Haloperidol versus placebo for schizophrenia.
BACKGROUND
Haloperidol was developed in the late 1950s for use in the field of analgesia. 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 to placebo.


METHODS
Electronic searches of Biological Abstracts (1985-1998), CINAHL (1982-1998), The Cochrane Library (1998, Issue 4), The Cochrane Schizophrenia Group's Register (December 2000), EMBASE (1980-1998), MEDLINE (1966-1998), PsycLIT (1974-1998), and SCISEARCH (January 1974-December 1998) were undertaken. References of all identified studies were searched for further trial citations. Authors of trials and pharmaceutical companies were contacted for further information and archive material.


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


METHODS
Reviewers 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, dichotomous data were analysed using relative risk (RR) and their 95% confidence intervals (CI) calculated. If appropriate, the number needed to treat (NNT) or number needed to harm (NNH) was estimated. For continuous data, weighted mean differences were calculated. Continuous data were excluded if loss to follow up was greater than 50%. All data were inspected for heterogeneity.


RESULTS
Seventy-four trials were identified but only 20 included. More people allocated to haloperidol improved in the first six weeks of treatment than those given placebo (three trials, 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 (n=313) also found a difference favouring haloperidol across the 6-24 week period (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 overestimate 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, 10 studies found a difference that favoured haloperidol (n=686, RR 0.82 CI 0.7 to 0.95, NNT 8 CI 5 to 17). Limited adverse effect data do, nevertheless, support the clinical impression that haloperidol is a potent cause of movement disorders, at least in the short term. Haloperidol promotes acute dystonia (three trials, n=135, RR 4.7 CI 1.7 to 44, NNH 5 CI 3 to 9 - not assuming those who left early from placebo suffered dystonis), akathisia (three trials, n=129, RR 6.5 CI 1.5 to 28, NNH 6 CI 4 to 14) and parkinsonism (four trials, n=165, RR 8.9 CI 2.6 to 31, NNH 3 CI 2 to 5).


CONCLUSIONS
Haloperidol is a potent antipsychotic drug but with a high propensity to cause adverse effects. Given no choice of drug, use of haloperidol to counter the damaging and potentially dangerous consequences of untreated schizophrenia is justified. If a choice of drug is available, however, people with schizophrenia and clinicians may wish to start another antipsychotic with less likelihood of causing parkinsonism, akathisia and acute dystonias. For countries where haloperidol is not widely used, it should not be a control drug of choice for randomised trials of new antipsychotics.
Joy
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CB
Cochrane Schizophrenia Group, Summertown Pavillion, Middle Way, Oxford, UK, OX2 7LG. claire@spoonbed.freeserve.co.uk
Adams
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CE
Lawrie
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SM
D014150:Antipsychotic Agents / Q000627:therapeutic use*; D006220:Haloperidol / Q000627:therapeutic use*; D006801:Humans; D015990:Placebo Effect; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000188:drug therapy*
D014150:Antipsychotic Agents; D006220:Haloperidol