Haloperidol versus placebo for schizophrenia
Abstract
Background
Haloperidol was developed in the late 1950s for use in the field of anaesthesia. Research subsequently demonstrated effects on hallucinations, delusions, aggressiveness, impulsiveness and states of excitement and led to the introduction of haloperidol as an antipsychotic.
Objectives
To evaluate the clinical effects of haloperidol for the management of schizophrenia and other similar serious mental illnesses compared to placebo.
Search methods
We initially electronically searched the databases of Biological Abstracts (1985‐1998), CINAHL (1982‐1998), The Cochrane Library (1998, Issue 4), The Cochrane Schizophrenia Group's Register (December 1998), EMBASE (1980‐1998), MEDLINE (1966‐1998), PsycLIT (1974‐1998), and SCISEARCH. We also checked references of all identified studies for further trial citations and contacted the authors of trials and pharmaceutical companies for further information and archive material. For the 2005 update we searched The Cochrane Library (2005, Issue 6).
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.
Main results
Twenty‐one trials randomising 1519 people are now included in this review. One new trial, Kane 2002 (n=414) has been added but it did not affect the overall results. More people allocated haloperidol improved in the first six weeks of treatment than those given placebo (3RCTs n=159, RR failing to produce a marked improvement 0.44 CI 0.3 to 0.6, NNT 3 CI 2 to 5). A further eight trials also found a difference favouring haloperidol across the 6‐24 week period (8 RCTs n=308 RR no marked global improvement 0.68 CI 0.6 to 0.8 NNT 3 CI 2.5 to 5) but this may be an over estimate of effect as small negative studies were not identified. About half of those entering studies failed to complete the short trials, although, at 0‐6 weeks, 11 studies found a difference that marginally favoured haloperidol (11 RCTs n=898, RR 0.8 CI 0.7 to 0.9, NNT 59 CI 38 to 200). Adverse effect data does, nevertheless, support clinical impression, that haloperidol is a potent cause of movement disorders, at least in the short term. Haloperidol promotes acute dystonia (3 RCTs n=93, RR 4.7 CI 1.7 to 44, NNH 5 CI 3 to 9), akathisia (4 RCTs n=333, RR 2.6 CI 1.4 to 4.8, NNH 7 CI 3 to 25) and parkinsonism (4 RCTs n=163, RR 11.7 CI 2.9 to 47, NNH 3 CI 2 to 5).
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.
PICOs
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)
