Haloperidol versus placebo for schizophrenia

 

Abstract

Background

Haloperidol was developed in the late 1950s for use in the field of anaesthesia. Research subsequently demonstrated effects on hallucinations, delusions, aggressiveness, impulsiveness and states of excitement and led to the introduction of haloperidol as an antipsychotic.

Objectives

To evaluate the clinical effects of haloperidol for the management of schizophrenia and other similar serious mental illnesses compared to placebo.

Search methods

We initially electronically searched the databases of Biological Abstracts (1985-1998), CINAHL (1982-1998), The Cochrane Library (1998, Issue 4), The Cochrane Schizophrenia Group's Register (December 1998), EMBASE (1980-1998), MEDLINE (1966-1998), PsycLIT (1974-1998), and SCISEARCH. We also checked references of all identified studies for further trial citations and contacted the authors of trials and pharmaceutical companies for further information and archive material. For the 2005 update we searched The Cochrane Library (2005, Issue 6).

Selection criteria

We included all relevant randomised controlled trials comparing the use of haloperidol (any oral dose) with placebo for those with schizophrenia or other similar serious, non-affective psychotic illnesses (however diagnosed). Our main outcomes of interest were death, loss to follow up, clinical and social response, relapse and severity of adverse effects.

Data collection and analysis

We evaluated data independently and analysed on an intention-to-treat basis, assuming that people who left the study early, or were lost to follow-up, had no improvement. Where possible and appropriate, we analysed dichotomous data using Relative Risk (RR) and calculated their 95% confidence intervals (CI). If appropriate, the number needed to treat (NNT) or number needed to harm (NNH) was estimated. For continuous data, we calculated weighted mean differences. We excluded continuous data if loss to follow up was greater than 50% and inspected data for heterogeneity.

Main results

Twenty-one trials randomising 1519 people are now included in this review. One new trial, Kane 2002 (n=414) has been added but it did not affect the overall results. More people allocated haloperidol improved in the first six weeks of treatment than those given placebo (3RCTs n=159, RR failing to produce a marked improvement 0.44 CI 0.3 to 0.6, NNT 3 CI 2 to 5). A further eight trials also found a difference favouring haloperidol across the 6-24 week period (8 RCTs n=308 RR no marked global improvement 0.68 CI 0.6 to 0.8 NNT 3 CI 2.5 to 5) but this may be an over estimate of effect as small negative studies were not identified. About half of those entering studies failed to complete the short trials, although, at 0-6 weeks, 11 studies found a difference that marginally favoured haloperidol (11 RCTs n=898, RR 0.8 CI 0.7 to 0.9, NNT 59 CI 38 to 200). Adverse effect data does, nevertheless, support clinical impression, that haloperidol is a potent cause of movement disorders, at least in the short term. Haloperidol promotes acute dystonia (3 RCTs n=93, RR 4.7 CI 1.7 to 44, NNH 5 CI 3 to 9), akathisia (4 RCTs n=333, RR 2.6 CI 1.4 to 4.8, NNH 7 CI 3 to 25) and parkinsonism (4 RCTs n=163, RR 11.7 CI 2.9 to 47, NNH 3 CI 2 to 5).

Authors' conclusions

Haloperidol is a potent antipsychotic drug but has a high propensity to cause adverse effects. Where there is no treatment option, use of haloperidol to counter the damaging and potentially dangerous consequences of untreated schizophrenia is justified. However, where a choice of drug is available, people with schizophrenia and clinicians may wish to prescribe an alternative antipsychotic with less likelihood of adverse effects such as parkinsonism, akathisia and acute dystonias. Haloperidol should not be a control drug of choice for randomised trials of new antipsychotics.

 

Plain language summary

Haloperidol versus placebo for schizophrenia

Schizophrenia is a distressing and long-term mental illness affecting 1% of the population. Medication has been available since the 1950s and Haloperidol was one of the first antipsychotics to be offered. Despite the introduction of many other antipsychotics it is still very widely used, and it is the antipsychotic most often used to judge the effectiveness of new medications. This review aims to update the knowledge on the clinical trials comparing placebo and haloperidol.

This review contains 21 studies involving a total of 1519 people who were either inpatients or living in the community.  Haloperidol has been found to be better than placebo in improving general functioning and some symptoms in the short term (0-6 weeks), and just general functioning in the medium term (greater than six but less than 24 weeks). None of the people in any of these trials have been followed up for longer than 24 weeks. A significant number of people on haloperidol compared to those on placebo suffered from at least one adverse effect, mainly stiffness (dystonia) and movement disorders such as shaking or restlessness (Parkinsonism). In addition six trials containing 307 people found a significant number of people suffered from sleepiness compared to the control. Overall the data from these trials are not good, with many outcomes being presented in a way that does not allow them to be used in this review. Moreover just less than half of those taking haloperidol and slightly more than half of those receiving placebo left the studies early, suggesting that the design of the trial was possibly not acceptable to these participants. In the light of these results it is therefore somewhat surprising that this medication is used so widely as a comparison for new medication.

(Plain language summary prepared for this review by Janey Antoniou of RETHINK, UK www.rethink.org)

 

摘要

背景

比較Haloperidol與安慰劑用於治療精神分裂症

Haloperidol發展在50年代後期原本是用在麻醉方面。後來的研究顯現其對幻覺，妄想，攻擊，衝動和激動狀態的效果，並導致引進Haloperidol作為抗精神病藥物。

目標

評估比較Haloperidol與安慰劑用於治療精神分裂症和其他類似的嚴重心理疾病的臨床效果。

搜尋策略

我們最初以電子方式搜尋資料庫包括生物文摘(1985年至1998年) ， cinahl (1982年至1998年) ， 考科藍圖書館(1998年第4期)，考科藍精神分裂症小組的註冊文獻(1998年12月)， embase (1980年至1998年)MEDLINE(1966年至1998年) ， psyclit (1974年至1998年)，和scisearch。我們還檢查了所有確定研究的參考文獻作進一步的文獻引用和接觸研究的作者和製藥公司提供進一步資料和檔案材料。為了2005年的更新,我們又搜查了考科藍圖書館(2005年第6期) 。

選擇標準

我們包括所有比較Haloperidol(任何口服劑量)與安慰劑用於治療精神分裂症或其他相同嚴重的非情感性精神病性疾病(已診斷)之相關隨機對照試驗。我們有興趣的主要結果為死亡，失去追蹤，臨床和社會的反應，復發和副作用的嚴重度。

資料收集與分析

我們獨立評估數據和以治療意向(intentiontotreat)為基礎分析，假設提早離開研究或失去追蹤的人已沒有任何改善。在可能且適當的情況下，我們的使用相對危險(RR)及其95 ％信賴區間(CI)來分析二分法數據。在適當的情況下，計算益一需治數/害一需治數(numbers needed to treat/harm, NNT/NNH)。我們使用加權平均差(weighted mean differences)來分析連續數據。如果失去追蹤的比例大於50 ％, 我們排除此連續數據，，並檢視數據的異質性。

主要結論

這個回顧包含了21個研究隨機分配1519人。增加一個新的研究為凱恩2002年所發表(414個個案)但並不影響整體結果。分配在Haloperidol這一組比那些給予安慰劑的有更多的人在前面6個星期的治療得到改善，(3個隨機對照試驗,共159人 ，RR未能表示出有顯著的改善:0.44;CI:0.3至0.6，NNT:3;CI:2至5)。另外有8個研究發現Haloperidol這組在6 – 24個星期的治療中表現較優異，(8個隨機對照試驗,共308人，RR沒有顯著的整體改善:0.68;CI:0.6至0.8，NNT:3;CI:2.5至5)。不過，這可能會因為小的負面研究沒有被納入而過度估計其效果。約半數在0 – 6週的這些試驗未能完成短期的研究，雖然有一些微的差距支持Haloperidol的治療較優異，(11個隨機對照試驗,共898人 ，RR:0.8;CI:0.7至0.9，NNT:59;CI:38至200)副作用的數據支持臨床印象，也就是至少在短期內Haloperidol是會導致運動障礙。Haloperidol促進急性肌張力障礙，(3個隨機對照試驗,共93人，RR:4.7;CI:1.7至44，NNH:5;CI:3至9)，靜坐不能，(4個隨機對照試驗,共333人，RR:2.6;CI:1.4至4.8，NNT:7;CI:3至25)和帕金森氏症，(4個隨機對照試驗,共163人，RR:11.7;CI:2.9至47，NNH:3;CI:2至5)

作者結論

Haloperidol是一種強力抗精神病藥，但具有較高的傾向造成副作用。如果沒有其他治療選擇，使用Haloperidol來對抗具有破壞和潛在危險後果的未經治療的精神分裂症患者是合理的。然而，如果有其他的藥物可選擇時，精神分裂症患者和臨床醫生可能希望去處方另一種較少副作用(如parkinsonism 帕金森症，靜坐不能和急性肌張力障礙) 的抗精神病藥物，。Haloperidol不應該作為新的抗精神病藥物試驗時的對照組藥物。

翻譯人

本摘要由彰化基督教醫院李謙益翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

比較Haloperidol與安慰劑用於治療精神分裂症。精神分裂症是一個嚴重的,失能的精神疾病,會影響患者大部分的成年生活;藥物治療是精神分裂症患者照顧的核心。在1950年的引進chlorpromazine及haloperidol這兩個典型的抗精神病藥物，徹底改變了嚴重精神病患的照顧。Haloperidol被稱為是一種突破並認為是最有力的抗精神病藥物，並使副作用到最低限度。儘管推出了新一代非典型抗精神病藥物，並日益關注haloperidol造成運動障礙的傾向，但haloperidol仍然是全球對精神病患最常見的處方藥物。它也經常被用來針對新的化合物作為基準比較，我們力求以系統化,客觀及量化的方式廣泛搜索所有已知的隨機對照試驗來評估比較這個藥物與安慰劑對精神分裂症治療的效果。我們發現了21個有關的研究,隨機分配1519人. 顯示haloperidol確實是一種有效的抗精神病藥物，尤其是在短期內。然而副作用的數據對於那些接受haloperidol治療而日益增加的運動障礙問題(如帕金森病，靜坐不能和急性肌張力障礙的數據)形成關注，haloperidol是常用在發展中國家，那裡的治療選擇是有限的，如果沒有其他藥物可用,以haloperidol治療精神病是合理的。但是，若有其他治療選擇,醫生和患者雙方都應該知道其不利影響，並考慮與其他較少副作用的抗精神病藥物。