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抗精神病薬の副作用のマネジメント

著者: 竹内啓善 慶應義塾大学医学部 精神・神経科学教室

監修: 上島国利 昭和大学

著者校正/監修レビュー済:2020/06/19
参考ガイドライン:
  1. David M.Taylor et al編, 内田裕之ほか訳:モーズレイ処方ガイドライン 第13版, 2019
  1. 米国神経学会(AAN):遅発性症候群の治療ガイドライン
患者向け説明資料

概要・推奨   

  1. 第2世代抗精神病薬は、遅発性ジスキネジアを含め、錐体外路症状のリスクが第1世代抗精神病薬よりも低いため、統合失調症治療の第1選択薬として推奨される(推奨度2)。
  1. 代表的な第2世代抗精神病薬のうち、錐体外路症状のリスクが最も高いのはリスペリドン/パリペリドン、次いでアリピプラゾール、クエチアピン、オランザピン、最も低いのはクロザピンである。このため、錐体外路症状に対応が必要な場合、相対的リスクが低い第2世代抗精神病薬への変更が考慮される(推奨度2)。
  1. アカシジアの治療は、多くのガイドラインやアルゴリズムが、まずは抗精神病薬の減量ないし第2世代抗精神病薬への変更を推奨している(推奨度2)。
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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:
竹内啓善 : 講演料(大塚製薬,大日本住友製薬)[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. 定期レビューを行い、全体的に加筆修正を行った。

まとめ

副作用のまとめ  
  1. 抗精神病薬の主要な副作用のうち、錐体外路症状(パーキンソン症候群、急性ジストニア、アカシジア、遅発性ジスキネジア)はどの抗精神病薬でも出現し得るが、第1世代抗精神病薬(特に高力価)で多くみられる。
  1. 高プロラクチン血症はどの抗精神病薬でも出現し得るが、第1世代抗精神病薬、リスペリドン/パリペリドンで多くみられる。
  1. 代謝系副作用(体重増加、糖代謝異常・糖尿病、脂質代謝異常・高脂血症)はどの抗精神病薬でも出現し得るが、アリピプラゾール以外の第2世代抗精神病薬、低力価の第1世代抗精神病薬で多くみられる。
  1. このほか、悪性症候群、QTc延長、性機能障害、抗コリン症状(口渇、便秘、霧視など)、眠気などさまざまな副作用がある。
 
各抗精神病薬の副作用プロフィール

モーズレイ処方ガイドラインの各抗精神病薬の副作用プロフィール一覧を示す。

 
  1. 第2世代抗精神病薬は、遅発性ジスキネジアを含め、錐体外路症状のリスクが第1世代抗精神病薬よりも低いため、統合失調症治療の第1選択薬として推奨される(推奨度2S)。
  1. 錐体外路症状のリスクについて、第2世代抗精神病薬と第1世代抗精神病薬を比較したメタアナリシス、大規模無作為化比較試験が存在する。
  1. 抗パーキンソン薬の使用を指標にして錐体外路症状のリスクを比較したメタアナリシス[1]では、高力価の第1世代抗精神病薬であるハロペリドールに比べて、すべての第2世代抗精神病薬(リスペリドン、オランザピン、クエチアピン、アリピプラゾール、クロザピン、ゾテピン、ziprasidone、amisulpride、sertindole)は有意に低かった。一方、低力価の第1世代抗精神病薬と比べて有意に少なかったのは、リスペリドン、オランザピン、クロザピンのみであった。(図<図表>
  1. 慢性期の統合失調症を対象にした大規模無作為化比較試験であるCATIE study[2]では、リスペリドン、オランザピン、クエチアピン、ziprasidoneは、中力価の第1世代抗精神病薬であるペルフェナジンと比べ、パーキンソン症候群、ジストニア、アカシジア、遅発性ジスキネジアの出現に有意な差がなかった。
  1. 以上より、少なくとも高力価の第1世代抗精神病薬と比較した場合、第2世代抗精神病薬は錐体外路症状のリスクは低い。よって、第2世代抗精神病薬が原則的に推奨される。
  1. 遅発性ジスキネジアの年間発生率について、第2世代抗精神病薬と第1世代抗精神病薬を比較したメアナリシス[3]が存在する。57の無作為化比較試験を統合した結果では、年間発生率は第2世代抗精神病薬では2.6%、第1世代抗精神病薬では6.5%であった。(図<図表>
  1. 以上より、第2世代抗精神病薬は第1世代抗精神病薬より遅発性ジスキネジアのリスクが低い。よって、難治性である遅発性ジスキネジアの発現予防からも、第2世代抗精神病薬が原則的に推奨される。
 
錐体外路症状:第2世代抗精神病薬と第1世代抗精神病薬との比較(メタアナリシス)

錐体外路症状について、第2世代抗精神病薬と第1世代抗精神病薬を比較したメタアナリシスの結果を示す。ハロペリドールに比べて、すべての第2世代抗精神病薬は、錐体外路症状のリスクが有意に低かった。一方、低力価の第1世代抗精神病薬と比べて有意に低かったのは、リスペリドン、オランザピン、クロザピンのみであった。

出典

img1:  Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.
 
 Lancet. 2009 Jan 3;373(9657):31-41. doi:・・・
 
遅発性ジスキネジア:第2世代抗精神病薬と第1世代抗精神病薬の比較(メタアナリシス)

遅発性ジスキネジアの1年間の発生率について、第2世代抗精神病薬と第1世代抗精神病薬を比較したシステマティック・レビューでは、第2世代抗精神病薬で2.1%、第1世代抗精神病薬で5.4%であった。

出典

img1:  Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis.
 
 World Psychiatry. 2018 Oct;17(3):330-340・・・
 
  1. 代表的な第2世代抗精神病薬のうち、錐体外路症状のリスクが最も高いのはリスペリドン/パリペリドン、次いでアリピプラゾール、クエチアピン、オランザピン、最も低いのはクロザピンである。このため、錐体外路症状に対応が必要な場合、相対的リスクが低い第2世代抗精神病薬への変更が考慮される(推奨度2)。
  1. 錐体外路症状のリスクについて、第2世代抗精神病薬間を比較したメタアナリシス、大規模無作為化比較試験が存在する。
  1. 抗パーキンソン薬の使用を指標にして錐体外路症状のリスクを比較したネットワークメタアナリシスでは[4]、代表的かつ現在本邦で使用可能な第2世代抗精神病薬のうち、最もリスクが高いのはリスペリドン/パリペリドン、次いでブレクスピプラゾール、アリピプラゾール、アセナピン、クエチアピン、オランザピン、最も低いのはクロザピンであった。(図<図表>
  1. 慢性期の統合失調症を対象にした大規模無作為化比較試験であるCATIE study[2]では、リスペリドン、オランザピン、クエチアピン、ziprasidoneでパーキンソン症候群、ジストニア、アカシジア、遅発性ジスキネジアの出現に有意な差がなかった。しかしながら、パーキンソン症候群に対する抗パーキンソン薬の使用に関しては、リスペリドンが多く、クエチアピンが少なかった。また、アカシジアに対する抗パーキンソン薬の使用に関しては、リスペリドンが多かった。
  1. 以上より、第2世代抗精神病薬のうち、錐体外路症状のリスクは、リスペリドン/パリペリドンが相対的に高く、クエチアピン、オランザピン、クロザピンが最も低い。よって、錐体外路症状に対応が必要な場合は、相対的にリスクが低い第2世代抗精神病薬への変更が考慮される。
 
錐体外路症状:第2世代抗精神病薬間の比較(メタアナリシス)

出典

img1:  Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis.
 
 Lancet. 2019 Sep 14;394(10202):939-951. ・・・
 
問診・診察のポイント  
  1. 錐体外路症状は、特に視診が重要になる。

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文献 

著者: Stefan Leucht, Caroline Corves, Dieter Arbter, Rolf R Engel, Chunbo Li, John M Davis
雑誌名: Lancet. 2009 Jan 3;373(9657):31-41. doi: 10.1016/S0140-6736(08)61764-X. Epub 2008 Dec 6.
Abstract/Text BACKGROUND: Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled trials to compare the effects of these two types of drugs in patients with schizophrenia.
METHODS: We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation.
FINDINGS: We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride -0.31 [95% CI -0.44 to -0.19, p<0.0001], clozapine -0.52 [-0.75 to -0.29, p<0.0001], olanzapine -0.28 [-0.38 to -0.18, p<0.0001], and risperidone -0.13 [-0.22 to -0.05, p=0.002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication.
INTERPRETATION: Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost.

PMID 19058842  Lancet. 2009 Jan 3;373(9657):31-41. doi: 10.1016/S0140-・・・
著者: Del D Miller, Stanley N Caroff, Sonia M Davis, Robert A Rosenheck, Joseph P McEvoy, Bruce L Saltz, Silvana Riggio, Miranda H Chakos, Marvin S Swartz, Richard S E Keefe, T Scott Stroup, Jeffrey A Lieberman, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators
雑誌名: Br J Psychiatry. 2008 Oct;193(4):279-88. doi: 10.1192/bjp.bp.108.050088.
Abstract/Text BACKGROUND: There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs.
AIMS: To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia.
METHOD: Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted.
RESULTS: There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine.
CONCLUSIONS: The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.

PMID 18827289  Br J Psychiatry. 2008 Oct;193(4):279-88. doi: 10.1192/b・・・
著者: Maren Carbon, John M Kane, Stefan Leucht, Christoph U Correll
雑誌名: World Psychiatry. 2018 Oct;17(3):330-340. doi: 10.1002/wps.20579.
Abstract/Text Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second-generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first-generation antipsychotics, FGAs). As some reports questioned this notion, we meta-analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head-to-head RCTs, including 32 FGA and 86 SGA arms, were meta-analyzed, yielding 32 FGA-SGA pairs and 35 SGA-SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3-7.8%) vs. 2.6% (95% CI: 2.0-3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39-0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28-0.45, p<0.0001, number-needed-to-treat, NNT=20). Meta-regression showed no FGA dose effect on FGA-SGA comparisons (Z=-1.03, p=0.30). FGA-SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non-clozapine SGAs in exploratory pairwise comparisons. SGA-SGA comparisons confirmed the olanzapine advantage vs. non-clozapine SGAs (RaR=0.66, 95% CI: 0.49-0.88, p=0.006, k=17, NNT=100). This meta-analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.

© 2018 World Psychiatric Association.
PMID 30192088  World Psychiatry. 2018 Oct;17(3):330-340. doi: 10.1002/・・・
著者: Maximilian Huhn, Adriani Nikolakopoulou, Johannes Schneider-Thoma, Marc Krause, Myrto Samara, Natalie Peter, Thomas Arndt, Lio Bäckers, Philipp Rothe, Andrea Cipriani, John Davis, Georgia Salanti, Stefan Leucht
雑誌名: Lancet. 2019 Sep 14;394(10202):939-951. doi: 10.1016/S0140-6736(19)31135-3. Epub 2019 Jul 11.
Abstract/Text BACKGROUND: Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials.
METHODS: We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919.
FINDINGS: We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low.
INTERPRETATION: There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences.
FUNDING: German Ministry of Education and Research and National Institute for Health Research.

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 31303314  Lancet. 2019 Sep 14;394(10202):939-951. doi: 10.1016/S0・・・
著者: J Rathbone, K Soares-Weiser
雑誌名: Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003727. doi: 10.1002/14651858.CD003727.pub3. Epub 2006 Oct 18.
Abstract/Text BACKGROUND: Neuroleptic-induced akathisia is one of the most common and distressing early-onset adverse effects of first generation 'typical' antipsychotic drugs. It is associated with poor compliance with treatment, and thus, ultimately, with an increased risk of relapse. We assessed the role of anticholinergic drugs as an adjunct therapy to standard antipsychotic medication in the pharmacological treatment of this adverse effect.
OBJECTIVES: To review anticholinergic drugs for neuroleptic-induced acute akathisia.
SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (October 1999), Biological Abstracts (1982-1999), CINAHL (1982-1999), Cochrane Library (Issue 4 1999), EMBASE (1980-1999), LILACS (1982-1999), MEDLINE (1966-1999) and PsycLIT (1974-1999). References of all identified studies were inspected for more trials and we contacted first authors. Each included study was sought as a citation on the Science Citation Index database. For this 2005-6 update, we searched the Cochrane Schizophrenia Group's Register (July 2005).
SELECTION CRITERIA: We included all randomised clinical trials of adjunctive anticholinergic drugs in addition to antipsychotic medication compared with placebo, for people with neuroleptic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: We quality assessed and extracted data independently. We calculated the fixed effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) for homogeneous dichotomous data on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD).
MAIN RESULTS: We identified no relevant randomised controlled trials.
AUTHORS' CONCLUSIONS: At present, there is no reliable evidence to support or refute the use of anticholinergics for people suffering from neuroleptic-induced acute akathisia. Akathisia is a distressing movement disorder that remains highly prevalent in people with schizophrenia, both in the developed and developing world. This review highlights the need for well designed, conducted and reported clinical trials to address the claims of open studies as regards the effects of the anticholinergic group of drugs for akathisia.

PMID 17054182  Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003727. d・・・
著者: Bora Baskak, E Cem Atbasoglu, Halise Devrimci Ozguven, Meram Can Saka, Ali Kemal Gogus
雑誌名: J Clin Psychopharmacol. 2007 Jun;27(3):289-94. doi: 10.1097/jcp.0b013e3180582439.
Abstract/Text Neuroleptic-induced acute akathisia (NIA) is a distressing condition and an important clinical problem because it is associated with treatment noncompliance and suicidal or impulsive behavior. Anticholinergics are among the treatment options; however, a review of the literature fails to identify a double-blind, randomized, placebo-controlled study of these medications in NIA. In a randomized, double-blind, placebo-controlled design, we studied the effectiveness of intramuscular biperiden (n = 15) or isotonic saline (n = 15) in the treatment of NIA diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Injections were repeated up to 3 times unless akathisia was completely treated (scored 0 for global akathisia with the Barnes Akathisia Rating Scale). Patients were assessed for akathisia, other movement disorders, and psychiatric symptoms at baseline and 3 times after the first injection at 2-hour intervals. Response was defined as at least a 2-point decline in the global akathisia score. The numbers of responders in the 2 groups were not significantly different (7 and 5 in the biperiden and placebo groups, respectively). The courses of individual items on the Barnes Akathisia Rating Scale were also similar. Our results suggest that intramuscular biperiden should not be considered as a first-line treatment of NIA.

PMID 17502777  J Clin Psychopharmacol. 2007 Jun;27(3):289-94. doi: 10.・・・
著者: A R Lima, J Bacalcthuk, T R E Barnes, K Soares-Weiser
雑誌名: Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001946. doi: 10.1002/14651858.CD001946.pub2. Epub 2004 Oct 18.
Abstract/Text BACKGROUND: Neuroleptic-induced akathisia is a common, distressing early-onset adverse effect of neuroleptic drugs. It has been associated with poor treatment compliance and an increased risk of relapse.
OBJECTIVES: To determine the effects of central action beta-blockers compared with placebo for people with neuroleptic-induced acute akathisia.
SEARCH STRATEGY: We updated previous searches of the Cochrane Schizophrenia Group Register (May 1999), Biological Abstracts (January 1982-March 1999), The Cochrane Library (issue 3 1999), EMBASE (January 1980-March 1999), LILACS (January 1982-March 1999), MEDLINE (January 1964-March 1999), PsycLIT (January 1974-March 1999), and SCISEARCH by searching the Cochrane Schizophrenia Group Register (November 2003). We sought further references from published trials and their authors.
SELECTION CRITERIA: We included all randomised controlled clinical trials of central action beta-blockers versus placebo for people with neuroleptic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). For continuous data we calculated Weighted Mean Differences (WMD).
MAIN RESULTS: We identified three randomised controlled trials (total n=51, maximum duration 72 hours). We were not able to draw any firm conclusions from such a small data set. In the two 48 hour studies no-one experienced full remission of akathisia, and only one person in each group experienced a 50% remission (n=11, 1 RCT, RR 1.04 CI 0.59 -1.83). One trial stated that no adverse effects occurred in the two groups (n=20, 1 RCT, RR not estimable). The 72 hour study did not show any statistical difference between the central acting beta-blocker (ICI 118,551) and placebo for the outcome 'no change/worse' (n=10, RR 0.22 CI 0.0 to 1.5).
REVIEWERS' CONCLUSIONS: There are insufficient data to recommend beta-blocking drugs for akathisia. These drugs are experimental for this problem, and this review highlights the need for more evaluative studies.

PMID 15495022  Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001946. d・・・
著者: A R Lima, K Soares-Weiser, J Bacaltchuk, T R Barnes
雑誌名: Cochrane Database Syst Rev. 2002;(1):CD001950. doi: 10.1002/14651858.CD001950.
Abstract/Text BACKGROUND: Neuroleptic-induced akathisia is one of the most common and distressing early-onset adverse effects of antipsychotic drugs, being associated with poor compliance with treatment, and thus, ultimately, to an increase risk of relapse. This review assesses the role of benzodiazepines in the pharmacological treatment of this problem.
OBJECTIVES: To determine the effects of benzodiazepines versus placebo for people with neuroleptic-induced acute akathisia.
SEARCH STRATEGY: Biological Abstracts (January 1982-March 1999), The Cochrane Library (Issue 3 1999), The Cochrane Schizophrenia Group's Register (May 2001), EMBASE (January 1980-March 1999), LILACS (January 1982-March 1999), MEDLINE (January 1964-March 1999), PsycLIT (January 1974-March 1999), and SCISEARCH were searched. Further references were sought from published trials and their authors.
SELECTION CRITERIA: All randomised clinical trials comparing benzodiazepines with placebo for people with antipsychotic-induced acute akathisia.
DATA COLLECTION AND ANALYSIS: Two reviewers, working independently, selected, quality assessed and extracted data. These data were then analysed on an intention-to-treat basis. For homogeneous dichotomous data the fixed effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, reviewers calculated weighted mean differences.
MAIN RESULTS: Two small (total N=27) randomised controlled trials were included. By seven to 14 days, there was a reduction in symptoms for those patients receiving clonazepam compared with placebo (2 RCTs, N=26, RR 0.09 CI 0.01 to 0.6, NNT 1.2 CI 0.9 to 1.5). No significant difference was found for adverse events (2 RCTs, N=26, RR 3.00 CI 0.2 to 62) or the need for anticholinergic medication (2 RCTs, N=26, RR 1.56 CI 0.9 to 2.7). No one left the two studies early. Data on mental, social and family outcomes could not be pooled and there was little or no data on user satisfaction, deaths, violence, criminal behaviour and costs.
REVIEWER'S CONCLUSIONS: Over a short follow-up period, the use of benzodiazepines may reduce the symptoms of antipsychotic-induced acute akathisia. This review highlights the need for well designed, conducted and reported clinical trials to address the claims of open studies.

PMID 11869614  Cochrane Database Syst Rev. 2002;(1):CD001950. doi: 10.・・・
著者: Roongroj Bhidayasiri, Onanong Jitkritsadakul, Joseph H Friedman, Stanley Fahn
雑誌名: J Neurol Sci. 2018 Jun 15;389:67-75. doi: 10.1016/j.jns.2018.02.010. Epub 2018 Feb 5.
Abstract/Text BACKGROUND: Management of tardive syndromes (TS) is challenging, with only a few evidence-based therapeutic algorithms reported in the American Academy of Neurology (AAN) guideline in 2013.
OBJECTIVE: To update the evidence-based recommendations and provide a practical treatment algorithm for management of TS by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TS treatment? 2) Does switching from typical to atypical DRBAs reduce TS symptoms? 3) What is the efficacy of pharmacologic agents in treating TS? 4) Do patients with TS benefit from chemodenervation with botulinum toxin? 5) Do patients with TS benefit from surgical therapy?
METHODS: Systematic reviews were conducted by searching PsycINFO, Ovid MEDLINE, PubMed, EMBASE, Web of Science and Cochrane for articles published between 2012 and 2017 to identify new evidence published after the 2013 AAN guidelines. Articles were classified according to an AAN 4-tiered evidence-rating scheme. To the extent possible, for each study we attempted to categorize results based on the description of the population enrolled (tardive dyskinesia [TD], tardive dystonia, tardive tremor, etc.). Recommendations were based on the evidence.
RESULTS AND RECOMMENDATIONS: New evidence was combined with the existing guideline evidence to inform our recommendations. Deutetrabenazine and valbenazine are established as effective treatments of TD (Level A) and must be recommended as treatment. Clonazepam and Ginkgo biloba probably improve TD (Level B) and should be considered as treatment. Amantadine and tetrabenazine might be considered as TD treatment (Level C). Pallidal deep brain stimulation possibly improves TD and might be considered as a treatment for intractable TD (Level C). There is insufficient evidence to support or refute TS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

Copyright © 2018 Elsevier B.V. All rights reserved.
PMID 29454493  J Neurol Sci. 2018 Jun 15;389:67-75. doi: 10.1016/j.jns・・・
著者: K Soares-Weiser, J Rathbone
雑誌名: Cochrane Database Syst Rev. 2006 Jan 25;(1):CD000459. doi: 10.1002/14651858.CD000459.pub2. Epub 2006 Jan 25.
Abstract/Text BACKGROUND: Since the 1950s neuroleptic medication has been extensively used to treat people with chronic mental illnesses such as schizophrenia. These drugs, however, have been also associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD). Various strategies have been examined to reduce a person's cumulative exposure to neuroleptics. These studies include dose reduction, intermittent dosing strategies such as drug holidays, and neuroleptic cessation.
OBJECTIVES: To determine whether a reduction or cessation of neuroleptic drugs is associated with a reduction in TD, for people with schizophrenia (or other chronic mental illnesses) who have existing TD. Our secondary objective was to determine whether the use of specific neuroleptics for similar groups of people could be a treatment for TD that was already established.
SEARCH STRATEGY: We updated previous searches of the Cochrane Schizophrenia Groups Register (1997), Biological Abstracts (1982-1997), EMBASE (1980-1997), LILACS (1982-1996), MEDLINE (1966-1997), PsycLIT (1974-1997), and SCISEARCH (1997) by searching the Cochrane Schizophrenia Groups Register (July 2003). We searched references of all identified studies for further trial citations. We also contacted the principal authors of trials for further unpublished trials.
SELECTION CRITERIA: We included reports if they assessed people with schizophrenia or other chronic mental illnesses who had established neuroleptic-induced TD, and had been randomly allocated to (a) neuroleptic maintenance versus neuroleptic cessation (placebo or no intervention), (b) neuroleptic maintenance versus neuroleptic reduction (including intermittent strategies), and (c) specific neuroleptics for the treatment of TD versus, placebo or intervention. A post hoc decision was made to broaden comparison (c) to include specific neuroleptics versus other neuroleptics for the treatment of TD.
DATA COLLECTION AND ANALYSIS: We (KSW, JR) independently inspected citations and, where possible, abstracts, ordered papers, and re-inspected and quality assessed these and extracted data. We analysed dichotomous data using random effects relative risk (RR) and estimated the 95% confidence interval (CI). Where possible we calculated the number needed to treat (NNT) or number needed to harm statistic (NNH). We excluded continuous data if more than 50% of people were lost to follow up, but, where possible, we calculated the weighted mean difference (WMD). It was assumed that those leaving the study early showed no improvement.
MAIN RESULTS: We included five trials and excluded 102. One small two week study (n=18), reported on the 'masking' effects of molindone and haloperidol on TD, which favoured haloperidol (RR 3.44 CI 1.1 to 5.8). Two (total n=17) studies found no reduction in TD associated with neuroleptic reduction (RR 0.38 CI 0.1 to 1.0). One study (n=20) found no significant differences in oral dyskinesia (RR 2.45 CI 0.3 to 19.7) when neuroleptics were compared as a specific treatment for TD. Dyskinesia was found to be not significantly different (n=32, RR 0.62 CI 0.3 to 1.26) between quetiapine and haloperidol when these neuroleptics were used as specific treatments for TD, although the need for additional neuroleptics was significantly lower in the quetiapine group (n=47, RR 0.49 CI 0.2 to 1.0) than in those given haloperidol.
AUTHORS' CONCLUSIONS: Limited data from small studies using neuroleptic reduction or specific neuroleptic drugs as treatments for TD did not provide any convincing evidence of the value of these approaches. There is a need for larger trials of a longer duration in order to fully investigate this area.

PMID 16437425  Cochrane Database Syst Rev. 2006 Jan 25;(1):CD000459. d・・・
著者: K V Soares, J J McGrath
雑誌名: Cochrane Database Syst Rev. 2000;(2):CD000204. doi: 10.1002/14651858.CD000204.
Abstract/Text BACKGROUND: Neuroleptic medication is used extensively to treat people with chronic mental illnesses. However, it is associated with a wide range of adverse effects, including movement disorders. Because of this, many acutely psychotic patients being treated with neuroleptic medication also receive anticholinergic drugs in order to reduce some of the associated movement side-effects.
OBJECTIVES: To determine whether the use or the withdrawal of anticholinergic drugs (benzhexol or benztropine or biperiden or orphenadrine or procyclidine or scopolamine or trihexylphenidyl) were clinically effective for the treatment of people with both neuroleptic-induced TD and schizophrenia or other chronic mental illnesses.
SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1995), Cochrane Schizophrenia Group's Register of trials (1995), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995), PsycLIT (1974-1995), and SCISEARCH (1995) were undertaken. References of all identified studies were searched for further trial citations. Principle authors of trials were contacted.
SELECTION CRITERIA: Reports identified in the search were included if they were controlled trials dealing with people with neuroleptic-induced TD and schizophrenia or other chronic mental illness who had been randomly allocated to either an anticholinergic agent or to a placebo (or no intervention).
DATA COLLECTION AND ANALYSIS: No data could be extracted from the seven randomised controlled trials identified.
MAIN RESULTS: No data were synthesized. The authors have been contacted to provide the relevant information. Two studies were excluded because no data are available and six others are still awaiting further information from the authors.
REVIEWER'S CONCLUSIONS: Based on currently available information, no confident statement can be made about the effectiveness of anticholinergics to treat people with neuroleptic-induced tardive dyskinesia. The same applies for the withdrawal of such medications. Whether the withdrawal of anticholinergics may benefit people with neuroleptic-induced TD, this should be evaluated in a parallel-group, placebo-controlled randomised trial, with adequate sample size and at least 6 weeks of follow up.

PMID 10796321  Cochrane Database Syst Rev. 2000;(2):CD000204. doi: 10.・・・
著者: I A Tammenmaa, J J McGrath, E Sailas, K Soares-Weiser
雑誌名: Cochrane Database Syst Rev. 2002;(3):CD000207. doi: 10.1002/14651858.CD000207.
Abstract/Text BACKGROUND: Tardive dyskinesia remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that tardive dyskinesia could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat tardive dyskinesia.
OBJECTIVES: To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating neuroleptic-induced tardive dyskinesia in people with schizophrenia or other chronic mental illness.
SEARCH STRATEGY: An electronic search of the Cochrane Schizophrenia Group's register (October 2001) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of conference proceedings and dissertations. References of all identified studies were searched for further trial citations. Principal authors of trials were contacted.
SELECTION CRITERIA: Reports identified by the search were included if they were of controlled trials dealing with people with neuroleptic-induced tardive dyskinesia and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two reviewers independently assessed methodological quality of trials.
DATA COLLECTION AND ANALYSIS: Two researchers extracted data and, where possible, estimated relative risks (RR) or weighted mean differences (WMD), with 95% confidence intervals (CI). Data were analysed on an intention-to-treat basis, with the assumption that people who dropped out had no improvement.
MAIN RESULTS: We included eleven studies investigating the use of older cholinergic drugs compared with placebo. Most studies involved small numbers of participants (5-20 people). We found no completed trials of the new cholinergic Alzheimer drugs for the treatment of tardive dyskinesia. Cholinergic drugs did not result in any substantial improvement in tardive dyskinesia symptoms when compared with placebo (8 RCTs, 170 people, RR no important improvement 0.84 CI 0.68 to 1.04). Neither did tardive dyskinesia symptoms increase (7 RCTs, 137 people, RR deterioration in tardive dyskinesia 1.17 CI 0.55 to 2.50). Pooled results for endpoint AIMS scores were equivocal (4 RCTs, 86 people, WMD -0.19 CI -0.53 to 0.14). Deanol may cause gastric adverse effects (5 RCTs, 61 people, RR 9.00 CI 0.55-148) and other adverse effects such as sedation and peripheral cholinergic effects (6 RCTs, 94 people, RR 6.83 CI 0.99-47). One study reported on global outcome. Meclofenoxate was neither clearly helpful nor harmful when compared with placebo (1 RCT, 60 people, RR not of global benefit 0.89 CI 0.59 to 1.32). We found no difference between people allocated cholinergics and those given placebo for the outcome of leaving the study before completion (10 RCTs, 240 people, RR 0.52 CI 0.21 to 1.33).
REVIEWER'S CONCLUSIONS: Tardive dyskinesia remains a major public health problem. The clinical effects of older cholinergic drugs are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with tardive dyskinesia, their effects should be demonstrated in well-designed, conducted and reported randomised trials.

PMID 12137608  Cochrane Database Syst Rev. 2002;(3):CD000207. doi: 10.・・・
著者: Joseph Bergman, Tzvi Dwolatzky, Izidor Brettholz, Vladimir Lerner
雑誌名: J Clin Psychiatry. 2005 Jan;66(1):107-10.
Abstract/Text BACKGROUND: Tardive dyskinesia and other delayed-onset abnormal involuntary movement disorders may occur as a result of the use of psychotropic drugs. A distinction is usually made between classic tardive dyskinesia (TD) (orobuccal-lingual-facial) and tardive dystonia, tardive tremor (TT), tardive akathisia, and other related syndromes. In spite of the development of atypical antipsychotics with fewer side effects, tardive movement disorders nevertheless continue to present a significant clinical and therapeutic challenge. Several reports have suggested that donepezil may be helpful in the treatment of TD.
METHOD: A preliminary study was conducted of 7 patients (5 women and 2 men) enrolled over a period of 6 months who had been experiencing TT for a period of at least 1 year. The ages of the patients ranged from 64 to 79 years, and all patients were on stable antipsychotic therapy. Donepezil was added to their usual treatment for 8 weeks. The severity of patients' extrapyramidal symptoms was assessed using the tremor subscale of the Simpson-Angus Scale (SAS) and self-rated with a modification of the Clinical Global Impressions scale, the Subjective Clinical Improvement Impression scale. The clinical response was evaluated by comparing the rating scores at baseline prior to donepezil treatment and every 2 weeks thereafter.
RESULTS: The addition of donepezil (up to 10 mg/day) was associated with a clinically significant improvement (from 37.5% to 63.6%) on the SAS tremor subscale following 4 weeks of therapy. Only 1 patient discontinued follow-up due to side effects.
CONCLUSION: The results suggest that donepezil may be effective in the treatment of TT, and this finding should be evaluated further by a randomized controlled study.

PMID 15669896  J Clin Psychiatry. 2005 Jan;66(1):107-10.
著者: Stanley N Caroff, Patricia Walker, Cabrina Campbell, Alan Lorry, Christopher Petro, Kevin Lynch, Robert Gallop
雑誌名: J Clin Psychiatry. 2007 Mar;68(3):410-5.
Abstract/Text OBJECTIVE: Recent evidence suggests that tar-dive dyskinesia may result from antipsychotic-induced damage to striatal cholinergic neurons. To test whether cholinesterase inhibitors compensate for diminished cholinergic activity, we conducted a 30-week randomized, double-blind, placebo-controlled crossover trial of galantamine in patients with tardive dyskinesia.
METHOD: Patients with tardive dyskinesia were recruited between June 2001 and June 2004. After a 2-week baseline period, 35 male schizophrenia patients, on stable doses of antipsychotics, were randomly assigned to receive galantamine (8-24 mg) or placebo for two 12-week phases separated by a 4-week washout period. Patients were evaluated every 2 weeks for changes in extrapyramidal symptoms and before and after each treatment for effects on psychiatric symptoms and cognition.
RESULTS: Galantamine reduced mean total Abnormal Involuntary Movement Scale (AIMS) scores more than placebo, but this difference was not statistically significant (p = .08). However, patients initially randomly assigned to galantamine showed a reversal of AIMS scores after switching to placebo. Simpson-Angus Scale ratings of parkinsonism were significantly higher with galantamine than placebo (p = .0005) and correlated with age. There were no significant differences between groups in akathisia, cognition, or psychiatric symptoms. More patients dropped out while receiving galantamine, but this outcome did not significantly influence the results.
CONCLUSIONS: In contrast to previous reports, reductions in tardive dyskinesia associated with galantamine were not statistically significant compared with placebo in this trial. However, galantamine was associated with a modest rebound in dyskinesia scores after discontinuation and clinically minor but statistically higher ratings of parkinsonism. These findings support the need for further investigations of cholinergic mechanisms underlying tardive dyskinesia and extrapyramidal effects of cholinesterase inhibitors when used in combination with antipsychotics in susceptible patients.
CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00164242.

PMID 17388711  J Clin Psychiatry. 2007 Mar;68(3):410-5.
著者: Karla Soares-Weiser, Nicola Maayan, John McGrath
雑誌名: Cochrane Database Syst Rev. 2011 Feb 16;(2):CD000209. doi: 10.1002/14651858.CD000209.pub2. Epub 2011 Feb 16.
Abstract/Text BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Vitamin E has been proposed as a treatment to prevent or decrease TD.
OBJECTIVES: To determine the effects of vitamin E for people with schizophrenia or other chronic mental illnesses who also developed neuroleptic-induced TD.
SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (March 2010), inspected references of all identified studies for further trials and contacted authors of trials for additional information.
SELECTION CRITERIA: We included reports if they were controlled trials dealing with people with neuroleptic-induced TD and schizophrenia who had been randomly allocated to either vitamin E or to a placebo or no intervention.
DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who dropped out had no improvement.
MAIN RESULTS: The review now includes 11 poorly reported randomised trials (total 427 people). There was no clear difference between vitamin E and placebo for the outcome of 'clinically relevant improvement in TD' (6 trials, 256 people, RR 0.95 CI 0.89 to 1.02). For the outcome of 'any improvement in TD symptoms', again, we found no clear difference between groups (7 trials, 311 people, RR 0.86 CI 0.75 to 1.00). However, people allocated to placebo showed more deterioration of their symptoms compared with those given vitamin E (5 trials, 98 people, RR 0.38 CI 0.16 to 0.9). There was no difference in the incidence of adverse effects (9 trials, 203 people, RR 1.29 CI 0.51 to 3.24) or leaving the study early (medium term 6 trials, 173 people, RR 1.29 CI 0.72 to 2.3). There is no trial-based information regarding the effect of vitamin E for those with early onset of TD.
AUTHORS' CONCLUSIONS: Small trials of limited quality suggest that vitamin E may protect against deterioration of TD. There is no evidence that vitamin E improves symptoms of this problematic and disfiguring condition once established. New and better trials are indicated in this under-researched area, and, of the many adjunctive treatments that have been given for TD, vitamin E would be a good choice for further evaluation.

PMID 21328246  Cochrane Database Syst Rev. 2011 Feb 16;(2):CD000209. d・・・
著者: P S Bhoopathi, K Soares-Weiser
雑誌名: Cochrane Database Syst Rev. 2006 Jul 19;(3):CD000205. doi: 10.1002/14651858.CD000205.pub2. Epub 2006 Jul 19.
Abstract/Text BACKGROUND: Tardive dyskinesia (TD) is a disfiguring movement disorder, often of the orofacial region, frequently caused by the use of neuroleptic drugs. A wide range of strategies have been used to help manage tardive dyskinesia, and for those who are unable to have their antipsychotic medication stopped or substantially changed, the benzodiazepine group of drugs have been suggested as a useful adjunctive treatment.
OBJECTIVES: To determine the effects of benzodiazepines for neuroleptic-induced tardive dyskinesia in people with schizophrenia or other chronic mental illnesses.
SEARCH STRATEGY: 1. Electronic searches. For the update of 2006, we searched The Cochrane Schizophrenia Group Trials Register (November 2005). For the previous two updates (1996, 2002) the review authors searched Biological Abstracts (1982-2002), the Cochrane Schizophrenia Group's Register of trials (February 2002), EMBASE (1980-2002), LILACS (1982-2002), MEDLINE (1966-2002), PsycLIT (1974-2002), SCISEARCH (2002), hand searched references of all included/excluded studies and contacted the first author of each included trial.
SELECTION CRITERIA: We included all randomised clinical studies focusing on people with schizophrenia (or other chronic mental illnesses) and neuroleptic-induced tardive dyskinesia that compared benzodiazepines with placebo or no intervention.
DATA COLLECTION AND ANALYSIS: We independently extracted data from the studies and ensured that they were reliably selected, and quality assessed. For homogenous dichotomous data we calculated random effects, relative risk (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat (NNT) on an intention-to-treat basis. We synthesised continuous data from valid scales by using a weighted mean difference (WMD). For continuous outcomes we preferred endpoint data to change data.
MAIN RESULTS: We identified three trials (total N=56, one additional trial since 2002, n=24). Using benzodiazepines as an adjunctive treatment did not result in any clear changes for a series of tardive dyskinesia medium-term outcomes (n=30, 2 RCTs, RR not improved to clinically important extent 1.08 CI 0.57 to 2.05). One trial (n=24) found end point abnormal movement scores to be better for those receiving adjunct benzodiazepines(WMD AIMS -3.22 CI -4.63 to -1.81 ). Less than 10% in both groups left these studies before completion and none of the studies reported clear adverse effects.
AUTHORS' CONCLUSIONS: One small study reports some preliminary evidence that benzodiazepines may have some effect in neuroleptic induced tardive dyskinesia. Inconclusive results from other studies means routine clinical use is not indicated and these treatments remain experimental.

PMID 16855954  Cochrane Database Syst Rev. 2006 Jul 19;(3):CD000205. d・・・
著者: Samer Alabed, Youssef Latifeh, Husam Aldeen Mohammad, Abdullah Rifai
雑誌名: Cochrane Database Syst Rev. 2011 Apr 13;(4):CD000203. doi: 10.1002/14651858.CD000203.pub3. Epub 2011 Apr 13.
Abstract/Text BACKGROUND: Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. Gamma-aminobutyric acid (GABA) agonist drugs, which have intense sedative properties and may exacerbate psychotic symptoms, have been used to treat TD.
OBJECTIVES: To determine the clinical effects of GABA agonist drugs (baclofen, gamma-vinyl-GABA, gamma-acetylenic-GABA, progabide, muscimol, sodium valproate and tetrahydroisoxazolopyridine (THIP) for people with schizophrenia or other chronic mental illnesses who also developed neuroleptic-induced tardive dyskinesia.
SEARCH STRATEGY: We updated the previous Cochrane review by searching the Cochrane Schizophrenia Group Register (June 2010).
SELECTION CRITERIA: We included reports if they were controlled trials dealing with people with neuroleptic-induced TD and schizophrenia or other chronic mental illness who had been randomly allocated to either non-benzodiazepine GABA agonist drugs with placebo or no intervention.
DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). For continuous data we calculated mean differences (MD).
MAIN RESULTS: We identified eight small poorly reported studies for inclusion. For the outcome of 'no clinically important improvement in tardive dyskinesia' GABA agonist drugs were not clearly better than placebo (n = 108, 3 RCTs, RR 0.83 CI 0.6 to 1.1). Deterioration in mental state was more likely to occur in people receiving GABA medication (n = 95, 4 RCTs, RR 2.47 CI 1.1 to 5.4), but this effect was influenced by the decision to assign a negative outcome to those who left early before the end of the study. A greater proportion of people allocated GABA medication may fail to complete the trial compared with those allocated placebo (20% versus 9%), but this difference was not statistically significant (n = 136, 5 RCTs, RR 1.99 CI 0.8 to 4.7). There is a suggestion of an increase in ataxia (loss of power of muscular coordination) for both baclofen and sodium valproate (n = 95, 2 RCTs, RR 3.26 CI 0.4 to 30.2), and in sedation (n = 113, 3 RCTs, RR 2.12 CI 0.8 to 5.4) compared with placebo, but this was not significant. Withdrawal of tetrahydroisoxazolopyridine (THIP) may cause seizures.
AUTHORS' CONCLUSIONS: Evidence of the effects of baclofen, progabide, sodium valproate, or THIP for people with antipsychotic-induced TD is inconclusive and unconvincing. Any possible benefits are likely to be outweighed by the adverse effects associated with their use.

PMID 21491376  Cochrane Database Syst Rev. 2011 Apr 13;(4):CD000203. d・・・
著者: Adib Essali, Hany Deirawan, Karla Soares-Weiser, Clive E Adams
雑誌名: Cochrane Database Syst Rev. 2011 Nov 9;(11):CD000206. doi: 10.1002/14651858.CD000206.pub3. Epub 2011 Nov 9.
Abstract/Text BACKGROUND: Schizophrenia and related disorders affect a sizable proportion of any population. Neuroleptic (antipsychotic) medications are the primary treatment for these disorders. Neuroleptic medications are associated with a variety of side effects including tardive dyskinesia. Dyskinesia is a disfiguring movement disorder of the orofacial region that can be tardive (having a slow or belated onset). Tardive dyskinesia is difficult to treat, despite experimentation with several treatments. Calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil) have been among these experimental treatments.
OBJECTIVES: To determine the effects of calcium-channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses.
SEARCH STRATEGY: We updated previous searches in May 2010 by searching the Cochrane Schizophrenia Group Register using the Cochrane Schizophrenia Group search strategy.
SELECTION CRITERIA: Randomised clinical trials comparing calcium-channel blockers with placebo, no intervention or any other intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness.
DATA COLLECTION AND ANALYSIS: We planned to extract and analyse data on an intention-to-treat (ITT) basis. We intended to calculate the relative risk (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data using a random-effects model, and, where possible, calculate the number needed to treat. We planned to calculate mean differences (MD) for continuous data.
MAIN RESULTS: We did not include any trials in this review. We excluded 15 studies; eight were not randomised, one did not use calcium channel blockers, five small, randomised, studies reported no usable data and one did not include people with both tardive dyskinesia and schizophrenia.
AUTHORS' CONCLUSIONS: The effects of calcium-channel blockers for antipsychotic induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well designed randomised clinical trials.

PMID 22071797  Cochrane Database Syst Rev. 2011 Nov 9;(11):CD000206. d・・・
著者: H G El-Sayeh, J P Lyra da Silva, J Rathbone, K Soares-Weiser
雑誌名: Cochrane Database Syst Rev. 2006 Jan 25;(1):CD000458. doi: 10.1002/14651858.CD000458.pub2. Epub 2006 Jan 25.
Abstract/Text BACKGROUND: Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of neuroleptic medication. Several strategies have been examined in the treatment of TD. Currently, however, there is no clear evidence of the effectiveness of these drugs in TD and they have been associated with many side effects. One particular strategy would be to use pharmaceutical agents which are known to influence the catecholaminergic system at various junctures.
OBJECTIVES: To determine whether catecholaminergic drugs for people with schizophrenia or other chronic mental illnesses are associated with a reduction in neuroleptic-induced tardive dyskinesia.
SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (January 1996), Biological Abstracts (1982-1995), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995) and PsycLIT (1974-1995). We searched the Cochrane Schizophrenia Group's Register again in December 2002 and September 2005. We also searched references of all relevant studies for further trial citations and contacted principal authors of trials.
SELECTION CRITERIA: We selected studies if they were randomised controlled trials focusing on people with schizophrenia or other chronic mental illnesses who also suffered from neuroleptic-induced tardive dyskinesia. We compared the use of catecholaminergic interventions versus placebo or no intervention.
DATA COLLECTION AND ANALYSIS: We independently extracted data. For homogenous dichotomous data, we calculated the random effects, relative risk (RR), and 95% confidence interval (CI) and, where appropriate, the numbers needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD).
MAIN RESULTS: We excluded 20 studies, mainly due to an inability to extract data from the first arm of the study crossover. One included study has shown that patients on placebo were no more likely to leave the study early than those on tiapride (n=24). The other included study (n=35) also reported equivocal data (RR 5.28 CI 0.3 to 102.6) for leaving the study early when participants were randomised to either celiprolol or placebo. However, in both studies, sample size was limited.
AUTHORS' CONCLUSIONS: Although there has been a large amount of research in this area, most studies were excluded due to inherent problems in the nature of their crossover designs. Usually data are not reported before the crossover and the nature of TD and its likely response to treatments makes it imprudent to use this data. The review provides little usable information for service users or providers and more well designed and reported studies are indicated.

PMID 16437424  Cochrane Database Syst Rev. 2006 Jan 25;(1):CD000458. d・・・
著者: K V Soares-Weiser, C Joy
雑誌名: Cochrane Database Syst Rev. 2003;(2):CD000208. doi: 10.1002/14651858.CD000208.
Abstract/Text BACKGROUND: Tardive dyskinesia is a disabling movement disorder associated with the prolonged use of neuroleptic medication. This review, one in a series examining the treatment of tardive dyskinesia, will cover miscellaneous treatments not covered elsewhere.
OBJECTIVES: To determine whether the following interventions were associated with a reduction of neuroleptic induced tardive dyskinesia: botulin toxin, endorphin, essential fatty acid, EX11582A, ganglioside, insulin, lithium, naloxone, oestrogen, periactin, phenylalanine, piracetam, stepholidine, tryptophan, neurosurgery, or ECT.
SEARCH STRATEGY: The initial search of Biological Abstracts (1982-1995), The Cochrane Schizophrenia Group's Register (January 1996), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995) and PsycLIT (1974-1995) was updated by searching Cochrane Schizophrenia Group's Register in July 2002. References of all relevant studies were searched for further trial citations. Principal authors of trials were contacted.
SELECTION CRITERIA: Studies were selected if they focused on people with schizophrenia or other chronic mental illnesses, with neuroleptic-induced tardive dyskinesia and compared the use of the interventions listed above versus placebo or no intervention.
DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality assessed and data extracted. Data were excluded where more than 50% of participants in any group were lost to follow up. For binary outcomes a random effects risk ratio (RR) and its 95% confidence interval (CI) was calculated. Where possible, the weighted number needed to treat/harm statistic (NNT/H), and its 95% confidence interval (CI), was also calculated. For continuous outcomes, endpoint data were preferred to change data. Non-skewed data from valid scales were to have been synthesised using a weighted mean difference (WMD).
MAIN RESULTS: Fifty-seven references describing 37 different trials were identified by the search strategy. Seven of these were included, 27 excluded, and three await assessment. Ceruletide was not clearly more effective than placebo (n=132, 2 RCTs, RR not any improvement in tardive dyskinesia 0.82 CI 0.6 to 1.1). This also applied to gamma-linolenic acid, although data were sparse (n=16, 1 RCT, RR no clinical improvement 1.00 CI 0.7 to 1.5), oestrogen (n=12, 1 RCT, RR no clinically important improvement 1.2 CI 0.8 to 1.7), and lithium (n=11, 1 RCT, RR no clinically important improvement 1.39 CI 0.6 to 3.1). Phenylalanine may even be detrimental (n=18, 1 RCT, MD AIMS score 4.40 CI 1.16 to 7.64). One small study (n=20) found that insulin was more likely to produce a clinical improvement in tardive dyskinesia than placebo (RR no clinical improvement 0.5 CI 0.3 to 0.9, NNT 2 CI 1 to 5).
REVIEWER'S CONCLUSIONS: There is no strong evidence to support the everyday use of any of the agents included in this review. All results must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.

PMID 12804390  Cochrane Database Syst Rev. 2003;(2):CD000208. doi: 10.・・・
著者: Ronald J Gurrera, John C Simpson, Ming T Tsuang
雑誌名: Compr Psychiatry. 2007 Mar-Apr;48(2):205-11. doi: 10.1016/j.comppsych.2006.10.004. Epub 2007 Jan 2.
Abstract/Text OBJECTIVE: The aim of this study was to examine published reports for sources of excessive variance in neuroleptic malignant syndrome (NMS) incidence estimates.
DATA SOURCES: An unrestricted computerized MEDLINE search was conducted with a comprehensive search logic and supplemented by secondary references and a manual search of an extensive personal library.
STUDY SELECTION: Studies were analyzed if they presented original data and provided at least 2 of the following: number of NMS cases, number of patients at risk, or ratio of cases to patients at risk. Twenty-six of the 28 candidate studies met these minimal criteria.
DATA EXTRACTION: Variables included incidence, year of study publication, mean year of NMS occurrence, patient population at risk, study design, diagnostic criteria, and country of origin.
DATA SYNTHESIS: Standard error, which reflects study size, accounted for 90.8% of the variance (beta = .953, P < .001) in this international series of 26 NMS incidence estimates. Incidence was significantly lower in 7 studies the time end points of which were set in advance of case identification (chi(2) = 71.08, P < .001). No other variable was significantly related to incidence.
CONCLUSIONS: Neuroleptic malignant syndrome incidence estimates to date are non-trivially biased such that larger study size (patients at risk) is strongly related to lower observed incidence. Future studies can minimize the contribution of this and other sources of experimental error by incorporating several very feasible recommendations.

PMID 17292713  Compr Psychiatry. 2007 Mar-Apr;48(2):205-11. doi: 10.10・・・
著者: Mark Olfson, Steven C Marcus, Patricia Corey-Lisle, A V Tuomari, Patricia Hines, Gilbert J L'Italien
雑誌名: Am J Psychiatry. 2006 Oct;163(10):1821-5. doi: 10.1176/appi.ajp.163.10.1821.
Abstract/Text OBJECTIVE: This study attempted to estimate the relative risk of developing hyperlipidemia after treatment with antipsychotics in relation to no antipsychotic treatment.
METHOD: A matched case-control analysis was performed with pharmacy and claims data from California Medicaid (Medi-Cal). Patients were excluded if they were treated for medical disorders or prescribed medications known to increase their risk of hyperlipidemia. Cases were ages 18 to 64 years with schizophrenia, major depression, bipolar disorder, or other affective psychoses and incident hyperlipidemia. Cases were matched to up to six control subjects by age, sex, race, and psychiatric diagnosis. Both groups were prescribed either no antipsychotic medication or had two or more prescriptions for one and only one antipsychotic medication during the 60 days prior to the first indication of hyperlipidemia (cases) or matched index date (controls) in the billing record. Conditional logistic regressions were used to derive odds ratios and 95% confidence intervals (95% CIs) of each antipsychotic medication in relation to no antipsychotic medication.
RESULTS: A total of 13,133 incident cases of hyperlipidemia were matched to 72,140 control subjects. As compared with no antipsychotic medication, treatment with clozapine (odds ratio: 1.82, 95% CI: 1.61-2.05), risperidone (odds ratio: 1.53, 95% CI: 1.43-1.64), quetiapine (odds ratio: 1.52, 95% CI: 1.40-1.65), olanzapine (odds ratio: 1.56, 95% CI: 1.47-1.67), ziprasidone (odds ratio: 1.40, 95% CI: 1.19-1.65), and first-generation antipsychotics (odds ratio: 1.26, 95% CI: 1.14-1.39), but not aripiprazole (odds ratio: 1.19, 95% CI: 0.94-1.52) was associated with a significant increase in risk of incident hyperlipidemia.
CONCLUSIONS: These findings suggest that most commonly prescribed antipsychotic medications increase the risk of developing hyperlipidemia in patients with schizophrenia or mood disorders.

PMID 17012695  Am J Psychiatry. 2006 Oct;163(10):1821-5. doi: 10.1176/・・・
著者: Michael J Sernyak, Douglas L Leslie, Renato D Alarcon, Miklos F Losonczy, Robert Rosenheck
雑誌名: Am J Psychiatry. 2002 Apr;159(4):561-6.
Abstract/Text OBJECTIVE: The development of both type I and type II diabetes after initiation of some atypical neuroleptics has been reported, primarily in studies involving small series of patients. This study used administrative data from a large national sample of patients with a diagnosis of schizophrenia to compare the prevalence of diabetes mellitus in patients receiving prescriptions for atypical and typical neuroleptics.
METHOD: All outpatients with schizophrenia treated with typical and atypical neuroleptics over 4 months in 1999 in the Veterans Health Administration of the Department of Veterans Affairs (VA) were included in this study. Patients treated with atypical neuroleptics were those who received prescriptions for clozapine, olanzapine, risperidone, or quetiapine. Patients with a diagnosis of diabetes were also identified by using ICD-9 codes in VA administrative databases. The prevalence of diabetes mellitus across age groups and among patients receiving prescriptions for different atypical neuroleptics was examined with multiple logistic regression.
RESULTS: A total of 38,632 patients were included in the study: 15,984 (41.4%) received typical neuroleptics and 22,648 (58.6%) received any atypical neuroleptic (1,207 [5.3%] received clozapine; 10,970 [48.4%], olanzapine; 955 [4.2%], quetiapine; and 9,903 [43.7%], risperidone; 387 patients received prescriptions for more than one atypical neuroleptic). When the effects of age were controlled, patients who received atypical neuroleptics were 9% more likely to have diabetes than those who received typical neuroleptics, and the prevalence of diabetes was significantly increased for patients who received clozapine, olanzapine, and quetiapine, but not risperidone. However, for patients less than 40 years old, all of the atypical neuroleptics were associated with a significantly increased prevalence of diabetes.
CONCLUSIONS: In this large group of patients with schizophrenia, receipt of a prescription for atypical neuroleptics was significantly associated with diabetes mellitus.

PMID 11925293  Am J Psychiatry. 2002 Apr;159(4):561-6.
著者: M Smith, D Hopkins, R C Peveler, R I G Holt, M Woodward, K Ismail
雑誌名: Br J Psychiatry. 2008 Jun;192(6):406-11. doi: 10.1192/bjp.bp.107.037184.
Abstract/Text BACKGROUND: The increased prevalence of diabetes in schizophrenia is partly attributed to antipsychotic treatment, in particular second-generation antipsychotics, but the evidence has not been systematically reviewed.
AIMS: Systematic review and meta-analysis comparing diabetes risk for different antipsychotics in people with schizophrenia.
METHOD: We searched MEDLINE, PsycINFO, EMBASE, International Pharmaceutical Abstracts, CINAHL and Web of Knowledge until September 2006. Studies were eligible for inclusion if the design was cross-sectional, case-control, cohort or a controlled trial in individuals with schizophrenia or related psychotic disorders, where second-generation antipsychotics (defined as clozapine, olanzapine, risperidone and quetiapine) were compared with first-generation antipsychotics and diabetes was an outcome. Data were pooled using random effects inverse variance weighted meta-analysis.
RESULTS: Of the studies that met the inclusion criteria (n=14), 11 had sufficient data to include in the meta-analysis. Four of these were retrospective cohort studies. The relative risk of diabetes in patients with schizophrenia prescribed one of the second-generation v. first-generation antipsychotics was 1.32 (95% CI 1.15-1.51). There were insufficient data to include aripiprazole, ziprasidone and amisulpride in this analysis.
CONCLUSIONS: There is tentative evidence that the second-generation antipsychotics included in this study are associated with a small increased risk for diabetes compared with first-generation antipsychotics in people with schizophrenia. Methodological limitations were found in most studies, leading to heterogeneity and difficulty interpreting data. Regardless of type of antipsychotic, screening for diabetes in all people with schizophrenia should be routine.

PMID 18515889  Br J Psychiatry. 2008 Jun;192(6):406-11. doi: 10.1192/b・・・
著者: Bruno Falissard, Mauro Mauri, Ken Shaw, Tilman Wetterling, Adam Doble, Agnès Giudicelli, Marc De Hert
雑誌名: Int Clin Psychopharmacol. 2011 Nov;26(6):291-302. doi: 10.1097/YIC.0b013e32834a5bf6.
Abstract/Text The objective of this crosssectional study was to estimate the prevalence of metabolic disorders and hypertension in patients with schizophrenia and to compare prevalence between patients treated with first-generation (FGA) and second-generation (SGA) antipsychotic drugs. The study included 2270 adults with schizophrenia. Patients were assigned to an FGA or SGA stratum on the basis of current treatment. Data were collected on sociodemographic, lifestyle and clinical variables. Blood pressure, waist and hip circumference, blood glucose, triglycerides and cholesterol were measured. The primary evaluation criterion was the prevalence of a glycaemic disorder. Secondary criteria were the prevalence of dyslipidaemia, obesity, hypertension and metabolic syndrome. A propensity score was used to control imbalance between strata. The prevalence of glycaemic disorders was 31.1% (FGA) and 27.6% (SGA). No between-strata difference in prevalence was observed for glycaemic disorders, dyslipidaemia or metabolic syndrome. The prevalence of hypertension was higher (P=0.033) in the FGA group. The proportion of women (but not men) who were overweight or obese was higher in the SGA group (P=0.035), as was the proportion reporting weight gain of more than 5 kg (P<0.001). In an exploratory unadjusted post-hoc analysis, significantly higher frequencies of dysglycaemia (28.5 vs. 22.0%; P=0.006), low HDL cholesterol (35.3 vs. 29.7%; P=0.023) and metabolic syndrome (36.7 vs. 30.7%; P=0.021) were observed in patients taking SGAs considered to carry high metabolic risk compared with those taking low-risk agents. In conclusion, metabolic disorders are prevalent in patients with schizophrenia treated with antipsychotics and are under-diagnosed and under-treated.

PMID 21876442  Int Clin Psychopharmacol. 2011 Nov;26(6):291-302. doi: ・・・
著者: A J Mitchell, V Delaffon, D Vancampfort, C U Correll, M De Hert
雑誌名: Psychol Med. 2012 Jan;42(1):125-47. doi: 10.1017/S003329171100105X. Epub 2011 Aug 10.
Abstract/Text BACKGROUND: Despite increased cardiometabolic risk in individuals with mental illness taking antipsychotic medication, metabolic screening practices are often incomplete or inconsistent.
METHOD: We undertook a systematic search and a PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) meta-analysis of studies examining routine metabolic screening practices in those taking antipsychotics both for patients in psychiatric care before and following implementation of monitoring guidelines.
RESULTS: We identified 48 studies (n=290 534) conducted between 2000 and 2011 in five countries; 25 studies examined predominantly schizophrenia-spectrum disorder populations; 39 studies (n=218 940) examined routine monitoring prior to explicit guidelines; and nine studies (n=71 594) reported post-guideline monitoring. Across 39 studies, routine baseline screening was generally low and above 50% only for blood pressure [69.8%, 95% confidence interval (CI) 50.9-85.8] and triglycerides (59.9%, 95% CI 36.6-81.1). Cholesterol was measured in 41.5% (95% CI 18.0-67.3), glucose in 44.3% (95% CI 36.3-52.4) and weight in 47.9% (95% CI 32.4-63.7). Lipids and glycosylated haemoglobin (HbA1c) were monitored in less than 25%. Rates were similar for schizophrenia patients, in US and UK studies, for in-patients and out-patients. Monitoring was non-significantly higher in case-record versus database studies and in fasting samples. Following local/national guideline implementation, monitoring improved for weight (75.9%, CI 37.3-98.7), blood pressure (75.2%, 95% CI 45.6-95.5), glucose (56.1%, 95% CI 43.4-68.3) and lipids (28.9%, 95% CI 20.3-38.4). Direct head-to-head pre-post-guideline comparison showed a modest but significant (15.4%) increase in glucose testing (p=0.0045).
CONCLUSIONS: In routine clinical practice, metabolic monitoring is concerningly low in people prescribed antipsychotic medication. Although guidelines can increase monitoring, most patients still do not receive adequate testing.

PMID 21846426  Psychol Med. 2012 Jan;42(1):125-47. doi: 10.1017/S00332・・・
著者: M De Hert, D Vancampfort, C U Correll, V Mercken, J Peuskens, K Sweers, R van Winkel, A J Mitchell
雑誌名: Br J Psychiatry. 2011 Aug;199(2):99-105. doi: 10.1192/bjp.bp.110.084665.
Abstract/Text BACKGROUND: Metabolic and cardiovascular health problems have become a major focus for clinical care and research in schizophrenia.
AIMS: To evaluate the content and quality of screening guidelines for cardiovascular risk in schizophrenia.
METHOD: Systematic review and quality assessment of guidelines/recommendations for cardiovascular risk in people with schizophrenia published between 2000 and 2010, using the Appraisal of Guidelines for Research and Evaluation (AGREE).
RESULTS: The AGREE domain scores varied between the 18 identified guidelines. Most guidelines scored best on the domains 'scope and purpose' and 'clarity of presentation'. The domain 'rigour of development' was problematic in most guidelines, and the domains 'stakeholder involvement' and 'editorial independence' scored the lowest. The following measurements were recommended (in order of frequency): fasting glucose, body mass index, fasting triglycerides, fasting cholesterol, waist, high-density lipoprotein/low-density lipoprotein, blood pressure and symptoms of diabetes. In terms of interventions, most guidelines recommended advice on physical activity, diet, psychoeducation of the patient, treatment of lipid abnormalities, treatment of diabetes, referral for advice and treatment, psychoeducation of the family and smoking cessation advice. Compared across all domains and content, four European guidelines could be recommended.
CONCLUSIONS: Four of the evaluated guidelines are of good quality and should guide clinicians' screening and monitoring practices. Future guideline development could be improved by increasing its rigour and assuring user and patient involvement.

PMID 21804146  Br J Psychiatry. 2011 Aug;199(2):99-105. doi: 10.1192/b・・・
著者: Toby Pillinger, Robert A McCutcheon, Luke Vano, Yuya Mizuno, Atheeshaan Arumuham, Guy Hindley, Katherine Beck, Sridhar Natesan, Orestis Efthimiou, Andrea Cipriani, Oliver D Howes
雑誌名: Lancet Psychiatry. 2020 Jan;7(1):64-77. doi: 10.1016/S2215-0366(19)30416-X. Epub 2019 Dec 17.
Abstract/Text BACKGROUND: Antipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment.
METHODS: We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change.
FINDINGS: Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with placebo ranged from -0·23 kg (95% CI -0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from -0·25 kg/m2 (-0·68 to 0·17) for haloperidol to 1·07 kg/m2 (0·90 to 1·25) for olanzapine; for total-cholesterol from -0·09 mmol/L (-0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26-0·86) for clozapine; for LDL cholesterol from -0·13 mmol/L (-0.21 to -0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for brexpiprazole to -0·10 mmol/L (-0·33 to 0·14) for amisulpride; for triglycerides from -0·01 mmol/L (-0·10 to 0·08) for brexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from -0·29 mmol/L (-0·55 to -0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p<0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=-0·35, p=0·035).
INTERPRETATION: Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. However, the choice of antipsychotic should be made on an individual basis, considering the clinical circumstances and preferences of patients, carers, and clinicians.
FUNDING: UK Medical Research Council, Wellcome Trust, National Institute for Health Research Oxford Health Biomedical Research Centre.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 31860457  Lancet Psychiatry. 2020 Jan;7(1):64-77. doi: 10.1016/S2・・・
著者: Davy Vancampfort, Christoph U Correll, Britta Galling, Michel Probst, Marc De Hert, Philip B Ward, Simon Rosenbaum, Fiona Gaughran, John Lally, Brendon Stubbs
雑誌名: World Psychiatry. 2016 Jun;15(2):166-74. doi: 10.1002/wps.20309.
Abstract/Text Type 2 diabetes mellitus (T2DM) is highly predictive of cardiovascular diseases and can have particularly deleterious health impacts in people with severe mental illness (SMI), i.e. schizophrenia, bipolar disorder or major depressive disorder. This meta-analysis aimed: a) to describe pooled frequencies of T2DM in people with SMI; b) to analyze the influence of demographic, illness and treatment variables as well as T2DM assessment methods; and c) to describe T2DM prevalence in studies directly comparing persons with each specific SMI diagnosis to general population samples. The trim and fill adjusted pooled T2DM prevalence among 438,245 people with SMI was 11.3% (95% CI: 10.0%-12.6%). In antipsychotic-naïve participants, the prevalence of T2DM was 2.9% (95% CI: 1.7%-4.8%). There were no significant diagnostic subgroup differences. A comparative meta-analysis established that multi-episode persons with SMI (N=133,470) were significantly more likely to have T2DM than matched controls (N=5,622,664): relative risk, RR=1.85, 95% CI: 1.45-2.37, p<0.001. The T2DM prevalence was consistently elevated in each of the three major diagnostic subgroups compared to matched controls. Higher T2DM prevalences were observed in women with SMI compared to men (RR=1.43, 95% CI: 1.20-1.69, p<0.001). Multi-episode (versus first-episode) status was the only significant predictor for T2DM in a multivariable meta-regression analysis (r(2) =0.52, p<0.001). The T2DM prevalence was higher in patients prescribed antipsychotics, except for aripriprazole and amisulpride. Routine screening and multidisciplinary management of T2DM is needed. T2DM risks of individual antipsychotic medications should be considered when making treatment choices.

© 2016 World Psychiatric Association.
PMID 27265707  World Psychiatry. 2016 Jun;15(2):166-74. doi: 10.1002/w・・・
著者: Davy Vancampfort, Brendon Stubbs, Alex J Mitchell, Marc De Hert, Martien Wampers, Philip B Ward, Simon Rosenbaum, Christoph U Correll
雑誌名: World Psychiatry. 2015 Oct;14(3):339-47. doi: 10.1002/wps.20252.
Abstract/Text Metabolic syndrome (MetS) and its components are highly predictive of cardiovascular diseases. The primary aim of this systematic review and meta-analysis was to assess the prevalence of MetS and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder, comparing subjects with different disorders and taking into account demographic variables and psychotropic medication use. The secondary aim was to compare the MetS prevalence in persons with any of the selected disorders versus matched general population controls. The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%-34.4%; N = 198; n = 52,678). Relative risk meta-analyses established that there was no significant difference in MetS prevalence in studies directly comparing schizophrenia versus bipolar disorder, and in those directly comparing bipolar disorder versus major depressive disorder. Only two studies directly compared people with schizophrenia and major depressive disorder, precluding meta-analytic calculations. Older age and a higher body mass index were significant moderators in the final demographic regression model (z = -3.6, p = 0.0003, r(2)  = 0.19). People treated with all individual antipsychotic medications had a significantly (p<0.001) higher MetS risk compared to antipsychotic-naïve participants. MetS risk was significantly higher with clozapine and olanzapine (except vs. clozapine) than other antipsychotics, and significantly lower with aripiprazole than other antipsychotics (except vs. amisulpride). Compared with matched general population controls, people with severe mental illness had a significantly increased risk for MetS (RR = 1.58; 95% CI: 1.35-1.86; p<0.001) and all its components, except for hypertension (p = 0.07). These data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness. Routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients. Risks of individual antipsychotics should be considered when making treatment choices.

© 2015 World Psychiatric Association.
PMID 26407790  World Psychiatry. 2015 Oct;14(3):339-47. doi: 10.1002/w・・・

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