Schizophrenia is a serious disorder characterised by delusions (including paranoid beliefs and hallucinations) and other symptoms such as blunted affect and reduced motivation. While relatively uncommon (lifetime prevalence is less than 1%), it is associated with serious social impairment (e.g., unemployment, homelessness), which in turn can result in physical health problems. As a result, the life expectancy of people with a diagnosis of schizophrenia is 10 or more years less than those without (Chang et al, 2011).

Haloperidol is a dopamine inverse agonist belonging to the typical antipsychotic class of treatments for schizophrenia and related conditions. It was originally developed, in the 1950s, for use in anaesthetics, but subsequent research indicated that it had potentially therapeutic effects on hallucinations, delusions, aggression and impulsivity, all of which are symptoms of psychotic illnesses such as schizophrenia. It was therefore introduced as one of the first anti-psychotic medications.

Methods

This review evaluated the effects of haloperidol, compared with placebo, for the management of schizophrenia and other related mental health problems. The authors searched a range of databases, using standard Cochrane Collaboration procedures. This version of the review is an update of a previous version which included searches up to 1998. A valuable feature of Cochrane Reviews is that they are periodically updated, as new evidence emerges.

Studies which compared any oral dose of haloperidol with placebo in those with schizophrenia or a related psychotic illness were included.

The main outcomes of interest were:

• Death
• Loss to follow-up
• Clinical and social response
• Relapse
• Severity of adverse events

These data were analysed using risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, including 95% confidence intervals. Studies with high loss to follow up (> 50%) were excluded.

Results 

A total of 25 trials, comprising 4,651 people randomised, were included in the updated review.

• The evidence generally supported a favourable effect of haloperidol:
  • More people showed improvement in the first six weeks of treatment (k = 4, n = 472, RR 0.67, 95% CI 0.56 to 0.80)
  • And across the six week to six months period (k = 8, n = 307, RR 0.67, 95% CI 0.58 to 0.78) when allocated to haloperidol,
  • With the evidence judged to be moderate quality
• Relapse data from two trials also favoured haloperidol, but in this case the evidence was judged to be very low quality

• Despite evidence for some clinical benefits of haloperidol (in particular in relation to symptom improvement), the evidence also supported the view that haloperidol causes side effects such as movement disorders, including:
  • Parkinsonism (k = 5, n = 485, RR 5.48, 95% CI 2.68 to 11.22)
  • Akathisia (k = 6, n = 695, RR 3.66, 95% CI 2.24 to 5.97)
  • Acute dystonia (k = 5, n = 471, RR 11.49, 95% CI 3.23 to 10.85), at least in the short term
• Data were not reported for death or patient satisfaction, so these outcomes could not be evaluated

• 

  Haloperidol can cause serious side effects such as acute dystonia. Image appears courtesy of James Heilman

Conclusions

Haloperidol is an effective antipsychotic, but it also causes adverse effects.

The authors conclude, therefore, that where a choice of treatment is available, an alternative antipsychotic with a lower likelihood of causing adverse effects, such as parkinsonism, akathisia and acute dystonias, may be preferable. The authors also conclude that haloperidol should also be less favoured as an active comparator for randomised trials of new antipsychotics.

Interestingly, the conclusions of this update are not substantially different from the original review. However, evidence continually evolves, and the regular updates which are a feature of Cochrane Reviews are one of the main reasons why they are so valuable. Meta-analyses can become out of date very soon after they are published, as new evidence emerges. By encouraging periodic updates, the Cochrane Collaboration ensures it reviews remain timely and relevant.

Links

Adams CE, Bergman H, Irving CB, Lawrie S. Haloperidol versus placebo for schizophrenia. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD003082. DOI: 10.1002/14651858.CD003082.pub3.

Chang C-K, Hayes RD, Perera G, Broadbent MTM, Fernandes AC, et al. (2011) Life Expectancy at Birth for People with Serious Mental Illness and Other Major Disorders from a Secondary Mental Health Care Case Register in London. PLoS ONE 6(5): e19590. doi:10.1371/journal.pone.0019590