今日の臨床サポート

パーキンソン病

著者: 野川茂 東海大学医学部付属八王子病院脳神経内科

監修: 高橋裕秀 昭和大学藤が丘病院 脳神経内科

著者校正済:2021/10/13
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 従来重視されてきた運動症状はパーキンソン病(Parkinson’s Disease; PD)の多彩な症状のうちの一部であり、非運動症状を含めた総合的な疾患の理解が重要である(推奨度2)。
  1. ドパミンアゴニストで治療を開始したほうが、L-ドパで開始したときよりも運動合併症の生じる頻度が少なくなる(推奨度1)。
  1. 突発的睡眠による事故の観点から、ドパミンアゴニストを使用している場合には、自動車運転、機械の操作、高所作業などの危険を伴う作業に従事させないように注意する必要がある(推奨度2)。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
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:
野川茂 : 特に申告事項無し[2021年]
監修:高橋裕秀 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 可逆的MAOB阻害薬サフィナミド(エクフィナ)、持続型COMT阻害薬オピカポン(オンジェンティス)、貼付型ロピニロール(ハルロピテープ)が発売された。また、非運動症状の治療を中心に補足を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. パーキンソン病(Parkinson’s Disease; PD)は、病理学的に中脳黒質のドパミン産生神経細胞の減少とレビー小体の蓄積を特徴とする運動障害疾患である。
  1. その有病率は人口10万人当たり100~180人と、神経変性疾患のなかではアルツハイマー型認知症に次いで多く、すべての診療科で遭遇し得る疾患である。また、高齢者ほど有病率が高いため、今後人口の高齢化と共に増加する可能性がある。
  1. 運動症状として安静時振戦、無動・寡動、筋強剛のほか、進行期では姿勢反射障害がみられる。また、最近では精神・認知症状、自律神経症状、感覚症状、睡眠症状などの非運動症状が注目されている。
  1. 精神・認知症状としては、幻覚・妄想、アンヘドニア、アパシー、うつ、認知症、衝動制御障害などがある。
  1. 自律神経症状としては、起立性低血圧、便秘、過活動膀胱、性機能障害などがある。
  1. 夜間症状として、中途覚醒のほか、レストレスレッグス症候群、レム期睡眠行動異常症(RBD)などを呈することがある。
  1. 難病の診断基準では、以下のことが挙げられている。
  1. パーキンソニズムがある(※1)。
  1. 脳CT又はMRIに特異的異常がない(※2)。
  1. パーキンソニズムを起こす薬物・毒物への曝露がない。
  1. 抗パーキンソン病薬にてパーキンソニズムに改善がみられる(※3)。
  1. 以上4項目を満たした場合、パーキンソン病と診断する。なお、1、2、3は満たすが、薬物反応を未検討の症例は、パーキンソン病疑い症例とする。
  1. ※1:パーキンソニズムの定義は、次のいずれかに該当する場合とする。
  1. 典型的な左右差のある安静時振戦(4~6Hz)がある。
  1. 歯車様筋固縮、動作緩慢、姿勢反射障害のうち2つ以上が存在する。
  1. ※2:脳CT又はMRIにおける特異的異常とは、多発脳梗塞、被殻萎縮、脳幹萎縮、著明な脳室拡大、著明な大脳萎縮など他の原因によるパーキンソニズムであることを明らかに示す所見の存在をいう
  1. ※3:薬物に対する反応はできるだけドパミン受容体刺激薬またはL-ドパ製剤により判定することが望ましい。
  1. 抗パーキンソン病薬に対する反応は良好で、少なくとも病初期では健常人と同様の生活が送れる。
  1. PDは、厚生労働省の指定難病であり、Hoehn & Yahrで重症度3度以上かつ生活機能障害度2以上の場合、申請し認定されると、保険料の自己負担分の一部が公費負担として助成される可能性がある(自己負担上限額指定あり)。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
 
PD患者の中脳断面

病理マクロ写真:健常人(右)に比し、PD患者(左)では、中脳黒質の色素沈着が減弱している(矢印)。

出典

img1:  (厚東篤生先生のご厚意による)
 
 
 
中脳神経細胞内のレビー小体(矢印)

病理ミクロ写真:拡大組織切片では、細胞内にエオジン好性を示すレビー小体(矢印)が認められる。

出典

img1:  (厚東篤生先生のご厚意による)
 
 
 
  1. 「パーキンソン病治療ガイドライン2011」の改訂版である「パーキンソン病診療ガイドライン2018」が作成された(J)。(参考文献:[1]
  1. 本ガイドラインは「Minds診療ガイドライン作成の手引き2014」に準拠し、日本神経学会「パーキンソン病診療ガイドライン」作成委員会が編集した。第Ⅰ編では「抗パーキンソン病薬、外科手術、リハビリテーションの有効性と安全性」が、第Ⅱ編では「Evidence Based Medicine (EBM) の手法(GRADEシステム)を用いた推奨」が、第Ⅲ編では「パーキンソン病診療治療に関するQ&A(クリニカルクエスチョン)」が取り上げられている。
  1. 本ガイドラインは、PD治療に関して、後期研修医を含めたすべての神経内科医が参考とすべき内容となっている。本ガイドラインはMINDS2014に従って編集されているが、特に第Ⅱ編で初めてEBMの手法(GRADEシステム)を用いて、早期および進行期の治療の推奨が記載された。また、第Ⅰ編では、前回の治療ガイドライン2011から新たに発売された薬剤が取り上げられ、また脳深部刺激療法 (DBS) と共にLCIGを用いたデュオドーパがDevice-aided Therapy (DAT) として紹介された。第Ⅲ編では「非運動症状の治療」を含めて、エキスパートオピニオンによる推奨治療が記載されている。
 
  1. 従来重視されてきた運動症状はPDの多彩な症状のうちの一部であり、非運動症状を含めた総合的な疾患の理解が重要である(推奨度2 o)。(参考文献:[2][3]
  1. PDの症状は多様な病理学的・生化学的変化を反映して多彩であり、Parkinson's complexとして理解し直す必要がある。
  1. 非運動症状はQOLの面から重要であり、現在では多面的な治療が可能となっている。また最近、後述のように、PD症状の新たな包括的評価スケールが開発されており、臨床上有用である。
 
病歴・診察のポイント  
  1. 問診では、いつからどのような症状が始まったか、その後症状は進行しているのか、認知症の有無、うつや消化器症状などで内服薬を服用していないかなどを尋ねる。

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文献 

著者: J William Langston
雑誌名: Ann Neurol. 2006 Apr;59(4):591-6. doi: 10.1002/ana.20834.
Abstract/Text
PMID 16566021  Ann Neurol. 2006 Apr;59(4):591-6. doi: 10.1002/ana.2083・・・
著者: K Ray Chaudhuri, Anthony H V Schapira
雑誌名: Lancet Neurol. 2009 May;8(5):464-74. doi: 10.1016/S1474-4422(09)70068-7.
Abstract/Text Several studies, including work from the Parkinson's disease (PD) non-motor group and others, have established that the non-motor symptoms of PD are common, occur across all stages of PD, are under-reported, and are a key determinant of quality of life. Research suggests that the non-motor symptoms of the disease are frequently unrecognised by clinicians and remain untreated. Even when identified, there is a common perception that many of these symptoms are untreatable. The role of dopaminergic drugs in treating the various non-motor problems of PD, although clinically recognised, has received little attention. In this Review, we investigate the dopaminergic basis of the range of non-motor symptoms that occur in PD such as depression, apathy, sleep disorders (including rapid-eye movement sleep behaviour disorder), and erectile dysfunction. We discuss the evidence that these symptoms are treatable, at least in part, with various dopaminergic strategies and, where relevant, we also refer to the use of deep-brain stimulation of appropriate targets in the brain. This Review provides a comprehensive overview of the management of this challenging aspect of PD.

PMID 19375664  Lancet Neurol. 2009 May;8(5):464-74. doi: 10.1016/S1474・・・
著者: Daniela Berg, Ronald B Postuma, Charles H Adler, Bastiaan R Bloem, Piu Chan, Bruno Dubois, Thomas Gasser, Christopher G Goetz, Glenda Halliday, Lawrence Joseph, Anthony E Lang, Inga Liepelt-Scarfone, Irene Litvan, Kenneth Marek, José Obeso, Wolfgang Oertel, C Warren Olanow, Werner Poewe, Matthew Stern, Günther Deuschl
雑誌名: Mov Disord. 2015 Oct;30(12):1600-11. doi: 10.1002/mds.26431.
Abstract/Text This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease-modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individual's risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available.

© 2015 International Parkinson and Movement Disorder Society.
PMID 26474317  Mov Disord. 2015 Oct;30(12):1600-11. doi: 10.1002/mds.2・・・
著者: Charles H Adler, Thomas G Beach
雑誌名: Mov Disord. 2016 Aug;31(8):1114-9. doi: 10.1002/mds.26605. Epub 2016 Mar 31.
Abstract/Text Nonmotor manifestations of Parkinson's disease (PD) can begin well before motor PD begins. It is now clear, from clinical and autopsy studies, that there is significant Lewy-type α-synucleinopathy present outside the nigro-striatal pathway and that this may underlie these nonmotor manifestations. This review discusses neuropathological findings that may underlie nonmotor symptoms that either predate motor findings or occur as the disease progresses. © 2016 International Parkinson and Movement Disorder Society.

© 2016 International Parkinson and Movement Disorder Society.
PMID 27030013  Mov Disord. 2016 Aug;31(8):1114-9. doi: 10.1002/mds.266・・・
著者: Ronald B Postuma, Daniela Berg, Matthew Stern, Werner Poewe, C Warren Olanow, Wolfgang Oertel, José Obeso, Kenneth Marek, Irene Litvan, Anthony E Lang, Glenda Halliday, Christopher G Goetz, Thomas Gasser, Bruno Dubois, Piu Chan, Bastiaan R Bloem, Charles H Adler, Günther Deuschl
雑誌名: Mov Disord. 2015 Oct;30(12):1591-601. doi: 10.1002/mds.26424.
Abstract/Text This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

© 2015 International Parkinson and Movement Disorder Society.
PMID 26474316  Mov Disord. 2015 Oct;30(12):1591-601. doi: 10.1002/mds.・・・
著者: Christopher G Goetz, Barbara C Tilley, Stephanie R Shaftman, Glenn T Stebbins, Stanley Fahn, Pablo Martinez-Martin, Werner Poewe, Cristina Sampaio, Matthew B Stern, Richard Dodel, Bruno Dubois, Robert Holloway, Joseph Jankovic, Jaime Kulisevsky, Anthony E Lang, Andrew Lees, Sue Leurgans, Peter A LeWitt, David Nyenhuis, C Warren Olanow, Olivier Rascol, Anette Schrag, Jeanne A Teresi, Jacobus J van Hilten, Nancy LaPelle, Movement Disorder Society UPDRS Revision Task Force
雑誌名: Mov Disord. 2008 Nov 15;23(15):2129-70. doi: 10.1002/mds.22340.
Abstract/Text We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.

PMID 19025984  Mov Disord. 2008 Nov 15;23(15):2129-70. doi: 10.1002/md・・・
著者: Kallol Ray Chaudhuri, Pablo Martinez-Martin, Anthony H V Schapira, Fabrizio Stocchi, Kapil Sethi, Per Odin, Richard G Brown, William Koller, Paolo Barone, Graeme MacPhee, Linda Kelly, Martin Rabey, Doug MacMahon, Sue Thomas, William Ondo, David Rye, Alison Forbes, Susanne Tluk, Vandana Dhawan, Annette Bowron, Adrian J Williams, Charles W Olanow
雑誌名: Mov Disord. 2006 Jul;21(7):916-23. doi: 10.1002/mds.20844.
Abstract/Text Nonmotor symptoms (NMS) of Parkinson's disease (PD) are not well recognized in clinical practice, either in primary or in secondary care, and are frequently missed during routine consultations. There is no single instrument (questionnaire or scale) that enables a comprehensive assessment of the range of NMS in PD both for the identification of problems and for the measurement of outcome. Against this background, a multidisciplinary group of experts, including patient group representatives, has developed an NMS screening questionnaire comprising 30 items. This instrument does not provide an overall score of disability and is not a graded or rating instrument. Instead, it is a screening tool designed to draw attention to the presence of NMS and initiate further investigation. In this article, we present the results from an international pilot study assessing feasibility, validity, and acceptability of a nonmotor questionnaire (NMSQuest). Data from 123 PD patients and 96 controls were analyzed. NMS were highly significantly more prevalent in PD compared to controls (PD NMS, median = 9.0, mean = 9.5 vs. control NMS, median = 5.5, mean = 4.0; Mann-Whitney, Kruskal-Wallis, and t test, P < 0.0001), with PD patients reporting at least 10 different NMS on average per patient. In PD, NMS were highly significantly more prevalent across all disease stages and the number of symptoms correlated significantly with advancing disease and duration of disease. Furthermore, frequently, problems such as diplopia, dribbling, apathy, blues, taste and smell problems were never previously disclosed to the health professionals.

(c) 2006 Movement Disorder Society.
PMID 16547944  Mov Disord. 2006 Jul;21(7):916-23. doi: 10.1002/mds.208・・・
著者: Parkinson Study Group
雑誌名: JAMA. 2002 Apr 3;287(13):1653-61.
Abstract/Text CONTEXT: Pramipexole and levodopa are effective medications to treat motor symptoms of early Parkinson disease (PD). In vitro and animal studies suggest that pramipexole may protect and that levodopa may either protect or damage dopamine neurons. Neuroimaging offers the potential of an objective biomarker of dopamine neuron degeneration in PD patients.
OBJECTIVE: To compare rates of dopamine neuron degeneration after initial treatment with pramipexole or levodopa in early PD by means of dopamine transporter imaging using single-photon emission computed tomography (SPECT) with 2beta-carboxymethoxy-3beta(4-iodophenyl)tropane (beta-CIT) labeled with iodine 123.
DESIGN: Substudy of a parallel-group, double-blind randomized clinical trial.
SETTING AND PATIENTS: Eighty-two patients with early PD who were recruited at 17 clinical sites in the United States and Canada and required dopaminergic therapy to treat emerging disability, enrolled between November 1996 and August 1997.
INTERVENTIONS: Patients were randomly assigned to receive pramipexole, 0.5 mg 3 times per day with levodopa placebo (n = 42), or carbidopa/levodopa, 25/100 mg 3 times per day with pramipexole placebo (n = 40). For patients with residual disability, the dosage was escalated during the first 10 weeks, and subsequently, open-label levodopa could be added. After 24 months of follow-up, the dosage of study drug could be further modified.
MAIN OUTCOME MEASURES: The primary outcome variable was the percentage change from baseline in striatal [(123)I]beta-CIT uptake after 46 months. The percentage changes and absolute changes in striatal, putamen, and caudate [(123)I]beta-CIT uptake after 22 and 34 months were also assessed. Clinical severity of PD was assessed using the Unified Parkinson Disease Rating Scale (UPDRS) 12 hours off anti-PD medications.
RESULTS: Sequential SPECT imaging showed a decline in mean (SD) [(123)I]beta-CIT striatal uptake from baseline of 10.3% (9.8%) at 22 months, 15.3% (12.8%) at 34 months, and 20.7% (14.4%) at 46 months-approximately 5.2% per year. The mean (SD) percentage loss in striatal [(123)I]beta-CIT uptake from baseline was significantly reduced in the pramipexole group compared with the levodopa group: 7.1% (9.0%) vs 13.5% (9.6%) at 22 months (P =.004); 10.9% (11.8%) vs 19.6% (12.4%) at 34 months (P =.009); and 16.0% (13.3%) vs 25.5% (14.1%) at 46 months (P =.01). The percentage loss from baseline in striatal [(123)I]beta-CIT uptake was correlated with the change from baseline in UPDRS at the 46-month evaluation (r = - 0.40; P =.001).
CONCLUSIONS: Patients initially treated with pramipexole demonstrated a reduction in loss of striatal [(123)I]beta-CIT uptake, a marker of dopamine neuron degeneration, compared with those initially treated with levodopa, during a 46-month period. These imaging data highlight the need to further compare imaging and clinical end points of PD progression in long-term studies.

PMID 11926889  JAMA. 2002 Apr 3;287(13):1653-61.
著者: Alan L Whone, Ray L Watts, A Jon Stoessl, Margaret Davis, Sven Reske, Claude Nahmias, Anthony E Lang, Olivier Rascol, Maria J Ribeiro, Philippe Remy, Werner H Poewe, Robert A Hauser, David J Brooks, REAL-PET Study Group
雑誌名: Ann Neurol. 2003 Jul;54(1):93-101. doi: 10.1002/ana.10609.
Abstract/Text Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinson's disease (PD), and a pilot clinical study using (18)F-dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2-year, randomized, double-blind, multinational study compared the rates of loss of dopamine-terminal function in de novo patients with clinical and (18)F-dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen (18)F-dopa uptake (Ki) between baseline and 2-year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region-of-interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (-13.4%; n = 68) compared with levodopa (-20.3%; n = 59; 95% confidence interval [CI], 0.65-13.06). Statistical parametric mapping localized lesser reductions in (18)F-dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, -14.1%; levodopa, -22.9%; 95% CI, 4.24-13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by (18)F-dopa PET.

PMID 12838524  Ann Neurol. 2003 Jul;54(1):93-101. doi: 10.1002/ana.106・・・
著者: Stanley Fahn, David Oakes, Ira Shoulson, Karl Kieburtz, Alice Rudolph, Anthony Lang, C Warren Olanow, Caroline Tanner, Kenneth Marek, Parkinson Study Group
雑誌名: N Engl J Med. 2004 Dec 9;351(24):2498-508. doi: 10.1056/NEJMoa033447.
Abstract/Text BACKGROUND: Despite the known benefit of levodopa in reducing the symptoms of Parkinson's disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson's disease.
METHODS: In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson's disease who were assigned to receive carbidopa-levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) uptake.
RESULTS: The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and -1.4 in those receiving 600 mg daily (P<0.001). In contrast, in a substudy of 116 patients the mean percent decline in the [123I]beta-CIT uptake was significantly greater with levodopa than placebo (-6 percent among those receiving levodopa at 150 mg daily, -4 percent in those receiving it at 300 mg daily, and -7.2 percent among those receiving it at 600 mg daily, as compared with -1.4 percent among those receiving placebo; 19 patients with no dopaminergic deficits on the baseline scans were excluded from the analysis) (P=0.036). The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo.
CONCLUSIONS: The clinical data suggest that levodopa either slows the progression of Parkinson's disease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson's disease remain uncertain.

Copyright 2004 Massachusetts Medical Society.
PMID 15590952  N Engl J Med. 2004 Dec 9;351(24):2498-508. doi: 10.1056・・・
著者: Bryan L Roth
雑誌名: N Engl J Med. 2007 Jan 4;356(1):6-9. doi: 10.1056/NEJMp068265.
Abstract/Text
PMID 17202450  N Engl J Med. 2007 Jan 4;356(1):6-9. doi: 10.1056/NEJMp・・・
著者: Louis C S Tan, Kenneth K C Ng, Wing-Lok Au, Raymond K K Lee, Yiong-Huak Chan, Nigel C K Tan
雑誌名: Mov Disord. 2009 Feb 15;24(3):344-9. doi: 10.1002/mds.22228.
Abstract/Text It has been reported that patients on pergolide and carbergoline have an increased risk of developing valvular heart disease. It is uncertain if bromocriptine, an ergot-derived dopamine agonist (DA) with partial 5-HT(2B) activity, is associated with a similar risk. We assessed the frequency of valvular heart disease in Parkinson's disease (PD) patients on bromocriptine compared to pergolide and a control group of PD patients who had not been treated on any DA. Seventy-two PD patients on bromocriptine, 21 patients on pergolide, and 47 control PD patients were recruited. Transthoracic echocardiographic studies were performed and reviewed by a blinded cardiologist. The risk for the bromocriptine group to develop any abnormal valvular regurgitation was 3.32 (adjusted OR, 95% CI: 1.11-9.92, P = 0.03) compared to controls, whereas the risk for the pergolide group was 3.66 (adjusted OR, 95% CI: 1.22-10.97, P = 0.02). When cumulative dose of bromocriptine was analyzed by quartiles, patients with a greater exposure to bromocriptine had significantly higher risk of developing both mild and moderate-severe regurgitations (P for trend, 0.005 and 0.019, respectively). This study demonstrated that bromocriptine use was associated with an increased risk of developing valvular heart disease, which occurred in a cumulative dose-dependent manner.

(c) 2008 Movement Disorder Society.
PMID 18989898  Mov Disord. 2009 Feb 15;24(3):344-9. doi: 10.1002/mds.2・・・
著者: Mitsutoshi Yamamoto, Tadahisa Uesugi, Takeo Nakayama
雑誌名: Neurology. 2006 Oct 10;67(7):1225-9. doi: 10.1212/01.wnl.0000238508.68593.1d.
Abstract/Text OBJECTIVE: To determine the frequency of cardiac valvulopathy in patients with Parkinson disease (PD) treated with or without dopamine agonists.
METHODS: We obtained transthoracic echocardiography and EKG in 210 consecutive patients with PD admitted to our hospital between September 2004 and September 2005. We analyzed the frequency according to the type of dopamine agonist. A case-control design was adopted with dopamine agonist nontreated group as the reference group, and multiple logistic regression analysis was conducted considering age, sex, and duration of illness to examine the relationships between each dopamine agonist and the presence of valvular abnormalities.
RESULTS: The frequency of valvulopathy was significantly higher in the cabergoline-treated group (68.8%, 11/16; affected patients/total) than in the dopamine agonist nontreated control group (17.6%, 15/85). The frequency was not different between the pergolide group (28.8%, 19/66) and the pramipexole group (25%, 4/16). The adjusted odds ratio was significantly higher in the cabergoline group (12.96, 95% CI = 3.59 to 46.85), compared with the pergolide group (2.18, 95% CI = 0.90 to 5.30) and pramipexole group (1.62, 95% CI = 0.45 to 5.87). The mean daily dose was 3.8 mg for cabergoline, 1.4 mg for pergolide, and 1.7 mg for pramipexole. The cumulative dose and treatment duration of cabergoline in the valvulopathy subgroup were significantly higher than in the nonvalvulopathy subgroup.
CONCLUSION: The frequency of valvulopathy was significantly increased in the cabergoline group. Our results indicate that high cumulative dose and long-term treatment with cabergoline are risk factors for valvulopathy in patients with Parkinson disease.

PMID 17030757  Neurology. 2006 Oct 10;67(7):1225-9. doi: 10.1212/01.wn・・・
著者: Kazuo Yamashiro, Miki Komine-Kobayashi, Taku Hatano, Takao Urabe, Hideki Mochizuki, Nobutaka Hattori, Yoshitaka Iwama, Hiroyuki Daida, Michi Sakai, Takeo Nakayama, Yoshikuni Mizuno
雑誌名: Mov Disord. 2008 May 15;23(7):935-41. doi: 10.1002/mds.22036.
Abstract/Text To investigate the frequency of cardiac valve regurgitation related with low dose dopamine agonists in patients with Parkinson's disease (PD), echocardiograms were analyzed in 527 consecutive PD patients (448 patients treated with dopamine agonists, 79 patients never treated with dopamine agonists as age-matched controls). The frequency of mild or above mild regurgitation of the aortic valve (AR) was significantly higher in the cabergoline group (13.7%, P < 0.05) compared with the controls (2.5%). Odds ratio adjusted by age and sex for AR was significantly higher in the cabergoline group (OR, 6.45; 95% CI, 1.46-28.60; P = 0.01): odds ratio was significantly higher in patients treated with higher daily doses (OR, 14.41; 95% CI, 3.08-67.38; P = 0.0007) and higher cumulative doses (OR, 15.29; 95% CI, 3.19-73.18; P = 0.0006). No statistical difference was identified in the frequency of the tricuspid and mitral regurgitation. None of the other dopamine agonist groups including pergolide gave higher frequency or higher odds ratio compared with the controls. None of our patients showed severe regurgitation or was operated for valvular heart disease. The question as to whether or not longer duration of low dose dopamine agonist treatment would yield the same results needs further studies.

PMID 18398916  Mov Disord. 2008 May 15;23(7):935-41. doi: 10.1002/mds.・・・
著者: PD Med Collaborative Group, Richard Gray, Natalie Ives, Caroline Rick, Smitaa Patel, Alastair Gray, Crispin Jenkinson, Emma McIntosh, Keith Wheatley, Adrian Williams, Carl E Clarke
雑誌名: Lancet. 2014 Sep 27;384(9949):1196-205. doi: 10.1016/S0140-6736(14)60683-8. Epub 2014 Jun 11.
Abstract/Text BACKGROUND: Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease.
METHODS: In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316.
FINDINGS: Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5-3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0-2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01-0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0·81, 95% CI 0·61-1·08, p=0·14), admissions to institutions (0·86, 0·63-1·18; p=0·4), and death (0·85, 0·69-1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001).
INTERPRETATION: Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists.
FUNDING: UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 24928805  Lancet. 2014 Sep 27;384(9949):1196-205. doi: 10.1016/S0・・・
著者: Robert G Holloway, Ira Shoulson, Stanley Fahn, Karl Kieburtz, Anthony Lang, Kenneth Marek, Michael McDermott, John Seibyl, William Weiner, Bruno Musch, Cornelia Kamp, Mickie Welsh, Aileen Shinaman, Rajesh Pahwa, Lynn Barclay, Jean Hubble, Peter LeWitt, Janis Miyasaki, Oksana Suchowersky, Mark Stacy, David S Russell, Blair Ford, John Hammerstad, David Riley, David Standaert, Frederick Wooten, Stewart Factor, Joseph Jankovic, Farah Atassi, Roger Kurlan, Michel Panisset, Ali Rajput, Robert Rodnitzky, Cliff Shults, Giselle Petsinger, Cheryl Waters, Ronald Pfeiffer, Kevin Biglan, Leona Borchert, Amy Montgomery, Laura Sutherland, Carolyn Weeks, Maryan DeAngelis, Elspeth Sime, Susan Wood, Carol Pantella, Mary Harrigan, Barbara Fussell, Sandra Dillon, Barbara Alexander-Brown, Pamela Rainey, Marsha Tennis, Elke Rost-Ruffner, Diane Brown, Sharon Evans, Debra Berry, Jean Hall, Theresa Shirley, Judith Dobson, Deborah Fontaine, Brenda Pfeiffer, Alicia Brocht, Susan Bennett, Susan Daigneault, Karen Hodgeman, Carolynn O'Connell, Tori Ross, Karen Richard, Arthur Watts, Parkinson Study Group
雑誌名: Arch Neurol. 2004 Jul;61(7):1044-53. doi: 10.1001/archneur.61.7.1044.
Abstract/Text BACKGROUND: The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear.
OBJECTIVE: To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes.
DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial.
SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada.
PATIENTS: Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001.
INTERVENTION: Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability.
MAIN OUTCOME MEASURES: Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events.
RESULTS: Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups.
CONCLUSIONS: Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.

PMID 15262734  Arch Neurol. 2004 Jul;61(7):1044-53. doi: 10.1001/archn・・・
著者: Robert A Hauser, Olivier Rascol, Amos D Korczyn, A Jon Stoessl, Ray L Watts, Werner Poewe, Peter P De Deyn, Anthony E Lang
雑誌名: Mov Disord. 2007 Dec;22(16):2409-17. doi: 10.1002/mds.21743.
Abstract/Text In a 5-year, double-blind study, subjects with Parkinson's disease (PD) who were randomized to initial treatment with ropinirole had a significantly lower incidence of dyskinesia compared with subjects randomized to levodopa, although Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were significantly more improved in the levodopa group. Subjects who completed the original study were eligible to participate in a long-term extension study conducted according to an open, naturalistic design and were evaluated approximately every 6 months until they had been followed for a total of 10 years. Comparing subjects randomized to initial treatment with ropinirole (n = 42) and levodopa (n = 27), the incidence of dyskinesia was significantly lower in the ropinirole group (adjusted odds ratio [OR] = 0.3; 95% confidence interval [CI]: 0.1, 1.0; P = 0.046) and the median time to dyskinesia was significantly longer (adjusted hazard ratio = 0.4; 95% CI: 0.2, 0.8; P = 0.007). The incidence of at least moderate wearing off ("off" time >/=26% of the awake day) was also significantly lower in the ropinirole group (adjusted OR = 0.3; 95% CI: 0.09, 0.03; P = 0.03). There were no significant differences in change in UPDRS activities of daily living or motor scores, or scores for the 39-item PD questionnaire, Clinical Global Impression, or the Epworth Sleepiness Scale. Early treatment decisions for individual patients depend largely on the anticipated risk of side effects and long-term complications. Both ropinirole and levodopa are viable treatment options in early PD.

PMID 17894339  Mov Disord. 2007 Dec;22(16):2409-17. doi: 10.1002/mds.2・・・
著者: Wolfgang H Oertel, Erik Wolters, Cristina Sampaio, Santiago Gimenez-Roldan, Bruno Bergamasco, Max Dujardin, Donald G Grosset, Guy Arnold, Klaus L Leenders, Hans-Peter Hundemer, Alberto Lledó, Andrew Wood, Paul Frewer, Johannes Schwarz
雑誌名: Mov Disord. 2006 Mar;21(3):343-53. doi: 10.1002/mds.20724.
Abstract/Text Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.

(c) 2005 Movement Disorder Society.
PMID 16211594  Mov Disord. 2006 Mar;21(3):343-53. doi: 10.1002/mds.207・・・
著者: Fulvio Bracco, Angelo Battaglia, Carlos Chouza, Erik Dupont, Oscar Gershanik, Jose Felix Marti Masso, Jean-Louis Montastruc, PKDS009 Study Group
雑誌名: CNS Drugs. 2004;18(11):733-46.
Abstract/Text OBJECTIVES: Cabergoline is an ergoline derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabergoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson's disease.
STUDY DESIGN AND METHODS: This study was a double-blind, multicentre trial that compared cabergoline and levodopa as initial therapy for Parkinson's disease. A total of 419 levodopa-, DA- and selegiline-naive patients with newly diagnosed Parkinson's disease were randomised to receive either cabergoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1-5, the cabergoline group was receiving cabergoline at average daily doses ranging from 2.8-2.9 mg, with added levodopa at mean daily doses ranging from 322 mg at year 1 to 431 mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784 mg. Thus, patients in the cabergoline group received <50% levodopa than patients in the levodopa group.
RESULTS: Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabergoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabergoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabergoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabergoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabergoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson's Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician- and patient- rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabergoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabergoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). Cabergoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabergoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabergoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly.
CONCLUSION: This study showed that, compared with levodopa, initial therapy with cabergoline in patients with Parkinson's disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.

PMID 15330687  CNS Drugs. 2004;18(11):733-46.
著者: S J Frucht, P E Greene, S Fahn
雑誌名: Mov Disord. 2000 Jul;15(4):601-3.
Abstract/Text
PMID 10928569  Mov Disord. 2000 Jul;15(4):601-3.
著者: Douglas E Hobson, Anthony E Lang, W R Wayne Martin, Ajmal Razmy, Jean Rivest, Jonathan Fleming
雑誌名: JAMA. 2002 Jan 23-30;287(4):455-63.
Abstract/Text CONTEXT: Somnolence is a recognized adverse effect of dopamine agonists. Two new dopamine agonists, pramipexole and ropinirole, have been reported to cause sudden-onset sleep spells in patients with Parkinson disease (PD) while they were driving. The frequency of these spells and whether driving should be restricted has yet to be established.
OBJECTIVE: To determine the frequency of and predictors for sudden-onset sleep and, particularly, episodes of falling asleep while driving among patients with PD.
DESIGN, SETTING, AND PARTICIPANTS: Prospective survey conducted between January and April 2000 in 18 clinics directed by members of the Canadian Movement Disorders Group; 638 consecutive highly functional PD patients without dementia were enrolled, of whom 420 were currently drivers.
MAIN OUTCOME MEASURES: Excessive daytime sleepiness and sudden-onset sleep as assessed by the Epworth Sleepiness Scale and the Inappropriate Sleep Composite Score. The latter score, designed for this study, addressed falling asleep in unusual circumstances. The 2 scales were combined in 3 separate formats: dozing off, sudden unexpected sleep, and sudden blank spells.
RESULTS: Excessive daytime sleepiness was present overall in 327 (51%) of the 638 patients and in 213 (51%) of the 420 drivers. Patients taking a variety of different dopamine agonists had no differences in Epworth sleepiness scores, in the composite score, or in the risk of falling asleep while driving. Sixteen patients (3.8%) had experienced at least 1 episode of sudden onset of sleep while driving (after the diagnosis of PD); in 3 (0.7%), it occurred without warning. The 2 risk factors associated with falling asleep at the wheel were the Epworth Sleepiness Scale score (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.24) and the Inappropriate Sleep Composite Score (OR, 2.54; 95% CI, 1.76-3.66). A standard Epworth Sleepiness Scale score of 7 or higher predicted 75% of episodes of sleep behind the wheel at a specificity of 50% (exclusion of the question related to driving provided 70% sensitivity and 52% specificity), whereas a score of 1 on the Inappropriate Sleep Composite Score generated a sensitivity of 52% and specificity of 82%.
CONCLUSIONS: Excessive daytime sleepiness is common even in patients with PD who are independent and do not have dementia. Sudden-onset sleep without warning is infrequent. The Epworth score has adequate sensitivity for predicting prior episodes of falling asleep while driving and its specificity can be increased by use of the Inappropriate Sleep Composite Score. It is unknown if routinely performing these assessments could be more effective in predicting future risk for these rare sleep attacks. Patients should be warned not to drive if they doze in unusual circumstances.

PMID 11798367  JAMA. 2002 Jan 23-30;287(4):455-63.
著者: S Frucht, J D Rogers, P E Greene, M F Gordon, S Fahn
雑誌名: Neurology. 1999 Jun 10;52(9):1908-10.
Abstract/Text The authors report a new side effect of the dopamine agonists pramipexole and ropinirole: sudden irresistible attacks of sleep. Eight PD patients taking pramipexole and one taking ropinirole fell asleep while driving, causing accidents. Five experienced no warning before falling asleep. The attacks ceased when the drugs were stopped. Neurologists who prescribe these drugs and patients who take them should be aware of this possible side effect.

PMID 10371546  Neurology. 1999 Jun 10;52(9):1908-10.
著者: Tomoko Oeda, Motoko Masaki, Kenji Yamamoto, Eiji Mizuta, Naoyuki Kitagawa, Tsuyoshi Isono, Satoshi Taniguchi, Kiyoshi Doi, Hitoshi Yaku, Chikao Yutani, Takashi Kawamura, Sadako Kuno, Hideyuki Sawada
雑誌名: J Neural Transm. 2009 Feb;116(2):171-8. doi: 10.1007/s00702-008-0160-2. Epub 2008 Dec 10.
Abstract/Text An association between ergot-derived dopamine agonists and asymptomatic valvular heart disease in Parkinson's disease has been established. For safe use of these agonists, it is important to specify those at high risk for valvular heart disease among patients with Parkinson's disease. We performed a nested case-control study of 223 patients with Parkinson's disease. In results of multivariable logistic analyses, use of pergolide, use of cabergoline, age, male sex, and hypertension were independent significant risk factors for left-sided valvular regurgitation. In patients receiving cabergoline or pergolide, elderly (>or=70 years) hypertensive patients had a markedly high risk for valvular regurgitation (odds ratio 94.5) as compared to non-elderly (<70 years) patients without hypertension. The risk of valvular regurgitation caused by pergolide or cabergoline was found to be highly enhanced by comorbid hypertension or aging, suggesting that special attention should be paid when prescribing cabergoline or pergolide for those patients.

PMID 19082526  J Neural Transm. 2009 Feb;116(2):171-8. doi: 10.1007/s0・・・
著者: Sabine Binder, Gunther Deuschl, Jens Volkmann
雑誌名: Eur Neurol. 2009;61(3):149-53. doi: 10.1159/000186505. Epub 2008 Dec 18.
Abstract/Text BACKGROUND: Tremor is one of the cardinal symptoms in Parkinson's disease, but only few clinical studies have focussed on its therapy as the primary endpoint. One reason is the substantial fluctuation of tremor severity over time, which is difficult to capture and may render momentary clinical assessments unreliable.
METHODS: We evaluated the usefulness of a novel wrist-worn actigraph allowing long-term recordings of tremor in a pilot study, in which we assessed the therapeutic effect of cabergoline on tremor in 10 patients with tremor-dominant Parkinson's disease. Clinical data were obtained by using the Unified Parkinson's Disease Rating Scale (UPDRS Part III, item 20) and simultaneously a patient's tremor diary.
RESULTS: We found a significant reduction in UPDRS motor and tremor scores, in tremor duration and tremor amplitude by actigraphy and diaries. Furthermore, we found significant correlations between actigraphy measurements and patient ratings of tremor intensity and occurrence in diaries.
CONCLUSION: Long-term actigraphy is a reliable method to assess tremor occurrence and severity and may be used to document antitremor effects in clinical studies.

Copyright (c) 2008 S. Karger AG, Basel.
PMID 19092251  Eur Neurol. 2009;61(3):149-53. doi: 10.1159/000186505. ・・・
著者: O Pogarell, T Gasser, J J van Hilten, S Spieker, S Pollentier, D Meier, W H Oertel
雑誌名: J Neurol Neurosurg Psychiatry. 2002 Jun;72(6):713-20.
Abstract/Text OBJECTIVE: To compare the tremorlytic properties of pramipexole, a non-ergoline dopamine agonist to those of placebo as add on medication in patients with Parkinson's disease.
METHODS: Eighty four patients with early or advanced Parkinson's disease and marked, drug resistant tremor under a stable and optimised antiparkinsonian medication were included in a double blind, randomised, placebo controlled, multicentre study and assigned to add on treatment (7 week dose titration interval, 4 week maintenance period) with either pramipexole (n=44) or placebo (n=40) as adjunct. The primary end point was the absolute change in tremor score, defined as the sum of tremor related items (16, 20, 21) of the unified Parkinson's disease rating scale (UPDRS) in "on" periods. Secondary end points included the percentage change in tremor score, the absolute and percentage changes in long term EMG tremor registration, and the change in tremor self rating scales. Safety and tolerability were assessed on the basis of adverse events, laboratory tests, ECG, and vital signs.
RESULTS: Pramipexole was significantly superior to placebo with a difference between treatment groups in the mean absolute change in tremor score of -4.4 (95% confidence interval (95% CI) -6.2 to -2.5) (p<0.0001), corresponding to a difference in the mean percentage change of -34.7% in favour of pramipexole. The secondary end points were consistent with the significant change in tremor score and provided further evidence for the benefit of pramipexole compared with placebo. Long term EMG registration as an objective measure showed a difference in mean absolute change in tremor occurrence of -15.2% (95%CI -21.4 to -9.0) (p<0.0001), and a difference in the mean percentage change of -45.7% in favour of pramipexole. The treatment effects increased during dose titration and remained stable during the 4 week maintenance dose period until the end of the study. The average daily pramipexole dose during maintenance was 4.1 (SD 0.9) mg. Safety analysis showed an increased rate of fatigue, insomnia, nausea, abdominal pain, and headache under pramipexole, comparable with previous studies.
CONCLUSION: Pramipexole proved to be an effective agent for patients with Parkinson's disease and drug resistant tremor.

PMID 12023411  J Neurol Neurosurg Psychiatry. 2002 Jun;72(6):713-20.
著者: Prithiva Navan, Leslie J Findley, Jim A R Jeffs, Ronald K B Pearce, Peter G Bain
雑誌名: Mov Disord. 2003 Nov;18(11):1324-31. doi: 10.1002/mds.10538.
Abstract/Text We compared the antitremor effect of pramipexole, pergolide, or placebo in Parkinson's disease (PD). A double-blind, randomly controlled, parallel protocol was deployed to examine the effects of placebo, pergolide, and pramipexole [doses escalated to 1.5 mg three times daily (t.i.d.) over 3 months] on a compound Tremor Index (TI) and Unified Parkinson's Disease Rating Scale (UPDRS) part III. Thirty PD patients (19 men, 11 women; mean age 69 years, range 54-80 years; mean disease duration 3.9 years, range, 0.5-10 years) participated in the study, with 10 patients in each arm. Six subjects failed to complete the study (4 on pergolide and 2 on placebo). Analysis of covariance demonstrated strong evidence for a treatment effect on both TI and UPDRS III. There was no significant difference between the active treatments on either TI or UPDRS III. Both pergolide and pramipexole were significantly better than placebo. The results indicate that pergolide and pramipexole (1.5 mg t.i.d.) have similar anti-PD tremor and UPDRS III actions that are significantly superior to placebo. Patients on pergolide were more likely to drop out because of adverse events than those on pramipexole.

PMID 14639675  Mov Disord. 2003 Nov;18(11):1324-31. doi: 10.1002/mds.1・・・
著者: P Navan, L J Findley, M B Undy, R K B Pearce, P G Bain
雑誌名: Eur J Neurol. 2005 Jan;12(1):1-8. doi: 10.1111/j.1468-1331.2004.01019.x.
Abstract/Text This study examined the relative anti-Parkinson's disease (PD) tremor potencies of pergolide and pramipexole in people with PD, using a 3-month double-blind cross-over design. Patients were randomly assigned to receive either pergolide and then pramipexole (n=9) or vice versa (n=8). The dose of the respective dopamine agonist was increased according to a titration schedule up to a maximum 1.5 mg t.d.s., with cross-over at 10 weeks. Assessments were performed at baseline, 4, 8 and 12 weeks. The primary outcome measures were the differences in the clinical (rest and postural) tremor scores on pergolide versus pramipexole. Seventeen PD patients (11 females and six males) with a mean age 68.4 years (range: 55-84 years) and a mean disease duration of 3.9 years (range: 2 months to 13 years) participated in the study. Twelve of the patients were taking other anti-parkinsonian medications. Two patients dropped out of the study whilst on pergolide. Fifteen of 16 patients were able to cross-over from one dopamine agonist to the other, without major retitration. There were no significant differences between the effects of the two drugs on the primary outcome measures, suggesting that the anti-PD tremor efficacies of dopaminergic medications are not dependent on differential affinities for dopamine receptor types.

PMID 15613140  Eur J Neurol. 2005 Jan;12(1):1-8. doi: 10.1111/j.1468-1・・・
著者: A Schrag, J Keens, J Warner, Ropinirole Study Group
雑誌名: Eur J Neurol. 2002 May;9(3):253-7.
Abstract/Text The effect of Ropinirole on tremor in early Parkinson's disease (PD) was assessed. The results of three multicentre, randomized, double-blind trials comparing ropinirole monotherapy with levodopa, bromocriptine and placebo treatment were analysed retrospectively with respect to improvement of resting tremor and postural/action tremor as measured by items 20 and 21 of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). Improvements in resting tremor were significantly better with ropinirole than placebo. There were no significant differences between the effect of ropinirole and those of levodopa (L-dopa) or bromocriptine on resting tremor. Postural/action tremor was mild in these early therapy studies, and there were no significant differences between treatment groups. These results suggest that ropinirole monotherapy is effective in treating resting tremor in early PD. On the other hand, response of postural/action tremor to dopaminergic treatment in early PD was not significantly better than to placebo at the dosages used in these trials.

PMID 11985633  Eur J Neurol. 2002 May;9(3):253-7.
著者: W C Koller
雑誌名: Arch Neurol. 1986 Feb;43(2):126-7.
Abstract/Text The relative efficacy of trihexiphenidyl hydrochloride, amantadine hydrochloride, and low-dose carbidopa-levodopa in reducing parkinsonian tremor was investigated using objective techniques. Trihexiphenidyl and carbidopa-levodopa decreased tremor by greater than 50%. Some patients responded to one drug but not to the other. Amantadine decreased tremor less than 25%. Monotherapy with trihexiphenidyl or carbidopa-levodopa should be the initial treatment for the tremor of Parkinson's disease.

PMID 3947248  Arch Neurol. 1986 Feb;43(2):126-7.
著者: Yoshikuni Mizuno, Nobuo Yanagisawa, Sadako Kuno, Mitsutoshi Yamamoto, Kazuko Hasegawa, Hideki Origasa, Hisayuki Kowa, Japanese Pramipexole Study Group
雑誌名: Mov Disord. 2003 Oct;18(10):1149-56. doi: 10.1002/mds.10508.
Abstract/Text We compared the efficacy and safety of pramipexole (PPX) with placebo in the treatment of advanced Parkinson's disease (PD) as an adjunct to levodopa. A bromocriptine (BR) group was included to enable determination of the noninferiority of PPX relative to BR as the standard treatment.

Copyright 2003 Movement Disorder Society
PMID 14534919  Mov Disord. 2003 Oct;18(10):1149-56. doi: 10.1002/mds.1・・・
著者: J E Ahlskog, M D Muenter
雑誌名: Mov Disord. 2001 May;16(3):448-58.
Abstract/Text There is no clear consensus regarding the frequency (and hence, the risk), of dyskinesias or motor fluctuations during chronic levodopa therapy for Parkinson's disease (PD). Multiple clinical series have tabulated these frequencies since the advent of levodopa over 30 years ago. We were interested in determining: (1) the aggregate frequency figures in the existing literature; and (2) how clinical series from the early levodopa era, which included patients with longer durations of parkinsonism, compare to more recent (modern era) series. We searched MEDLINE for all English language publications reporting the cumulative frequency of levodopa-induced dyskinesias or motor fluctuations during discrete intervals of treatment. This generated 2,478 publications spanning 1966 through September 2000. Papers with appropriate titles or abstracts were reviewed; reference lists from published clinical series were a source of additional papers for review. This ultimately yielded 74 publications with adequate data, relating to 112 intervals of levodopa treatment. Series that included patients with PD-onset well before levodopa availability (pre-levodopa era) were separately analyzed from all subsequent series. Series were grouped by duration of levodopa therapy and the median frequencies of dyskinesias and motor fluctuations were tabulated for each group. The data were analyzed both with and without adjustment for the number (N) in each series. Among series containing pre-levodopa era patients, the median dyskinesia frequency was already 50% by 5-6 months of treatment. This contrasts with the modern era series where dyskinesias were reported later in treatment. The median dyskinesia frequency was slightly less than 40% by 4-6 years of levodopa therapy among modern era patients. Motor fluctuations (wearing-off) were not tabulated in most of the early levodopa series. Among modern era reports, motor fluctuations were nil during the first year of levodopa therapy but were experienced by approximately 40% of patients by 4-6 years of treatment. Similar results were found when the analyses were restricted to only prospective studies where levodopa motor complications were targeted outcome measures. The conclusions reached were: (1) patients from the pre-levodopa era experienced dyskinesias much earlier during levodopa treatment than modern era patients, perhaps because of longer durations of pre-existing PD; (2) in the present era, patients treated with levodopa therapy for 4-6 years have approximately a 40% likelihood of experiencing motor fluctuations and a risk of dyskinesias just short of 40%; and (3) these findings represent incident data and the prevalence of clinically important morbidity may be substantially less.

Copyright 2001 Movement Disorder Society.
PMID 11391738  Mov Disord. 2001 May;16(3):448-58.
著者: A Thomas, D Iacono, A L Luciano, K Armellino, A Di Iorio, M Onofrj
雑誌名: J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):141-3.
Abstract/Text BACKGROUND: Recent short-term studies suggested that amantadine (Ama) might ameliorate dyskinesia in patients with Parkinson's disease. A double-blind study programmed over 12 months was designed to assess the duration of the antidyskinetic effect of amantadine on levodopa induced dyskinesia.
METHODS: 40 patients treated for 7.5 (2.2) years with levodopa (729.3 (199.4) mg/day) and dopaminoagonists, having peak dose or dyphasic dyskinesia with or without pain, were assessed with the Unified Parkinson's Disease Rating Scale subscale IV, Items 32-34, the Dyskinesia Rating Scale and Investigator Global Assessment. Twenty patients received amantadine chloridrate (100 mg) and 20 received a placebo. The Ama or placebo could be withdrawn when scores indicated worsening of dyskinesia, after agreement with the patient.
RESULTS: After 15 days of amantadine treatment there was a reduction by 45% in the total dyskinesia scores. All patients in the placebo group were withdrawn in 1-3 months and all patients in the Ama group were withdrawn in 3-8 months (p = 0.01, p<0.001). Ama withdrawal induced a rebound with increase of dyskinesia by 10-20% in 11 patients.
CONCLUSION: 300 mg amantadine reduces dyskinesia in Parkinson's disease by approximately 45% but the benefit lasted less than eight months.

PMID 14707325  J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):141-3.
著者: Francisco Pereira da Silva-Júnior, Pedro Braga-Neto, Francisca Sueli Monte, Veralice Meireles Sales de Bruin
雑誌名: Parkinsonism Relat Disord. 2005 Nov;11(7):449-52. doi: 10.1016/j.parkreldis.2005.05.008. Epub 2005 Sep 9.
Abstract/Text We evaluated the effects of amantadine on levodopa-induced dyskinesia (LID) in eighteen consecutive Parkinson's disease (PD) patients in a randomized, double-blind, placebo-controlled study. The primary outcomes were the Clinical Dyskinesia Rating Scale (CDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS) part IVa score changes. The secondary outcomes were the UPDRS II and III score changes. Amantadine did not change the CDRS score for hyperkinesia or dystonia, but decreased the duration of LID and its influence on daily activities (p=0.04) and the UPDRS II score (p=0.01) more than placebo. These findings show that amantadine reduces the duration of LID and improves motor disability in PD.

PMID 16154788  Parkinsonism Relat Disord. 2005 Nov;11(7):449-52. doi: ・・・
著者: C Paci, A Thomas, M Onofrj
雑誌名: Neurol Sci. 2001 Feb;22(1):75-6.
Abstract/Text 20 patients (12 men and 8 women, mean age 65 years) affected by severe Parkinson's disease (PD) with peak-dose and/or diphasic dyskinesias or painful dyskinesia were treated with amantadine (300 mg/day) as adjunctive therapy to current levodopa, carbidopa and dopaminoagonist. UPDRS (Unified Parkinson's disease rating scale), dyskinesias rating scale (DRS) and IGA (investigator global assessment) scale were used to evaluate the severity of PD symptoms during follow-up. After 15 days with amantadine treatment all patients improved with an average 38% reduction in dyskinesias (p<0.001). After 2-8 months. amantadine was withdrawn in all patients. After amantadine withdrawal, 2 patients experienced severe hyperthermia (39 degrees C and 40 degrees C). No difference was found between end of treatment dyskinesia scores and final withdrawal scores (p<0.5). In the two patients with hyperthemia amantadine was reintroduced; after four days hyperthermia subsided and amantadine was finally tapered over 15 days without further adverse reactions.

PMID 11487209  Neurol Sci. 2001 Feb;22(1):75-6.
著者: Hideyuki Sawada, Tomoko Oeda, Sadako Kuno, Masahiro Nomoto, Kenji Yamamoto, Mitsutoshi Yamamoto, Kinya Hisanaga, Takashi Kawamura, Amantadine Study Group
雑誌名: PLoS One. 2010 Dec 31;5(12):e15298. doi: 10.1371/journal.pone.0015298. Epub 2010 Dec 31.
Abstract/Text BACKGROUND: Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias.
METHODS: In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg/day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinson's Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function).
RESULTS: RDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores.
CONCLUSIONS: Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60-70% of patients.
TRIAL REGISTRATION: UMIN Clinical Trial Registry UMIN000000780.

PMID 21217832  PLoS One. 2010 Dec 31;5(12):e15298. doi: 10.1371/journa・・・
著者: W H Poewe, G Deuschl, A Gordin, E-R Kultalahti, M Leinonen, Celomen Study Group
雑誌名: Acta Neurol Scand. 2002 Apr;105(4):245-55.
Abstract/Text OBJECTIVES: To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients.
PATIENTS AND METHODS: In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests.
RESULTS: In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results.
CONCLUSION: Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.

PMID 11939936  Acta Neurol Scand. 2002 Apr;105(4):245-55.
著者: Kelvin L Chou, Marian Evatt, Vanessa Hinson, Katie Kompoliti
雑誌名: Mov Disord. 2007 Dec;22(16):2306-13. doi: 10.1002/mds.21646.
Abstract/Text A significant number of patients with Parkinson's disease (PD) experience sialorrhea. This problem can cause social embarrassment, and because saliva pools in the mouth, may lead to aspiration pneumonia. Sialorrhea in PD is thought to be caused by impaired or infrequent swallowing, rather than hypersecretion. Oral medications, botulinum toxin injections, surgical interventions, radiotherapy, speech therapy, and trials of devices may be used to treat sialorrhea in PD, but few controlled trials have been published. This article reviews current knowledge regarding the frequency, etiology, assessment, and treatment of sialorrhea in PD.

2007 Movement Disorder Society
PMID 17659637  Mov Disord. 2007 Dec;22(16):2306-13. doi: 10.1002/mds.2・・・
著者: Lon S Schneider, Karen S Dagerman, Philip Insel
雑誌名: JAMA. 2005 Oct 19;294(15):1934-43. doi: 10.1001/jama.294.15.1934.
Abstract/Text CONTEXT: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns have arisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortality with their use.
OBJECTIVE: To assess the evidence for increased mortality from atypical antipsychotic drug treatment for people with dementia.
DATA SOURCES: MEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register (2005, Issue 1), meetings presentations (1997-2004), and information from the sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial.
STUDY SELECTION: Published and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease or dementia were selected by consensus of the authors.
DATA EXTRACTION: Trials, baseline characteristics, outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure was obtained or estimated. Data were checked by a second reviewer.
DATA SYNTHESIS: Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis.
CONCLUSIONS: Atypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. This risk should be considered within the context of medical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety of alternatives. Individual patient analyses modeling survival and causes of death are needed.

PMID 16234500  JAMA. 2005 Oct 19;294(15):1934-43. doi: 10.1001/jama.29・・・
著者: B Ravina, M Putt, A Siderowf, J T Farrar, M Gillespie, A Crawley, H H Fernandez, M M Trieschmann, S Reichwein, T Simuni
雑誌名: J Neurol Neurosurg Psychiatry. 2005 Jul;76(7):934-9. doi: 10.1136/jnnp.2004.050682.
Abstract/Text OBJECTIVE: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD).
METHODS: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog).
RESULTS: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale.There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant.
CONCLUSIONS: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.

PMID 15965198  J Neurol Neurosurg Psychiatry. 2005 Jul;76(7):934-9. do・・・
著者: Iracema Leroi, Jason Brandt, Stephen G Reich, Constantine G Lyketsos, Stephen Grill, Richard Thompson, Laura Marsh
雑誌名: Int J Geriatr Psychiatry. 2004 Jan;19(1):1-8. doi: 10.1002/gps.993.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of donepezil, an acetylcholinesterase inhibitor, as a treatment for cognitive impairment and dementia in patients with Parkinson' s disease (PD).
METHODS: Using a randomized, double-blind, placebo-controlled design, nine patients received placebo and seven patients received donepezil (2.5-10 mg/day) for a mean (SD) duration of 15.2 (3.4) weeks. The primary efficacy outcomes were derived from a neuropsychological battery that assessed global cognitive status as well as memory, attention, psychomotor speed, and visuospatial and executive functions. Secondary efficacy outcomes were psychiatric symptom and activities of daily living ratings. Primary safety measures were motor signs and assessments of adverse effects.
RESULTS: Patients on donepezil showed selective and significant (p<0.05) improvement on the memory subscale of the Dementia Rating Scale. There was also a trend toward improvement on a measure of psychomotor speed and attention. There were no group differences in psychiatric status, motor function, or activities of daily living as measured at baseline or end-point. Adverse effects resulted in premature withdrawal of four patients on donepezil, two for peripheral cholinergic effects and one for increased parkinsonism. Side effects were associated with dosage increases.
CONCLUSION: Donepezil has a beneficial effect on memory and may improve other cognitive deficits in patients with PD and cognitive impairment. However, variable tolerability in our sample underscores the need for careful monitoring when prescribing donepezil to patients with PD, especially with dosage increases.

Copyright 2004 John Wiley & Sons, Ltd.
PMID 14716693  Int J Geriatr Psychiatry. 2004 Jan;19(1):1-8. doi: 10.1・・・
著者: V Voon, K Hassan, M Zurowski, M de Souza, T Thomsen, S Fox, A E Lang, J Miyasaki
雑誌名: Neurology. 2006 Oct 10;67(7):1254-7. doi: 10.1212/01.wnl.0000238503.20816.13. Epub 2006 Sep 6.
Abstract/Text We surveyed 297 patients with Parkinson disease (PD) with systematic screens and rigorous definitional criteria. Pathologic hypersexuality lifetime prevalence was 2.4%. Compulsive shopping was 0.7%. Combined with our pathologic gambling data, the lifetime prevalence of these behaviors was 6.1% and increases to 13.7% in patients on dopamine agonists.

PMID 16957130  Neurology. 2006 Oct 10;67(7):1254-7. doi: 10.1212/01.wn・・・
著者: M Menza, R D Dobkin, H Marin, M H Mark, M Gara, S Buyske, K Bienfait, A Dicke
雑誌名: Neurology. 2009 Mar 10;72(10):886-92. doi: 10.1212/01.wnl.0000336340.89821.b3. Epub 2008 Dec 17.
Abstract/Text BACKGROUND: Parkinson disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Depression affects up to 50% of these patients and is associated with a variety of poor outcomes for patients and their families. Despite this, there are few evidence-based data to guide clinical care.
METHODS: An NIH-funded, randomized, controlled trial of paroxetine CR, nortriptyline, and placebo in 52 patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks.
RESULTS: Nortriptyline was superior to placebo for the change in HAM-D (p < 0.002); paroxetine CR was not. There was a trend for superiority of nortriptyline over paroxetine CR at 8 weeks (p < 0.079). Response rates favored nortriptyline (p = 0.024): nortriptyline 53%, paroxetine CR 11%, placebo 24%. In planned contrasts of response rates, nortriptyline was superior to paroxetine CR (p = 0.034). Nortriptyline was also superior to placebo in many of the secondary outcomes, including sleep, anxiety, and social functioning, while paroxetine CR was not. Both active drug treatments were well tolerated.
CONCLUSIONS: Though relatively modest in size, this is the largest placebo-controlled trial done to date in patients with Parkinson disease (PD) and depression. Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not. When compared directly, nortriptyline produced significantly more responders than did paroxetine CR. The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors.

PMID 19092112  Neurology. 2009 Mar 10;72(10):886-92. doi: 10.1212/01.w・・・
著者: Emily Bomasang-Layno, Iris Fadlon, Andrea N Murray, Seth Himelhoch
雑誌名: Parkinsonism Relat Disord. 2015 Aug;21(8):833-42; discussion 833. doi: 10.1016/j.parkreldis.2015.04.018. Epub 2015 May 16.
Abstract/Text CONTEXT: Depression affects 50-70% of patients with Parkinson's disease resulting in significant comorbidity, executive dysfunction, and poorer quality of life. Divergent results from studies of different treatments preclude definite treatment recommendations.
OBJECTIVE: To perform a systematic review and meta-analysis of published randomized controlled trials (RCTS) evaluating the efficacy of pharmacologic and behavioral interventions, and repetitive transcranial magnetic stimulation (rTMS) for depression among patients with idiopathic Parkinson's disease.
DATA SOURCES: Trial registers and the following databases were searched: PubMed, CINAHL, EMBASE, and PsycInfo. Bibliographies of relevant articles were cross-referenced.
STUDY SELECTION AND DATA EXTRACTION: RCTs comparing pharmacologic, behavioral, or rTMS with a placebo/other drugs or methods with no restrictions on participant age, gender, and duration or setting of treatment were included. Eligibility assessment was performed independently. Identified records were sequentially screened according to eligibility criteria. Differences in mean depression score and 95% confidence intervals were calculated.
RESULTS: A total of 893 idiopathic Parkinson's disease patients with clinical depression across 20 RCTs were included. The overall standard mean difference for all pharmacologic interventions was 0.30 (95% CI -0.00, 0.61, p = 0.054). On stratification, there was a distinct difference in effect between antidepressants (SMD of 0.54, 95%CI 0.24, 0.83, p = 0.000) and non-antidepressants (SMD of -0.29, 95% CI -0.86, 0.29, p = 0.328). Behavioral interventions demonstrated significant efficacy with an effect size of 0.87 (95% CI 0.41, 1.33, p = 0.000).
CONCLUSIONS: This meta-analysis demonstrates that pharmacologic treatment with antidepressant medications, specifically the selective serotonin reuptake inhibitors (SSRIs), and behavioral interventions (CBT) significantly improved depression among Parkinson's disease patients.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 26037457  Parkinsonism Relat Disord. 2015 Aug;21(8):833-42; discu・・・
著者: S E Starkstein, H S Mayberg, T J Preziosi, P Andrezejewski, R Leiguarda, R G Robinson
雑誌名: J Neuropsychiatry Clin Neurosci. 1992 Spring;4(2):134-9.
Abstract/Text The authors examined a consecutive series of 50 patients for the presence of apathy, depression, anxiety, and neuropsychological deficits using a neuropsychological battery that included a recently designed apathy scale. This scale was found to be reliable and valid in the diagnosis of apathy in patients with PD. Of patients in the study, 12% showed apathy as their primary psychiatric problem, and 30% were both apathetic and depressed. Patients with apathy (with or without depression), showed significantly more deficits in both tasks of verbal memory and time-dependent tasks. Results suggest that apathy is a frequent finding in PD, is significantly associated with specific cognitive impairments, and may have a different mechanism than depression.

PMID 1627973  J Neuropsychiatry Clin Neurosci. 1992 Spring;4(2):134-9・・・
著者: Kenn Freddy Pedersen, Jan Petter Larsen, Guido Alves, Dag Aarsland
雑誌名: Parkinsonism Relat Disord. 2009 May;15(4):295-9. doi: 10.1016/j.parkreldis.2008.07.006. Epub 2008 Sep 17.
Abstract/Text The objective of this study was to examine the prevalence and clinical correlates of apathy in a population-based sample of patients with Parkinson's disease (PD) and to assess whether apathy may present as a primary behavioural disturbance independent from depression and cognitive impairment. A total of 232 patients derived from an epidemiological study of PD in Rogaland county, Western Norway, completed a comprehensive evaluation of motor, cognitive, and depressive symptoms. Apathy was assessed with the motivation/initiative item of the Unified Parkinson's Disease Rating Scale. The majority of the population had mild to moderate PD with mean disease duration of 9.1+/-5.7 years. Apathy was diagnosed in 38% of the 232 patients. In 11% of the total sample apathy coexisted with depression and dementia, whereas 10% had apathy and depression without dementia, 6.5% apathy and dementia without depression, and 9% were apathetic without dementia or depression (data missing in 1.5% patients). Apathy was significantly associated with higher depression scores, lower cognitive functioning, and more severe motor symptoms. When excluding patients with depression, dementia, cognitive impairment with no dementia (population-based age- and education-corrected norms for the Mini-Mental State Examination), and those using psychotropic medication, 5% of the 232 patients had apathy. In conclusion, our study shows that apathy is common in the general PD population, may present as an independent behavioural disorder, and suggests that apathy in PD may be related to dysfunction of the nigro-striatal pathway or that brain pathology underlying apathy and progression of motor symptoms develops in parallel.

PMID 18801696  Parkinsonism Relat Disord. 2009 May;15(4):295-9. doi: 1・・・
著者: G Schifitto, J H Friedman, D Oakes, L Shulman, C L Comella, K Marek, S Fahn, Parkinson Study Group ELLDOPA Investigators
雑誌名: Neurology. 2008 Aug 12;71(7):481-5. doi: 10.1212/01.wnl.0000324862.29733.69.
Abstract/Text BACKGROUND: Fatigue is a common complaint in Parkinson disease (PD). We investigated fatigue in a cohort of previously untreated patients with early PD enrolled in the Earlier vs Later Levodopa (ELLDOPA) clinical trial.
METHODS: A total of 361 patients were enrolled in the randomized, double-blind, placebo-controlled ELLDOPA trial and assigned to receive placebo or carbidopa-levodopa 37.5/150 mg, 75/300 mg, or 150/600 mg daily for 40 weeks, followed by a 2-week medication washout period. Subjects who scored >4 on the Fatigue Severity Scale were classified as fatigued. PD severity was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn-Yahr scale, and Schwab-England Activities of Daily Living Scale. A subgroup of subjects underwent [(123)I]-beta-CIT SPECT to measure striatal dopamine transporter density.
RESULTS: Of the 349 ELLDOPA subjects who completed fatigue measures, 128 were classified as fatigued at baseline. The fatigued group was significantly more impaired neurologically (UPDRS, all subscales and Hoehn and Yahr staging) and functionally (Schwab-England Scale) but no significant differences were observed in beta-CIT measurements between the two groups. Analysis of covariance showed a greater increase in fatigue score from baseline to the end of the 2-week washout in the placebo group (0.75 points) than in the three groups receiving levodopa (increases of 0.30 [150 mg/day], 0.36 [300 mg/day], and 0.33 [600 mg/day]; p = 0.03 for heterogeneity).
CONCLUSIONS: Fatigue is a frequent symptom in early, untreated, non-depressed patients with Parkinson disease (PD), affecting over 1/3 of the patients in this cohort at baseline and 50% by week 42. Fatigue was associated with the severity of PD, and progressed less in patients treated with levodopa.

PMID 18695158  Neurology. 2008 Aug 12;71(7):481-5. doi: 10.1212/01.wnl・・・

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