在成年後會持續符合完整的診斷標準， $40-60\mathrm{\%}$$40-60\mathrm{\%}$40-60%40-60 \% 的患者會被歸類為部分緩解者。 ${}^{27}$${}^{27}$^(27){ }^{27} 成人的患病率比兒童的持續率預期的要高，這表示在成長過程中會出現新的病例。事實上，對具有代表性的社區樣本進行的前瞻性隨訪研究顯示，ADHD出現於青春期和成年期，顯示此症有新的發展亞型， ${}^{28}$${}^{28}$^(28){ }^{28} 本研討會後續章節將進一步討論這項發現。

ADHD seldom affects only one functional domain but impacts many aspects of an individual’s wellbeing, including physical health, and academic, social, and occupational functioning. Often arising in childhood, ADHD can also be chronic in nature, frequently continuing through adolescence and beyond, at least at the level of impairment. Evaluation of treatment outcomes therefore should incorporate multiple components, such as psychoeducation, learning and academic support, school accommodation, intervention for management of symptoms, parental practices, and assessment and treatment of associated disorders. Treatment approaches are also likely to evolve as a patient matures. For example, parental practices have a large role in the treatment of a child aged 6-12 years, whereas psychoeducation regarding the risk of substance abuse and motor vehicle accidents becomes more central when a patient reaches adolescence. In our proceeding discussion of different approaches to managing ADHD, the degree of unmet clinical need in many countries where
ADHD 很少只影響一個功能領域，而是會影響個人福祉的許多方面，包括身體健康、學業、社交和職業功能。ADHD 常見於兒童時期，也可能是慢性的，經常持續到青春期以後，至少在功能受損的程度上是如此。因此，對治療結果的評估應包含多項內容，例如心理教育、學習和學業支援、學校調適、症狀管理干預、父母的做法，以及相關障礙的評估和治療。治療方法也可能隨著病患的成熟而改變。舉例來說，在治療 6-12 歲的兒童時，父母的行為扮演著重要的角色，而當病患進入青春期時，有關藥物濫用和車禍風險的心理教育則變得更為重要。在我們接下來關於管理 ADHD 的不同方法的討論中，許多國家未滿足臨床需求的程度，其中包括

針對治療的長期效果，文件中指出現有的藥物治療在短期内有效，但長期效果仍不明確，尤其是對學業和社會功能等領域的影響。
only a small percentage of individuals with the condition receive any treatment should be acknowledged. ${}^{29}$${}^{29}$^(29){ }^{29}
我們應該承認，只有少數患者接受任何治療。 ${}^{29}$${}^{29}$^(29){ }^{29}

With respect to the management of ADHD symptoms, US, ${}^{30}$${}^{30}$^(30){ }^{30} Canadian, ${}^{31}$${}^{31}$^(31){ }^{31} Latin American, ${}^{32}$${}^{32}$^(32){ }^{32} and European ${}^{33}$${}^{33}$^(33){ }^{33} medical organisations all recommend the use of psychostimulant medications. Many of these ADHD resources and guidelines can be found online. ${}^{33,34}$${}^{33,34}$^(33,34){ }^{33,34} However, most of these organisations recommend beginning with psychoeducation and behavioural management, particularly for individuals with mild symptoms and impairment. 6,35 US guidelines differ and suggest that medication is considered with initial treatment. ${}^{30}$${}^{30}$^(30){ }^{30} For children younger than 6 years old, there is consensus that treatment should start with behaviour management in the form of parent training and that medication should be reserved for more severe or unresponsive cases. The National Institute for Health and Care Excellence (NICE) guidelines, ${}^{33}$${}^{33}$^(33){ }^{33} for example, recommend that medication management for children younger than 5 years be considered only when parent training has been attempted and a second opinion has been obtained from a provider with expertise in ADHD in young children.
關於 ADHD 症狀的處理，美國、 ${}^{30}$${}^{30}$^(30){ }^{30} 加拿大、 ${}^{31}$${}^{31}$^(31){ }^{31} 拉丁美洲、 ${}^{32}$${}^{32}$^(32){ }^{32} 和歐洲的 ${}^{33}$${}^{33}$^(33){ }^{33} 醫學組織都建議使用精神興奮劑藥物。您可以在網路上找到許多這些 ADHD 資源和指引。 ${}^{33,34}$${}^{33,34}$^(33,34){ }^{33,34} 然而，這些組織大多建議從心理教育和行為管理開始，尤其是對於症狀和功能障礙較輕的患者。6,35 美國的指導方針有所不同，建議在初期治療時考慮藥物治療。 ${}^{30}$${}^{30}$^(30){ }^{30} 對於 6 歲以下的兒童，一致認為治療應從行為管理開始，以家長訓練的形式進行，而藥物治療應保留給較嚴重或無反應的病例。例如，美國國家健康與照護卓越研究所（NICE）的指導方針 ${}^{33}$${}^{33}$^(33){ }^{33} 就建議，對於5歲以下的兒童，只有在嘗試過家長訓練，並取得具有幼童ADHD專業知識的醫療人員的第二意見後，才可考慮藥物治療。

Medications for ADHD are categorised into stimulants (or psychostimulants) and nonstimulants, with several different formulations, delivery systems, and pharmacokinetic profiles available (table). Importantly, the availability of medications varies worldwide, with very few options accessible in some countries.
治療 ADHD 的藥物可分為興奮劑 (或精神興奮劑) 和非興奮劑，有多種不同的配方、給藥系統和藥物動力學特性 (表)。重要的是，世界各地的藥物供應情況不盡相同，有些國家只有很少的藥物可供選擇。

First used in children in the 1930s, psychostimulants continue to be first-line medications for management of ADHD symptoms and consist of formulations of methylphenidate and amphetamine. Mechanisms of action for both are similar. Methylphenidate blocks presynaptic dopamine and norepinephrine transporters, thereby increasing catecholamine transmission; amphetamine also inhibits both transporters, but additionally increases the presynaptic efflux of dopamine. ${}^{36}$${}^{36}$^(36){ }^{36} The efficacy of psychostimulants in reducing ADHD symptoms in short-term treatment has been shown in numerous clinical trials of both children and adults with ADHD. For instance, a meta-analysis including more than 10000 children and adolescents (with trials lasting approximately 3 months) found that methylphenidate and amphetamine both had moderate-to-large effect sizes when symptom change was rated by clinicians (SD for methylphenidate $0\cdot 78$$0\cdot 78$0*780 \cdot 78; SD for amphetamine 1.02) and teachers (SD for methylphenidate $0\cdot 82$$0\cdot 82$0*820 \cdot 82; data not available for amphetamine). ${}^{37}$${}^{37}$^(37){ }^{37} A metaanalysis of 18 studies suggested that methylphenidate is also efficacious in adults, with an effect size of 0.6 based on self-reported and clinician-reported symptom change. ${}^{38}$${}^{38}$^(38){ }^{38} Moreover, another meta-analysis encompassing more than 8000 adult participants showed moderate effect sizes for both methylphenidate $(0\cdot 49)$$(0\cdot 49)$(0*49)(0 \cdot 49) and amphetamine $(0\cdot 79).{}^{37}$$(0\cdot 79).{}^{37}$(0*79).^(37)(0 \cdot 79) .{ }^{37} An additional meta-analysis of children with ADHD across 22 trials and adolescents with ADHD across nine trials compared methylphenidate and amphetamine and found both interventions highly efficacious, with slightly larger effects sizes for amphetamine (0.99) relative to methylphenidate $(0\cdot 72).{}^{39}$$(0\cdot 72).{}^{39}$(0*72).^(39)(0 \cdot 72) .{ }^{39} The side-effect profiles of these drugs are similar, with the most common side-effects being appetite suppression, insomnia, dry mouth, and nausea, but amphetamine might be somewhat more prone to side-effects. ${}^{40}$${}^{40}$^(40){ }^{40} Side-effects are generally
精神興奮劑於 1930 年代首次用於兒童，至今仍是治療 ADHD 症狀的第一線藥物，包括哌醋甲酯和安非他命的配方。兩者的作用機制相似。哌醋甲酯會阻斷突觸前多巴胺和去甲腎上腺素轉運體，從而增加兒茶酚胺的傳導；安非他命也會抑制這兩種轉運體，但會增加突觸前多巴胺的外流。 ${}^{36}$${}^{36}$^(36){ }^{36} 精神興奮劑在短期治療中減少 ADHD 症狀的功效，已在許多針對 ADHD 兒童和成人的臨床試驗中證實。例如，一項包括 10000 多名兒童和青少年（試驗持續約 3 個月）的薈萃分析發現，在臨床醫生（哌醋甲酯的 SD 值為 $0\cdot 78$$0\cdot 78$0*780 \cdot 78 ；苯丙胺的 SD 值為 1.02）和教師（哌醋甲酯的 SD 值為 $0\cdot 82$$0\cdot 82$0*820 \cdot 82 ；苯丙胺的數據不詳）評估症狀改變時，哌醋甲酯和苯丙胺均具有中等到較大的效果大小。 ${}^{37}$${}^{37}$^(37){ }^{37} 18 項研究的薈萃分析顯示，哌醋甲酯對成人也有療效，根據自我報告和臨床醫師報告的症狀改變，其效應大小為 0.6。 ${}^{38}$${}^{38}$^(38){ }^{38} 此外，另一項涵蓋 8000 多名成人參與者的薈萃分析顯示，哌醋甲酯 $(0\cdot 49)$$(0\cdot 49)$(0*49)(0 \cdot 49) 和安非他命 $(0\cdot 79).{}^{37}$$(0\cdot 79).{}^{37}$(0*79).^(37)(0 \cdot 79) .{ }^{37} 均具有中等程度的療效。 $(0\cdot 79).{}^{37}$$(0\cdot 79).{}^{37}$(0*79).^(37)(0 \cdot 79) .{ }^{37} 另一項薈萃分析對 22 項試驗中的 ADHD 兒童和 9 項試驗中的 ADHD 青少年進行了比較，發現哌醋甲酯和安非他命均具有高度療效，其中安非他命的療效稍大（0.99）相對於哌醋甲酯 $(0\cdot 72).{}^{39}$$(0\cdot 72).{}^{39}$(0*72).^(39)(0 \cdot 72) .{ }^{39} 這些藥物的副作用類似，最常見的副作用是食慾抑制、失眠、口乾和噁心，但苯丙胺可能更容易產生一些副作用。 ${}^{40}$${}^{40}$^(40){ }^{40} 副作用一般為
similar for adults and children, but might be more common in young children (ie, aged 5 years and younger). ${}^{41}$${}^{41}$^(41){ }^{41} NICE guidelines ${}^{33}$${}^{33}$^(33){ }^{33} recommend that medication treatment should begin with methylphenidate for children older than 5 years, but to then switch to amphetamine if the response is inadequate. For adults aged 18 years and older, the NICE guidelines recommend starting with either methylphenidate or the amphetamine formulation, lisdexamfetamine.
${}^{41}$${}^{41}$^(41){ }^{41} NICE 指導方針 ${}^{33}$${}^{33}$^(33){ }^{33} 建議 5 歲以上的兒童應從哌醋甲酯開始藥物治療，但如果反應良好，則應轉用苯丙胺。 ${}^{41}$${}^{41}$^(41){ }^{41} NICE指導方針 ${}^{33}$${}^{33}$^(33){ }^{33} 建議，對於5歲以上的兒童，藥物治療應從哌醋甲酯開始，但如果反應不夠，再轉用安非他命。對於 18 歲以上的成人，NICE 指導方針建議從哌醋甲酯或苯丙胺制劑 lisdexamfetamine 開始治療。

Three additional areas of concern with stimulant medications merit further consideration. First, there are the effects of long-term stimulant treatment on growth, specifically height and weight velocity. Although studies have yielded mixed results, most suggest that consistent stimulant use over several years can affect growth trajectories. ${}^{42,43}$${}^{42,43}$^(42,43){ }^{42,43} Based on childhood growth models, consistent long-term stimulant use might lead to modest reductions in adulthood height (approximately $1-3\mathrm{cm}$$1-3\mathrm{cm}$1-3cm1-3 \mathrm{~cm} ), but more substantial increases of weight and body-mass index (although initial treatment can cause modest weight loss). ${}^{41}$${}^{41}$^(41){ }^{41} These effects, however, are potentially attenuated by introducing so-called drug holidays (eg, not taking medication over holiday periods or summers) and are arguably outweighed by the benefits of treatment. ${}^{44,45}$${}^{44,45}$^(44,45){ }^{44,45} Second, given the potential euphorigenic effects of stimulants, concern that stimulant use might increase the likelihood of subsequent substance abuse and dependence has been considerable. ${}^{46}$${}^{46}$^(46){ }^{46} However, this concern is not reflected in longitudinal research as studies have either suggested that stimulant use has no effect on, or can even lower, substance abuse risk. ${}^{46-48}$${}^{46-48}$^(46-48){ }^{46-48} In many developed countries, stimulant diversion is a related concern, by which individuals without ADHD acquire stimulants, often with the goal of increasing academic or vacation productivity. ${}^{49}$${}^{49}$^(49){ }^{49} Further research is needed to understand the prevalence and impact of such use. Finally, a third concern is that stimulants, with their sympathomimetic properties, increase the likelihood of cardiovascular events. Although initial research from small, retrospective samples indicated the presence of associations between stimulant use and sudden cardiac death, ${}^{49}$${}^{49}$^(49){ }^{49} large scale registry studies have generally been reassuring, showing no relationship between serious cardiovascular events and stimulant use. ${}^{51,52}$${}^{51,52}$^(51,52){ }^{51,52}
興奮劑藥物還有三個值得關注的地方值得進一步考慮。首先是長期服用興奮劑對成長的影響，特別是身高和體重速度。雖然研究結果不一，但大多數研究顯示，持續使用興奮劑數年可能會影響成長軌跡。 ${}^{42,43}$${}^{42,43}$^(42,43){ }^{42,43} 根據兒童成長模型，長期持續使用興奮劑可能會導致成年身高適度降低（約 $1-3\mathrm{cm}$$1-3\mathrm{cm}$1-3cm1-3 \mathrm{~cm} ），但體重和體質指數會有較大幅度的增加（雖然最初的治療可能會導致體重適度下降）。 ${}^{41}$${}^{41}$^(41){ }^{41} 不過，這些影響可能會因為引入所謂的藥物假日（例如，在假日期間或夏季不服藥）而減弱，而且可以說這些影響會被治療的好處所抵銷。 ${}^{44,45}$${}^{44,45}$^(44,45){ }^{44,45} 其次，鑒於興奮劑的潛在興奮作用，使用興奮劑可能會增加後續藥物濫用和依賴的可能性，這一問題一直備受關注。 ${}^{46}$${}^{46}$^(46){ }^{46} 然而，這種憂慮並未反映在縱向研究中，因為研究顯示使用興奮劑對藥物濫用的風險沒有影響，或甚至可以降低。 ${}^{46-48}$${}^{46-48}$^(46-48){ }^{46-48} 在許多已開發國家，興奮劑轉用是一個相關的問題，沒有 ADHD 的人會藉此獲得興奮劑，目的通常是提高學業或假期的生產力。 ${}^{49}$${}^{49}$^(49){ }^{49} 我們需要進一步研究，以瞭解這種使用的普遍性和影響。最後，第三個問題是興奮劑具有類交感神經的特性，會增加發生心血管事件的可能性。 雖然最初的小規模回溯樣本研究顯示，使用興奮劑與心臟性猝死之間存在關聯，但 ${}^{49}$${}^{49}$^(49){ }^{49} 大規模的登錄研究通常令人安心，顯示嚴重心血管事件與使用興奮劑之間沒有關係。 ${}^{51,52}$${}^{51,52}$^(51,52){ }^{51,52}

Relative to stimulants, non-stimulant medications have lower responses and effect sizes and thus are typically reserved for patients who respond poorly or have intolerable side-effects to trials of stimulant formulations. Non-stimulant medications include the norepinephrine transporter inhibitor, atomoxetine, and the a-2 agonists, guanfacine and clonidine (table). Most treatment guidelines deem non-stimulant medications second-line treatments to be considered if treatment with stimulants proves inadequate. NICE guidelines, ${}^{33}$${}^{33}$^(33){ }^{33} for example, suggest that children with ADHD are switched to atomoxetine or guanfacine if their response to methylphenidate or amphetamine is poor; for adults, the recommendation is to switch to atomoxetine, as there is less evidence for a-2 agonists in adult ADHD.
相較於興奮劑，非興奮劑藥物的反應和效果較低，因此通常用於對興奮劑配方試驗反應不佳或有無法忍受副作用的病患。非刺激劑藥物包括去甲腎上腺素轉運抑制劑 atomoxetine，以及 a-2 促效劑 guanfacine 和 clonidine（表）。大多數治療指南認為，如果刺激劑治療效果不佳，可考慮使用非刺激劑藥物進行二線治療。例如，NICE 指導方針 ${}^{33}$${}^{33}$^(33){ }^{33} 建議，如果患有 ADHD 的兒童對哌醋甲酯或苯丙胺的反應不佳，可改用阿托西汀或胍法辛；對於成人，則建議改用阿托西汀，因為在成人 ADHD 的治療中，a-2 促效劑的證據較少。

A meta-analysis of 25 trials of atomoxetine in children with ADHD indicated a moderate effect size (SD 0.64); however, a large portion of patients (approximately 40%) had persistent symptoms requiring additional clinical intervention. ${}^{53}$${}^{53}$^(53){ }^{53} Atomoxetine is also effective in adults, albeit with a more modest effect size (approximately $0\cdot 33$$0\cdot 33$0*330 \cdot 33 ) based on a meta-analysis of 12 trials. ${}^{54}$${}^{54}$^(54){ }^{54} Trials of long-acting a-2 agonist formulations (extended-release guanfacine and extended-release clonidine) in children indicated medium effect sizes (0•-
一項對阿托莫西汀治療 ADHD 兒童的 25 項試驗進行的薈萃分析顯示，阿托莫西汀具有中等程度的效果（SD 0.64）；然而，大部分患者（約 40%）的症狀持續，需要額外的臨床干預。 ${}^{53}$${}^{53}$^(53){ }^{53} 阿托莫西汀對成人也有效，儘管根據12項試驗的薈萃分析，其效應規模較小（約 $0\cdot 33$$0\cdot 33$0*330 \cdot 33 ）。 ${}^{54}$${}^{54}$^(54){ }^{54} 長效 a-2 促效劑配方 (緩釋胍法辛和緩釋氯硝安定) 在兒童中的試驗顯示出中等效果 (0--)
$0\cdot 6).{}^{55,56}$$0\cdot 6).{}^{55,56}$0*6).^(55,56)0 \cdot 6) .{ }^{55,56} These formulations are often used as adjuvants to stimulants in patients with inadequate response to monotherapy, or in patients with comorbid aggression, insomnia, or tic disorders. ${}^{57}$${}^{57}$^(57){ }^{57} A clinical trial of extended-release guanfacine suggested similar effect sizes for adults with ADHD, but additional research is still needed to confirm these results. ${}^{58}$${}^{58}$^(58){ }^{58} In summary, the efficacy of ADHD medications has been clearly shown in the short term, with effect sizes and side-effects generally similar for adults and children. However, nonmedication interventions do often differ between the age groups. Cognitive behavioural therapy and occupational coaching have a more substantial role in adult management, whereas home-based and school-based behavioural treatments are recommended for children (as we discuss later).
$0\cdot 6).{}^{55,56}$$0\cdot 6).{}^{55,56}$0*6).^(55,56)0 \cdot 6) .{ }^{55,56} 這些制劑通常用於單一療法反應不佳的患者，或併發攻擊、失眠或抽搐障礙的患者，作為興奮劑的輔助藥物。 ${}^{57}$${}^{57}$^(57){ }^{57} 一項關法辛(guanfacine)緩釋劑的臨床試驗顯示，成人ADHD患者也有類似的療效，但仍需進一步的研究來確認這些結果。 ${}^{58}$${}^{58}$^(58){ }^{58} 總而言之，ADHD 藥物的療效已在短期內清楚展現，成人和兒童的效果大小和副作用大致相同。然而，非藥物干預在不同年齡組別之間常有差異。認知行為治療和職業輔導在成人的管理上有較大的作用，而以家庭為基礎和學校為基礎的行為治療則建議用於兒童（稍後將會討論）。

In the context of well controlled randomised controlled trials (RCTs), medications undoubtedly show short-term efficacy; however, their more general clinical value has been questioned. For example, once out of the rigorous context of an RCT, adherence is generally low, especially in adolescence, which undermines the practical effectiveness of medication treatments. ${}^{59}$${}^{59}$^(59){ }^{59} Long-term, naturalistic follow-up studies also cast doubt on the persistence of treatment effects, perhaps because of the development of tolerance with chronic dosing. ${}^{60}$${}^{60}$^(60){ }^{60} Taking academic-related outcomes as an example, a meta-analysis including 34 trials found that methylphenidate had only small and inconsistent effects on academic performance, improving general productivity, and accuracy in mathematics, but not reading. ${}^{61}$${}^{61}$^(61){ }^{61} Furthermore, in a sample of 370 children with ADHD followed up prospectively, stimulants were observed to have no effect on the number of school dropouts. ${}^{62}$${}^{62}$^(62){ }^{62} Similarly, in an 8-year, naturalistic follow-up of the Multimodal Treatment of ADHD (MTA) study, ${}^8$${}^8$^(8){ }^{8} null effects of psychostimulant treatment were reported across several functional domains, including academic achievement, social function, and overall levels of impairment. Findings from national registries have been more encouraging. For example, a Swedish registry found a substantial lowering of criminality during periods of stimulant use, ${}^{63}$${}^{63}$^(63){ }^{63} a US-based insurance registry described a reduction in motor vehicle accidents, ${}^{64}$${}^{64}$^(64){ }^{64} and a Taiwanese registry suggested a lowering of depression risk. ${}^{65}$${}^{65}$^(65){ }^{65} Additional positive effects on shorter-term outcomes such as traumas and injuries notwithstanding, ${}^{66}$${}^{66}$^(66){ }^{66} long-term functional outcomes are an essential area for further attention in the clinical management of ADHD.
在控制良好的隨機對照試驗 (RCT) 中，藥物毫無疑問顯示出短期療效；然而，其更普遍的臨床價值卻受到質疑。舉例來說，一旦脫離嚴格的 RCT 環境，依從性通常很低，尤其是在青少年時期，這會削弱藥物治療的實際效果。 ${}^{59}$${}^{59}$^(59){ }^{59} 長期的自然隨訪研究也對治療效果的持續性表示懷疑，這也許是因為長期用药會產生耐受性。 ${}^{60}$${}^{60}$^(60){ }^{60} 以學業相關的結果為例，一項包含34項試驗的薈萃分析發現，哌醋甲酯對學業表現只有輕微且不一致的影響，只能改善一般生產力和數學的準確性，但無法改善閱讀能力。 ${}^{61}$${}^{61}$^(61){ }^{61} 此外，在對370名患有ADHD的兒童進行前瞻性隨訪的樣本中，觀察到興奮劑對退學人數沒有影響。 ${}^{62}$${}^{62}$^(62){ }^{62} 同樣地，在一項為期8年、自然隨訪的ADHD多模式治療（MTA）研究中， ${}^8$${}^8$^(8){ }^{8} 精神興奮劑治療在多個功能領域（包括學業成績、社交功能和整體損傷程度）均無影響。來自國家註冊的結果則更令人鼓舞。舉例來說，瑞典的一份統計資料發現，在使用興奮劑期間，犯罪率大幅降低； ${}^{63}$${}^{63}$^(63){ }^{63} 美國的一份保險統計資料指出，汽車事故減少； ${}^{64}$${}^{64}$^(64){ }^{64} 台灣的一份統計資料則指出，憂鬱症的風險降低。 ${}^{65}$${}^{65}$^(65){ }^{65} 儘管對創傷和受傷等短期結果有額外的正面影響， ${}^{66}$${}^{66}$^(66){ }^{66} 長期功能結果是 ADHD 臨床管理中需要進一步關注的重要領域。

The limitations of medication treatment for ADHD highlight the importance of the continued search for new and improved approaches to its management. In this regard, several new compounds are being explored. For example, the association between ADHD and de novo mutations in genes related to the expression of metabotropic glutamate receptors ${}^{67}$${}^{67}$^(67){ }^{67} has led to trials of glutamate modulators (eg, fasoracetam) in children with ADHD. ${}^{68}$${}^{68}$^(68){ }^{68} Trials are also underway to examine the effects of agents targeting nicotinic acetylcholine receptors, because of the putative role of acetylcholine in regulating arousal and attention. ${}^{69}$${}^{69}$^(69){ }^{69} Small studies of transdermal nicotine in adults and children with ADHD have shown promising initial results, but still require confirmation with larger RCTs. ${}^{70,71}$${}^{70,71}$^(70,71){ }^{70,71}
藥物治療 ADHD 的局限性突顯出持續尋找新的、改進的治療方法的重要性。在這方面，我們正在探索幾種新的化合物。 ${}^{67}$${}^{67}$^(67){ }^{67} 例如，由於ADHD與代謝性谷氨酸受體表達相關基因的新突變有關，因此在ADHD兒童中進行了谷氨酸調節劑（如fasoracetam）的試驗。 ${}^{68}$${}^{68}$^(68){ }^{68} 由於乙酰膽鹼在調節喚醒和注意力方面的推定作用，針對菸鹼性乙酰膽鹼受體的藥物效果試驗也在進行中。 ${}^{69}$${}^{69}$^(69){ }^{69} 對成人和患有ADHD的兒童進行的經皮尼古丁小規模研究顯示，初步結果很有希望，但仍需更大規模的RCT研究來確認。 ${}^{70,71}$${}^{70,71}$^(70,71){ }^{70,71}

Non-pharmacological approaches have either been adapted from other clinical areas or newly developed to complement medication treatment, and are recommended as part of the
非藥物療法有的來自其他臨床領域，有的則是為了輔助藥物治療而新開發的，建議將其視為藥物治療的一部分。
multimodal approach. ${}^{33}$${}^{33}$^(33){ }^{33} Access to effective non-pharmacological approaches is especially important for children aged 3-5 years for whom medication is not recommended, when there is a preference against medication expressed by families, or when there is resistance to medication use from clinicians and national organisations. ${}^{29}$${}^{29}$^(29){ }^{29} The MTA ${}^{72}$${}^{72}$^(72){ }^{72} study has provided important evidence about the value of generic psychosocial treatments when applied to ADHD. The MTA was a US-based, multisite study of young children aged 7-9•9 years with ADHD that allowed for comorbid conditions other than bipolar, autism, or psychosis, as long as the comorbidity did not require treatment incompatible with the study treatments. The MTA study found that treatment with either methylphenidate alone or in combination with psychosocial treatment (including home-based and school-based behavioural treatments and a summer school-based treatment) provided similar effects on ADHD symptoms after 14 months. However, combined treatment was superior to methylphenidate alone in improving some other functional outcomes, such as academic performance, parent-child relations, and social skills. ${}^{72}$${}^{72}$^(72){ }^{72} Analogous findings from other studies have led to recommendations that combined treatment (a stimulant and parent training) is preferable to medication alone for most children with ADHD. ${}^{35}$${}^{35}$^(35){ }^{35} Conversely, the benefits of parent training as the sole intervention are less clear. One meta-analysis suggested that symptom improvement with parent training is minimal when assessments are based on raters probably masked to treatment allocation (eg, teachers). ${}^{73}$${}^{73}$^(73){ }^{73} Similarly, neurofeedback, another popular non-pharmacological intervention, has shown promise in single arm or uncontrolled studies, but the effects do not separate from placebo with rigorous placebo control (eg, mock or sham neurofeedback) and masked raters. ${}^{74}$${}^{74}$^(74){ }^{74} Attentional and executive functioning training with interactive computer games (eg, Cogmed Working Memory Training) produces robust performance improvements on the training tasks. ${}^{75}$${}^{75}$^(75){ }^{75} However, the translation of these effects to improvements in ADHD symptoms has not been replicated, ${}^{75,76}$${}^{75,76}$^(75,76){ }^{75,76} despite promising findings from initial studies. ${}^{77}$${}^{77}$^(77){ }^{77} Placebo-controlled trials of dietary treatments (such as the exclusion of additives or supplements with free fatty acids) have shown value; ${}^{78}$${}^{78}$^(78){ }^{78} however, the effects are generally modest, although larger for exclusions when food intolerance is present. Interventions like physical exercise and meditation might have complementary benefits, but evidence for their short-term or long-term control of symptoms remains sparse. 79,80 Because of the equivocal effects of non-pharmacological interventions on ADHD symptoms to date, additional research is needed to show the efficacy of these interventions, and their combination, within the context of multimodal treatments. ${}^{81}$${}^{81}$^(81){ }^{81}
多模式方法。 ${}^{33}$${}^{33}$^(33){ }^{33} 對於不建議接受藥物治療的3-5歲兒童，當家人表示不願意接受藥物治療，或是臨床醫師和國家組織對藥物治療有抗拒時，獲得有效的非藥物治療方法尤其重要。 ${}^{29}$${}^{29}$^(29){ }^{29} MTA ${}^{72}$${}^{72}$^(72){ }^{72} 研究提供了重要的證據，證明一般心理社會治療在應用於ADHD時的價值。MTA是一項以美國為基礎的多地點研究，研究對象為7-9-9歲患有ADHD的幼童，研究允許雙相情感、自閉症或精神病以外的併發症，只要併發症不需要與研究治療不相容的治療即可。MTA 研究發現，單獨使用哌醋甲酯或結合社會心理治療 (包括以家庭和學校為基礎的行為治療，以及以暑期學校為基礎的治療) 在 14 個月後對 ADHD 症狀有類似的效果。然而，在改善某些其他功能結果（如學業成績、親子關係和社交技巧）方面，結合治療的效果優於單獨使用哌醋甲酯。 ${}^{72}$${}^{72}$^(72){ }^{72} 來自其他研究的類似發現已經建議，對於大多數 ADHD 兒童而言，聯合治療（興奮劑和家長訓練）比單獨用藥更為可取。 ${}^{35}$${}^{35}$^(35){ }^{35} 相反地，以家長訓練作為唯一介入方式的好處則不太清楚。一項薈萃分析指出，如果評估是基於評分者（例如教師），而評分者可能不知道治療的分配，那麼家長訓練對症狀的改善是微乎其微的。 ${}^{73}$${}^{73}$^(73){ }^{73} 同樣地，神經回饋作為另一種流行的非藥物干預，在單臂或非對照研究中顯示出了前景，但在嚴格的安慰劑控制（例如，模擬或假神經回饋）和蒙蔽評分者的情況下，其效果並不能與安慰劑區分開來。 ${}^{74}$${}^{74}$^(74){ }^{74} 使用互動式電腦遊戲（例如，Cogmed工作記憶訓練）進行注意力和執行功能訓練，可以在訓練任務上產生強大的表現改善。 ${}^{75}$${}^{75}$^(75){ }^{75} 然而，儘管最初的研究結果令人鼓舞，但這些效果轉化為 ADHD 症狀的改善尚未得到驗證。 ${}^{77}$${}^{77}$^(77){ }^{77} 飲食治療的安慰劑對照試驗（例如排除添加劑或含游離脂肪酸的補充劑）已顯示出價值； ${}^{78}$${}^{78}$^(78){ }^{78} 然而，效果通常不大，不過在食物不耐症時排除的效果較大。體能鍛鍊和冥想等干預行為可能具有輔助效益，但其短期或長期控制症狀的證據仍然稀少。79,80 由於到目前為止，非藥物干預對 ADHD 症狀的效果不夠明確，因此需要進行更多研究，以顯示這些干預及其結合在多模式治療中的療效。 ${}^{81}$${}^{81}$^(81){ }^{81}

Having reviewed the clinical consensus about ADHD as represented in DSM-5 and ICD-11, we now provide an overview of scientific developments in our understanding of the pathogenesis, causes, and pathophysiology of ADHD. Through this overview, we want to convey the great strides made by researchers in understanding the disorder. These developments will create a platform for our exploration of the ways in which science is challenging our conceptions of ADHD and how these insights might stimulant new treatment approaches.
在回顧了 DSM-5 和 ICD-11 所代表的 ADHD 臨床共識之後，我們現在將概述我們在了解 ADHD 的發病機制、成因和病理生理方面的科學發展。透過這份概述，我們希望傳達研究人員在瞭解此症方面所取得的長足進展。這些發展將提供一個平台，讓我們探索科學如何挑戰我們對 ADHD 的觀念，以及這些觀念如何刺激新的治療方法。

A more thorough review of the published literature on genetic influences in ADHD is provided in the appendix (pp 3-4) but, briefly, the heritability for ADHD is high and most estimates range between $70\mathrm{\%}$$70\mathrm{\%}$70%70 \% and $80\mathrm{\%}.{}^{82}$$80\mathrm{\%}.{}^{82}$80%.^(82)80 \% .{ }^{82} Genome-wide association studies have successfully identified 12 genome-wide significant risk loci, yet these associations account for approximately 22% of the disorder’s heritability (as discussed later). Studies have also shown enrichment of certain copy-number variants in ADHD, ${}^{83,84}$${}^{83,84}$^(83,84){ }^{83,84} but these results require replication.
附錄 (pp 3-4)對已發表的 ADHD 遺傳影響文獻進行了更詳盡的回顧，但簡單來說，ADHD 的遺傳率很高，大多數的估計值介於 $70\mathrm{\%}$$70\mathrm{\%}$70%70 \% 和 $80\mathrm{\%}.{}^{82}$$80\mathrm{\%}.{}^{82}$80%.^(82)80 \% .{ }^{82} 之間。 全基因組關聯研究已成功找出 12 個全基因組顯著的風險基因位點，但這些關聯約佔此症遺傳率的 22%（稍後會討論）。研究還顯示某些拷貝數變異在 ADHD 中富集， ${}^{83,84}$${}^{83,84}$^(83,84){ }^{83,84} 但這些結果需要複製。

Numerous environmental exposures are associated with ADHD and have been suggested as putative causal factors. Nevertheless, given the complexity of the causal process (including the correlations between genetic and environmental exposures) and the reliance on observational (rather than experimental) study designs, most of these associations have yet to be shown as causal. In this context, many prenatal and perinatal risk factors, such as prematurity and low birthweight, have been more consistently associated with ADHD, with family studies suggesting that these effects cannot be explained by genetic confounding. 85-87 Intrauterine exposure to tobacco, and maternal stress and obesity during pregnancy, are also associated with ADHD, but they can be explained, at least in part, by confounding genetic factors. ${}^{88}$${}^{88}$^(88){ }^{88} Evidence is inconclusive or insufficient in relation to intrauterine exposure to alcohol and drugs and prenatal and perinatal birth-related complications.
許多環境暴露與注意力缺失過動症有關，並被認為是可能的因果關係。然而，鑑於因果過程的複雜性 (包括遺傳與環境暴露之間的相關性)，以及對觀察性 (而非實驗性) 研究設計的依賴，這些關聯大多尚未被證實為因果關係。在此背景下，許多產前與圍產期風險因素，例如早產與低出生體重，與 ADHD 有較一致的關係，家族研究顯示這些影響無法用遺傳混淆來解釋。85-87 宮內接觸煙草、母親在懷孕期間的壓力和肥胖也與 ADHD 有關，但至少部分可以用混雜的遺傳因素來解釋。 ${}^{88}$${}^{88}$^(88){ }^{88} 有關宮內暴露於酒精和藥物以及產前和圍產期出生相關併發症的證據不確定或不充分。

Postnatal factors and social determinants have also been implicated in ADHD. For instance, experimental evidence shows that exposure to artificial food colourings and flavourings increases the severity of ADHD symptoms, but the effects are small. ${}^{89}$${}^{89}$^(89){ }^{89} The links between ADHD and exposure to pollutants and pesticides are largely correlational in nature. Innovative designs such as mendelian randomisation are starting to be used to test causal interpretations of these effects, albeit initial attempts have been disappointing. ${}^{90}$${}^{90}$^(90){ }^{90} Although associations between ADHD and parenting style have been noted, they are likely to be due to an evocative gene-environment correlation whereby a child’s behaviour elicits harsh and unsupportive parenting, which leads to an escalation of problems and the development of coercive cycles within families. ${}^{91}$${}^{91}$^(91){ }^{91} Evidence that supports social determinants of ADHD comes from a naturally created experiment: the adoption of children exposed, from soon after birth, to extreme deprivation in state institutions before the fall of the Communist regime in Romania in the late 1980s. Following on from earlier studies showing an association between institutional neglect and ADHD, Kennedy and colleagues ${}^{92}$${}^{92}$^(92){ }^{92} reported a 7-times increase in ADHD in individuals who had experienced more than 6 months of deprivation as children compared with those who experienced less than 6 months. The magnitude of this effect, combined with the strength of the design (contrasting those with more and less than 6 months deprivation), means that this result is unlikely to be attributable to pre-existing genetic or intrauterine risk. ${}^{93}$${}^{93}$^(93){ }^{93} However, the severity of the adversity experienced by these children is an extraordinary, or rare, environmental variant and the effect of less extreme exposures on ADHD risk is not as clear.
產後因素和社會決定因素也與 ADHD 有關。例如，實驗證據顯示，接觸人工食品色素和調味料會增加 ADHD 症狀的嚴重性，但影響較小。 ${}^{89}$${}^{89}$^(89){ }^{89} ADHD與接觸污染物和殺蟲劑的關係大多屬於相關性研究。雖然最初的嘗試令人失望，但創新的設計（如湊整隨機化）已開始用於測試這些影響的因果解釋。 ${}^{90}$${}^{90}$^(90){ }^{90} 儘管ADHD與養育方式之間的關聯已被注意到，但它們很可能是由於基因與環境之間的誘發關聯，即孩子的行為會引起嚴厲和不支持的養育方式，從而導致問題升級，並在家庭中形成強制性循環。 ${}^{91}$${}^{91}$^(91){ }^{91} 支持ADHD社會決定性因素的證據來自於一個自然創造的實驗：在1980年代末羅馬尼亞共產政權垮台之前，領養的兒童從出生後不久就暴露在國家機構的極度匱乏環境中。Kennedy 及其同事 ${}^{92}$${}^{92}$^(92){ }^{92} 繼早期研究顯示機構疏忽與多動症 (ADHD) 之間的關係之後，他們又報告指出，與經歷不到 6 個月匱乏生活的兒童相比，童年時經歷超過 6 個月匱乏生活的兒童，其多動症 (ADHD) 發病率增加了 7 倍。這種影響的程度，再加上設計的強度（將匱乏經驗超過 6 個月和少於 6 個月的人進行對比），意味著這個結果不太可能是由於先前存在的遺傳或宮內風險造成的。 ${}^{93}$${}^{93}$^(93){ }^{93} 然而，這些兒童所經歷過的逆境的嚴重程度屬於非常、或罕見的環境變異，而較不極端的暴露對 ADHD 風險的影響則不那麼明確。

The mismatch between twin-based estimates of ADHD heritability (approximately 70-80%) and the estimates of genetic contribution based on the aforementioned genome-wide association study (about 22%) challenges researchers to account for the approximate 50%
根據雙胞胎估計的 ADHD 遺傳率（約 70-80%）與根據上述全基因組關聯研究估計的遺傳貢獻率（約 22%）之間的錯配，挑戰了研究人員如何解釋約 50% 的 ADHD 遺傳率。
gap in the familial transmission of ADHD. Clearly, this gap cannot be explained by rare de novo mutations, which, by definition, are not inherited. To answer this question, some have looked to the study of gene-environment interactions. The plausibility of this hypothesis (ie, that gene-environment interactions account for the gap between heritability estimates and genetic contributions based on the genome-wide association study), in part, rests on the fact that the standard twin heritability model pools genetic main effects with gene-environment interactions into a single heritability term. To differentiate gene-environment interactions from genetic main effects, studies have combined specific risk alleles (mainly relating to neurotransmitter genes) and specific exposures (eg, social stressors such as intrauterine exposure to substances and psychosocial risk factors). Despite some studies finding suggestive results, to date convincing replications are absent. ${}^{94}$${}^{94}$^(94){ }^{94} Another approach focuses on epigenetic modifications in individuals with ADHD. Although this approach cannot, by itself, account for missing heritability, it has so far indicated differential DNA methylation in genes related to monoaminergic and GABAergic systems, and also in genes involved in neurodevelopmental processes. ${}^{95}$${}^{95}$^(95){ }^{95} However, partly because of their reliance on the harvesting of genetic material from peripheral tissues (which might not reflect changes in the brain), the actual extent to which these modifications are causal remains to be seen. ${}^{96}$${}^{96}$^(96){ }^{96} To improve our understanding of gene-environment interactions, and presumably ADHD causality, largescale prospective studies such as the UK Biobank and the US-based ECHO and ABCD studies might prove helpful. These studies include biospecimens for genome-wide sequencing, detailed measures of phenotypic variance, and longitudinal assessments of environmental exposures, with adequate power to detect interactions and small effects. Over the next 5-10 years, we anticipate that these efforts will yield good results.
ADHD 家族遺傳的缺口。很明顯，這個差距無法用罕見的新發變異來解釋，因為根據定義，新發變異不會遺傳。為了回答這個問題，有些人開始研究基因與環境的互動關係。這個假設的合理性（即基因環境互作是造成遺傳率估計值與全基因組關聯研究的遺傳貢獻值之間差距的原因），部分是基於標準雙胞胎遺傳率模型將基因主效應與基因環境互作匯集為單一遺傳率項目。為了區分基因環境互作與遺傳主要效應，研究結合了特定風險等位基因 (主要與神經遞質基因有關) 和特定暴露 (例如，社會壓力因素，如宮內暴露於物質和社會心理風險因素)。儘管有些研究發現了暗示性的結果，但至今仍缺乏令人信服的複製。 ${}^{94}$${}^{94}$^(94){ }^{94} 另一種方法著重於ADHD患者的表觀遺傳學改變。儘管這種方法本身無法解釋遺傳性的缺失，但到目前為止，它已經指出了與單胺能系統和 GABA 能系統相關的基因以及與神經發育過程相關的基因中存在的 DNA 甲基化差異。 ${}^{95}$${}^{95}$^(95){ }^{95} 然而，部分原因是這些研究依賴從週邊組織取得遺傳物質（可能無法反映腦部的變化），因此這些改變的實際因果關係程度仍有待觀察。 ${}^{96}$${}^{96}$^(96){ }^{96} 為了增進我們對基因與環境互動關係的瞭解，以及對ADHD因果關係的推測，大型前瞻性研究（如英國生物資料庫、美國ECHO和ABCD研究）可能會有所幫助。 這些研究包括用於全基因組測序的生物標本、表型變異的詳細測量，以及環境暴露的縱向評估，並有足夠的力量來偵測互作作用和微小的影響。在未來的 5-10 年內，我們預期這些努力將會獲得良好的成果。

ADHD is associated with deficits across a range of cognitive domains (panel 2). Global cognitive effects, as reflected in IQ below population norms, are well documented, ${}^{97}$${}^{97}$^(97){ }^{97} as are more circumscribed cognitive and motivational correlates. For example, laboratory studies have found replicated evidence of deficits in executive functions such as behavioural inhibition, working memory, set-shifting, and planning and organisation in groups of individuals with ADHD compared with non-affected controls. ${}^{98,99}$${}^{98,99}$^(98,99){ }^{98,99} However, within such groups, the specific pattern of individual executive function impairment varies dramatically from one individual with ADHD to another. This variation means that, although some individuals will show a pervasive pattern of impairment across different executive functions, others will display profound impairment in a particular executive function (eg, working memory) but be unaffected in other areas (eg, the ability to inhibit). Some patients will show no executive function impairment at all. This further emphasises the importance of issues of heterogeneity for current conceptions of ADHD. ${}^{100,101}$${}^{100,101}$^(100,101){ }^{100,101} Moreover, deficits in executive functions are by no means specific to ADHD and are similarly reported in many other psychiatric conditions. ${}^{102-104}$${}^{102-104}$^(102-104){ }^{102-104}
ADHD與一系列認知領域的缺陷有關（面板2）。整體認知能力的影響（反映在智商低於人口標準）已經有充分的文獻記載， ${}^{97}$${}^{97}$^(97){ }^{97} 更周延的認知和動機相關性也是如此。例如，實驗室研究發現，與未受影響的對照組相比，ADHD患者在執行功能（如行為抑制、工作記憶、設定轉換、規劃和組織）方面存在缺陷，這一點已被證實。 ${}^{98,99}$${}^{98,99}$^(98,99){ }^{98,99} 然而，在這些群體中，不同ADHD患者個別執行功能障礙的具體模式有很大差異。這種差異意味著，儘管有些患者會在不同的執行功能上表現出廣泛的損傷模式，但有些患者會在特定的執行功能（如工作記憶）上表露出嚴重的損傷，但在其他方面（如抑制能力）卻不受影響。有些患者則完全沒有執行功能的障礙。這進一步強調了異质性問題對目前ADHD概念的重要性。 ${}^{100,101}$${}^{100,101}$^(100,101){ }^{100,101} 此外，執行功能的障礙絕非ADHD所特有，許多其他精神科疾病也有類似的報告。 ${}^{102-104}$${}^{102-104}$^(102-104){ }^{102-104}

Other cognitive domains, separable from (although potentially interacting with) executive functions, have also been implicated in ADHD. These include difficulties in regulating one’s psychological state in response to changing environmental circumstances by, for instance, trying to moderate one’s degree of arousal (so-called cognitive energetic factors). Clinically,
其他可與執行功能分開（雖然可能與之互動）的認知領域也與 ADHD 有關。這些包括因應環境變化而調節心理狀態的困難，例如，嘗試調節自己的喚醒程度（所謂的認知能量因素）。臨床上、
this means that ADHD symptoms are exacerbated during lengthy and seemingly mundane tasks. ${}^{105}$${}^{105}$^(105){ }^{105} Furthermore, some people with ADHD show altered patterns of motivation ${}^{106}$${}^{106}$^(106){ }^{106} and respond differently to positive and negative reinforcement. ${}^{107,108}$${}^{107,108}$^(107,108){ }^{107,108} In this regard, difficulties in delaying gratification or waiting for important outcomes are motivational hallmarks for many with ADHD. These could be the result of either an inability to curb behavioural urges (ie, behavioural inhibition), or atypical responses to the expectation of future rewards, which often present as a heighted aversion to delay. ${}^{109}$${}^{109}$^(109){ }^{109} Once again, there is great heterogeneity in the expression of these motivational and cognitive impairments. ${}^{100}$${}^{100}$^(100){ }^{100}
${}^{105}$${}^{105}$^(105){ }^{105} 這意味著，ADHD 症狀會在冗長且看似平凡的工作中惡化。 ${}^{105}$${}^{105}$^(105){ }^{105} 此外，有些ADHD患者的動機模式會有所改變 ${}^{106}$${}^{106}$^(106){ }^{106} ，他們對正面和負面強化的反應也不同。 ${}^{107,108}$${}^{107,108}$^(107,108){ }^{107,108} 在這方面，延遲滿足感或等待重要結果的困難是許多ADHD患者的動機特徵。這可能是由於無法抑制行為衝動（即行為抑制），或是對未來獎勵期望的非典型反應（通常表現為對延遲的高度反感）所導致。 ${}^{109}$${}^{109}$^(109){ }^{109} 再一次，這些動機和認知障礙的表現有很大的差異性。 ${}^{100}$${}^{100}$^(100){ }^{100}

By highlighting the context-specific and dynamic nature of cognitive deficits in ADHD, the growing evidence of cognitive-energetic and motivational problems in ADHD has changed the way the pathophysiology of ADHD is considered. An especially important emergence has been the idea that ADHD is not always the result of a fixed deficit that affects performance across all settings, but rather it varies considerably from setting to setting. 110,111 For instance, ADHD symptoms and associated cognitive problems are much more common on tasks that are long and repetitive (with a low amount of stimulation) than they are on interesting tasks, in which there are frequent and engaging things happening. The most robust laboratory indication of the power of context, or setting, to shape the performance of people with ADHD is seen in how reaction time and accuracy change as the rate of stimulus presentation is varied. Patients with ADHD make more mistakes than controls only under very fast and very slow conditions. ${}^{112}$${}^{112}$^(112){ }^{112}
越來越多的證據顯示，ADHD 的認知能量和動機問題具有特定情境和動態性質，因此改變了考慮 ADHD 病理生理學的方式。一個特別重要的新觀點是，ADHD 並非總是由於固定的缺陷而影響所有環境下的表現，而是在不同環境下有相當大的差異。110,111例如，ADHD症狀和相關的認知問題，在長時間重複性的任務（刺激量低）上，比在有趣的任務上更常見，因為在有趣的任務中，經常會有引人入勝的事情發生。情境或環境對於影響 ADHD 患者表現的力量，最有力的實驗室證明就是當刺激呈現的速度改變時，反應時間和準確度的變化。只有在非常快和非常慢的情況下，ADHD 患者才會比對照組患者犯更多錯誤。 ${}^{112}$${}^{112}$^(112){ }^{112}

Regarding brain structure and function, findings from neuroimaging research complement the cognitive and motivational profiles associated with ADHD. Because of its important role in executive functions, early neuroimaging research focused principally on the prefrontal cortex, showing functional and maturational abnormalities associated with ADHD. ${}^{113,114}$${}^{113,114}$^(113,114){ }^{113,114} For example, youth with ADHD show on average a 2-3 year delay in reaching peak thickness of much of the cerebrum, including the prefrontal cortex. ${}^{115}$${}^{115}$^(115){ }^{115} Over the last decade, neuroimaging research in ADHD, along with other psychiatric disorders, has shifted its focus of inquiry away from discrete neural substrates and towards the role of distributed neural circuits, recognising the importance of understanding the function, organisation, and development of interacting brain regions. ${}^{116}$${}^{116}$^(116){ }^{116} Emerging from this work, several large neural networks have been implicated in ADHD, including the default mode network (DMN), dorsal and ventral attentional networks, salience networks, and frontostriatal and mesocorticolimbic circuits (or the dopaminergic meso- limbic system). ${}^5$${}^5$^(5){ }^{5} Functional neuroimaging studies have shown reduced connectivity within the DMN of children aged 617 years with ADHD and a pattern suggestive of delayed DMN neuromaturation, ${}^{117}$${}^{117}$^(117){ }^{117} consistent with earlier structural MRI studies pointing to delayed maturation of the cerebral cortex. ${}^{115}$${}^{115}$^(115){ }^{115} The function of the DMN is hypothesised to underlie the normative capacity for mind-wandering and introspection, but in ADHD might reflect a tendency towards distractibility, potentially due to impaired regulation of attentional resources. ${}^{118}$${}^{118}$^(118){ }^{118} Similar research highlights atypical interactions between the DMN and the dorsal and ventral attentional networks, and the salience network, suggesting that the DMN, and its relationship to mindwandering, might interfere with, or disrupt, attentional networks’ capacity to maintain externally, focused attention. ${}^{5,118}$${}^{5,118}$^(5,118){ }^{5,118}
在腦部結構和功能方面，神經影像研究的結果補充了與 ADHD 相關的認知和動機特徵。由於前額皮質在執行功能中扮演重要角色，早期的神經影像研究主要集中在前額皮質，顯示出與 ADHD 相關的功能和成熟異常。 ${}^{113,114}$${}^{113,114}$^(113,114){ }^{113,114} 例如，患有 ADHD 的青少年在大腦（包括前額葉皮質）達到峰值厚度的時間平均延遲 2-3 年。 ${}^{115}$${}^{115}$^(115){ }^{115} 過去十年來，ADHD 與其他精神科疾病的神經影像研究，已將探討重點從離散的神經基底轉移到分散式神經回路的作用，並認識到了解互動腦區的功能、組織和發展的重要性。 ${}^{116}$${}^{116}$^(116){ }^{116} 在這項工作中，有幾個大型神經網路與ADHD有關，包括預設模式網路（DMN）、背側和腹側注意力網路、顯著性網路，以及前肋骨和皮層中膜環路（或稱多巴胺能中-邊緣系統）。 ${}^5$${}^5$^(5){ }^{5} 功能性神經影像研究顯示，617歲的ADHD兒童DMN內的連接性降低，其模式提示DMN神經成熟延遲， ${}^{117}$${}^{117}$^(117){ }^{117} 與早期結構性MRI研究指向大腦皮層成熟延遲一致。 ${}^{115}$${}^{115}$^(115){ }^{115} DMN的功能被假設為心靈遊蕩和內省的正常能力的基礎，但在ADHD中可能反映了分心的傾向，這可能是由於注意力資源的調節功能受損所致。 ${}^{118}$${}^{118}$^(118){ }^{118} 類似的研究突顯了DMN與背側和腹側注意網路以及突出網路之間的非典型互動，表明DMN及其與思維遊蕩的關係可能會干擾或破壞注意網路維持外部專注的能力。 ${}^{5,118}$${}^{5,118}$^(5,118){ }^{5,118}

In addition to the DMN and attentional networks, individuals with ADHD also manifest abnormalities within the dopaminergic mesolimbic system, a neural circuit associated with motivated behaviours, anticipated outcomes, and reinforced learning. ${}^{98}$${}^{98}$^(98){ }^{98} For example, relative to healthy controls, individuals with ADHD show reduced volumes of the nucleus accumbens (a key node within the mesolimbic system), ${}^{119,120}$${}^{119,120}$^(119,120){ }^{119,120} reduced activation of the mesolimbic system when anticipating rewarding outcomes, ${}^{121}$${}^{121}$^(121){ }^{121} and reduced fractional anisotropy (a diffusion MRI indicator of white matter organisation) within white matter tracts of the mesolimbic system. ${}^{122}$${}^{122}$^(122){ }^{122}
除了DMN和注意力網路之外，ADHD患者還會在多巴胺能中間葉系統（一種與動機行為、預期結果和強化學習有關的神經迴路）中出現異常。 ${}^{98}$${}^{98}$^(98){ }^{98} 例如，相對於健康對照組，ADHD患者的陰囊核（中島系統中的一個關鍵節點）體積減少， ${}^{119,120}$${}^{119,120}$^(119,120){ }^{119,120} 中島系統在預期獎勵結果時的激活程度降低， ${}^{121}$${}^{121}$^(121){ }^{121} 中島系統白質束中的分數各向異性（白質組織的擴散MRI指標）降低。 ${}^{122}$${}^{122}$^(122){ }^{122}

Despite these advances in our understanding of the neurobiology of ADHD, several concerns persist. First, most neuroimaging studies of ADHD have been cross-sectional in design, and thus unable to reach causal interpretations. For example, adaptations to a disorder versus underlying causes cannot be disambiguated from cross-sectional, casecontrol designs. Combining neuroimaging and RCTs is a potentially fruitful approach to overcome the limitations of correlational neuroimaging research, identifying causal effects of interventions (although not causal factors that give rise to the disorder itself) on brain structure and function. ${}^{123}$${}^{123}$^(123){ }^{123} Second, neuroimaging studies of ADHD often have small samples and poor reproducibility. False findings might have arisen from inadequate control over multiple statistical comparisons, imaging confounds such as head motion and partial averaging, and inadequate clinical phenotyping (eg, relying solely upon parental reports for diagnostics). By contrast, one mega-regression analysis of structural MRI studies from more than 1700 youth with ADHD reported reduced volumes in multiple subcortical structures, including those associated with the aforementioned attentional and reward systems. ${}^{120}$${}^{120}$^(120){ }^{120} However, the effect sizes across all regions were small (Cohen’s d $<0\cdot 2$$<0\cdot 2$< 0*2<0 \cdot 2 ), highlighting the fact that many previous neuroimaging studies were underpowered and risked false-positive results. Finally, the small effect sizes reported by large mega-analyses, such as ENIGMA, suggest that neuroimaging is unlikely to have clinical use as a diagnostic tool, at least not until substantial methodological advances have been made.
儘管我們對 ADHD 的神經生物學有了這些進展，但仍有幾個問題值得關注。首先，大多數關於 ADHD 的神經影像研究都是橫切面設計，因此無法達到因果解釋。例如，橫斷面的病例對照設計無法分辨疾病的適應性與潛在原因。結合神經影像和 RCT 是一種有可能克服關聯性神經影像研究局限性的富有成效的方法，它可以確定干預對大腦結構和功能的因果效應（雖然不是引起失調本身的因果因素）。 ${}^{123}$${}^{123}$^(123){ }^{123} 第二，ADHD 的神經影像研究通常樣本較小，重現性較差。假結果可能是由於多重統計比較、影像混淆（如頭部運動和部分平均）以及臨床表型不足（如僅依賴父母報告進行診斷）等因素造成的。相比之下，一項對1700多名ADHD青少年進行的結構性MRI研究的大型回歸分析報告指出，多種皮層下結構的容量減少，包括那些與上述注意力和獎勵系統相關的結構。 ${}^{120}$${}^{120}$^(120){ }^{120} 然而，所有區域的效應大小都很小（Cohen's d $<0\cdot 2$$<0\cdot 2$< 0*2<0 \cdot 2 ），這突顯出許多先前的神經影像研究力量不足，有可能出現假陽性結果。最後，大型巨型分析（如 ENIGMA）報告的小效應量表明，神經影像不太可能作為診斷工具用於臨床，至少在方法學取得重大進展之前不會。

In this final section, we briefly discuss four means by which scientific findings are challenging the way ADHD is conceptualised and explore the prospect that these can improve the diagnosis and treatment of ADHD in the future.
在最後一節中，我們將簡單討論科學發現挑戰ADHD概念化方式的四種方法，並探討這些方法在未來改善ADHD診斷和治療的前景。

All evidence confirms that ADHD is best understood as the extreme end of a continuum and that people with ADHD differ from those without ADHD by degree rather than in kind. Yet, both DSM-5 and ICD-11 continue to operationalise ADHD as a categorical diagnosis: a syndrome defined by symptom thresholds that suggest the existence of discrete boundaries between health and disorder, and between unaffected and impaired. However, there is no evidence that this definition of ADHD is correct, and so current clinical boundaries are somewhat arbitrary, built on clinical experience about the number and severity of symptoms or degree of impairment that warrants intervention. Are there viable alternatives to the
所有證據都證實，ADHD 最好被理解為一個連續體的極端，ADHD 患者與非 ADHD 患者的差別在於程度而非種類。然而，DSM-5 和 ICD-11 仍然將 ADHD 視為一種分類診斷：一種由症狀臨界值所定義的綜合症狀，這些臨界值顯示健康與失調之間、未受影響與受損之間存在分離的界線。然而，沒有證據顯示 ADHD 的這個定義是正確的，因此目前的臨床界線有點武斷，是根據臨床經驗來判斷症狀的數量和嚴重性，或是需要介入治療的受損程度。是否有其他可行的方法來取代
current categorical models that better reflect the underlying reality of the condition? Despite concerns about clinical applicability, several different dimensional models have been proposed, but none have been judged to have the simplicity and immediacy of the current approaches. ${}^{124}$${}^{124}$^(124){ }^{124}
目前的分類模型更能反映病情的基本現實？儘管有關臨床適用性的疑慮，幾種不同的維度模型已被提出，但沒有一種被判定為具有目前方法的簡單性及直接性。 ${}^{124}$${}^{124}$^(124){ }^{124}

As aforementioned, science leaves us in no doubt that ADHD is a complex and heterogeneous disorder. Individuals with the condition differ from one another in myriad ways and at multiple levels, such as in their genetic risks, environmental exposures, brain structures, and cognitive and motivational profiles. Recognising that ADHD is a heterogeneous disorder presents appreciable challenges to researchers (studies designed to explore this heterogeneity require large samples, multiple measures that capture the full range of deficits, and the use of sophisticated multivariate analytical approaches), but also offer potential clinical opportunities. Acknowledging heterogeneity might lead to the adoption of precision medicine: the tailoring of treatments to target an individual’s underlying cognitive and brain processes. ${}^{125}$${}^{125}$^(125){ }^{125} For instance, executive training might be efficacious for individuals with ADHD and executive dysfunctions, but not for those with motivational or cognitive energetic abnormalities. Neuropsychological subtyping of ADHD populations has been proposed to facilitate this sort of approach. ${}^{98,125}$${}^{98,125}$^(98,125){ }^{98,125} However, progress is hampered by a lack of consensus regarding the pathophysiological dimensions of greatest clinical relevance and whether individuals cluster along these dimensions to form identifiable subgroups. Addressing the challenges of heterogeneity is central to the Research Domain Criteria (RDoC) initiative of the US-based National Institute of Mental Health.
如前所述，科學研究毫無疑問地告訴我們，ADHD 是一種複雜且多樣化的疾病。患有 ADHD 的個人在遺傳風險、環境曝露、腦部結構、認知和動機狀況等多個層面上都存在著無數的差異。認識到 ADHD 是一種異质性疾病，對研究人員而言是一大挑戰（為探究這種異质性而設計的研究需要大量樣本、能捕捉全部缺陷範圍的多重量測方法，以及複雜的多元分析方法），但也提供了潛在的臨床機會。承認異质性可能會導致精準醫學的採用：針對個人的潛在認知和大腦過程量身定制治療方法。 ${}^{125}$${}^{125}$^(125){ }^{125} 例如，執行力訓練可能對患有多動症（ADHD）和執行機能障礙的個體有效，但對那些動機或認知能量異常的個體卻無效。有人建議對 ADHD 人群進行神經心理學分類，以促進這種方法的實施。 ${}^{98,125}$${}^{98,125}$^(98,125){ }^{98,125} 然而，由於對於最具有臨床相關性的病理生理層面以及個體是否根據這些層面聚集以形成可識別的亞群缺乏共識，因此研究進展受阻。解決異质性的挑戰是美國國家心理健康研究所的研究領域標準 (Research Domain Criteria, RDoC) 倡議的核心。

ADHD is a lifespan disorder with roots in early childhood ${}^{126}$${}^{126}$^(126){ }^{126} and branches extending into adolescence and adulthood. ${}^{127}$${}^{127}$^(127){ }^{127} We’ve previously highlighted evidence that several different developmental forms of ADHD appear to exist, which are currently not distinguished in diagnostic approaches. The developmental core of the ADHD phenotype will remain marked by childhood onset and adulthood persistence, but four developmental types with potential clinical relevance are starting to emerge. However, much still needs to be learned about differential prognosis or treatment response of individuals with these distinct developmental phenotypes. Taking a developmental perspective focuses attention on the likely value of early intervention and prevention strategies. ${}^{128}$${}^{128}$^(128){ }^{128} Interventions aimed at delaying the initial onset or reducing the impact of ADHD continue to be hindered by a lack of understanding of the early cognitive and behavioural precursors and predictors of later ADHD that would allow for the cost-effective early identification of at-risk individuals. ${}^{129}$${}^{129}$^(129){ }^{129} We are also devoid of effective interventions that can be implemented during the first years of life, although novel approaches to strengthening underlying brain networks are being trialled. ${}^{130}$${}^{130}$^(130){ }^{130}
ADHD是一種終生失調的疾病，其根源在於兒童早期 ${}^{126}$${}^{126}$^(126){ }^{126} ，分支則延伸至青少年期和成年期。 ${}^{127}$${}^{127}$^(127){ }^{127} 我們先前已強調有證據顯示，ADHD 似乎存在數種不同的發展型態，目前診斷方法並未區分這些型態。ADHD表型的發育核心仍將以童年期發病和成年期持續存在為標誌，但具有潛在臨床相關性的四種發育類型已開始出現。然而，對於具有這些不同發育表型的個人的不同預後或治療反應，仍有許多問題需要了解。從發展的角度來看，早期干預及預防策略可能具有的價值更值得關注。 ${}^{128}$${}^{128}$^(128){ }^{128} 由於缺乏對早期認知和行為前兆以及日後發生ADHD的預測因素的瞭解，旨在延遲ADHD最初發病時間或降低其影響的干預行動仍然受到障礙，而這些早期認知和行為前兆以及日後發生ADHD的預測因素可以讓我們以具有成本效益的方式及早識別高危個體。 ${}^{129}$${}^{129}$^(129){ }^{129} 儘管我們正在試驗強化基礎大腦網路的新方法，但仍缺乏可在生命最初幾年實施的有效干預措施。 ${}^{130}$${}^{130}$^(130){ }^{130}
Additional strategies, aimed at reducing the escalation and effect of the disorder, have effectively focused on the use of parent training, psychoeducation, and support to reduce the risk of emergence of comorbid conditions and associated impairment. ${}^{131}$${}^{131}$^(131){ }^{131}
其他策略旨在減少失調的升級和影響，有效地將重點放在使用家長訓練、心理教育和支援，以降低出現併發症和相關損害的風險。 ${}^{131}$${}^{131}$^(131){ }^{131}

Our Seminar highlights a surprising degree of overlap between ADHD and other psychiatric conditions in terms of both aetiology and pathophysiology. This overlap, like evidence of dimensionality and heterogeneity, challenges current diagnostic systems, and lends conceptual support for approaches that attempt to identify common pathophysiological processes that cut across traditional diagnostic boundaries (eg, RDoC initiative), rather than those that diverge at the level of the clinical DSM or ICD phenotypes. ${}^{132}$${}^{132}$^(132){ }^{132} The assumption of a transdiagnostic framework, such as RDoC, is that shared vulnerability processes can be successfully targeted to treat different clinical conditions. For example, where similar executive deficits are present across a range of different neurodevelopmental conditions (ADHD, autism spectrum disorder, and psychosis), the same executive control training approaches could have clinical value. ${}^{133}$${}^{133}$^(133){ }^{133} Similarly, a transdiagnostic framework might provide some insight into why causal factors can give rise to ADHD, and other psychiatric conditions. For instance, gestational diabetes is associated with increased risk for ADHD in the offspring. ${}^{134}$${}^{134}$^(134){ }^{134} Although genetic confounding has not been excluded, preclinical research suggests that this observation might be attributable, at least in part, to the effects of maternal hyperinsulinaemia or adiposity on the development of the fetal mesolimbic system. ${}^{135,136}$${}^{135,136}$^(135,136){ }^{135,136} One could therefore hypothesise that this same prenatal exposure has transdiagnostic implications, increasing risk for other conditions related to mesolimbic dysfunction, such as Tourette’s syndrome and substance use disorders. ${}^{135,137}$${}^{135,137}$^(135,137){ }^{135,137} However, to date, evidence supporting treatment or causal implications of a transdiagnostic framework is largely absent.
我們的研討會強調ADHD與其他精神科疾病在病因學與病理生理學上有令人驚訝的重疊程度。這種重疊性，就像多維性和異质性的證據一樣，挑戰了目前的診斷系統，並為嘗試找出跨越傳統診斷邊界的共同病理生理過程的方法（例如，RDoC計畫）提供了概念上的支持，而不是那些在臨床DSM或ICD表型層面上存在分歧的方法。 ${}^{132}$${}^{132}$^(132){ }^{132} 跨診斷架構（例如 RDoC）的假設是，共同的脆弱過程可以成功地針對不同的臨床狀況進行治療。例如，當一系列不同的神經發育狀況（ADHD、自閉症譜系障礙和精神病）出現類似的執行缺陷時，相同的執行控制訓練方法可能具有臨床價值。 ${}^{133}$${}^{133}$^(133){ }^{133} 同樣地，跨診斷架構也可能提供一些洞察力，讓我們了解為什麼因果因素會導致ADHD和其他精神科疾病。例如，妊娠糖尿病與後代患 ADHD 的風險增加有關。 ${}^{134}$${}^{134}$^(134){ }^{134} 儘管遺傳混亂並未排除，但臨床前研究顯示，這項觀察可能至少部分歸因於母體高胰島素血症或肥胖對胎兒間葉系統發育的影響。 ${}^{135,136}$${}^{135,136}$^(135,136){ }^{135,136} 因此，我們可以假設，同樣的產前暴露具有跨診斷的影響，會增加罹患與中樞神經系統功能障礙有關的其他疾病的風險，例如妥瑞症和藥物使用障礙。 ${}^{135,137}$${}^{135,137}$^(135,137){ }^{135,137} 然而，到目前為止，支持跨診斷架構的治療或因果影響的證據大多不存在。