Haloperidol Versus Placebo for Schizophrenia

Haloperidol versus placebo for schizophrenia

Item Type Article

Authors Irving, Claire B.; Adams, Clive E.

Citation Irving, C. B., Adams, C. E. & Lawrie, S. (2006). Haloperidol versus placebo for schizophrenia. Cochrane Database of Systematic Reviews, (4), pp.1-69.

Download date 25/09/2021 21:20:50

Link to Item http://hdl.handle.net/20.500.12904/9860 Haloperidol versus placebo for schizophrenia (Review)

Irving CB, Adams CE, Lawrie S

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2006, Issue 4 http://www.thecochranelibrary.com

Haloperidol versus placebo for schizophrenia (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER...... 1 ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 BACKGROUND ...... 2 OBJECTIVES ...... 3 METHODS ...... 3 RESULTS...... 6 DISCUSSION ...... 10 AUTHORS’CONCLUSIONS ...... 11 ACKNOWLEDGEMENTS ...... 11 REFERENCES ...... 12 CHARACTERISTICSOFSTUDIES ...... 25 DATAANDANALYSES...... 67

Haloperidol versus placebo for schizophrenia (Review) i Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Haloperidol versus placebo for schizophrenia

Claire B Irving1, Clive E Adams1, Stephen Lawrie2

1Cochrane Schizophrenia Group, The University of Nottingham, Nottingham, UK. 2Department of Psychiatry, University of Edin- burgh, Edinburgh, UK

Contact address: Claire B Irving, Cochrane Schizophrenia Group, The University of Nottingham, Institute of Mental Health, Sir Colin Campbell Building, University of Nottingham Innovation Park, Triumph Road, Nottingham, NG7 2TU, UK. [email protected]. [email protected].

Editorial group: Cochrane Schizophrenia Group. Publication status and date: Edited (no change to conclusions), published in Issue 7, 2012. Review content assessed as up-to-date: 23 August 2006.

Citation: Irving CB, Adams CE, Lawrie S. Haloperidol versus placebo for schizophrenia. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003082. DOI: 10.1002/14651858.CD003082.pub2.

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). We updated this search 15 May 2012 and added the results to the awaiting classification section of the review. 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.

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).

Update search 2012: the 72 new citations in the awaiting classiﬁcation section of the review may alter the results and conclusions of the review once assessed.

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)

BACKGROUND 1992). Central to the treatment of this disabling mental illness are antipsychotic drugs, the earliest of which, chlorpromazine Schizophrenia affects about 1% of the world’s population irrespec- and haloperidol, were formulated and introduced in the 1950’s. tive of race, gender, social class or country of origin (Jablensky

Haloperidol versus placebo for schizophrenia (Review) 2 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This introduction caused a revolution in the care of those with While an up-to-date systematic review of chlorpromazine has been serious mental illnesses (Dally 1967, Awad 1997). Despite the undertaken (Thornley 1998b) the use of haloperidol is currently formulation of a newer generation of atypical antipsychotics, based on traditional reviews that lack methods or quantification chlorpromazine and haloperidol are still the most frequently pre- (Ayd 1972, Ayd 1978, Settle 1983). scribed antipsychotic drugs world-wide (Ayd 1978, Carpenter 1994, Waddington 1997). Haloperidol was developed in the late 1950s for use in the field of OBJECTIVES anaesthesia and was initially used to prevent surgical shock. Re- To evaluate the clinical effects of haloperidol for the management search subsequently demonstrated its beneficial effect on halluci- of schizophrenia and other similar serious mental illnesses com- nations, delusions, aggressiveness, impulsiveness and states of ex- pared to placebo. citement (Ayd 1972, Ayd 1978, and Settle 1983). These findings led to the introduction of haloperidol as an antipsychotic. Hailed If possible, to undertake sensitivity analyses to assess the differen- as a breakthrough, it was considered to be the most potent antipsy- tial efficacy of haloperidol regarding: chotic known, effective for a wide range of psychotic disorders, and in addition, appeared to keep side effects to a minimum (Settle 1. Gender: male versus female. 1983). Since its introduction, clinical experience has suggested 2. Age: a. elderly (>65 years) versus adult (18-65 years); and b. that haloperidol is indeed an effective antipsychotic, particularly adult (18-65 years) versus child (<18 years). beneficial for those who are experiencing acute hallucinations and delusions. Haloperidol’s efficacy as an antipsychotic seems to vary. 3. Phase of illness: acute versus chronic (however defined within Some research suggests factors such as drug dose, administration the studies). of antiparkinson medication, recipient age, sex, and individual 4. Dose: low (<5mg/day or however defined within the studies) physiology may all change efficacies (Ayd 1972, Ayd 1978, Settle versus high (5+mg/day or however defined within the studies). 1983). More recently there has been increasing concern and debate surrounding the long-term use of haloperidol and the subsequent 5. Anti-Parkinson drugs: administration of any anti-Parkinson development of serious adverse side effects (Settle 1983). drug (any dose) versus administration of haloperidol alone.

Antipsychotic drugs block, to a greater or lesser extent, the 6. Diagnosis of schizophrenia: operational criteria versus non-op- transmission of dopamine, which is implicated in the cause of erational diagnoses. schizophrenia, in the brain (Willner 1997). The action of these drugs is not speciﬁc and unwanted blockade can occur. This produces a wide range of side effects including lethargy, sedation, dry mouth, blurred vision, constipation, weight gain, and stiffness. METHODS Haloperidol has higher potency dopamine blockade compared to most other antipsychotics so low dose haloperidol can be used to achieve an antipsychotic effect. This keeps the sort of adverse ef- Criteria for considering studies for this review fects described above to a minimum. Haloperidol’s high potency for dopamine blockade, however, means that it may cause more disorders of movement and expression (parkinsonism), involuntary and perhaps irreversible movements (dyskinesia), overwhelm- Types of studies ing feelings of restlessness (akathisia) and dangerous disturbances We included all relevant randomised controlled trials. We included of the body’s temperature and blood pressure regulatory systems trials that implied randomisation, i.e. the trial was described as (neuroleptic malignant syndrome) (Settle 1983). ’double-blind’ and the participants’ demographic details in each Despite these recent concerns, research in general has consistently group were similar. We excluded quasi-randomised studies, such found haloperidol to be an effective, well tolerated antipsychotic as those allocating by using alternate days of the week. that produces minimal side effects (Ayd 1972, Ayd 1978, Settle 1983). Consequently, in accordance with the recommendations of drug regulatory authorities, such as the Food and Drug Adminis- Types of participants tration of the United States of America, haloperidol is increasingly We included anyone with schizophrenia or similar serious, non- used as a comparator drug in clinical trials (Settle 1983, Thornley affective psychosis diagnosed by any criteria irrespective of gender, 1998a). To an even greater extent than chlorpromazine, haloperi- age or race. We accepted a trial including people with less serious dol remains the benchmark by which all other antipsychotics are mental illnesses if the majority of participants suffered from serious measured. functional psychotic illnesses, such as schizophrenia.

Haloperidol versus placebo for schizophrenia (Review) 3 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Types of interventions Search methods for identification of studies 1. Haloperidol: any means of administration, any oral dose.* 1. For the original search in 1998, we electronically searched the 2. Placebo: active or inactive. following databases: * Depot administration of haloperidol has been evaluated in an- 1.1 Biological Abstracts on Silver Platter (1985 to February 1998) other Cochrane Review (Quraishi 1999), and trials relevant to this using the Cochrane Schizophrenia Group’s terms for randomised comparison will be sent to the contact author of this review. A controlled trials and schizophrenia combined with the phrase: systematic review of haloperidol, one dose verses another, has also [and ((haloperi* or R-1625 or haldol* or alased* or aloperidi* been published (Waraich 2001) and relevant studies will also or bioperido* or buterid* or ceree* or dozic* or duraperido* or be supplied to this reviewer. fortuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or zafri*))] 1.2 CINAHL on Silver Platter (1982 to February 1998) using the Types of outcome measures Cochrane Schizophrenia Group’s terms for randomised controlled We grouped outcomes into seven main areas of interest. trials and schizophrenia combined with the phrase: 1. Service utilisation [and ((haloperi* or R-1625 or haldol* or alased* or aloperidi* 1.1 Hospital admission.* or bioperido* or buterid* or ceree* or dozic* or duraperido* or 1.2 Number of re-admissions to hospital. fortuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or 1.3 Number of days in hospital. zafri* or explode “HALOPERIDOL”/ all topical subheadings / all 2. Clinical response age subheadings))] 2.1 Death/Suicide.* 1.3 The Cochrane Library (1998, Issue 4) using the Cochrane 2.2 Symptom improvement, general and specific.* Schizophrenia Group’s terms for schizophrenia combined with the 2.3 Number of relapses.* phrase: 2.4 Dose. [and ((haloperi* or R-1625 or haldol* or alased* or aloperidi* 2.5 Compliance with medication. or bioperido* or buterid* or ceree* or dozic* or duraperido* or 2.6 Use of antiparkinson drugs. fortuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or 3. Social response zafri* or HALOPERIDOL*:ME))] 3.1 Improvement in social functioning, general and specific*. 1.4 The Cochrane Schizophrenia Group’s Register (December 3.2 Behavioural changes*. 1998) using the phrase: 3.3 Employment status, including attendance at school/college. [and ((haloperi* or R-1625 or haldol* or alased* or aloperidi* 3.4 Living status, including living skills. or bioperido* or buterid* or ceree* or dozic* or duraperido* or 3.5 Community burden, including trouble with police and service fortuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or use. zafri* or #42 = 14)] 4. Adverse effects #42 is the ’Intervention’ field and ’14’ is the code for haloperidol. 4.1 Extrapyramidal, including tardive dyskinesia and neuroleptic 1.5 EMBASE (January 1980 to February 1998) using the malignant syndrome.* Cochrane Schizophrenia Group’s terms for randomised controlled 4.2 Autonomic, including dry mouth, sedation, blurred vision* trials and schizophrenia combined with the phrase: 4.3 Cardiovascular and gastrointestinal. [and ((haloperi* or R-1625 or haldol* or alased* or aloperidi* 4.4.Other, general and specific. or bioperido* or buterid* or ceree* or dozic* or duraperido* or 5. Satisfaction with treatment fortuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or 5.1 Loss to follow up.* zafri* or explode “HALOPERIDOL / all subheadings))] 5.2 Patient satisfaction with treatment. 1.6 MEDLINE on Silver Platter (January 1966 to February 1998) 5.3 Staff satisfaction with treatment. using the Cochrane Schizophrenia Group’s terms for randomised 6. Cost of treatment controlled trials and schizophrenia combined with the phrase: 6.1 Total cost of medical and mental health care.* [and ((haloperi* or R-1625 or haldol* or alased* or aloperidi* 7. Cognitive response or bioperido* or buterid* or ceree* or dozic* or duraperido* or 7.1 Improvement, general and specific. fortuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or * Primary outcomes of interest. zafri* or explode ”HALOPERIDOL“ / all subheadings))] Where possible, we dichotomised outcomes into ’clinically signif- 1.7 PsycLIT on Silver Platter (January 1974 to February 1998) icant change’ or ’ no clinically significant change’ - as defined by using the Cochrane Schizophrenia Group’s terms for randomised each of the included studies. controlled trials and schizophrenia combined with the phrase: We also grouped outcomes into immediate (0 to six weeks), short [and ((haloperi* or R-1625 or haldol* or alased* or aloperidi* (six weeks to six months), medium (six months to one year), and or bioperido* or buterid* or ceree* or dozic* or duraperido* or long (over one year) terms. fortuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or

Haloperidol versus placebo for schizophrenia (Review) 4 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. zafri* or explode ”HALOPERIDOL“))] between allocation concealment and the potential for bias in the 2. Cited reference searching results. The categories are defined below: We inspected the references of all identified trials for more stud- A. Low risk of bias (adequate allocation concealment) ies. We sought each of the included studies as a citation on the B. Moderate risk of bias (some doubt about the results) SCISEARCH database. We also inspected reports of articles that C. High risk of bias (inadequate allocation concealment) had cited these studies in order to identify further trials. For the purpose of the analysis in this review, we included trials if 3. Personal contact they met the criteria A or B. We contacted primary authors of all studies initially selected for 3. Data collection inclusion in order to identify further relevant trials. We also con- We (CJ and SL) independently extracted data from selected trials tacted companies producing relevant compounds for copies of and CEA re-extracted information from a sample of 20%. When published, unpublished and archived trials. disputes arose, resolution was attempted by discussion. If this was 4. Hand Searching not possible and further information was necessary to resolve the High yield journals identified by electronic searches, if not already dilemma, we did not enter the data. Again, for the 2005 update hand searched, will be chosen for full page by page inspection. we (CJ and CEA) followed the same procedures. 5. 2005 Search 4. Data synthesis For the 2005 update we searched The Cochrane Schizophrenia 4.1 Incomplete data Group’s Trials Register (July 2005) using the phrase: With the exception of the outcome of leaving the study early, we [((haloperi* or R-1625 or haldol* or alased* or aloperidi* or did not include trial outcomes if more than 50% of people were bioperido* or buterid* or ceree* or dozic* or duraperido* or for- not reported in the final analysis. tuna* or serena* or serenel* or seviu* or sigaperid* or sylad* or zafri* 4.2 Dichotomous data in REFERENCE title, abstract and index fields) OR ((haloperi- We used an intention to treat analysis, on the condition that more dol* and placebo*) in STUDY intervention field)] than 50% of people completed the study and everyone allocated 6. Cochrane Schizophrenia Group Trials Register (May 2012) to the intervention was counted regardless of whether they com- We updated this search. The Trials Search Co-ordinator searched pleted the follow up. We assumed that those leaving the study early the Cochrane Schizophrenia Group’s Trials Register (15 May had the negative outcome, with the exception of death. We cal- 2012). culated the Relative risk (RR) and their 95% confidence interval The Cochrane Schizophrenia Group’s Trials Register is compiled (CI) based on the random effects model. This takes into account by systematic searches of major databases, handsearches and con- any differences between studies even if there is no statistically sig- ference proceedings (see group module). Trials identified through nificant heterogeneity. We inspected the data to see if analysis us- the searching activities are each assigned to awaiting classification ing a fixed effects model made any substantive difference. Where of relevant review titles. possible we estimated the number needed to treat (NNT). 4.3 Continuous data 4.3.1 Normal data: data on continuous outcomes are frequently skewed, the mean not being the centre of the distribution. The Data collection and analysis statistics for meta-analysis are thought to be able to cope with some skew, but were formulated for parametric data. To avoid 1. Selection of trials this potential pitfall, we applied the following standards to all data We (CJ and SL) independently inspected all abstracts of studies before inclusion: (a) standard deviations and means were reported identified by the above search terms. In addition, to ensure reliabil- or obtained from authors, (b) for data with finite limits, such as ity, CEA inspected a random sample of these abstracts, comprising endpoint scale data, the standard deviation (SD), when multiplied 10% of the total. We ordered full articles of relevant reports and by two, was less than the mean. Otherwise the mean is unlikely carefully inspected these for a final decision on inclusion (see se- to be an appropriate measure of the centre of the distribution lection criteria). We were not blinded to the names of the authors, (Altman 1996). We reported data that did not meet the first or institutions or journal of publication. In turn, we (CJ and SL) second standard in ’other data’ tables. inspected all full reports. Again, a random 10% sample of reports For change data (endpoint minus baseline), the situation is even were re-inspected by CEA in order to ensure reliable selection. For more problematic. In the absence of individual patient data it is the 2005 update CJ inspected all abstracts and subsequent reports impossible to know if data are skewed, though this is likely to be from the new 2005 electronic search. CEA carried out the relia- the case. As carried out in other CSG reviews, we presented change bility check. data in MetaView in order to summarise available information. 2. Assessment of methodological quality In doing this, it was assumed either that data were not skewed or We assessed the methodological quality of trials included in this that the analyses could cope with the unknown degree of skew- review using the criteria described in the Cochrane Handbook ness. Without individual patient data it is impossible to test this (Higgins 2005) which is based on evidence of a strong relationship

Haloperidol versus placebo for schizophrenia (Review) 5 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. assumption. Where both change and endpoint data were available statistic, but we presented these separately and investigated reasons for the same outcome category, we only presented endpoint data. for heterogeneity. We acknowledge that by doing this much of the published change 6. Addressing publication bias data were excluded, but argue that endpoint data is more clinically We entered data from all identified and selected trials into a funnel relevant and that if change data were to be presented along with graph (trial effect versus trial size) in an attempt to investigate the endpoint data it would be given undeserved equal prominence. likelihood of overt publication bias. Authors of studies reporting only change data are being contacted 7. Sensitivity analysis for endpoint figures. We reported non-normally distributed data We anticipated that this review, like chlorpromazine, would be in the ’Other data types’ tables. large in comparison to many within the field of mental health and 4.3.2 Rating scales: a wide range of instruments are available to this would allow several sensitivity analyses (see Objectives). We measure mental health outcomes. These instruments vary in qual- (CJ and SL) selected trials suitable for such analyses at the data ity and many are not valid, or even ad hoc. For outcome instru- extraction stage of the review. ments some minimum standards have to be set. These were that: (a) the psychometric properties of the instrument should have been described in a peer-reviewed journal, (b) the instrument should either be: (i) a self-report, or (ii) completed by an independent RESULTS rater or relative (not the therapist) and (c) the instrument should be a global assessment of an area of functioning (Marshall 2000). 4.3.3 Cluster trials Description of studies Studies increasingly employ ’cluster randomisation’ (such as ran- See: Characteristics of included studies; Characteristics of domisation by clinician or practice) but analysis and pooling of excluded studies; Characteristics of studies awaiting classification; clustered data poses problems. Firstly, authors often fail to account Characteristics of ongoing studies. for intra class correlation in clustered studies, leading to a ’unit 1. Excluded studies of analysis’ error (Divine 1992) whereby p values are spuriously We inspected thousands of citations, most of which were clearly low, confidence intervals unduly narrow and statistical significance not relevant to this review. We excluded fifty-six but only after a overestimated. This causes type I errors (Bland 1997,Gulliford hard copy had been acquired for clarification and we have pre- 1999). sented details of these in the ’Excluded studies’ table. We excluded Where clustering was not accounted for in primary studies, we eighteen of the 56 because they were not randomised and/or al- presented the data in a table, with a (*) symbol to indicate the location was unclear. We excluded another five because the par- presence of a probable unit of analysis error. In subsequent ver- ticipants were not suffering from schizophrenia. We excluded five sions of this review we will seek to contact first authors of studies more studies because they were withdrawal trials. In these trials, to obtain intra-class correlation co-efficients of their clustered data people stable on haloperidol were randomised to placebo or to con- and to adjust for this using accepted methods (Gulliford 1999). tinue their usual dose of haloperidol. As this review is, at present, Where clustering has been incorporated into the analysis of pri- focusing on instigation studies of haloperidol, we excluded these mary studies, we will also present these data as if from a non-clus- trials. We eventually excluded a further seventeen studies because ter randomised study, but adjusted for the clustering effect. all outcome data were impossible to use. Seven of these were only We have sought statistical advice and have been advised that the published as a conference proceeding and information was not binary data as presented in a report should be divided by a ’design available in the short abstract. We have contacted the authors of effect’. This is calculated using the mean number of participants these studies for additional data and this data may be included per cluster (m) and the intraclass correlation co-efficient (ICC) in later versions of this review. We excluded one crossover study [Design effect = 1+(m-1)*ICC] (Donner 2002). If the ICC was (Rees 1965) as no data were provided for the first arm of the trial. not reported it was assumed to be 0.1 (Ukoumunne 1999). The other nine either reported data incorrectly or had a greater 5. Heterogeneity than 50% loss to follow up (see ’Methods 5.1 How data were man- Firstly, we undertook consideration of all the included studies aged in general’). We had to exclude Pool 1976 and Price 1987 within any comparison to estimate clinical heterogeneity. Then because they replaced people who withdrew from the trial with we used visual inspection of graphs to investigate the possibility people who they did not randomise and presented outcomes that of statistical heterogeneity. This was supplemented employing, included data from these non-random additions. primarily, the I-squared statistic. This provides an estimate of the Again for the 2005 update we found hundreds of citations in the percentage of inconsistency thought to be due to chance. Where search and most were not relevant. Eventually, we added six stud- the I-squared estimate was greater than or equal to 75% this was ies to the excluded studies table (Arvanitis 2002, Kasper 1996, interpreted as evidence of high levels of heterogeneity (Higgins Lemmer 1993, Lindborg 2003, Potkin 2000 and Stankovska 2003). We did not summate data with 75% or greater I-squared 2002) taking the total number of excluded studies to sixty-two.

Haloperidol versus placebo for schizophrenia (Review) 6 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. We excluded four of these new studies due to all data being un- Borison 1989 did not describe the sex of participants. usable. It was unclear if the participants have been randomised to 4.3 Setting treatment groups in Stankovska 2002 and Lindborg 2003 was not Trials took place in a mixture of inpatient and outpatient set- a randomised trial but a meta-analysis. tings. Six studies were multi-centre (Arvanitis 1997, Beasley 1996, 2. Awaiting assessment Borison 1992a, Chouinard 1993, Kane 2002 and Marder 1994). One new study (Cucchaiaro 2001) is awaiting assessment. The 4.4 Study size only publication available at the moment is a conference proceed- 1519 participated in the included studies. The largest trials (Kane ing and no usable data were presented. We will contact the authors 2002 and Marder 1994) randomised 414* and 388 people respec- for further information as this trial is relevant to this review. After tively while the smallest included only 12 (Spencer 1992). Over- a search in 2012 a further 72 trials await assessment. all, study size was small. Nine of the 20 studies randomised fewer 3. Ongoing than 50 people and only four were greater than 100. Four of these As far as we are aware, there are two ongoing trials (George 2000 randomised over three hundred (Arvanitis 1997, Beasley 1996, and Paykel 2000) relevant to this review. We await their publica- Kane 2002 and Marder 1994). tion. * although this review only uses data for haloperidol (n=104) and 4. Included placebo groups (106). We only added one new trial (Kane 2002 ) to the included studies 4.5 Interventions table from the 2005 search taking the total number of included A wide range of doses of haloperidol was used in the trials. The studies to twenty-one. These studies randomised 1519 people. smallest doses were given in Spencer 1992 who used a range of 4.1 Length of trials 0.5 to 10 mg/day for children under 12 years of age and the Schizophrenia is often chronic, and, in some cases, lifelong. This greatest in Howard 1974 (doses up to 200 mg/day). Most studies review categorised data into ’immediate’ (0-6 weeks), ’short-term’ used doses in the range of 4mg/day to 20 mg/day. The major- (>6-24 weeks), ’medium’ (six months to one year) and ’long - ity of trials adjusted dose according to need with only four stud- term’ (over one year) follow-up. Not one of the studies presented ies appearing to give a ﬁxed dose throughout the trial (Klieser usable data on ’long-term’ follow-up and only two (Nishikawa 1989, Marder 1994, Simpson 1967, Vichaiya 1971). Most tri- 1982, Nishikawa 1984) had a follow up of one year. Nine studies als randomised to other drugs in addition to placebo. The other lasted for less than six weeks. Reschke 1974 presented results at comparators included amitriptyline, aripirazole, chlorpromazine, 24 hours only and Durost 1964 at between ten days and three clopenthixol, diazepam, imipramine, loxapine, olanzapine, queti- months, with an average follow-up of three weeks. The other ten apine, risperidone, thioridazine, thiothixene and trazodone. Only studies presented data that fell into the ’short-term’ category. A six studies had the single comparison of haloperidol with placebo placebo washout or a medication-free period preceded treatment (Bechelli 1983, Durost 1964, Garry 1962, Jann 1997, Spencer in all but six trials. 1992, Vichaiya 1971). Of these Vichaiya 1971 and Spencer 1992 were also cross-over trials. Nine studies stated that they used other 4.2 Participants medications to alleviate adverse effects or behaviour as required. Eleven studies included people with schizophrenia diagnosed by These drugs included benztropine mesylate, biperiden, chloral hy- DSM-III, DSM-III-R or DSM-IV criteria. The other ten included drate, lorazepam, nitrazepam, paraldehyde, procyclidine, sodium people with schizophrenia, but did not describe the means of diag- amytal and trihexyphenidyl. nosis. Reschke 1974 included people who were described as suffer- 4.6 Outcomes ing from current and acute psychiatric symptoms with an impli- 4.6.1 Missing outcomes cation that these people did suffer from schizophrenia. Nishikawa None of the studies evaluated patient or staff satisfaction. Death, 1982 and Nishikawa 1984 included people who were in stable suicide or self harm was also not mentioned in any study. Out- and in remission. Other studies also included a few people with comes such as employment status, living status and community other mental illnesses such as neurosis (Durost 1964) and ma- burden were not investigated in the included studies. jor depressive disorder (Klieser 1989), in addition to people with 4.6.2 Scales schizophrenia. In these studies, only data for those suffering from Twenty different instruments were used to collect data. Although schizophrenia were used. The majority of participants were hospi- all of the scales used were validated through peer review, only two, talised and chronically ill. Four studies speciﬁcally stated that par- the BPRS, in Bechelli 1983 and Borison 1992a, collected con- ticipants were currently acutely ill (Arvanitis 1997, Beasley 1996, tinuous data useful to this review. Details of this scale are shown Reschke 1974, Selman 1976). Only one included people who were below. Reasons for exclusion of data from the other instruments under 18 years old (Spencer 1992) and none included people who are given under ’Outcomes’ in the ’Included studies’ section. Fre- were over 65 years of age. Three quarters of the trials were of mixed quently, despite using a scale, no data were presented, or means sex. Howard 1974 and Vichaiya 1971 were women only studies, were reported without a variance. while Simpson 1967 and Bechelli 1983 included only men. Only Brief Psychiatric Rating Scale - BPRS (Overall 1962)

Haloperidol versus placebo for schizophrenia (Review) 7 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This is used to assess the severity of abnormal mental state. The ences and obtained hard copies for thorough inspection. In addi- original scale has 16 items, but a revised 18-item scale is commonly tion to our own search, Dr Jo Wood, at Janseen-Cilag UK Limited, used. Each item is defined on a seven-point scale varying from kindly carried out a search of an in-house databases and provided ’not present’ to ’extremely severe’, scoring from 0-6 or 1-7. Scores a further 104 possible references. After multiple publications of can range from 0-126, with high scores indicating more severe trials had been accounted for, these two searches finally produced symptoms. a total of 74 trials, 54 of which we excluded and 20 we included. For the 2005 update, again the electronic search produced nearly 1000 references from which we only found one new trial that was Risk of bias in included studies of relevance to this review. There are a two ongoing studies and one awaiting assessment that we may include in a future version. 1. Randomisation 2. COMPARISON: HALOPERIDOL versus PLACEBO All included studies were reported as randomised but none de- 2.1 Global effect: improved/not improved scribed how this was achieved. A few studies mentioned the use of Results favoured haloperidol. Three trials found that failing to ’randomised blind schedules’ (Borison 1989, Klieser 1989 ) and/or produce a marked improvement was significantly less likely at 0- patient codes (Bechelli 1983, Spencer 1992, Simpson 1967) but 6 weeks with haloperidol (3RCTS n=159, RR 0.44 CI 0.3 to 0.6, it was not stated how these were generated or used. We therefore NNT 3 CI 2 to 5). A further eight trials also found a significant dif- categorised all studies as B - moderate risk of bias with some doubt ference favouring haloperidol across the 6-24 week period (8RCTs about the results (see ’Methods 2. Assessment of methodological n=308, RR no marked global improvement 0.68 CI 0.6 to 0.8 quality). NNT 3 CI 2.5 to 5). This result, however, displayed asymmetry 2. Blindness of the funnel plot (see ’4. Publication biases below). Serafetinides All studies were reported to be double blind although this was dif- 1972 (n=28) reported results for ’nurse rated’ global improvement ficult to maintain due to the appearance of characteristic adverse across this time period, as opposed to the other ’clinician-rated’ side effects when administering haloperidol. Some trials tried to trials. We assumed that ’clinician-rated’ meant ’doctor-rated’. In overcome this by masking some of the side effects with antiparkin- any event, the Serafetinides 1972 study reported similar results son medication. Seven studies specifically stated blindness was favouring haloperidol (1RCT n=28, RR 0.57 CI 0.4 to 0.9 NNT achieved through use of identical capsules and/or bottles of med- 2 CI 1 to 6). ication (Howard 1974, Jann 1997, Nishikawa 1982, Nishikawa Only Howard 1974 reported usable data on the outcome of dis- 1984, Serafetinides 1972, Selman 1976, Vichaiya 1971), but no charge from hospital. This small trial found no difference between trial tested whether their attempts at blinding had been successful. haloperidol and placebo for this outcome between six weeks and 3. Leaving the study early. six months (1 RCT n=33, RR 1.23 CI 0.6 to 2.8). Nishikawa Overall, the description of how many and why people left the 1982 and Nishikawa 1984 found that once a person’s illness was studies early was good. Only four studies did not describe losses in stable in remission, if haloperidol was started, it was more likely the text (Borison 1992a, Durost 1964, Simpson 1967, Vichaiya to keep people in remission than placebo (2 RCTs n=70, RR 0.69 1971). The numbers leaving these studies, however, could be cal- CI 0.6 to 0.8, NNT 3 CI 2 to 5). culated from their tables of results. 2.2 Mental state 4. Data reporting Data are limited. Results appear to favour haloperidol. A slight dif- Data reporting was poor. Overall, there were very little data that ference favouring haloperidol was found at 0-6 weeks by Borison were possible to use from the seventeen included trials. Contin- 1992a when he measured clinical improvement by reduction in uous data were particularly problematic. The most common rea- BPRS scores but this difference was not statistically significant son for exclusion was a lack of standard deviations and/or failure (1RCT n=24 RR 0.75 CI 0.5 to 1.04). Another two studies to give any information about outcomes at all. Many studies also (Bechelli 1983, Jann 1997) however, found a significant differ- presented findings in graphs, in percentiles or by inexact p-values. ence, favouring haloperidol, for the average end point BPRS score ’P’-values are commonly used as a measure of association between at six weeks (2RCTs n=72, WMD -11.9 CI -7 to -17). intervention and outcomes instead of showing the strength of the 2.3 Leaving the study early association. We were able to obtain data for this outcome from all but one of the 20 studies (Nishikawa 1982). At nought to six weeks, 11 studies found a difference that just favoured haloperidol (11 RCTs Effects of interventions n=898, RR 0.8 CI 0.7 to 0.9, NNT 59 CI 38 to 200). By six weeks to six months, eight studies also found a difference favouring 1. The search haloperidol but this result was not statistically significant (8 RCTs The electronic search produced 1161 references. After scanning n=304, RR 0.56 CI 0.3 to 1.04). By one year, only one study titles we reduced this to a possible 254 references. Through further (Nishikawa 1984) found no difference between groups (1 RCT inspection of the abstracts we further reduced this list to 126 refer-

Haloperidol versus placebo for schizophrenia (Review) 8 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. n=50, RR 2.58 CI 0.1 to 47). to 41). No difference between groups was found for insomnia (6 2.4 Adverse events RCTs n=307, RR 1.7 CI 0.8 to 3.6), 2.4.1 Anticholinergic effects Limited data from three studies found no difference in anticholin- 2.4.5 Other various effects ergic effects. Selman 1976 and Kane 2002 found haloperidol ap- No significant difference between groups was found for any of peared more likely to produce blurred vision than placebo, but the following outcomes: confusion (1 RCT n=33, RR 2.5 CI 0.1 just failed to reach conventional levels of statistical significance to 58); drooling (2 RCTs n=83, RR 2.75 CI 0.3 to 25); facial (2 RCTs n=240, RR 3.42 CI 0.91 to 12.91). Reschke 1974 and oedema (1 RCT n=33, RR 2.83 CI 0.1 to 65); headache (2 RCTs Selman 1976 also found no clear differences between the ’active’ n=231, RR 1.06 CI 0.7 to 1.7); infection (1 RCT n=24, RR 7 CI drug and placebo for dry mouth (2 RCTs n=73, RR 1.81 CI 0.7 0.4 to 122); nausea/vomiting (2 RCTs n=231, RR 0.9 CI 0.5 to to 4.6). 1.7); perspiration (2 RCTs n=93, RR 4.7 CI 0.6 to 39) and weight 2.4.2 Cardiovascular effects loss (1 RCT n=27, RR 0.8 CI 0.4 to 1.8). Kane 2002 did find Four studies were not able to demonstrate clear differences between haloperidol more likely to cause weight gain (1 RCT n=207, RR groups for incidences of low blood pressure (4 RCTs n=285, RR 10.1 CI 1.3 to 77, NNH 3 CI 2 to 59) 1.13 CI 0.43 to 2.95). Borison 1989 also found no effect for raised 3. Sensitivity analyses blood pressure (1 RCT n=16, RR 3 CI 0.1 to 64). 3.1 On dishonest researchers 2.4.3. Movement Disorders It has come to our attention that Dr Richard Borison and Dr Bruce 2.4.3.1 Acute Diamond have been convicted of theft, making false statements Three studies (Bechelli 1983, Borison 1992a, Selman 1976) found and violations of state racketeering law in the USA. At this point, the haloperidol group was much more likely to suffer from dysto- it seems that crimes were to do with criminal diversion of funds, nia than the placebo group (3 RCTs n=93, RR 4.7 CI 1.7 to 44, rather than falsifying study data (http://www.the-scientist.com/ NNH 5 CI 3 to 9). Another two studies (Garry 1962, Howard yr1998/oct/notebook_981026.html). Nevertheless we temporar- 1974) however, found no difference between groups for oculogyric ily removed studies with either of these authors from the analyses crises (2 RCTs n=83, RR 0.96 CI 0.1 to 8.9). to see if this made a substantive difference to the findings. Arvanitis 2.4.3.2 Non-acute 1997 only provided data for leaving the study early. Borison 1989 A few studies found significant differences favouring placebo for and Borison 1992a also reported on this outcome but also pre- the outcomes of akathisia, parkinsonism and need of antiparkin- sented usable data on mental state (<20% reduction in BPRS), and son medication. Bechelli 1983, Borison 1989, Garry 1962 and a range of adverse effects. In every case, where data from these trials Kane 2002 found that haloperidol frequently caused akathisia (4 are added to those of others, removal of the studies never resulted RCTs n=333, RR 2.6 CI 1.3 CI 1.4 to 4.8, NNH 7 CI 3 to 25) in substantive changes in the findings. For example, most data is and Bechelli 1983, Jann 1997, Reschke 1974, and Serafetinides available for the outcome of leaving the study early. With all trials 1972 that it caused parkinsonism (4 RCTs n=163, RR 11.7 CI included, the results favour the haloperidol group (12 RCTs n= 2.9 to 47, NNH 3 CI 2 to 5). Borison 1989, Kane 2002 and 688, RR 0.82 CI 0.7 to 0.95). Removing the three studies results Simpson 1967 found more people needed to use antiparkinson in little change (9 RCTs n=545, RR 0.77 CI 0.7 to 0.9). Where medication in the haloperidol group than those allocated placebo difficulties arise is where Borison 1992a reports unique outcomes. (3 RCTs n=333, RR 2.7 CI 1.5 to 4.7, NNH 4 CI 2 to 11). No In these cases, of course, removal of the study results in the deletion statistically significant differences were found between haloperidol of the complete outcome. This applies to the outcome of <20% and placebo for rigidity or tremor. Haloperidol was more likely to reduction in BPRS, and the adverse effects of high blood pressure, cause rigidity, although this did not reach statistical significance (3 headache, infection, and nausea or vomiting (see Discussion). RCTs n=99, RR 4.3 CI 0.9 to 19.7). Finally, Garry 1962, Howard 3.2 Heterogeneity and sensitivity analyses 1974, Kane 2002 and Selman 1976 found no difference between Overall data were homogeneous. We have not yet undertaken the groups for tremor (4 RCTs n=323, RR 2.5 CI 0.6 to 10.5). series of sensitivity analyses stipulated in the ’Objectives’. In the 2.4.3.3 Chronic light of the relatively small data set now presented in this review, One study (Howard 1974) failed to find a statistically significant the list of variables on which the sensitivity of results was to have difference between groups for dyskinesia and tardive dyskinesia (1 been tested now seems over-ambitious. RCT n=33, RR 2.83 CI 0.1 to 65) but the study was small. Again, 4. Publication bias one underpowered study (Selman 1976) found no difference for Only two of the outcomes in this review really lent themselves to the outcome ’teeth grinding’ (1 RCT n=33, RR 2.53 CI 0.1 to producing a funnel plot; the clinician rated ’No global improve- 57.8) and ’thick speech’ (RR 5.9 CI 0.3 to 106). ment’ at between six and 24 weeks, and leaving the study before 2.4.4 Sleep related adverse effects seven weeks. The funnel plot for the latter was symmetrical but for Six studies found haloperidol more likely to induce sleepiness than the former, the primary outcome for this review and one that, with placebo (6 RCTs n=307, RR 3.4 CI 1.5 to 7.7, NNH 9 CI 4 the advantage of hindsight, could be said to influence publication

Haloperidol versus placebo for schizophrenia (Review) 9 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. bias more than attrition, asymmetry was present. 4. General ﬁndings from the 2005 update

Only one trial Kane 2002 added any data to this review and unfor- tunately all scale data were unusable, so addition of this trial did DISCUSSION not affect results for global effect or mental state. Adverse effect data were usable and overall the data did not change outcomes, 1. Strengths and weaknesses just added weight as this was a relatively large trial randomising The strength of this review is that it attempts to be objective and 414 people. One new outcome, weight gain, was presented by quantitative. Given that haloperidol is so widely used in routine Kane 2002 and haloperidol was more likely to produce this ad- practice across the world, and is a common control drug for ran- verse effect. domised trials of new compounds, readers may have expected more 5. Specific findings data; certainly we did. Hopefully, as more data becomes apparent, we will be able to update the findings of this review and report 5.1 Global effect results with greater confidence. Nevertheless, to date, this system- As discussed above, the principal outcome of this review is the clin- atic review represents a rare attempt to quantify the effects of this ician rated global impression. Probably an over generous estimate potent antipsychotic in some clinically meaningful terms. of effect (see above) suggests that only three people with the signs 2. Quantity and quality of trials and symptoms of schizophrenia have to be given haloperidol in order to allow one to have an important improvement. Even if this It is possible that even after another search which did find some estimate of ’NNT’ doubles to six, in the real clinical environment, trials from the 1980’s and 1990’s we had missed initially (although haloperidol is clearly a valuable antipsychotic. However, with this these were eventually excluded), we still have failed to identify conservative estimate of effect, five of the six will not gain a clin- some trials (see discussion of publication bias). Despite Janssen- ically meaningful improvement and may encounter problematic Cilag UK helping the original search, it is reasonable to assume adverse effects. that no dataset is complete for haloperidol, one of the oldest antipsychotic drugs. We do not feel that we have omitted very many 5.2 Mental state highly influential studies. Of those studies that we identified, quality scoring was better than average, suggesting a lower than average We expected more data on the specific symptoms of schizophrenia. risk of inclusion of bias. Despite this, data presentation was poor, One set of mental state data were presented in a study undertaken with most scale data rendered unusable (see Included Studies ta- by dishonest researchers (Borison 1992a). On the other hand, ble). With closer adherence to the CONSORT statement (Begg Bechelli1983 and Jann 1997 (n=72) found a significant difference, 1996) data reporting should improve although it should be noted favouring haloperidol, by approximately 12 points on the BPRS that the most recent trial Kane 2002 still failed to present SDs for at six weeks. We are unsure whether this is a clinically significant their continuous data. finding. 3. Publication bias 5.3 Leaving the study early The primary outcome of this review is a simple global impression Just less than half those allocated haloperidol and just over half of clinicians; and this impression favours haloperidol over placebo. of those given placebol did not complete the six week stud- The dataset however should present a symmetrical distribution ies. Although the result does favour haloperidol, this is a shock- around the summary statistic. Large studies will fall nearly on the ing loss of data and much greater than is seen in the compan- summary statistic and smaller studies will vary more, falling either ion review, ’Chlorpromazine versus placebo for schizophrenia’ on the positive or negative side. A simple way of doing this within (Thornley 2001). There is no suggestion that this attrition, much the results displayed on The Cochrane Library is to ’Sort’ by ’Effect greater than would be expected in normal clinical practice, has size’. If the small negative studies are absent, as they are in this case, changed over three decades of trials. Clearly the trial design is ei- and the outcome is one that could possibly influence publication, ther unacceptable to participants or is asking researchers to with- as this one is, publication bias is a possibility. Study attrition is draw participants for reasons that are not apparent to those reading not often presented as a primary outcome, unlike ’global clinical the final reports. In any event this is not acceptable. Kane 2002 impression’. There was no suggestion of asymmetry in the graph also had a high attrition rate and addition of this data did not of study attrition. We do recognize that funnel plot asymmetry is significantly affect the overall result. also caused by other biases, but think that publication bias may 5.4 Adverse events be operating. We have no reason to think that Janssen-Cilag UK did not supply all data available to them, but the current company Despite clinical experience, where adverse effects are common, may not have complete records and data could be missing from randomised trials do not provide as much data on anticholinergic studies undertaken nearly 50 years ago. effects as one might have expected. Use of haloperidol, however,

Haloperidol versus placebo for schizophrenia (Review) 10 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. has long been associated with movement disorders, and trial-de- treatment should be reassured that the evidence for haloperidol’s rived data would seem to fit with clinical experience. About one antipsychotic effect is borne out by trials and that it should remain in five people given haloperidol within randomised trials suffer as one useful treatment option. Where several antipsychotics are some sort of acute dystonia. Approximately one in six people given available to a clinician, the comparative effects, including adverse haloperidol would be expected to become restless due to akathisia, effects of each antipsychotic, should be carefully considered. but one in three suffer parkinsonism. There were so few long term 3. For managers and policy makers data that rates of tardive dyskinesia were difficult to quantify with confidence. Although not noted as being a sedating antipsychotic, Haloperidol is inexpensive and effective. Initial cost savings could haloperidol does commonly induce drowsiness (NNH 9 CI 4 to be offset by the consequences of adverse effects, with may include 41). poor compliance with medication. It is important that a person with schizophrenia is treated for their illness. Policy makers must 6. Sensitivity analyses on dishonest researchers take into account the evidence as presented in this review and for- We felt that it would be harsh to immediately delete all trial data mulate humane, culturally sensitive, policy optimising a persons’ associated with Drs Borison and Diamond without empirical data. chance of maintaining recovery. That removal of their data makes no discernable difference to any outcome is reassuring. Implications for research 7. Publication bias 1. General It seems likely that small negative studies are not accounted for. More well designed, conducted and reported randomised trials The cause of this bias is more difficult to be certain about. It is would probably have allowed this review to be more authoritative possible that studies not published in English were omitted. The and comprehensive. Much data were lost due to poor reporting, searches were on databases that are English-language biased, but even in the 2002 study. the search by Janssen-Cilag UK should have accounted for this. 2. Specific It is probably that small negative studies have been destroyed and their data lost. As discussed above, this probably means that the It is unfortunate to have to mention that there is still scope for estimates of effect in this review are somewhat more favourable to better designed, conducted and reported randomised trials on the haloperidol than those of a full trial dataset would have been. absolute effects of haloperidol after nearly five decades of research. Although such trials might be of academic interest, we recognise that new placebo-controlled studies are unlikely. However, using haloperidol as the control drug in randomised controlled trials AUTHORS’ CONCLUSIONS evaluating new antipsychotics is likely to continue to be common practice. Haloperidol is an effective antipsychotic. However with Implications for practice such common, marked, and unacceptable adverse effects, any com- 1. For people with schizophrenia parison with almost any other antipsychotic is going to suggest that the experimental compound has a more favourable adverse ef- Even with this limited data set it can be seen that haloperidol is fect profile. Haloperidol should be less favoured as a control drug. a potent antipsychotic drug but has a high propensity to cause adverse effects. The addition of new data further strengthens this observation. Given the choice, people with schizophrenia may wish to switch to another antipsychotic with less likelihood of ACKNOWLEDGEMENTS causing parkinsonism, akathisia and acute dystonias. The reviewers would like to thank the funders (NHS R&D, UK) 2. For clinicians who had the vision to support this important review. Dr Jo Wood, Haloperidol remains a benchmark for modern treatments. This then of Janssen-Cilag Limited, UK, was also generous of her time review supports and, perhaps for the first time, objectively quanti- and supplied a stream of rare reports of trials. We would also like fies evidence of clinical experience. Clinicians with little choice of to thank those who have provided editorial input to this review.

References to studies included in this review European College of Neuropsychopharmacology Congress. September 21-25th; Amsterdam, The Netherlands. 1996. Arvanitis 1997 {published data only} Hong WW, Arvanitis LA, Miller BG. (ICI 204,636) does Arvanitis LA, Miller BG. (ICI 204,636): An atypical not differ from placebo in the incidence of EPS or effect antipsychotic: Results from a multiple fixed dose, on plasma prolactin. Proceedings of the XXth Collegium placebo-controlled study. Proceedings of XXth Collegium Internationale Neuro-psychopharmacologicum. June 23- Internationale Neuro-Psychopharmacologicum. June 23- 27th; Melbourne, Australia. 1996. 27th; Melbourne, Australia. 1996. Hong WW, Arvanitis LA, Miller BG. Quetiapine does Arvanitis LA, Miller BG. Quetiapine, an atypical not differ from placebo in the incidence of extrapyramidal antipsychotic - results from a multiple fixed dose, placebo- syndrome of effect on plasma prolactin. Proceedings of the controlled study. 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Tollefson GD, Sanger T, Beasley CM. The course of Borison 1989 {published data only} ∗ primary and secondary negative symptoms in a controlled Borison RL, Sinah D, Haverstock S, McLarnon MC, trial with olanzapine. Proceedings of 149th American Diamond B. Efficacy and safety of tiospirone vs haloperidol Psychiatric Association Annual Meeting. May 4-9th. 1996. and thioridazine in a double-blind, placebo-controlled trial. Tollefson GD, Sanger TM. Negative symptoms: A Psychopharmacology Bulletin 1989;25:190–3. path analytic approach to a double-blind, placebo and haloperidol controlled clinical trial with olanzapine. Borison 1992a {published data only} American Journal of Psychiatry 1997;154:466–74. Borison R, Pathiraga A, Diamond B, Meibach R. Tollefson GD, Sanger TM, Beasley CM. The course of Risperidone and Schizophrenia. Proceedings of 5th World primary and secondary negative symptoms in a controlled Congress of Biological Psychiatry. June 9-14th; Florence, trial with olanzapine. Proceedings of XXth Collegium Italy. 1991. Internationale Neuro-psychopharmacologicum. June 23- Borison RL, Diamond BI, Augusta GA. Serotonin 27th; Melbourne, Australia. 1996. modulation of dopaminergic-medicated extrapyramidal Tollefson GD, Sanger TM, Beasley CM, Tran PV. A double- side effects. Proceedings of 43rd Annual Meeting of the blind, controlled comparison of the novel antipsychotic American Academy of Neurology. April 21-27th; Boston, olanzapine versus haloperidol or placebo on anxious USA. 1991. and depressive symptoms accompanying schizophrenia. Borison RL, Diamond BI, Pathiraja A, Meibach RC. Biological Psychiatry 1998;43:803–10. Clinical profile of risperidone in chronic schizophrenia. Tollefson GD, Sanger TM, Beasley CM, Tran PV. Is there a Proceedings of 17th Congress of Collegium Internationale relationship between EPSE and efficacy: faction or fiction. Neuro-psychopharmacologicum. 1993. ∗ Proceedings of Campaign on Schizophrenia. March 10- Borison RL, Pathiraja AP, Diamond B, Meibach RC. 12th; Florence, Italy. 1995. Risperidone: Clinical safety and efficacy in schizophrenia. Tran P, Beasley C, Tollefson G, Beuzen J, Dellva M, Psychopharmacology Bulletin 1992;28:213–8. Sanger T, Paul S. Acute and long-term results of the North American double-blind Olanzapine trial. Proceedings of 8th Chouinard 1993 {published data only} ECNP (European College of Neuropsychopharmacology) Chouinard G. Effects of risperidone in tardive dyskinesia: Congress. September 30th - October 4th; Venice, Italy. An analysis of the Canadian multicentre risperidone study. 1995. Journal of Clinical Psychopharmacology 1995;15:S36–44. Tran P, Beasley C, Tollefson G, Dellva M, Hamilton S, Van Chouinard G, Albright P. Economic and health state utility determinations for schizophrenic patients treated

Haloperidol versus placebo for schizophrenia (Review) 13 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. with risperidone or haloperidol. Journal of Clinical American Psychiatric Association. May 1-6; New York, Psychopharmacology 1997;17:298–307. USA. 2004. Chouinard G, Arnott W. The effect of risperidone on ∗ Kane JM, Carson WH, Saha AR, McQuade RD, extrapyramidal symptoms in chronic schizophrenic patients. Ingenito GG, Zimbroff DL, Ali MW. Efficacy and Safety Proceedings 47th Annual Convention and Scientific of Aripiprazole and Haloperidol versus placebo in patients Program of the Society of Biological Psychiatry. April 29th - with schizophrenia and schizoaffective disorder. Journal of May 3rd; Washington DC, USA. 1992. Clinical Psychiatry 2002;63:763–71. ∗ Chouinard G, Jones B, Remington G, Bloom D, Kane JM, Ingenito G, Ali M. Efficacy of aripiprazole in Addington D, MacEwan GW, Labelle A, Beauclair L, psychoitc disorders: comparison with haloperidol and Arnott W. A Canadian Multicentre placebo-controlled placebo. 153rd Annual Meeting of the American Psychiatric study of fixed doses of risperidone and haloperidol in the Association. May 13-8; Chicago, USA. 2000. treatment of chronic schizophrenic patients. Journal of Kane JM, Ingenito G, Ali M. Efficacy of aripiprazole in Clinical Psychopharmacology 1993;13:25–40. psychotic disorders: comparison with haloperidol and Chouinard G, Vainer JL, Beauclair L. Dose regimens of placebo. 155th Annual Meeting of the American Psychiatric neuroleptics in negative symptoms. Proceedings of 19th Association. May 18-23; Philadelphia, PA, USA. 2002. Collegium Internationale Neuro-Psychopharmacologicum Kane JM, Ingenito G, Ali M. Efficacy of aripiprazole in Congress. June 27th - July 1st; Washington DC, USA. psychotic disorders: comparison with haloperidol and 1994. placebo. Abstracts of the XII CINP Congress, Brussels, Chouindard G, Arnott W. Antidyskinetic effect Belgium, July 9-13. 2000. of risperidone in chronic schizophrenic patients. Proceedings of 18th Collegium Internationale Neuro- Klieser 1989 {published data only} ∗ Psychopharmacologicum Congress. June 28th - July 2nd; Klieser E, Lehmann E. Experimental examination of Nice, France. 1992. trazodone. Clinical Neuropharmacology 1989;12:S18–24.

Durost 1964 {published data only} Marder 1994 {published data only} ∗ ∗ Durost H, Lee H, Arthurs D. An early evaluation of Marder SR, Meibach RC. Risperidone in the treatment Haloperidol. The Butyrophenones in Psychiatry. Edited by of schizophrenia. American Journal of Psychiatry 1994;151: HE Lehmann and TA Ban. Channel Press Inc, 1964:70–3. 825–35.

Garry 1962 {published data only} Nishikawa 1982 {published data only} ∗ Garry JW, Leonard TJ. Haloperidol: A controlled trial in ∗ Nishikawa T, Tsuda A, Tanaka M, Koga I, Uchida chronic schizophrenia. British Journal of Psychiatry 1962; Y. Prophylactic effect of neuroleptics in symptom-free 108:105–7. schizophrenics. Psychopharmacology 1982;77:301–4. Howard 1974 {published data only} ∗ Nishikawa 1984 {published data only} Howard J. Haloperidol for chronically hospitalised ∗ Nishikawa T, Tsuda A, Tanaka M, Hoaki Y, Koga I, psychotics: A double-blind comparison with thiothixene Uchida Y. Prophylactic effect of neuroleptics in symptom- and placebo; a follow-up open evaluation. Diseases of the free schizophrenics: A comparative dose-response study of Nervous System 1974;35:458–63. haloperidol and propericiazine. Psychopharmacology 1984; Jann 1997 {published data only} 82:153–6. ∗ Jann MW, Crabtree BL, Pitts WM, Francis Lam YW, Reschke 1974 {published data only} Carter JG. Plasma alpha-one acid glycoprotein and ∗ Reschke RW. Parenteral haloperidol for rapid control of haloperidol concentrations in schizophrenic patients. severe, disruptive symptoms of acute schizophrenia. Diseases Neuropsychobiology 1997;36:32–6. of the Nervous System 1974;35:112–5.

Kane 2002 {published data only} Selman 1976 {published data only} Anutosh S, Ali MW, Ingenito G, Carson WH. Controlled ∗ Selman FB, McClure RF, Helwig H. Loxapine succinate: study of aripiprazole and haloperidol in schizophrenia. 11th A double-blind comparison with haloperidol and placebo in Association of European Psychiatrists Congress. May 4-8, acute schizophrenics. Current Therapeutic Research 1976; Stockholm, Sweden. 2002. 19:645–52. Carson WH, Kane JM, Ali M, Dunbar GC, Ingenito G. Selman FB, McClure RF, Helwig H. Loxapine succinate: Efﬁcacy of aripiprazole in psychotic disorders: comparison essai comparatif en double aveugle avec l’haloperidol et un with haloperidol and placebo. 13th Congress of the placebo dans les psychoses aigues. Psychololgie Medicale European College of Neuropsychopharmacology [CD- 1979;11:1533–40. ROM]: Conifer Excerpta Medica Medical Communications BV. P2075. 2000. Serafetinides 1972 {published data only} Daniel D, Stock E, Wilber C, Marcus R, Carson Jr WH, ∗ Sefafetinides EA, Willis D, Clark ML. Haloperidol, Manos G, Iwamoto T. Intramuscular Aripiprazole in acutely Clopenthixol and Chlorpromazine in chronic schizophrenia: agitated psychotic patients. 157th Annual Meeting of the II The electroencephalographic effects of chemically

Haloperidol versus placebo for schizophrenia (Review) 14 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. unrelated antipsychotics. The Journal of Nervous and Mental 23rd Congress of the Collegium Internationale Neuro- Disease 1972;155:366–9. Psychopharmacologicum) 2002;5:S188. Serafentinides EA. Consistency and similarity of drug EEG Rein W, Arvanitis L. Antipsychotic effect of four different responses in chronic schizophrenic patients. International compounds - results of the metatrial. Journal of the European Pharmacopsychiatry 1973;8:214–6. College of Neuropsychopharmacology 2003;13:S95. Serafetinides EA. Voltage laterality in the EEG of psychiatric Augustin 1996 {published data only} patients. Diseases of the Nervous System 1973;34:190–1. ∗ Augustin BG, Jann MW, Crabtree BL, Pitts WM, Serafetinides EA, Clark ML. Psychological effects of single Carter JG. Plasma alpha-one acid glycoprotein (AAG) dose antipsychotic medication. Biological Psychiatry 1973;7: and haloperidol (H) concentrations in schizophrenic 263–7. patients. Proceedings of XXth Collegium Internationale Serafetinides EA, Collins S, Clark ML. Haloperidol, Neuropsychopharmacologicum. June 23-27th; Melbourne, Clopenthixol and Chlorpromazine in chronic schizophrenia: Australia. 1996. Chemically unrelated antipsychotics as therapeutic alternatives. The Journal of Nervous and Mental Disease Azima 1960 {published data only} ∗ 1972;154:31–42. Azima H, Durost H, Arthurs D. The effect of R-1625 (Haloperidol) in mental syndromes: A multiblind study. Simpson 1967 {published data only} American Journal of Psychiatry 1960;117:546–7. ∗ Simpson GM, Angus JWS, Edwards JG. A controlled study of haloperidol in chronic schizophrenia. Current Ban 1969 {published data only} ∗ Therapeutic Research 1967;9:407–12. Ban TA. Treatment of acute and chronic psychoses with haloperidol: review of clinical results. Current Therapeutic Spencer 1992 {published data only} Research 1969;11(5):284–8. Spencer E, Alpert M, Pouget E. Scales for the assessment Bateman 1979 {published data only} of neuroleptic response in schizophrenic children: Specific ∗ measures derived from the CPRS. Psychopharmacology Bateman DN, Dutta DK, McCelland HA, Rawlins MD. Bulletin 1994;30:199–202. Metoclopramide and haloperidol in tardive dyskinesia. Spencer EK, Alpert M, Pouget ER. [Two sensitive and British Journal of Psychiatry 1979;135:505–8. specific scales derived from the CPRS for assessing Ben-dor 1998 {published data only} haloperidol response in hospitalised schizophrenic children]. ∗ Ben-dor A, Gelkoph M. Vitamin E: An alternative to Proceedings of 33rd Annual Meeting of the New Clinical anticholinergic drugs?. Proceedings of 9th Congress of the Drug Evaluation Unit. June 1-4th; Boca Raton, USA. Association of European Psychiatrists. September 20-24th; 1993. Copenhagen, Denmark. 1998. ∗ Spencer EK, Kafantaris V, Padron-Gayol MV, Rosenberg CR, Campbell M. Haloperidol in schizophrenic children: Beuzen 1996 {published data only} ∗ Early findings from a study in progress. Psychopharmacology Beuzen JN, Taylor N, Wesnes K, Wood A. Olanzapine - Bulletin 1992;28:183–6. cognitive and motor effects in healthy elderly. Proceedings of Xth World Congress of Psychiatry. August 23-28th; Vichaiya 1971 {published data only} Madrid, Spain. 1996. ∗ Vichaiya V. Clinical trial of haloperidol in schizophrenia. Journal of Psychiatric Association of Thailand 1971;16(1): Blum 1969 {published data only} 31–43. Blum RA, Livingston PB, Shader RI. Changes in cognition, attention and language in acute schizophrenia. Diseases of References to studies excluded from this review the Nervous System 1969;30:31–6. Brandrup 1961 {published data only} Alpert 1995 {published data only} ∗ Brandrup E, Kristjansen P. A controlled clinical test of ∗ Alpert M, Pouget ER, Sison C, Yahia M, Allan E. a new psycholeptic drug (Haloperidol). British Journal of Clinical and Acoustic Measures of the Negative Syndrome. Psychiatry 1961;107:778–82. Psychopharmacology Bulletin 1995;31:312–26. Browne 1988 {published data only} ∗ Alphs 1993 {published data only} Browne FWA, Cooper SJ, Wilson R, King DJ. Serum ∗ Alphs LD. [Response of negative symptom subtypes to haloperidol levels and clinical response in chronic, remoxipride]. Proceedings of 146th American Psychiatric treatment resistant schizophrenic patients. Journal of Association Annual Meeting. May 22-27th; San Francisco, Psychopharmacology 1988;2:94–103. USA. 1993. Buchsbaum 1992 {published data only} Arvanitis 2002 {published data only} ∗ Buchsbaum MS, Potkin SG, Siegel Jr BV, Lohr J, Katz M, ∗ Arvanitis L, Bauer D, Rein W. Results of the metatrial Gottschalk LA, Gulasekaram B, Marshll JF, Lottenberg S, project: efficacy and tolerability of four novel compounds Teng CY, Plon L, Bunney WF. Striatal metabolic rate and in schizophrenia and schizoaffective disorder. International clinical response to neuroleptics in schizophrenia. Archives Journal of Neuropsychopharmacology (Abstracts of the of General Psychiatry 1992;49:966–74.

Haloperidol versus placebo for schizophrenia (Review) 15 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Caroli 1975 {published data only} Itil 1981 {published data only} ∗ Caroli F, Littre-Poirier MF, Ginestet D, Deniker P. Essai ∗ Itil TM, Shapiro D, Schneider SJ, Francis IB. d’interruption des antiparkinsoniens dans les traitements Computerized EEG as a predictor of drug response in neruoleptiques au long cours. L’Encephale 1975;1:69–74. treatment resistant schizophrenics. The Journal of Nervous Cho-Boon 1989 {published data only} and Mental Disease 1981;169:629–37. ∗ Cho-Boon S, Ying-Chiao L, Jeng-Ping H. [Haloperidol Jolley 1990 {published data only} for schizophrenic inpatients with dosage regimens]. ∗ Jolley AG, Hirsch SR, Morrison E, McRink A, Wilson Proceedings of 8th World Congress of Psychiatry. October L. Trial of brief intermittent neuroleptic prophylaxis for 12-19th; Athens, Greece. 1989. selected schizophrenic outpatients: clinical and social Contreas 1988 {published data only} outcome at two years. BMJ 1990;301:837–42. ∗ Contreas SA, Maas JW, Seleshi E, Bowden CL. Urine Kasper 1996 {published data only} and plasma levels of dopamine metabolites in response to ∗ Kapser S. Negative symptoms and Sertindole. 9th Congress apomorphine and neuroleptics in schizophrenics. Biological of the European College of Neuropsychopharmacology. Psychiatry 1988;24:815–8. Sep21-25; Amsterdam, The Netherlands. 1996. Craft 1965 {published data only} Wehnert A, Stilwell C, Mack R, Sloth-Nielsen M. ∗ Craft M. A trial of haloperidol in schizophrenia. Clinical Extrapyramidal symptoms and sertindole - analysis of three Trials Journal 1965;3:140–2. double-blind, haloperidol-referenced, phase III clinical Crow 1986 {published data only} trials. 10th European College of Neuropsychopharmacology ∗ Crow TJ, MacMillan JF, Johnson AL, Johnstone EC. II. Congress. Sep 13-17; Vienna, Austria. 1997. A randomised controlled trial of prophylactic neuroleptic Ko 1989 {published data only} treatment. British Journal of Psychiatry 1986;148:120–7. ∗ Ko GN, Korpi ER, Kirch DG. Haloperidol and reduced Deberdt 1971 {published data only} haloperidol concentrations in plasma and red blood cells ∗ Deberdt R, Luyssaert W. Le traitement de psychoses from chronic schizophrenic patients. Journal of Clinical dellrantes chroniques par la pipothiazine (19.366 RP) et Psychopharmacology 1989;9:186–90. l’ester palmitique de pipothiazine (19.55 RP). Proceedings Kramer 1989 {published data only} of Vth World Congress of Psychiatry. November 28th - ∗ Kramer MS, Vogel WH, DiJohnson C, Dewey DA, Sheves December 4th; Cuidad de Mexico, Mexico. 1971. P,Cavicchia S, Little P,Schmidt R, Kimes I. Antidepressants Diamond 1991 {published data only} in ’depressed’ schizophrenic inpatients. Archives of General Diamond BI, O’Neal E, Wang J, Borison RL. [Plasma Psychiatry 1989;46:922–7. homovanillic acid in schizophrenia]. Proceedings of 5th Kramer MS, Voger WH, DiJohnson C, Sheves P, Cavicchia World Congress of Biological Psychiatry. June 9-14th; S, Litle P. Antidepressants in depressed schizophrenics. Florence, Italy. 1991. Proceedings of 141st American Psychiatric Association ∗ Diamond BI, O’Neal E, Wang J, Borison RL. [Plasma Annual Meeting. May 7-12th; Quebec, Canada. 1998. homovanillic acid and drug response in schizophrenia]. Proceedings of III International Congress on Schizophrenia Kurland 1981 {published data only} ∗ Research. April 21-25th; Tucson, USA. 1991. Kurland AA, Nagaraju A. Viloxazine and the depressed Gelders 1986 {published data only} schizophrenic - Methodological issues. Journal of Clinical Gelders Y, Ceulemans D, Hoppenbrouwers ML, Reyntjens Pharmacology 1981;21:37–41. A, Mesotten F. [Ritanserin, a selective serotonin antagonist Labarca 1993 {published data only} in chronic schizophrenia]. Proceedings of IVth World ∗ Labarca R, Silva H, Jerez S, Ruiz, A, Forray MI, Gysling Congress of Biological Psychiatry. September 8-13th; K, Andres ME, Bustos G, Castillo Y, Hono J. Differential Philadelphia, USA. 1985. effects of haloperidol on negative symptoms in drug naive ∗ Gelders Y, Vanden Bussche G, Reytjens A, Janssen P. schizophrenic patients: effects on plasma homovanillic acid. Serotonin S2 receptor blockers in the treatment of chronic Schizophrenia Research 1993;9:29–34. schizophrenia. Clinical Neuropharmacology 1986;9:325–7. Lee 1968 {published data only} Glovinsky 1992 {published data only} ∗ ∗ Lee H. Use of haloperidol in a ”hard-core“ chronic Glovinsky D, Kirch DG, Wyatt RJ. Early antipsychotic schizophrenic population. Psychosomatics 1968;9:267–71. response to resumption of neuroleptics in drug-free chronic schizophrenic patients. Biological Psychiatry 1992;31: Lehmann 1967 {published data only} ∗ 968–70. Lehmann HE, Ban TA, Lee H. The effectiveness of Huygens 1973 {published data only} combined phenothiazine and butyrophenone treatment ∗ Huygens H, Vereecken JLTM, Tanghe A. Dexetimide in chronic schizophrenic patients. Current Therapeutic (R 16 470) in the control of neuroleptic-induced Research 1967;9:36–7. extrapyramidal side-effects: Its prophylactic value and Lemmer 1993 {published data only} duration of action. Psychiatria Neurologia Neurochirurgia Lemmer W, Klieser E, Klimke A. Experimental comparison 1973;76:251–9. of the efﬁcacy of the dopamine autoreceptor agonist

Haloperidol versus placebo for schizophrenia (Review) 16 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. pramipexole versus haloperidol and placebo in acute Antagonists in Psychiatry; January 7th; New Orleans, USA. schizophrenia. Pharmacopsychiatry 1993;26:102. 1994. Lindborg 2003 {published data only} Marder SR. Risperidone: Clinical development: North Lindborg SR, Beasley CM, Alaka K, Taylor CC. Effects American Results. Clinical Neuropharmacology 1992;15(1): of intramuscular olanzapine vs haloperidol and placebo S92–3. on QTc intervals in acutely agitated patients. Psychiatry Marder SR, Chouinard G, Davis JM. [The clinical actions of Research 2003;119:113–23. risperidone]. Proceedings of 10th Congress of the European College of Neuropsychopharmacology; September 13-17th; Magelund 1979 {published data only} Vienna, Austria. 1997. ∗ Magelund G, Gerlach J, Casey DE. Neuroleptic- Marder SR, Chouinard G, Davis JM. [The clinical actions potentiating effect of alpha-methyl-p-tyrosine compared of risperidone]. Proceedings of 35th Annual Meeting with haloperidol and placebo in a double-blind cross-over of the American College of Neuropsychopharmacology; trial. Acta Psychiatrica Scandivica 1979;60:185–9. December 9-13th; San Juan, Puerto Rico. 1996. Malaspina 1997 {published data only} Marder SR, Chouinard G, Davis JM. [The clinical actions ∗ Malaspina D, Johnson J, Bruder G, Gorman J, Kaufmann of risperidone]. Proceedings of 6th World Congress of C, Amador X, Goetz R. [Brain laterality and haloperidol Biological Psychiatry; June 22-27th; Nice, France. 1997. response in schizophrenia]. Proceedings of 52nd Annual ∗ Marder SR, Davis JM, Chouinard G. The effects of Convention and Scientific Program of the Society of risperidone on the five dimensions of schizophrenia derived Biological Psychiatry. May 14-18th; San Diego, USA. 1997. by factor analysis: combined results of the North American Nagaraja 1977 {published data only} trials. Journal of Clinical Psychiatry 1997;58:538–46. ∗ Nagaraja J. Clinical use of haloperidol (Serenace) in child McEvoy JP. Efficacy of risperidone on positive features of psychiatry. Child Psychiatry Quarterly 1977;10:14–20. schizophrenia. Journal of Clinical Psychiatry 1994;55(5): S18–21. Necomer 1992 {published data only} Meibach RC, Risperidone Study Group. [A fixed–dose, ∗ Newcomer JW, Riney SJ, Vinogradov S, Csernansky parallel group study of risperidone vs haloperidol vs JG. Plasma prolactin and homovanillic acid as markers placebo]. Proceedings of 4th International Congress on for psychopathology and abnormal movements after Schizophrenia Research; April 17-21st; Colorado Springs, neuroleptic dose decrease. Psychopharmacology Bulletin USA. 1993. 1992;28:101–7. Moller HJ. [Incidence of EPS under risperidone therapy]. Nguyen 1984 {published data only} Proceedings of 1st International Risperidone Investigators ∗ Nguyen J, Tamminga C, Alphs L, Stolk J, Heinrichs D, Meeting; March 9-10th; Paris, France. 1992. Carpenter WT. Acute and steady state kinetics of haloperidol Schooler NR. [Negative symptoms, risperidone and dose]. in schizophrenia. Journal of Clinical Pharmacology 1984;24: Proceedings of 146th American Psychiatric Association 339. Annual Meeting; May 22-27th; San Fransico, USA. 1993. Nth America 1997 {published data only} Schooler NR. Negative symptoms in schizophrenia: Anderson C, True J, Ereshefsky L, Miller A. [Risperidone. assessment of the effect of risperidone. Journal of Clinical Clinical efficacy: role of the metabolite 9–hydroxy– Psychiatry 1994;55(5):S22–8. risperidone]. Proceedings of 33rd Annual Meeting of the Simpson GM, Lindenmayer JP. Extrapyramidal Symptoms New Clinical Drug Evaluation Unit. June 1-4th; Boca in patients treated with risperidone. Journal of Clinical Raton, USA. 1993. Psychopharmacology 1997;17:194–201. Anderson CB, True J, Miller AL, Peters B, Velligan DI. [Risperidone dose, plasma levels and response]. Proceedings Okasha 1964 {published data only} of 146th Annual Meeting of the American Psychiatric ∗ Okasha A, Tewfik GI. Haloperidol: A controlled clinical Association. May 22-27th; San Fransico, USA. 1993. trial in chronic disturbed psychotic patients. British Journal Lindenmayer JP. [Incidence of EPS with risperidone of Psychiatry 1964;110:56–60. compared with haloperidol and placebo in patients with chronic schizophrenia]. Proceedings of 146th Meeting of Ortega-Soto 1994 {published data only} the American Psychiatric Association. May 22-27th; San ∗ Ortega-Soto HA, Brunner E, Apiquian R, de la Torre Fransico, USA. 1993. P. [Therapeutic minimum dose of haloperidol (HLP) Marder SR. [Risperidone: Clinical development: North in schizophrenia]. Proceedings of XIXth Collegium American Results]. 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Haloperidol versus placebo for schizophrenia (Review) 17 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Pathiraja 1995 {published data only} Ruskin 1991 {published data only} ∗ Pathiraja AP, Diamond BI, Borison RL, Meibach RC, ∗ Ruskin PE, Nyman G. Discontinuation of neuroleptic Anand R. [Relationship between creatine phosphokinase, medication in older, outpatient schizophrenics: A placebo- psychotic symptoms and novel antipsychotic drugs]. controlled, double-blind trial. The Journal of Nervous and Proceedings of 5th International Congress on Schizophrenia Mental Disease 1991;179:212–5. Research; April 6-12th; Wormsprings, USA. 1995. Samuels 1961 {published data only} ∗ Pool 1976 {published data only} Samuels S. A controlled study of haloperidol: the effects ∗ Pool D, Bloom W, Mielker DH, Roniger JJ, Gallant DM. of small dosages. Clinical Notes 1961;118:253–4. A controlled evaluation of loxitane in seventy-five adolescent Singh 1972 {published data only} schizophrenic patients. Current Therapeutic Research 1976; ∗ Singh MM, Discipo WJ. Changes in staff anxiety and 19:99–104. attitudes during a double blind study of haloperidol in acute Potkin 1984 {published data only} schizophrenics within a structured milieu. The Journal of ∗ Potkin SG, Shen YC, Pardes H, Zhou DF, Phelps B, Nervous and Mental Disease 1972;155(4):245–56. Shu L, Poland R. [Failure of insulin coma and presence Soloff 1986 {published data only} of a therapeutic window for haloperidol in chinese ∗ Soloff PH, George A, Swami NR, Schulz P,Ulrich RF,Perel schizophrenics]. Proceedings of 14th (CINP) Collegium JM. Progress in pharmacotherapy of borderline disorders: Internationale Neuro-Psychopharmacologicum Congress; a double-blind study of amitriptyline, haloperidol, and June 19-23rd; Florence, Italy. 1984. placebo. Pharmacotherapy 1986;43:691–7. Potkin 1995 {published data only} Stankovska 2002 {published data only} Potkin S, Wu J, Anand R, Bear R, Carreon D, Hartman R, ∗ Stankovska GN. The effects of risperidone in the treatment Keator D. Neuroimaging to evaluate atypical antipsychotic of schizophrenia. XIIth World Congress of Psychiatry; Aug compounds: An FDG PET study of SDZ MAR 327. 24-9; Yokohama, Japan. 2002. Proceedings of XXth Collegium Internationale Neuro- Psychopharmacologicum; June 23-27th; Melbourne, Taverna 1972 {published data only} ∗ Australia. 1996. Taverna P,Ghisoni T, Poggi E. Etude controlee de l’activite ∗ Potkin S, Wu J, Fallon F, Anand R, Hartman R, antipsychotique du dogmatil. Psychologie Medicale 1972;4: Bear R, Carreon D, Telford J, Plon L, Keator D. 811–8. Functional Neuroimaging to evaluate atypical antipsychotic Teja 1975 {published data only} compounds: An FDG PET study of SDZ MAR ∗ Teja JS, Grey WH, Clum JM, Warren C. Tranquilzers or 327. Proceedings of 8th ENCP (European College of anti-depressants for chronic schizophrenics: a long term Neuropsychopharmacology) Congress; September 30th - study. Australian and New Zealand Journal of Psychiatry October 4th; Venice, Italy. 1995. 1975;9:241–7. Potkin 2000 {published data only} Van Lommel 1974 {published data only} Potkin SG, Basile VS, Badri F, Keator D, Wu JC, Alva G, ∗ Van Lommel R, Baro F, Dom R. The influence of Doo M, Bunney Jr WE, Kennedy JL. D1 receptor alleles haloperidol and penfluridol on the learning capacity of the predict PET metabolic correlates of clinical response to schizophrenic. Arzneimittelforschung 1974;24:1072–4. clozapine. International Journal of Neuropsychopharmacology Volavka 1992 {published data only} 2000;3:S6. Czobor P, Volavka J. Dimensions of the Brief Psychiatric Price 1985 {published data only} Rating Scale: An examination of stability during haloperidol ∗ Price W, Giannini AJ, Loiselle R. [Antischizophrenia treatment. Comprehensive Psychiatry 1996;37:201–15. effects of verapamil]. Proceedings of IVth World Congress Czobor P, Volavka J. Positive and negative symptoms: Is of Biological Psychiatry; September 8-13th; Philadelphia, their change related?. Schizophrenia Bulletin 1996;22: USA. 1985. 577–90. ∗ Price 1987 {published data only} Volavka J, Cooper T, Czobor P,Bitter I, Meisner M, Laska ∗ Price WA. Antipsychotic effects of Verapamil in E, Gastanga P, Krakowski M, Chan JC, Crowner M, et schizophrenia. Hillside Journal of Clinical Psychiatry 1987;9: al.Haloperidol blood levels and clinical effects. Archives of 225–30. General Psychiatry 1992;49:354–61. Rees 1965 {published data only} Zimbroff 1997 {published data only} ∗ Rees L, Davies B. A study of the value of haloperidol in Baker R, Mack R, Morris D, Sebree T, Kashkin K. the management and treatment of schizophrenic and manic The efficacy and safety of three doses of sertindole patients. 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Haloperidol versus placebo for schizophrenia (Review) 18 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. International Conference Schizophrenia: Breaking down KB, Sertindole Study Group. Controlled, dose-response the Barriers; October 6-9th; Vancouver BC, Canada. 1996. study of sertindole and haloperidol in the treatment of Daniel D, Targum S, Zimbroff D, Mack R, Zborowski schizophrenia. American Journal of Psychiatry 1997;154(6): J, Morris D, Sebree T, Wallin B. Efficacy, safety, and 782–91. dose response of three doses of sertindole and three doses of haldol in schizophrenic patients. Proceedings References to studies awaiting assessment of 34th Annual Meeting of the American College of Neuropsychopharmacology; December 11-15th; San Juan, Akhondzadeh 2005 {published data only} Puerto Rico. 1995. Akhondzadeh S, Safarcherati A, Amini H. Beneficial Glick ID, Ramirez L, McCarthy BG, Kohlbeck antipsychotic effects of allopurinol as add-on therapy P. [Extrapyramidal symptom profile of sertindole]. for schizophrenia: a DOUBLE BLIND, RANDOMized Proceedings of 53rd Annual Convention and Scientific and PLACEBO controlled trial. Progress in Neuro- Program of the Society of Biological Psychiatry; May 27- Psychopharmacology and Biological Psychiatry 2005;29(2): 31st; Toronto, Canada. 1998. 253–9. [MEDLINE: 15694232] Larson GK, Mack RJ, Zborowski J, Morris DD, Sebree TB, Allison 2007 {published data only} Wallin BA. Three doses each of sertindole and haloperidol Allison D, Loebel A, Lombardo I, Siu C. Effect of regression in schizophrenics. Proceedings of Xth World Congress of to the mean on drug-induced weight change. Schizophrenia Psychiatry; August 23-28th; Madrid, Spain. 1996. Bulletin 2007;33(2):418. Mack R, Zborowski J, Morris D, Sebree T, Wallin B. [Efficacy, safety and dose response of three doses of Andrezina 2006a {published data only} sertindole and three doses of haldol in schizophrenic Andrezina R, Marcus RN, Oren DA, Manos G, Stock E, patients]. Proceedings of 34th Annual Meeting of the Carson WH, et al.Intramuscular aripiprazole or haloperidol American College of Neuropsychopharmacology; December and transition to oral therapy in patients with agitation 11-15th; San Juan, Puerto -Rico. 1995. associated with schizophrenia: sub-analysis of a DOUBLE- Potkin SG, Zborowski J, Joseph N, Wu C, Mack RJ, Sebree BLIND study. Current Medical Research and Opinion 2006; TB, Wallin BA. [Brain Imaging to determine the effects of 22(11):2209–19. [MEDLINE: 17076982] sertindole in schizophrenic patients]. Proceedings of 149th Ascher-Svanum 2005 {published data only} Annual Meeting American Psychiatric Association; May 4- Ascher-Svanum H, Stensland MD, Kinon BJ, Tollefson 9th. 1996. GD. Weight gain as a prognostic indicator of therapeutic Schulz SC, Mack R, Zborowski J, Morris D, Sebree T, improvement during acute treatment of schizophrenia Wallin B. [Efficacy, safety and dose response of three doses with PLACEBO or active antipsychotic. Journal of of sertindole and three doses of haldol in schizophrenic Psychopharmacology 2005;19(6 Suppl):110–7. [MEDLINE: patients]. Proceedings of 8th Biennial Winter Workshop 16280344] on Schizophrenia, Crans Montana; March 16-22nd; Switzerland. 1996. AstraZeneca 2001 {published data only} Tamminga C, Mack RJ, Zborowski JG, Morris D, Sebree AstraZeneca. A multicentre, DOUBLE-BLIND, B. Efficacy and safety of three doses of sertindole and haldol RANDOMised trial to compare the effects of quetiapine in schizophrenic patients. Proceedings of XXth Collegium and haloperidol treatment strategies on treatment outcomes Internationale Neuro-Psychopharmacologicum; June 23- (5077IL/0050 ESTO ). http://www.clinicalstudyresults.org/ 27th; Melbourne, Australia. 1996. 2001. Tamminga CA, Mack RA, Granneman GR, Silber CJ, Barbee 1992 {published data only} Kashkin KB. Sertindole in the treatment of psychosis in Barbee JG, Mancuso DM, Freed CR, Todorov AA. schizophrenia: efficacy and safety. International Clinical ”Alprazolam as a neuroleptic adjunct in the emergency Psychopharmacology 1997;12:S29–35. treatment of schizophrenia“: correction. American Journal Targum S, Zborowski J, Schmitz HM, Sebree T, of Psychiatry 1992;149(8):1129. Wallin B. [Efficacy and safety of sertindole in two Battaglia 2005 {published data only} double–blind, placebo–controlled trials of schizophrenic Battaglia J, Houston JP, Ahl J, Meyers AL, Kaiser CJ. A patients]. Proceedings of 8th ENCP (European College of post hoc analysis of transitioning to oral treatment with Neuropsychopharmacology) Congress; September 30th - olanzapine or haloperidol after 24-hour intramuscular October 4th; Venice, Italy. 1995. treatment in acutely agitated adult patients with Zimbroff D, Mack RJ, Zborowski JG, Morris DD. The schizophrenia. Clinical Therapeutics 2005;27(10):1612–8. efficacy and safety of three doses of sertindole versus three [MEDLINE: 16330297] doses of haloperidol in schizophrenic patients. Proceeding of 149th American Psychiatric Association Annual Meeting; Baymiller 2002 {published data only} May 4-9th. 1996. Baymiller SP, Ball P, Mcmahon RP, Buchanan RW. ∗ Zimbroff DL, Kane JM, Tamminga CA, Daniel DG, Weight and blood pressure change during clozapine Mack RJ, Wozniak PJ, Sebree TB, Wallin BA, Kashkin treatment. Clinical Neuropharmacology 2002;25(4):202–6. [MEDLINE: 12151907]

Haloperidol versus placebo for schizophrenia (Review) 19 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Bech 2010 {published data only} on ”Treatments in Psychiatry: An Update“; 2004 Nov 10- Bech P, Tanghoj P, Andreasson KT, Overo K. Sertindole 13; Florence, Italy. 2004. and haloperidol revisited; the psychometric triangle. Modell S, Daniel D, Stock E, Wilber R, Marcus R, Carson Schizophrenia Research 2010;117(2-3):259. W, et al.Intramuscular aripiprazole treatment for acute agitation in patients with psychosis. Proceedings of the 24th Bersudsky 2006 {published data only} Collegium Internationale Neuro-Psychopharmacologicum Bersudsky Y. Phenytoin: an anti-bipolar anticonvulsant?. Congress; 2004 June 20-24; Paris, France 2004. International Journal of Neuropsychopharmacology 2006;9(4): Tran-Johnson TK, Sack DA, Marcus RN, Auby P, 479–84. McQuade RD, Oren DA. Efficacy and safety of Bogeum 2008 {published data only} intramuscular aripiprazole in patients with acute agitation: Bogeum KK, Shim J-C, Lee S-K. The effect of cyp2d6/ a RANDOMized, DOUBLE-BLIND, PLACEBO- 3a5 genotypes on plasma concentrations of aripiprazole controlled trial. Journal of Clinical Psychiatry 2007;68(1): and haloperidol. Proceedings of the 161st Annual Meeting 111–9. [MEDLINE: 17284138] of the American Psychiatric Association; 2008 May 3-8; Yocca F, Daniel D, Stock E, Oren D, Marcus R, Carson Washington DC, USA. 2008. W, et al.Efficacy and safety of intramuscular aripiprazole treatment for acute agitation in patients with psychosis. Bristol-Myers 2004 {published data only} Proceedings of the 43rd Annual Meeting of the American Bristol-Myers S. A RANDOMized, DOUBLE-BLIND College of Neuro-Psychopharmacology; 2004 Dec 12-16; comparison of the efficacy and safety of aripiprazole San Juan, Puerto Rico. 2004. intramuscular formula, haloperidol, or PLACEBO in the Daniel 2007 {published data only} treatment of acutely agitated patients with a diagnosis Daniel DG, Currier GW, Zimbroff DL, Allen MH, Oren of schizophrenia or schizoaffective disorder. http:// D, Manos G, et al.Efficacy and safety of oral aripiprazole www.clinicalstudyresults.org/ 2004. compared with haloperidol in patients transitioning from Cai 2009 {published data only} acute treatment with intramuscular formulations. Journal Cai H. Bezoar xiexin tang for schizophrenia. Stanley of Psychiatric Practice 2007;13(3):170–7. [MEDLINE: Foundation Research Programs 2009. 17522560]

Cao 2006 {published data only} Dillenschneider 2005a {published data only} Cao K-S, Yao J, Li L-H. Safety and efficacy of Dillenschneider A, Oren D, Marcus R, Kostic D, McQuade ziprasidone and haloperidol in patients with schizophrenia R, Iwamoto T, et al.Intramuscular aripiprazole in acute schizophrenia: a pivotal phase III study. Proceedings of [ ]. the 18th European College of Neuropsychopharmacology Chinese Journal of New Drugs and Clinical Remedies Congress; 2005 Oct 22-26; Amsterdam, Netherlands 2005. Eklund 1990 {published data only} [ ] 2006;25(6):431–4. Eklund K. Low dose of haloperidol decanoate is Chou 1998 {published data only} effective against relapses in schizophrenia patients. Chou JC, Douyon R, Czobor P, Volavka J, Cooper TB. A DOUBLE-BLIND PLACEBO controlled study. Change in plasma prolactin and clinical response to Proceedings of the 17th Collegium Internationale Neuro- haloperidol in schizophrenia and schizoaffective disorder. Psychopharmacologicum Congress; 1990 Sep 10-14; Kyoto, Psychiatry Research 1998;81(1):51–5. [MEDLINE: Japan. 1990:287. 1999045115] Eli 2005 {published data only} Czobor 1992 {published data only} Eli LandC. A DOUBLE-BLIND RANDOMized Czobor P, Volavka J. Level of haloperidol in plasma is comparison of the efficacy and safety of short acting related to electroencephalographic findings in patients intramuscular olanzapine, short acting intramuscular who improve. Psychiatry Research 1992;42(2):129–44. haloperidol and intramuscular PLACEBO in patients with [MEDLINE: 92335471] schizophrenia. http://www.clinicalstudyresults.org/ 2005.

Daniel 2004 b {published data only} Eli 2005a {published data only} Kungel M, Daniel D, Stock E, Wilber R, Marcus R, Carson Eli LandC. A DOUBLE-BLIND dose-response study W, et al.Efficacy and safety of intramuscular aripiprazole in comparing short acting intramuscular olanzapine, short acutely agitated patients with psychosis. Proceedings of the acting intramuscular haloperidol, and intramuscular Thematic Conference of the World Psychiatric Association PLACEBO in patients with schizophrenia. http:// on ”Treatments in Psychiatry: An Update“; 2004 Nov 10- www.clinicalstudyresults.org/ 2005. 13; Florence, Italy. 2004. Garcia 2009 {published data only} Kungel M, Daniel D, Stock E, Wilber R, Marcus R, Carson Garcia E, Robert M, Peris F, Nakamura H, Sato N, Terazawa W, et al.Efficacy and safety of intramuscular aripiprazole in Y. The efficacy and safety of blonanserin compared with acutely agitated patients with psychosis. Proceedings of the haloperidol in acute-phase schizophrenia: a RANDOMized, Thematic Conference of the World Psychiatric Association DOUBLE-BLIND, PLACEBO-controlled, multicentre

Haloperidol versus placebo for schizophrenia (Review) 20 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. study. CNS Drugs 2009;23(7):615–25. [MEDLINE: haloperidol for the cognitive impairments in patients with 19552488] chronic schizophrenia. Schizophrenia Bulletin 2005;31:490. Kim YH, Lee BJ. A 12 week, DOUBLE-BLIND, GlaxoSmithKline 2005 {published data only} PLACEBO controlled trial of donepezil adjunctive to GlaxoSmithKline. A RANDOMized, DOUBLE- haloperidol for the cognitive impairments in patients with BLIND, PLACEBO-controlled, crossover evaluation of chronic schizophrenia. Proceedings of the 8th World the effects of GR68755C on plasma levels of haloperidol Congress of Psychiatry; 2005 Sep 10-15; Cairo, Egypt. in patients with a diagnosis of schizophrenia. http:// 2005. www.clinicalstudyresults.org/ 2005. Kujawa 2002 {published data only} Herrera 2005 {published data only} Archibald DG, Kostic D, Manos G, Stock EG, Jody DN, Herrera M. DOUBLE-BLIND study with risperidone vs Tourkodimitris S, et al.Effects of long-term aripiprazole haloperidol in schizophrenic patients with agitation and/ therapy on the negative symptoms of schizophrenia. or aggression. Proceedings of the 8th World Congress of Proceedings of the 12th Biennial Winter Workshop on Psychiatry; 2005 Sep 10-15; Cairo, Egypt. 2005. Schizophrenia; 2004 Feb 7-13; Davos, Switzerland. 2004. Crandall D, Pikalov A, Kostic D, Kaplita S, Berman R, IRCT138809201457N6 {published data only} McQuade R, et al.Is sedation needed for effective reduction IRCT138809201457N6. Celecoxib add-on therapy of acute schizophrenia symptoms?. Proceedings of the 158th compared to haloperidol alone in schizophrenia: A Annual Meeting of the American Psychiatric Association; DOUBLE-BLIND, RANDOMized, PLACEBO-controlled 2005 May 21-26; Atlanta, Georgia, USA. 2005. clinical trial. http://www.irct.ir/ 2004. Kane JM, Swyzen W, Wu X, McQuade R, Gutierrez- IRCT138809201457N7 {published data only} Esteinou R, Van Tran Q, et al.Long-term symptomatic IRCT138809201457N7. Beneficial antipsychotic effects of remission in schizophrenia patients treated with aripiprazole ascorbic acid add-on therapy compared to halloperidol alone or haloperidol. Proceedings of the 159th Annual Meeting in schizophrenia, (a RANDOMized, DOUBLE-BLIND, of the American Psychiatric Association; 2006 May 20-25; PLACEBO-controlled clinical trial). http://www.irct.ir/ Toronto, Canada. 2006. 2003. Kostic D, Marcus RN, Stock EG, Carson WH, Tourkodimitris S, Archibald DG. Maintenance of response Jung 2007 {published data only} in chronic schizophrenia: effects of aripiprazole and Jung D, Shin J, Kelly DL, Seo Y, Liu K, Sohn J, et haloperidol on affective symptoms. Schizophrenia Bulletin al.Drug interactions between aripiprazole and haloperidol: 2005;31:492. DOUBLE BLIND, PLACEBO controlled study. Marder SR, Archibald DG, Manos G, Stock EG, Jody DN, Schizophrenia Bulletin 2007;33(2):434–5. Tourkodimitris S, et al.Long-term effects of aripiprazole Kane 2008 {published data only} therapy on the negative symptoms of schizophrenia. Kane J, Zhao J, Cohen M, Panagides J. Efficacy and Proceedings of the 24th Collegium Internationale Neuro- safety of asenapine in patients with acute exacerbation of Psychopharmacologicum Congress; 2004 June 20-24; Paris, schizophrenia. Schizophrenia Research 2008;98:14. France 2004. Stock EG, Archibald DG, Tourkodimitris S, Kujawa MJ, Kane 2010 {published data only} Marcus R, Carson WH. Long-term effects of aripiprazole Kane JM, Cohen M, Zhao J, Alphs L, Panagides J. Efficacy on affective symptoms of schizophrenia. Proceedings of and safety of asenapine in a PLACEBO- and haloperidol- the 156th Annual Meeting of the American Psychiatric controlled trial in patients with acute exacerbation of Association; 2003 May 17-22; San Francisco, California, schizophrenia. Journal of Clinical Psychopharmacology 2010; USA 2003. 30(2):106–15. Lee 2007 {published data only} Kapur 2004 {published data only} Lee B-J, Lee J-G, Kim Y-H. A 12-week, DOUBLE-BLIND, Kapur S. Linking the biology, phenomenology and PLACEBO-controlled trial of donepezil as an adjunct to pharmacology of psychosis - a feasible project or just a haloperidol for treating cognitive impairments in patients delusion. European Neuropsychopharmacology 2004;14 with chronic schizophrenia. Journal of Psychopharmacology (Suppl 3):S155. 2007;21(4):421–7. [MEDLINE: 17092979] Li 2007 {published data only} Kapur 2005 {published data only} Li C, Zhu S, Wang H, Chen H, Yu Y, Liu D, et Kapur S, Arenovich T, Agid O, Zipursky R, Lindborg al.Safety and efficacy of clonazepam, haloperidol S, Jones B. Evidence for onset of antipsychotic effects and haloperidol combined with clonazepam in the within the first 24 hours of treatment. American Journal of Psychiatry 2005;162(5):939–46. [MEDLINE: 15863796] [ ].

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Haloperidol versus placebo for schizophrenia (Review) 21 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Liang 1987 {published data only} Meltzer 2006 {published data only} Liang S. Comparison of therapeutic effects between Meltzer HY. Testing multiple novel mechanisms for treating haloperidol and insulin coma for schizophrenia and the schizophrenia in a single trial. In: Cummings JL editor(s). optimal blood level of haloperidol. Chinese Journalof Progress in Neurotherapeutics and Neuropsychopharmacology. Neurology and Psychiatry 1987;20(1):43–8. New York, NY, US: Cambridge University Press, 2006: Maoz 2000 {published data only} 115–20. Maoz G, Stein D, Meged S, Kurzman L, Levine J, Valevski Meltzer 2008 {published data only} A, et al.The antiaggressive action of combined haloperidol- Meltzer H, Peters P, Elkis H, Ruschel S, Rosenthal M, Mills propranolol treatment in schizophrenia. European R. Co-therapy with pimavanserin and risperidone 2 mg Psychologist 2000;5(4):312–25. provides an improved clinical profile. Schizophrenia Research Marder 1991 {published data only} 2008;98:16. Marder S. Risperidone versus haloperidol versus PLACEBO Modell 2004 {published data only} in the treatment of chronic schizophrenia. Clinical Research Modell S, Daniel D, Stock E, Wilber R, Marcus R, Carson Report RIS-INT-3 1991. W, et al.Intramuscular aripiprazole treatment for acute Marder 1996 {published data only} agitation in patients with psychosis. Proceedings of the 24th Marder SR, Chouinard G, Davis JM. The clinical actions of Collegium Internationale Neuro-Psychopharmacologicum risperidone. Proceedings of the 35th Annual Meeting of the Congress; 2004 June 20-24; Paris, France 2004. American College of Neuropsychopharmacology; 1996 Dec Mossaheb 2006 {published data only} 9-13; San Juan, Puerto Rico. 1996. Mossaheb N, Sacher J, Wiesegger G, Klein N, Spindelegger Marder 1997 {published data only} CJ, Asenbaum S, et al.Haloperidol in combination Marder SR, Chouinard G, Davis JM. The clinical actions with clozapine in treatment-refractory patients with of risperidone. Proceedings of the 10th Congress of the schizophrenia. European Neuropsychopharmacology 2006;16 European College of Neuropsychopahrmacology; 1997 Sep (Suppl 4):S416. 13-17, Vienna, Austria. 1997. NCT00018850 {published data only} Marder 1997a {published data only} NCT00018850. 5HT3 antagonism and auditory gating in Marder SR, Chouinard G, Davis JM. The clinical actions schizophrenia. http://www.clinicaltrials.gov 2001. of risperidone. Proceedings of the 6th World Congress of NCT00044044 {published data only} Biological Psychiatry; 1997 Jun 22-27; Nice, France. 1997. NCT00044044. A 6-week, DOUBLE-BLIND, Marder 1997b {published data only} RANDOMized, fixed-dose, parallel-group study of the Marder SR, Davis JM, Chouinard G. The effects of efficacy and safety of three dose levels of SM-13496 risperidone on the five dimensions of schizophrenia compared to PLACEBO and haloperidol in patients with derived by factor analysis: combined results of the North schizophrenia who are experiencing an acute exacerbation American trials. Journal of Clinical Psychological Medicine of symptoms. http://www.clinicaltrials.gov 2002. [ ] 1997;58(12):538–46. NCT00156065 {published data only} McQuade 2006 {published data only} NCT00156065. A multicenter, DOUBLE-BLIND, McQuade R, Auby P, Oren D, Marcus R, Kostic D, flexible dose, long-term extension trial of the safety and Iwamoto T, et al.Intramuscular aripiprazole in acute maintenance of effect of asenapine using a haloperidol schizophrenia: a DOUBLE-BLIND, PLACEBO-controlled positive control in subjects who complete protocol 041023. comparison with IM haloperidol. Proceedings of the 13th http://www.clinicaltrials.gov 2005. 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Haloperidol versus placebo for schizophrenia (Review) 22 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Octavio 2004 {published data only} Potkin 2008 {published data only} Octavio I, Stock EG, Archibald DG, Tourkodimitris Potkin SG, Litman RE, Torres R, Wolfgang CD. Efficacy of S, Kujawa MJ, Marcus R, et al.Long-term effects of iloperidone in the treatment of schizophrenia: initial phase aripiprazole on affective symptoms of schizophrenia. 3 studies. Journal of Clinical Psychopharmacology 2008;28(2 Proceedings of the 24th Collegium Internationale Neuro- Suppl 1):S4–S11. Psychopharmacologicum Congress; 2004 June 20-24; Paris, Romeo 2009 {published data only} France 2004. Romeo R, Knapp M, Tyrer P, Crawford M, Oliver-Africano Oren 2005 {published data only} P. The treatment of challenging behaviour in intellectual Andrezina R, Josiassen RC, Marcus RN, Oren DA, Manos disabilities: cost-effectiveness analysis. Journal of Intellectual G, Stock E, et al.Intramuscular aripiprazole for the treatment Disability Research 2009;53:633–43. of acute agitation in patients with schizophrenia or Shim 2007 {published data only} schizoaffective disorder: a DOUBLE-BLIND, PLACEBO- Shim JC, Jae YM, Shin JG, Jung DW, Seo YS, Liu KH, et controlled comparison with intramuscular haloperidol. al.Drug interactions between aripiprazole and haloperidol: Psychopharmacology 2006;188(3):281–92. [MEDLINE: DOUBLE BLIND PLACEBO controlled study. European 16953381] Neuropsychopharmacology 2007;17(Suppl 4):S438. Citrome LL, Vester-Blokland E, Archibald D, McQuade Veser 2006 {published data only} R, Kostic D, Pikalov A, et al.Benefits of a second dose Chou JC, Douyon R, Czobor P, Volavka J, Cooper TB. of intramuscular (IM) aripiprazole to control agitation Change in plasma prolactin and clinical response to in patients with schizophrenia or bipolar I disorder. haloperidol in schizophrenia and schizoaffective disorder. 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Open clozapine treatment following a aripiprazole, haloperidol or PLACEBO in acutely agitated controlled clinical trial of lithium augmentation of patients with schizophrenia or schizoaffective disorder. haloperidol for refractory schizophrenia. Lithium 1994;5 Proceedings of the 158th Annual Meeting of the American (2):113–4. Psychiatric Association; 2005 May 21-26; Atlanta, Georgia, Zhan 2000 {published data only} USA 2005. Zhan Y, Xu X, Guo Y. The relationship be- Oren D, Marcus R, Kostic D, McQuade R, Iwamoto tween the schizophrenia and the immune index T, Archibald D. Efficacy and safety of intramuscular aripiprazole, haloperidol or PLACEBO in acutely agitated [ ]. patients with schizophrenia or schizoaffective disorder. Schizophrenia Bulletin 2005;31:499. 2000;12(2):69–71. Yocca F, Marcus R, Oren D, Manos G, Carson W, Iwamoto Zhang 2002 {published data only} T, et al.Intramuscular aripiprazole in acute schizophrenia: a Zhang XY, Zhou DF, Zhang PY. Extract of ginkgo biloba pivotal phase III study. Proceedings of the 158th Annual added to haloperidol was effective for positive symptoms Meeting of the American Psychiatric Association; 2005 May in refractory schizophrenia. Evidence-Based Mental Health 21-26; Atlanta, Georgia, USA 2005. 2002;5(3):90. Zhang 2006 {published data only} Oren 2007 {published data only} Zhang Z-J, Kang W-H, Li Q, Wang X-Y, Yao S-M, Ma Oren DA, Marcus RN, Manos G, Carson WH, McQuade A-Q. Beneficial effects of ondansetron as an adjunct to D. Non-inferiority of intramuscular aripiprazole versus haloperidol for chronic, treatment-resistant schizophrenia: intramuscular haloperidol for the treatment of agitation a DOUBLE-BLIND, RANDOMized, PLACEBO- associated with schizophrenia/schizoaffective disorder. controlled study. Schizophrenia Research 2006;88(1-3): Schizophrenia Bulletin 2007;33(2):451. 102–10. [MEDLINE: 16959472] Oren 2007a {published data only} Zhang 2006a {published data only} Oren DA, Manos G, Markovic O, McQuade RD. Zhang XY, Zhou DF, Cao LY, Wu GY. The effects of ginkgo Intramuscular aripiprazole for the treatment of acute biloba extract added to haloperidol on peripheral T cell agitation associated with schizophrenia: Sub-analysis of subsets in drug-free schizophrenia: a DOUBLE-BLIND, a DOUBLE-BLIND, controlled, dose-ranging study. PLACEBO-controlled trial. Psychopharmacology 2006;188 European Psychiatry 2007;22:S124–S. (1):12–7. [MEDLINE: 16906395]

Haloperidol versus placebo for schizophrenia (Review) 23 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Zimbroff 1998 {published data only} Donner 2002 Zimbroff DL, Kane JM, Tamminga CA. ”Sertindole versus Donner A, Klar N. Issues in the meta-analysis of cluster haloperidol for schizophrenia“: Dr. Zimbroff and colleagues randomized trials. Statistics in Medicine 2002;21:2971–80. reply. American Journal of Psychiatry 1998;155(9):1303–4. Gulliford 1999 , 2009 {published data only} Gulliford MC. Components of variance and intraclass correlations for the design of community-based surveys , , , , . A clinical study on aripiprzole and intervention studies: data from the Health Survey for in the treatment of female hyperprolactinemia by haloperidol England 1994. American Journal of Epidemiology 1999;149: [ ]. 876–83. Higgins 2003 Chinese Journal of Health Psychology [ ] Higgins JP, Thompson SG, Deeks JJ, Altman DG. 2009;17(2):194–5. Measuring inconsistency in meta-analyses. BMJ 2003;327: References to ongoing studies 557–60. Higgins 2005 George 2000 {published data only} Higgins JPT, Green S, editor(s). Cochrane Handbook A double-blind randomised comparison of the efﬁcacacy for Systematic Reviews of Interventions. The Cochrane and safety of short acting intramuscular olanzapine, short Collaboration. Chichester, UK: John Wiley & Sons Ltd, acting intramuscular haloperidol and intramuscular placebo 2005, issue 4.2.5. in patients with schizophrenia. Ongoing study 2000. Jablensky 1992 Paykel 2000 {published data only} Jablensky A, Sartorius N, Ernberg G, Anker M, Korten Prophylaxis of puerperal psychosis. Ongoing study 2000. A, Cooper JE, Day R, Bertelsen A. Schizophrenia: Additional references manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychological Altman 1996 Medicine Monograph Supplement 1992;20:1–97. Altman DG, Bland JM. Detecting skewness from summary Marshall 2000 information. BMJ 1996;313:1200. Marshall M, Lockwood A, Bradley C, Adams C, Joy C, Awad 1997 Fenton M. Unpublished rating scales: a major source Awad GA, Voruganti LNP,Heslegrave RJ. Measuring quality of bias in randomised controlled trials of treatments for of life in patients with schizophrenia. PharmacoEconomics schizophrenia. British Journal of Psychiatry 2000;176: 1997;11:32–47. 249–52. Ayd 1972 Overall 1962 Ayd FJ. Haloperidol: ﬁfteen years of clinical experience. Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Diseases of the Nervous System 1972;33:459–69. Psychological Reports 1962;10:799–812. Ayd 1978 Quraishi 1999 Ayd FJ. Haloperidol: twenty years’ clinical experience. Quraishi S, David A. Depot haloperidol decanoate for Journal of Clinical Psychiatry 1978;39:807–14. schizophrenia. Cochrane Database of Systematic Reviews Begg 1996 1999, Issue 1. [DOI: 10.1002/14651858.CD001361] Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin Settle 1983 I, Pitkin R, Rennie D, Schulz KF, Simel D, Stroup DF. Settle EC, Ayd FJ. Haloperidol: a quarter century of Improving the quality of reporting of randomized controlled experience. Journal of Clinical Psychiatry 1983;44:440–8. trials: the CONSORT statement. JAMA 1996;276(8): 637–9. Thornley 1998a Bland 1997 Thornley B, Adams C. Content and quality of 2000 Bland JM. Statistics notes. Trials randomised in clusters. controlled trials in schizophrenia over 50 years. BMJ 1998; BMJ 1997;315:600. 317:1181–4. Carpenter 1994 Thornley 1998b Carpenter WT, Buchanan RW. Schizophrenia. New England Thornley B, Adams CE, Awad G. Chlorpromazine versus Journal of Medicine 1994;330:681–90. placebo for those with schizophrenia. Cochrane Database Dally 1967 of Systematic Reviews 1998, Issue 4. [DOI: 10.1002/ Dally P. Chemotherapy of Psychiatric Disorders. Logo Press 14651858.CD000284.pub2] Limited 1967. Thornley 2001 Divine 1992 Thornley B, Adams CE, Awad G. Chlorpromazine Divine GW, Brown JT, Frazier LM. The unit of analysis versus placebo for schizophrenia. Cochrane Database error in studies about physicians’ patient care behavior. of Systematic Reviews 2001, Issue 1. [DOI: 10.1002/ Journal of General Internal Medicine 1992;7(6):623–9. 14651858.CD000284.pub2]

Haloperidol versus placebo for schizophrenia (Review) 24 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Ukoumunne 1999 Waraich 2001 Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Waraich P, Soares K, Marti J, Roque M. Haloperidol dose Burney PGJ. Methods for evaluating area-wide and for exacerbation of schizophrenia. Cochrane Database organistation-based intervention in health and health care: of Systematic Reviews 2001, Issue 1. [DOI: 10.1002/ a systematic review. Health Technology Assessment 1999;3(5): 14651858.CD001951] 1–75. Willner 1997 Waddington 1997 Willner P. The dopamine hypothesis of schizophrenia: Waddington JL, Scully PJ, O’Callaghan E. The new Current status, future prospects. International Clinical antipsychotics, and their potential for early intervention in Psychopharmacology 1997;12:297–308. schizophrenia. Schizophrenia Research 1997;28:207–22. ∗ Indicates the major publication for the study

Characteristics of included studies [ordered by study ID]

Arvanitis 1997

Methods Allocation: random assignment. Blindness: double. Duration: 6 weeks (preceded by a 7 day single blind placebo washout). Location: multicentre. Consent: written.

Participants Diagnosis: (DSM-III-R) schizophrenia. N = 361. History: sub/chronic hospitalised, currently experiencing acute exacerbation of psychotic symptoms. Sex: 76% M, 24% F. Age: 18 - 64 years (mean ~ 37 years). Exclusions: BPRS score <27, CGI score <4, history of seizures, other signiﬁcant medical condition, participation in other drug trial within 30 days, use of depot antipsychotics within 1 dosing interval, pregnancy, placebo responders, non completion of dose escalation

Interventions 1. Haloperidol: ﬁxed dose (FD) 12 mg/day, increased day 1-14. N=52 2. Placebo. N=51. 3. Quetiapine: (FD) 75 mg/day, increased day 1-14. N=53. 4. Quetiapine: (FD) 150 mg/day, increased day 1-14. N=48. 5. Quetiapine: (FD) 300 mg/day, increased day 1-14. N=52. 6. Quetiapine: (FD) 600 mg/day, increased day 1-14. N=51. 7. Quetiapine: (FD) 750 mg/day, increased day 1-14. N=54. Chloral hydrate, lorazepam, benztropine mesylate as required

Outcomes Leaving the study early. Unable to use - Global effect: improved/not improved, CGI (>50% loss). Dose response (>50% loss). Time to response (>50% loss). Mental state: BPRS, SANS (>50% loss). Adverse events: AIMS, SAS, other various observed effects (>50% loss)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Methods Allocation: random assignment. Blindness: double. Duration: 6 weeks (preceded by a 4-7 day single blind placebo washout). Location: multicentre. Consent: written.

Participants Diagnosis: (DSM-III-R) schizophrenia. N = 335. History: currently suffering from acute exacerbation of symptoms. Sex: 88% M, 12% F. Age: 18 - 65 years. Exclusions: other serious physical or neurological disorder/condition, substance abuse within 3 months of study, abnormal lab results, placebo responders

Interventions 1. Haloperidol: dose 10, 15 or 20 mg/day; initial dose 15 mg/day, adjusted accordingly thereafter. N=69. 2. Placebo. N=68. 3. Olanzapine: dose 2.5, 5 or 7.5 mg/day; initial dose 5 mg/day, adjusted accordingly thereafter. N=65. 4. Olanzapine: dose 7.5, 10 or 12.5 mg/day; initial dose 10 mg/day, adjusted accordingly thereafter. N=64. 5. Olanzapine: dose 12.5, 15 or 17.5 mg/day; initial dose 15 mg/day, adjusted accordingly thereafter. N=69. Lorazepam, benztropine mesylate as required.

Outcomes Leaving the study early. Unable to use - Global effect: CGI, PGI (>50% loss). Hospitalisation: admission/discharge, days in hospital (>50% loss). Dose response (>50% loss). Mental state: BPRS, SANS (>50% loss). Adverse events: SAS, AIMS, BAS, other observed effects (>50% loss). Compliance (>50% loss).

Notes data only taken from the initial ’acute phase’ trial.

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Methods Allocation: random assignment. Blindness: double. Duration: 21 days (preceded by 3 days stabilisation with chlorpromazine and haloperidol followed by 2 day washout). Location: hospital. Consent: not stated.

Participants Diagnosis: (ICD-9) schizophrenia. N=90. History: recently admitted to hospital, currently acute. Sex: male. Age: mean ~ 29 years. Exclusions: substance abuse, other clinically signiﬁcant medical or neurological pathologies

Interventions 1. Haloperidol: dose 5 - 20 mg/day. N=30. 2. Placebo: N=31. 3. Pipotiazine: dose 10 - 40 mg/day. N=29. Biperiden and trihexyphenidyl as required on day 1 - 3 only.

Outcomes Adverse event: various observed effects. Global effect: improved/not improved. Leaving the study early. Mental state: BPRS.

Notes If, after entering the trial, participants showed improvement they could be discharged from hospital. If, however, they were readmitted due to relapse they could then re-enter the study

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Borison 1989

Methods Allocation: random assignment. Blindness: double. Duration: 6 weeks (preceded by a 7 day single blind placebo wash out). Location: not stated. Consent: written.

Participants Diagnosis: (DSM-III) schizophrenia. N = 32. History: not stated. Sex: not stated. Age: 18 - 60 years. Exclusions: unstable physical health.

Interventions 1. Haloperidol: dose 15 - 75 mg/day. N=8. 2. Placebo. N=8. 3. Tiospirone: dose 45 - 225 mg/day. N=8. 4. Thioridazine: dose 150 - 750 mg/day. N=8. Chloral hydrate as required.

Outcomes Adverse events: various observed effects, use of antiparkinson medication. Leaving the study early. Unable to use - Mental state: BPRS (no SD).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Borison 1992a

Methods Allocation: random assignment. Blindness: double. Duration: 7 weeks (preceded by a 7 day single blind placebo washout). Location: multicentre, part of larger trial. Consent: written.

Participants Diagnosis: (DSM-III-R) schizophrenia. N = 36. History: chronic. Sex: 97% M, 3% F. Age: ~ 31-52 years. Exclusions: substance abuse, other clinically signiﬁcant medical or neurological pathologies, women of child bearing capacity

Interventions 1. Haloperidol: dose 4-10 mg/day, dose adjusted as required days 1-18. N=12. 2. Placebo. N=12. 3. Risperidone: dose 2-10 mg/day, dose adjusted as required days 1-18. N=12. Lorazepam, sodium amytal, chloral hydrate, benztropine or trihexyphenidyl as required

Outcomes Adverse events: various observed effects. Leaving study early. Mental state: no clinical improvement (<20% reduction in BPRS score) Unable to use - Adverse events: AIMS (no data), ESRS (no SD). Global effect: CGI (no SD). Mental state: BPRS, SANS (no SD).

Notes participants already part of larger multicentre trial. may be part of Nth American Trial.

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Chouinard 1993

Methods Allocation: random assignment. Blindness: double. Duration: 8 weeks (preceded by a 7 day single blind placebo washout). Location: multicentre. Consent: written.

Participants Diagnosis: (DSM-III-R) schizophrenia. N = 135. History: chronic, hospitalised. Sex: 71% M, 29% F. Age: mean ~ 37 years. Exclusions: other clinically signiﬁcant neurological or psychical disorder, substance abuse, pregnancy, placebo responders

Interventions 1. Haloperidol: dose 20 mg/day, initial dose 2 mg/day increased in fixed increments day 2- 7. N=21. 2. Placebo. N=22. 3. Risperidone: dose 2 mg/day 4. Risperidone: dose 6 mg/day, initial dose 2 mg/day increased in fixed increments day 2- 4. 5. Risperidone: dose 10 mg/day, initial dose 2 mg/day, increased in fixed increments day 2-5. 6. Risperidone: dose 16 mg/day, initial dose 2 mg/day, increased in fixed increments day 2-7. Chloral hydrate, benzodiazepine, biperiden or procyclidine as required

Outcomes Leaving the study early. Unable to use - Global effect: CGI (>50% loss). Level of medication required (>50% loss). Mental state: BPRS, GPS, PANSS (>50% loss). Adverse events: ESRS, various observed effects (UKU), use of antiparkinson medication (>50% loss). Cost of treatment (>50% loss).

Notes Part of Nth American Trial.

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Durost 1964

Methods Allocation: random assignment. Duration: 10 days - 3 months (mean 3 weeks). Location: hospital. Consent: unknown.

Participants Diagnosis: schizophrenia (40%), neurosis (60%).* N = 84 (schizophrenia 34, neurosis 50). History: unknown. Sex: 60% M, 40% F. Age: mean ~ 39 years. Exclusions: unknown.

Interventions 1. Haloperidol: dose 2-25 mg/day, mean 6 mg/day. N=19. 2. Placebo. N=15.

Outcomes Global effect: improved/not improved. Leaving the study early. Unable to use - Adverse events: various observed effects (no data).

Notes * use only data for those suffering from schizophrenia

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Garry 1962

Methods Allocation: random assignment. Blindness: double. Duration: 12 weeks (preceded by a 2 week medication free period). Location: not stated. Consent: not stated.

Participants Diagnosis: schizophrenia. N = 52. History: chronic, hospitalised.

Sex: 62% M, 38% F. Age: mean ~ 46 years. Exclusions: not stated.

Interventions 1. Haloperidol: dose 0.75 - 4.5 mg/day, increased day 1 - 42. N=26. 2. Placebo. N=26.

Outcomes Adverse events: various observed effects* Global effect: improved/not improved. Leaving the study early.

Notes * Adverse effects reported for haloperidol group only, reviewers assumed that placebo group had no adverse effects

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Howard 1974

Methods Allocation: random assignment. Blindness: double. Duration: max 12 weeks (preceded by a 14 day placebo washout). Location: hospital. Consent: not stated.

Participants Diagnosis: schizophrenia (80%). N = 49. History: treatment resistant, hospitalised. Sex: female. Age: 25 - 65 years. Exclusions: other serious physical or neurological disorder, pregnancy, severe hyposensitivity to haloperidol or thiothixene, placebo responders

Interventions 1. Haloperidol: dose < 200 mg/day. N=17. 2. Placebo. N=16. 3. Thiothixene: dose < 200 mg/day. N=16.

Outcomes Global effect: improved/not improved. Hospital discharge. Leaving the study early. Adverse events: various observed effects. Unable to use - Behaviour: NOSIE (no SD). Mental state: BPRS (no mean, no SD), MSC (data given only for those remaining in hospital)

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Jann 1997

Methods Allocation: random assignment. Blindness: unsure. Duration: 6 weeks. Location: not stated. Consent: written.

Participants Diagnosis: (DSM-III-R) schizophrenia. N = 36. History: not stated. Sex: not stated. Age: ~ 25 - 43 years. Exclusions: not stated.

Interventions 1. Haloperidol: dose up to 75 mg/day, dose individually adjusted weekly. N=18. 2. Placebo. N=18. Lorazepam or chloral hydrate as required.

Outcomes Adverse events: various observed effects. Leaving the study early. Mental state: BPRS. Unable to use - Adverse events: AIMS (no data).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Methods Allocation: random. Blindness: double. Duration: 4 weeks. Location: hospital, multicentre. Consent: given.

Participants Diagnosis: (DSM-IV) schizophrenia or schizoaffective disorder. N=414*. History: acute relapse, hospitalised. Age: 18 - 65 years. Sex: 70% M, 30% F. Exclusions: other psychiatric disorder, history of violence or self-harm

Interventions 1. Aripiprazole: dose 15 mg/day. N=102. 2. Aripiprazole: dose 30 mg/day. N=102. 3. Haloperidol: dose 10 mg/day. N=104. 4. Placebo. N=106. lozepam for anxiety or insomnia

Outcomes Leaving the study early. Adverse events: various observed effects. Unable to use: Global effect: CGI (no SD). Mental state: BPRS, PANSS (no SD).

Notes data taken from haloperidol and placebo groups only. data provided for some outcomes have only 103 people in haloperidol group and 104 in placebo group

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Klieser 1989

Methods Allocation: random assignment. Blindness: double. Duration: 3 weeks. Location: hospital. Consent: not stated.

Participants Diagnosis: schizophrenia (63%), major depressive disorder (37%). N = 120. History: chronic, hospitalised. Sex: 41% M, 59% F. Age: mean ~ 43 years. Exclusions: not stated.

Interventions 1. Haloperidol: dose 20 mg/day. N=20*. 2. Placebo. N=16. 3. Trazodone: dose 400 mg/day. N=17. 4. Amitriptyline: dose 150 mg/day. N=22. Biperiden as required.

Outcomes Leaving the study early Mental state: BPRS.

Notes * number of people with schizophrenia.

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Marder 1994

Methods Allocation: random assignment. Blindness: double. Duration: 8 weeks (preceded by 1 week placebo wash out). Location: multicentre. Consent: given.

Participants Diagnosis: (DSM-III-R) schizophrenia. N = 388. History: hospitalised, chronic. Sex: 89% M, 11% F. Age: mean ~37 years. Exclusions: physically unhealthy, schizoaffective disorder.

Interventions 1. Haloperidol: dose 20 mg/day. N=66. 2. Placebo: N=66. 3. Risperidone: dose 2 mg/day. N=63. 4. Risperidone: dose 6 mg/day. N=64. 5. Risperidone: dose 10 mg/day. N=65. 6. Risperidone: dose 16 mg/day. N=64. Lorazepam or chloral hydrate as required.

Outcomes Leaving the study early Unable to use - Global state: CGI (>50% loss). Mental state: PANSS (>50% loss). Adverse events: EPS, UKU scale (>50% loss).

Notes Part of ’Nth America 1997’.

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Nishikawa 1982

Methods Allocation: random assignment. Blindness: double. Duration: 3 years*. Location: not stated. Consent: not stated.

Participants Diagnosis: schizophrenia N = 55. History: outpatients, currently in remission, but have a history of several relapse episodes. Sex: 67% M, 33% F. Age: ~ 25 - 41 years. Exclusions: history of taking medication irregularly.

Interventions 1. Haloperidol: dose 3 mg/day. N=10. 2. Placebo. N=10. 3. Chlorpromazine: dose 75 mg/day. N=10. 4. Diazepam: dose 15 mg/day. N=13. 5. Imipramine: dose 50 mg/day. N=12. Nitrazepam or biperiden as required.

Outcomes Relapse: number remaining in remission < 1 year. Unable to use - Leaving the study early (unclear when losses occured, no individual group data given)

Notes *Initial ’cross-over’ design of trial was disregarded after participant/clinician reluctance to switch neuroleptics. Data taken from ﬁrst arm only

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Methods Allocation: random assignment. Blindness: double. Duration: 1 year. Location: not stated. Consent: not stated.

Participants Diagnosis: (DSM III) schizophrenia. N = 87. History: in recovery stage of remission. Sex: 61% M, 39% F. Age: ~ 28 - 54 years. Exclusions: not stated.

Interventions 1. Haloperidol: dose 1 mg/day. N=13. 2. Haloperidol: dose 3 mg/day. N=12. 3. Haloperidol: dose 6 mg/day. N=12. 4. Placebo. N=13. 5. Propericiazine: dose 10 mg/day. N=13. 6. Propericiazine: dose 30 mg/day. N=13. 6. Propericiazine: dose 60 mg/day. N=13. Each drug combined with nitrazepam and biperiden.

Outcomes Relapse: number remaining in remission < 1 year. Leaving the study early.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Reschke 1974

Methods Allocation: random assignment. Blindness: double. Duration: < 24 hrs. Location: not stated. Consent: not stated.

Participants Diagnosis: psychiatric symptoms. N = 50. History: presenting at emergency clinic. Sex: 4% M, 96% F. Age: totals not stated. Exclusions: substance abuse, epilepsy, personality disorder, psychoneurosis, chronic brain syndrome, pregnancy

Interventions 1. Haloperidol: dose 1 mg/ml. N=8 2. Haloperidol: dose 2 mg/ml. N=11. 3. Haloperidol: dose 5 mg/ml. N=10. 4. Placebo. N=11. 5. Chlorpromazine: dose 25 mg/ml. N=10.

Outcomes Adverse events: various observed effects. Global effect: improved/not improved. Leaving the study early. Unable to use - Mental state: BPRS (no SD).

Notes Data only taken from intial double blind phase.

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Selman 1976

Methods Allocation: random assignment. Blindness: double. Duration: 12 weeks (preceded by a 2 week medication free period). Location: not stated. Consent: not stated.

Participants Diagnosis: schizophrenia. N = 87. History: acute, hospitalised. Sex: 80% M, 20% F. Age: mean ~ 33 years. Exclusions: other signiﬁcant physical or neurological disorder, <16 or >60 years, females of child bearing age, epileptics, substance abuse

Interventions 1. Haloperidol: dose 4-12 mg/day. N=29. 2. Loxapine: dose 50-150 mg/day. N=29. 3. Placebo. N=29. Chloral hydrate or paraldehyde as required.

Outcomes Adverse effects: various observed effects. Global effect: CGI improved/not improved. Leaving the study early. Unable to use - Mental state: BPRS (no SD). Behaviour: NOSIE (no SD).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Serafetinides 1972

Methods Allocation: random assignment. Blindness: double. Duration 3 months. Location: not stated. Consent: not stated

Participants Diagnosis: schizophrenia. N = 57. History: chronic. Sex: 42% M, 48% F . Age: mean ~ 42 years. Exclusions: other physical or neurological disorder.

Interventions 1. Haloperidol: dose up to 15 mg/day. N=14. 2. Placebo. N=14. 3. Clopenthixol: dose up to 250 mg/day. N=15. 4. Chlorpromazine: dose up to 1000 mg/day. N=14.

Outcomes Adverse events: various observed effects. Global effect: CGI improved/not improved. Leaving the study early. Unable to use - Mental state: BPRS (no SD). Behaviour: NOSIE, OBRS (no SD). Cognitive response (no data given).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Methods Allocation: random assignment. Blindness: double. Duration: 14 weeks. Location: not stated. Consent: not stated.

Participants Diagnosis: schizophrenia. N = 24. History: chronic, hospitalised. Sex: male. Age: ~ 37 years. Exclusions: other signiﬁcant physical or neurological disorder

Interventions 1. Haloperidol: dose 6 mg/day. N=8. 2. Haloperidol: dose 30 mg/day. N=8. 3. Placebo. N=8. Benztropine mesylate as required.

Outcomes Adverse events: use of antiparkinson medication. Global effect: improved/not improved. Leaving the study early. Unable to use - Mental state: IMS, PRP (no SD).

Notes Group numbers not stated in text, reviewers have assumed that they were divided into three sets of 8 (see table 1)

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Spencer 1992

Methods Allocation: random assignment. Blindness: double, cross-over. Duration: 10 weeks (preceded by a 2 week single blind placebo washout). Location: not stated. Consent: not stated.

Participants Diagnosis: (DSM-III-R) schizophrenia. N = 12. History: hospitalised. Sex: 75% M, 25% F. Age: ~ 6 - 12 years. Exclusions: other signiﬁcant physical or neurological disorder, receipt of psychoactive medication within 4 weeks of study

Interventions 1. Haloperidol: dose 4 wks 0.5-10 mg/day followed by 4 wks placebo. N=12. 2. Placebo: 4 wks followed by 4 wks 0.5-10 mg/day haloperidol. N=12

Outcomes Global effect: improved/not improved. Leaving the study early. Unable to use - Global effect: CGI (no SD). Mental state: CPRS, BPRS-C (no SD). Adverse events: various observed effects (no data for placebo group). Cognitive response: WISC-R, WPPSI, DICA-R (no data).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Vichaiya 1971

Methods Allocation: random assignment. Blindness: double, cross-over. Duration: 12 weeks (preceded by 4 weeks drug free period). Location: hospital. Consent: unknown.

Participants Diagnosis: schizophrenia. N = 30. History: hospitalised, chronic. Sex: female. Age: mean ~ 40 years. Exclusions: unknown.

Interventions 1. Haloperidol: dose 6 weeks 4.5 mg/day followed by 6 weeks placebo. N=30. 2. Placebo: 6 wks placebo followed by 6 wks 4.5 mg/day haloperidol. N=30

Outcomes Global effect: FFS, improved/not improved. Unable to use - Adverse events: various observed effects (no group data). Leaving the study early (no group data).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

AIMS - Assessment of Involuntary Movement Scale. BAS - Barnes Akathisa Scale. BHGRS - Bunney-Hamburg Global Rating Scale. BPRS - Brief Pyschiatric Rating Scale. BPRS-C - Brief Psychiatric Rating Scale for Children. CCS - Clinical Change Scale. CGI - Clinical Global Impression. CPRS - Comprehensive Psychophathological Rating Scale. CPRS - Childrens Psychiatric Rating Scale. DICA-R - Diagnostic Interview for Children & Adolescents (Revised). DSM-III-R - Diagnositic and statistical manual of mental disorders: 3rd edition - revised. EPS - Extrapyramidal Sypmtoms. ESRS - Extrapyramidal Symptom Rating Scale. FC - Feighners Criteria. FFS - Fergus Falls Scale. GPS - General Psychopathology Subscale. ICD-9 - 9th International Classiﬁcation of Diseases. IMPS - Inpatient Multidimensional Psychiatric Scale. KRS - Krawiecka Rating Scale. MSC - Mental Status Checklist. PGI - Patient Global Impression. PRP - Psychotic Reaction Proﬁle. RDC - Research Diagnostic Criteria. SANS - Scale for the Assessment of Negative Symptoms. SAS - Simpson Angus Scale. UKU - side effect rating scale. WBRS - Ward Behaviour Rating Scale. WISC-R - Wechsler Intelligence Scale for Children (Revised). WPPSI - Wechsler Preschool & Primary Scale of Intelligence.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Alpert 1995 Allocation: unclear.

Alphs 1993 Allocation: unclear. Participants: people with schizophrenia. Interventions: haloperidol versus remoxipride versus placebo. Outcomes: all data unusable - conference proceedings.

Arvanitis 2002 Allocation: random. Participants: people with schizophrenia. Interventions: SR compound, haloperidol or placebo. Outcomes: all data unusable, conference proceedings.

Augustin 1996 Allocation: random. Participants: people with schizophrenia. Interventions: haloperidol versus placebo. Outcomes: all data unusable - conference proceedings.

Azima 1960 Allocation: unclear. Participants: only 34/84 were people with schizophrenia.

Ban 1969 Allocation: unclear. Participants: people with schizophrenia. Interventions: haloperidol + phenothiazine medication versus triﬂuperidol + phenothiazine medication versus placebo, not haloperidol alone

Bateman 1979 Allocation: random. Participants: unclear if people with schizophrenia. Interventions: supplementation of original neuroleptic with haloperidol or placebo

Ben-dor 1998 Allocation: random. Participants: people hospitalised with chronic schizophrenia. Interventions: haloperidol + vitamin E versus haloperidol + placebo, no placebo only group

Beuzen 1996 Allocation: random. Participants: healthy elderly, not people with schizophrenia

Blum 1969 Allocation: unclear.

Brandrup 1961 Allocation: random, crossover study . Participants: people with chronic schizophrenia. Intervention: haloperidol 8 mg/day versus placebo. Outcomes: no usable data from period before ﬁrst crossover.

Browne 1988 Allocation: random. Participants: people with chronic schizophrenia. Intervention: haloperidol 10-160 mg/day versus placebo. Outcomes: all data unusable, >50% loss during double-blind phase, people relapsing could re-enter study under single-blind conditions

Buchsbaum 1992 Allocation: unclear, no recording of random allocation.

Caroli 1975 Allocation: not random, ABA design.

Cho-Boon 1989 Allocation: random. Participants: people with schizophrenia. Interventions: haloperidol 12-18, 30-45, 60-90 mg/day versus placebo. Outcomes: all data unusable - conference proceeding.

Contreas 1988 Allocation: not random, ABA design.

Craft 1965 Allocation: unclear.

Crow 1986 Allocation: random. Participants: 120 people with schizophrenia. Interventions: haloperidol withdrawal versus continuation, not instigation of haloperidol treatment

Deberdt 1971 Allocation: not random, ABA design.

Diamond 1991 Allocation: random. Participants: men with schizophrenia. Interventions: haloperidol 5-75 mg/day versus tiospirone 75-375 mg/day versus placebo. Outcomes: all data unusable - conference proceedings.

Gelders 1986 Allocation: random. Participants: people with chronic schizophrenia. Interventions: haloperidol 10 mg/day versus ritanserin 20/mg/day versus placebo. Outcomes: all data unusable, no group numbers given for CGI, no data given for BPRS or adverse effects

Glovinsky 1992 Allocation: not random, ABA design.

Huygens 1973 Allocation: random. Participants: 40 women with psychosis. Interventions: dexetimide versus placebo, adjunct to haloperidol

Itil 1981 Allocation: not random, ABA design.

Jolley 1990 Allocation: random. Participants: people in remission from schizophrenia. Interventions: haloperidol withdrawal versus placebo, no instigation of haloperidol

Kasper 1996 Allocation: random. Participants: people with schizophrenia. Intervention: 4, 8 and 16 mg/day haloperidol versus 12, 20 and 24 mg/day sertindole or placebo. Outcomes: all data unusable, conference proceedings.

Ko 1989 Allocation: not random, ABA design.

Kramer 1989 Allocation: random. Participants: 56 people with schizophrenia. Interventions: amitriptyline versus desmethylimipramine versus placebo in addition to haloperidol and benztropine, haloperidol not randomised

Kurland 1981 Allocation: random. Participants: 28 people with schizophrenia and scoring >17 on HAM-D. Interventions: adjunctive viloxazine versus placebo, antipsychotics, such as haloperidol, continued as normal

Labarca 1993 Allocation: not random, ABA design.

Lee 1968 Allocation: unclear.

Lehmann 1967 Allocation: random. Participants: 30 people with chronic schizophrenia. Interventions: continued on current phenothiazine medication, then randomised to adjunctive haloperidol (1. 5 mg/day) versus triﬂuperidol (0.75 mg/day) versus placebo, not haloperidol alone

Lemmer 1993 Allocation: random. Participants: people with acute schizophrenia. Interventions: pramipexole versus haloperidol or placebo. Outcomes: all data unusable, study stopped early.

Lindborg 2003 Allocation: not random, meta-analysis.

Magelund 1979 Allocation: random, crossover. Participants: 12 people hospitalised with schizophrenia. Interventions: AMPT versus haloperidol, placebo given after each active treatment period, not randomised

Malaspina 1997 Allocation: random. Participants: people with schizophrenia. Interventions: haloperidol decanoate 0.3 mg/kg versus placebo. Outcomes: all data unusable - conference proceedings.

Nagaraja 1977 Allocation: not random.

Necomer 1992 Allocation: random. Participants: 24 males with schizophrenia. Interventions: haloperidol withdrawal versus placebo, not instigation of haloperidol

Nguyen 1984 Allocation: unclear. Participants: people with chronic schizophrenia. Interventions: haloperidol versus placebo. Outcomes: all data unusable - conference proceedings.

Nth America 1997 Allocation: random. Participants: 523 people with chronic schizophrenia. Interventions: haloperidol 20 mg/day versus placebo versus risperidone 2, 6, 10 or 16 mg/day. Outcomes: combines data from several centres but all unique data from these reports of combined analyses is unusable due to >50% loss; data from publications of speciﬁc centres can be included (Chouinard 1993, Marder 1994)

Okasha 1964 Allocation: random. Participants: 80 people hospitalised with chronic psychosis. Interventions: haloperidol 4.5 mg/day versus placebo. Outcomes: no usable data, leaving study early (no group data), behaviour (no total scale score)

Ortega-Soto 1994 Allocation: random. Participants: drug free people with acute schizophrenia. Interventions: threshold dose of haloperidol + 20 mg haloperidol versus threshold dose of haloperidol + placebo, not haloperidol versus placebo

Ota 1973 Allocation: unclear . Participants: 54 people with chronic schizophrenia. Interventions: haloperidol withdrawal versus placebo, not instigation of haloperidol

Pathiraja 1995 Allocation: random. Participants: men with schizophrenia. Interventions: haloperidol 5-20 mg/day versus risperidone 2-16 mg/day versus MAR 327 50-400 mg/day versus placebo. Outcomes: all data unusable - conference proceedings.

Pool 1976 Allocation: random but with non-random additions. Participants: 75 people with schizophrenia. Interventions: haloperidol versus loxapine versus placebo. Outcomes: no usable data - those who withdrew during the study were replaced with new patients and data for those randomised not reported separately

Potkin 1984 Allocation: random. Participants: people with schizophrenia. Interventions: haloperidol + IC (insulin coma therapy) versus placebo + IC, not haloperidol alone. Outcomes: all data unusable - conference proceeding.

Potkin 1995 Allocation: random. Participants: people with schizophrenia. Interventions: haloperidol versus MAR 327 150-300 mg/day versus placebo. Outcomes: all data unusable - conference proceeding.

Potkin 2000 Allocation: random. Participants: people with schizophrenia. Interventions: haloperidol versus clozapine or placebo. Outcomes: PET scan study, outcomes not relevant, data unusable

Price 1985 Allocation: not random, ABA design.

Price 1987 Allocation: random. Participants: people with schizophrenia. Interventions: haloperidol 10-4- mg/day versus verapamil 80 mg/day versus placebo. Outcomes: all data unusable.

Rees 1965 Allocation: random, cross-over. Participants: 14 people with schizophrenia. Interventions: haloperidol versus placebo. Outcomes: all data unusable, none available before cross-over

Roitman 1989 Allocation: random. Participants: 16 people with schizoaffective disorder. Interventions: adjunctive demeclocycline (DMC) versus placebo, all received haloperidol

Ruskin 1991 Allocation: random. Participants: 35 people with schizophrenia. Interventions: haloperidol withdrawal versus placebo, not instigation of haloperidol

Samuels 1961 Allocation: unclear.

Singh 1972 Allocation: not random, ABA design.

Soloff 1986 Allocation: random. Participants: people with ”Borderline disorders“, not schizophrenia

Stankovska 2002 Allocation: unclear if randomised.

Taverna 1972 Allocation: quasi-randomised.

Teja 1975 Allocation: random. Participants: people with chronic schizophrenia. Interventions: haloperidol 36 mg/week versus chlorpromazine >1800 mg/week versus triﬂuoperazine >90 mg/ week versus thiothixene >90 mg/week versus placebo. Outcomes: all data unusable.

Van Lommel 1974 Allocation: random. Participants: 19 psychotic males. Interventions: haloperidol withdrawal versus placebo, not instigation of haloperidol

Volavka 1992 Allocation: random. Participants: 173 people with acutely exacerbated schizophrenia. Interventions: dosage levels of haloperidol, no placebo group

Zimbroff 1997 Allocation: random. Participants: people with schizophrenia. Interventions: haloperidol 4, 8, 16 mg/day versus sertindole 12, 20, 24 mg/day versus placebo. Outcomes: all data unusable due to >50% loss, leaving study early (not given as individual group data)

ABA: Before and after trial. EPS: Extrapyramidal Symptoms. HAM-D: Hamilton Depression Scale.

Haloperidol versus placebo for schizophrenia (Review) 47 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Characteristics of studies awaiting assessment [ordered by study ID]

Akhondzadeh 2005

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Allison 2007

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Andrezina 2006a

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Ascher-Svanum 2005

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Barbee 1992

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Battaglia 2005

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Baymiller 2002

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Bersudsky 2006

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Bogeum 2008

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Bristol-Myers 2004

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Cao 2006

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Chou 1998

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Czobor 1992

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes

Daniel 2007

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Dillenschneider 2005a

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Eklund 1990

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Eli 2005a

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Garcia 2009

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

GlaxoSmithKline 2005

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

IRCT138809201457N6

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

IRCT138809201457N7

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Jung 2007

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Kane 2010

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Kapur 2004

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Kapur 2005

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Kujawa 2002

Methods

Participants

Interventions

Outcomes

Notes

Lee 2007

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Li 2007

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Maoz 2000

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Marder 1991

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Marder 1996

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Marder 1997a

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Marder 1997b

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

McQuade 2006

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Meehan 2001

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Meltzer 2006

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Meltzer 2008

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Mossaheb 2006

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

NCT00018850

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

NCT00044044

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

NCT00189995

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

NCT00249132

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

NCT00947375

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Octavio 2004

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Oren 2005

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Oren 2007

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Potkin 2008

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Romeo 2009

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Shim 2007

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Wilson 1994

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Zhan 2000

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Zhang 2002

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Zhang 2006a

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

Zimbroff 1998

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

, 2009

Methods

Participants

Interventions

Outcomes

Notes To be assessed.

George 2000

Trial name or title A double-blind randomised comparison of the efﬁcacacy and safety of short acting intramuscular olanzapine, short acting intramuscular haloperidol and intramuscular placebo in patients with schizophrenia

Methods

Participants people with schizophrenia, schizophreniform disorder or schizoaffective disorder, aged over 18 years

Interventions intramuscular and oral olanzapine versus haloperidol or placebo

Outcomes efﬁcacy and safety

Starting date 2000

Contact information National Research Register

Notes

Paykel 2000

Trial name or title Prophylaxis of puerperal psychosis

Methods

Participants people who have already had peurperal psychosis and about to have another baby

Interventions within 72hrs of delivery participants started on lithiun, haloperidol or placebo, followed by regular visits as outpatients every two weeks for two months

Outcomes prevention of further attacks

Starting date 2000

Contact information National Research Register

Notes

Comparison 1. HALOPERIDOL versus PLACEBO

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Global effect: 1. No marked 10 Risk Ratio (M-H, Random, 95% CI) Subtotals only global improvement 1.1 0-6 weeks (clinician 3 159 Risk Ratio (M-H, Random, 95% CI) 0.44 [0.31, 0.62] rated). 1.2 >6-24 weeks (clinician 8 308 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.59, 0.81] rated) 1.3 >6-24 weeks (nurse rated) 1 28 Risk Ratio (M-H, Random, 95% CI) 0.59 [0.37, 0.92] 2 Global effect: 2. Not discharged 1 33 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.47, 1.52] from hospital (>6-24 weeks) 3 Global effect: 3. Relapse or not 2 70 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.57, 0.87] remaining in remission (<52 weeks) 4 Mental state: 1. No clinical 1 24 Risk Ratio (M-H, Random, 95% CI) 0.76 [0.54, 1.08] improvement (<20% reduction in BPRS score, 0-6 weeks) 5 Mental state: 2. Average end 2 72 Mean Difference (IV, Fixed, 95% CI) -11.89 [-17.04, -6. point BPRS score by 6 weeks 74] (high = poor) 6 Mental state: 3. Change in BPRS Other data No numeric data total score by 3 weeks (high = good, data likely to be skewed) 7 Leaving the study early 20 Risk Ratio (M-H, Random, 95% CI) Subtotals only 7.1 0-6 weeks 12 898 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.73, 0.95] 7.2 >6-24 weeks 8 304 Risk Ratio (M-H, Random, 95% CI) 0.56 [0.30, 1.04] 7.3 < 52 weeks 1 50 Risk Ratio (M-H, Random, 95% CI) 2.58 [0.14, 46.83] 8 Adverse events: 1. 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only Anticholinergic effects 8.1 blurred vision 2 240 Risk Ratio (M-H, Random, 95% CI) 3.42 [0.91, 12.91] 8.3 dry mouth 2 73 Risk Ratio (M-H, Random, 95% CI) 1.81 [0.71, 4.59] 9 Adverse events: 2. Cardiovascular 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only effects 9.1 blood pressure - dizziness 4 285 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.43, 2.95] / low BP 9.2 blood pressure - high BP 1 16 Risk Ratio (M-H, Random, 95% CI) 3.0 [0.14, 64.26] 10 Adverse events: 3a. Movement 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only disorders - acute 10.1 dystonia 3 109 Risk Ratio (M-H, Random, 95% CI) 8.52 [1.66, 43.85] 10.2 oculogyric crises 2 83 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.10, 8.89] 11 Adverse events: 3b. Movement 10 Risk Ratio (M-H, Random, 95% CI) Subtotals only disorders - non-acute 11.1 akathisia 4 333 Risk Ratio (M-H, Random, 95% CI) 2.57 [1.39, 4.75] 11.2 needing antiparkinson 3 246 Risk Ratio (M-H, Random, 95% CI) 2.69 [1.53, 4.72] medication