Haloperidol versus placebo for schizophrenia.
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.


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


METHODS
Initially, we 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 2012 update, on 15 May 2012, we searched the Cochrane Schizophrenia Group's Trials Register.


METHODS
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.


METHODS
We evaluated data independently and extracted, re-inspected and quality assessed the data. We analysed dichotomous data using risk ratio (RR) and calculated their 95% confidence intervals (CI). For continuous data, we calculated mean differences (MD). We excluded continuous data if loss to follow-up was greater than 50% and inspected data for heterogeneity. We used a fixed-effect model for all analyses. For the 2012 update, we assessed risk of bias of included studies and used the GRADE approach to create a 'Summary of findings' table.


RESULTS
Twenty-five trials randomising 4651 people are now included in this review. We chose seven main outcomes of interest for the 'Summary of findings' table. More people allocated haloperidol improved in the first six weeks of treatment than those given placebo (4 RCTs n = 472, RR 0.67 CI 0.56 to 0.80, moderate quality evidence). A further eight trials also found a difference favouring haloperidol across the six weeks to six months period (8 RCTs n = 307 RR 0.67 CI 0.58 to 0.78, moderate quality evidence). Relapse data from two trials favoured haloperidol at < 52 weeks but the evidence was very low quality (2 RCTs n = 70, RR 0.69 CI 0.55 to 0.86). Moderate quality evidence showed about half of those entering studies failed to complete the short trials (six weeks to six months), although, at up to six weeks, 16 studies found a difference that marginally favoured haloperidol (n = 1812, RR 0.87 CI 0.80 to 0.95). Adverse effect data does, nevertheless, support clinical impression that haloperidol is a potent cause of movement disorders, at least in the short term. Moderate quality evidence indicates that haloperidol caused parkinsonism (5 RCTs n = 485, RR 5.48 CI 2.68 to 11.22), akathisia (6 RCTs n = 695, RR 3.66 CI 2.24 to 5.97, and acute dystonia (5 RCTs n = 471, RR 11.49 CI 3.23 to 10.85). Discharge from hospital was equivocal between groups (1 RCT n = 33, RR 0.85 CI 0.47 to 1.52, very low quality evidence). Data were not reported for death and patient satisfaction.


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 be less favoured as a control drug for randomised trials of new antipsychotics.
Cochrane Schizophrenia Group, The University of Nottingham, Institute of Mental Health, University of Nottingham Innovation Park, Triumph Road,, Nottingham, UK, NG7 2TU.
Clive E
CE
Adams
Hanna
H
Bergman
Claire B
CB
Irving
Stephen
S
Lawrie
D017109:Akathisia, Drug-Induced / Q000209:etiology; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004421:Dystonia / Q000139:chemically induced; D006220:Haloperidol / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D020734:Parkinsonian Disorders / Q000139:chemically induced; D015990:Placebo Effect; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D006220:Haloperidol