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発達障害(自閉スペクトラム症・ADHD)

著者: 岡田俊 国立精神・神経医療研究センター精神保健研究所

監修: 上島国利 昭和大学

著者校正/監修レビュー済:2020/08/27
参考ガイドライン:
  1. 児童・青年期精神疾患の薬物治療ガイドライン
  1. 子どもの注意欠如・多動性障害(ADHD)の診断・治療ガイドライン第4版
  1. 特異的発達障害診断・治療のための実践ガイドライン -わかりやすい診断手順と支援の実際

概要・推奨   

  1. 自閉スペクトラム症の治療に当たっては、薬物療法だけでなく行動療法を組み合わせるほうが有効性が高い(推奨度1)。
  1. 自閉スペクトラム症の児童の、易刺激性、多動、常同行動にアリピプラゾールエビリファイは有効である(推奨度1)。
  1. 自閉スペクトラム症の児童の、易刺激性、反復行動、引きこもりにリスペリドンリスパダールは有効である(推奨度1)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
岡田俊 : 講演料(塩野義製薬,持田製薬)[2021年]
監修:上島国利 : 原稿料(大日本住友製薬)[2021年]

改訂のポイント:
  1. 厚生労働科学研究「発達障害を含む児童・思春期精神疾患の薬物治療ガイドライン作成と普及(中村和彦班)」「向精神薬の処方実態の解明と適正処方を実践するための薬物療法ガイドラインに関する研究(三島和夫班)」の成果を反映した。
  1. 「ビバンセカプセル20mg、30mg」「メラトベル顆粒小児用0.2%」の承認を反映した。

病態・疫学・診察

疾患情報  
  1. 発達障害(神経発達症)とは、人生早期より認められる脳機能の偏りにより、物事のとらえ方や行動のパターンが一定の様式を示し、そのために日常生活に支障を来す状態をいう。遺伝的要因が強いが、胎生期から幼少期の環境要因も関与する。
  1. 発達障害には、知的障害(知的能力障害)、自閉スペクトラム症(広汎性発達障害)、注意欠如・多動症(ADHD)、学習症、運動症(トゥレット症や常同運動症など)が含まれる。
  1. 知的障害(知的能力障害)は、知能検査や発達検査で調べた全般的な知的機能が、標準に比べて偏倚し、そのために日常生活に支障のある状態をいう。
  1. 自閉スペクトラム症は、コミュニケーションと対人相互作用の障害、関心と活動の限局(感覚異常を含む)によって特徴づけられる。このなかには、従来、広汎性発達障害と診断されていた自閉性障害〔自閉症〕、アスペルガー障害、特定不能の広汎性発達障害が含まれる。特定用語として、レット障害についても言及されている。
  1. 自閉スペクトラム症は、人生早期から認められる対人コミュニケーションと対人相互作用の障害、関心と活動の限局(感覚過敏または鈍麻を含む)によって特徴づけられる。
  1. レット障害は、主としてX染色体上に存在するMeCP2遺伝子の変異によって引き起こされるもので、女児にのみ認められる。生後5カ月まで正常な発達を遂げるが、その後、成長の停滞が起こり、合目的的な運動の喪失、常同的な手の動き、対人反応の喪失、体幹失調を伴う。
  1. ADHDは、12歳以前から学校と家庭などの複数の状況で認められる発達水準に不相応な多動性-衝動性、不注意によって特徴づけられる。
  1. トゥレット症は、18歳以前から1年以上にわたり持続する多彩な運動チック、音声チックによって診断される。典型的には、10~15歳に症状のピークを迎え、成人期には軽減することが多いが、個人差が大きい。
  1. 学習症では、知的障害がないにもかかわらず、読字、書字、算数の能力に特異的な障害が認められる。
問診・診察のポイント  
  1. 妊娠中の経過、周産期の異常、発育歴、保育園/幼稚園や学校、家庭、仲間関係での様子を聞く。

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文献 

著者: Heidi Ching, Tamara Pringsheim
雑誌名: Cochrane Database Syst Rev. 2012 May 16;5:CD009043. doi: 10.1002/14651858.CD009043.pub2. Epub 2012 May 16.
Abstract/Text BACKGROUND: Autism spectrum disorders (ASD) include Autistic Disorder, Asperger's Disorder and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). Irritability related to ASD has been treated with antipsychotics. Aripiprazole, a third generation atypical antipsychotic, is a relatively new drug that has a unique mechanism of action different from other antipsychotics.
OBJECTIVES: To determine the safety and efficacy of aripiprazole for individuals with ASD.
SEARCH METHODS: We searched the following databases on 4th May 2011: Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1948 to April Week 3 2011), EMBASE (1980 to 2011 Week 17), PsycINFO (1887 to current), CINAHL (1937 to current), WorldCat, ZETOC, Autism Data, Conference Proceedings Index-S, Conference Proceedings Index -SSH, ClinicalTrials.gov, and WHO ICTRP. We searched for records published in 1990 or later, as this was the year aripiprazole became available.
SELECTION CRITERIA: Randomized controlled trials of aripiprazole versus placebo for the treatment of individuals with a diagnosis of ASD.
DATA COLLECTION AND ANALYSIS: Two review authors independently collected, evaluated, and analyzed data. We performed meta-analysis for primary and secondary outcomes, when possible.
MAIN RESULTS: Two randomized controlled trials with similar methodology have evaluated the use of aripiprazole for a duration of eight weeks in 316 children with ASD. The included trials had a low risk of bias. Although we searched for studies across age groups, only studies in children and youths were found. Meta-analysis of study results revealed a mean improvement of 6.17 points on the Aberrant Behavior Checklist (ABC) irritability subscale, 7.93 points on the ABC hyperactivity subscale, and 2.66 points in the stereotypy subscale in children treated with aripiprazole relative to children treated with a placebo. In terms of adverse side effects, children treated with aripiprazole had a greater increase in weight with a mean increase of 1.13 kg relative to placebo, and had a higher risk ratio for sedation (RR 4.28) and tremor (RR 10.26).
AUTHORS' CONCLUSIONS: Evidence from two randomized controlled trials suggests that aripiprazole can be effective in treating some behavioral aspects of ASD in children. After treatment with aripiprazole, children showed less irritability, hyperactivity, and stereotypies (repetitive, purposeless actions). Notable side effects must be considered, however, such as weight gain, sedation, drooling, and tremor. Longer studies of aripiprazole in individuals with ASD would be useful to gain information on long-term safety and efficacy.

PMID 22592735  Cochrane Database Syst Rev. 2012 May 16;5:CD009043. doi・・・
著者: O S Jesner, M Aref-Adib, E Coren
雑誌名: Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005040. doi: 10.1002/14651858.CD005040.pub2. Epub 2007 Jan 24.
Abstract/Text BACKGROUND: Autistic spectrum disorder encompasses a wide variety of behavioural and communicative problems. Both the core features and non-core features of autism have been targeted in a variety of therapies. Atypical antipsychotic medications, including risperidone, have been used for symptom and behaviour improvement and have shown beneficial outcomes, particularly in certain aspects of the disorder. However, given the nature of the condition presenting in young patients, the risks of these potentially long term therapies must be weighed against the benefits.
OBJECTIVES: To determine the efficacy and safety of risperidone for people with autism spectrum disorder.
SEARCH STRATEGY: Electronic databases: CENTRAL (Cochrane Central Register of Controlled Trials) 2006 (Issue 3); MEDLINE (1966 to April 2006); EMBASE (1980 to April 2006);PsycINFO (1887 to April 2006); CINAHL (1982 to April 2006); LILACS (1982 to April 2006 ); Clinicaltrials.gov (USA) (accessed April 2006); ZETOC (1993 to April 2006); National Research Register (NRR) (UK) 2006 (Issue 1) were searched. In addition further data were retrieved through contact with pharmaceutical companies and authors of published trials.
SELECTION CRITERIA: All randomised controlled trials of risperidone versus placebo for patients with a diagnosis of autism spectrum disorder. All trials had to have at least one standardised outcome measure used for both intervention and control group.
DATA COLLECTION AND ANALYSIS: Data were independently evaluated and analysed by the reviewers. Data were evaluated at the end of each randomised controlled trial. Unpublished data were also considered and analysed.
MAIN RESULTS: Only three randomised controlled trials were identified. Meta-analysis was possible for three outcomes. Some evidence of the benefits of risperidone in irritability, repetition and social withdrawal were apparent. These must however be considered against the adverse effects, the most prominent being weight gain.
AUTHORS' CONCLUSIONS: Risperidone can be beneficial in some features of autism. However there are limited data available from studies with small sample sizes. In addition, there lacks a single standardised outcome measure allowing adequate comparison of studies, and long-term followup is also lacking. Further research is necessary to determine the efficacy pf risperidone in clinical practice.

PMID 17253538  Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005040. d・・・
著者: Alain Joseph, Rajeev Ayyagari, Meng Xie, Sean Cai, Jipan Xie, Michael Huss, Vanja Sikirica
雑誌名: Eur Child Adolesc Psychiatry. 2017 Aug;26(8):875-897. doi: 10.1007/s00787-017-0962-6. Epub 2017 Mar 3.
Abstract/Text This study compared the clinical efficacy and safety of attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in children and adolescents 6-17 years of age. A systematic literature review was conducted to identify randomized controlled trials (RCTs) of pharmacologic monotherapies among children and adolescents with ADHD. A Bayesian network meta-analysis was conducted to compare change in symptoms using the ADHD Rating Scale Version IV (ADHD-RS-IV), Clinical Global Impression-Improvement (CGI-I) response, all-cause discontinuation, and adverse event-related discontinuation. Thirty-six RCTs were included in the analysis. The mean (95% credible interval [CrI]) ADHD-RS-IV total score change from baseline (active minus placebo) was -14.98 (-17.14, -12.80) for lisdexamfetamine dimesylate (LDX), -9.33 (-11.63, -7.04) for methylphenidate (MPH) extended release, -8.68 (-10.63, -6.72) for guanfacine extended release (GXR), and -6.88 (-8.22, -5.49) for atomoxetine (ATX); data were unavailable for MPH immediate release. The relative risk (95% CrI) for CGI-I response (active versus placebo) was 2.56 (2.21, 2.91) for LDX, 2.13 (1.70, 2.54) for MPH extended release, 1.94 (1.59, 2.29) for GXR, 1.77 (1.31, 2.26) for ATX, and 1.62 (1.05, 2.17) for MPH immediate release. Among non-stimulant pharmacotherapies, GXR was more effective than ATX when comparing ADHD-RS-IV total score change (with a posterior probability of 93.91%) and CGI-I response (posterior probability 76.13%). This study found that LDX had greater efficacy than GXR, ATX, and MPH in the treatment of children and adolescents with ADHD. GXR had a high posterior probability of being more efficacious than ATX, although their CrIs overlapped.

PMID 28258319  Eur Child Adolesc Psychiatry. 2017 Aug;26(8):875-897. d・・・
著者: Noa Tsujii, Takashi Okada, Masahide Usami, Hidenori Kuwabara, Junichi Fujita, Hideki Negoro, Michiyo Kawamura, Junzo Iida, Takuya Saito
雑誌名: J Clin Psychiatry. 2020 Mar 24;81(3). doi: 10.4088/JCP.19r13015. Epub 2020 Mar 24.
Abstract/Text OBJECTIVE: This study aimed to compare the effect of continuing and discontinuing medications on quality of life of patients with attention-deficit/hyperactivity disorder (ADHD).
DATA SOURCES: PubMed, Cochrane Library, and Embase databases were searched using generic terms for ADHD, discontinuing, continuing, pharmacotherapy, and randomized controlled trials without date or language restrictions.
STUDY SELECTION: Of the 3,672 screened studies, 9 met the predefined inclusion criteria on patients with ADHD; 5 of these 9 studies reporting on 1,463 patients (children and adolescents, n = 894; adults, n = 569) measured quality of life and were included in this meta-analysis. Only randomized, double-blind, placebo-controlled withdrawal trials of ADHD medications were included.
DATA EXTRACTION: Data were independently extracted according to the Cochrane Handbook for Systematic Reviews of Interventions. Analyses were based on random-effects models.
RESULTS: Compared with continuing medications, discontinuing them significantly worsened quality of life score in patients with ADHD (standardized mean difference [SMD] = 0.19; 95% CI, 0.08 to 0.30]). Moreover, discontinuing medications worsened this score in children and adolescents with ADHD (SMD = 0.21; 95% CI, 0.06 to 0.36) but not in adults with ADHD (SMD = 0.02; 95% CI, -0.46 to 0.50).
CONCLUSIONS: Discontinuing medications was associated with a small but statistically significant decrease in quality of life among children and adolescents with ADHD but not in adults with ADHD. Quality of life can be applied in pharmacologic interventions regarding continuing and discontinuing medication because this concept is related to individuals' appraisal of their situation. Quality of life is an important factor for planning individualized ADHD medication treatment.

© Copyright 2020 Physicians Postgraduate Press, Inc.
PMID 32237294  J Clin Psychiatry. 2020 Mar 24;81(3). doi: 10.4088/JCP.・・・
著者: Wei Zheng, Xian-Bin Li, Ying-Qiang Xiang, Bao-Liang Zhong, Helen F K Chiu, Gabor S Ungvari, Chee H Ng, Grace K I Lok, Yu-Tao Xiang
雑誌名: Hum Psychopharmacol. 2016 Jan;31(1):11-8. doi: 10.1002/hup.2498. Epub 2015 Aug 26.
Abstract/Text OBJECTIVE: To review the efficacy and safety of aripiprazole (ARI) for Tourette's syndrome (TS).
METHODS: This review included randomized controlled trials (RCTs) of children and adolescents (6-18 years) with TS comparing ARI monotherapy with another monotherapies in relation to clinical improvement and adverse events.
RESULTS: Six RCTs with a total of 528 subjects (ARI treatment group: n = 253; control group: n = 275) met the inclusion criteria. These included two RCTs (n = 255) that compared ARI monotherapy with tiapride (TIA). Tic symptoms control assessed by Yale Global Tic Severity Scale (Standard Mean Difference (SMD) = -0.38 (Confidence Interval (CI) = -1.32 to 0.56); I(2) = 90%, P = 0.42) revealed no significant differences between the two groups. Extrapyramidal symptoms were significantly different when ARI (1.5%) was compared with haloperidol (HAL) (43.5%). No significant group differences were found in the rates of nausea/vomiting, dizziness, and dry mouth between ARI and TIA (RR = 0.57 to 1.00 (95%CI = 0.14-4.20); I(2) = 0% to 69%, P = 0.35 to 1.00).
CONCLUSION: This review found that ARI has similar efficacy to TIA and HAL for TS, while extrapyramidal symptoms were significantly less with ARI than with HAL. ARI can be considered as an alternative treatment option for TS.

Copyright © 2015 John Wiley & Sons, Ltd.
PMID 26310194  Hum Psychopharmacol. 2016 Jan;31(1):11-8. doi: 10.1002/・・・
著者: Beata Rzepka-Migut, Justyna Paprocka
雑誌名: Brain Sci. 2020 Apr 7;10(4). doi: 10.3390/brainsci10040219. Epub 2020 Apr 7.
Abstract/Text Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with disturbed melatonin secretion profile and sleep problems. The growing incidence of ASD and ADHD inspires scientists to research the underlying causes of these conditions. The authors focused on two fundamental aspects, the first one being the presentation of the role of melatonin in ASD and ADHD and the second of the influence of melatonin treatment on sleep disorders. The authors present the use of melatonin both in the context of causal and symptomatic treatment and discuss melatonin supplementation: Dosage patterns, effectiveness, and safety. Sleep disorders may have a different clinical picture, so the assessment of exogenous melatonin efficacy should also refer to a specific group of symptoms. The review draws attention to the wide range of doses of melatonin used in supplementation and the need to introduce unified standards especially in the group of pediatric patients.

PMID 32272607  Brain Sci. 2020 Apr 7;10(4). doi: 10.3390/brainsci10040・・・

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