Haloperidol dose for the acute phase of schizophrenia

Abstract

Background: Haloperidol is a benchmark, accessible antipsychotic against which the effects of newer treatments are gauged.

Objectives: The primary goal of this review is to determine the best range of doses for haloperidol for the treatment of people acutely ill with schizophrenia.

Search strategy: The reviewers searched Biological Abstracts (1980-1999), CINAHL (1982-1999), The Cochrane Library (1999, Issue 2), The Cochrane Schizophrenia Group's Register (December 1999), EMBASE (1980-1999), MEDLINE (1966-1999) and PsycLIT (1887-1999). They also inspected all references of all identified trials and included studies sought as a citation on SCISEARCH database (1980-1999). Authors of identified studies and pharmaceutical companies were also contacted.

Selection criteria: Studies were selected if they involved people being treated for acute schizophrenia, randomised to two or more dose ranges of non-depot haloperidol, and if they reported clinically meaningful outcomes.

Data collection and analysis: The reviewers independently and blindly inspected citations (10% reliability check), they ordered papers, and reliably re-inspected and quality assessed the full reports. The reviewers, again working independently, also extracted data. For homogeneous dichotomous data the relative risk (RR), 95% confidence intervals (CI) were calculated on an intention-to-treat basis. Reviewers assumed that people who left the study early or were lost to follow-up had a negative outcome. Weighted mean differences (WMD) were calculated for continuous outcomes that reported intention to treat (ITT), last observation carried forward (LOCF) data. Data was excluded if loss to follow-up was greater than 50%.

Main results: Sixteen trials with nineteen different randomised dose comparisons were included. No studies reported data on relapse rates, quality of life and none compared >1.5-3.0 mg/day haloperidol to higher dose ranges. Using low doses (>3-7.5mg/day) did not clearly result in loss of efficacy (no clinically important improvement in global state, versus >7.5-15mg/day n=48, 1 RCT, RR 1.09 CI 0.7 to 1.8; versus >15-35mg/day n=81, 2 RCTs, 0.95 CI 0.8 to 1.2). Doses of haloperidol in the range of >3-7.5 mg/day had a lower rate of development of clinically significant extrapyramidal adverse effects than higher doses (clinically significant extrapyramidal adverse effects, versus >7.5-15mg/day n=64, 2 RCTs, RR 0.12 CI 0.01 to 2.1; versus >15-35mg/day n=144, 3 RCTs RR 0.59 CI 0.5 to 0.8, NNH 3 CI 2 to 6; versus >35mg/day n=86, 2 RCTs, RR 0.70 CI 0.5 to 1.1). All other comparisons between dose ranges did not yield statistically significant differences, but several, particularly with lower dose ranges, were underpowered to detect clinically meaningful differences.

Reviewer's conclusions: No results are conclusive and all are based on small, short, studies. It would be understandable, however, if clinicians were cautious in prescribing doses in excess of 7.5 mg/day of haloperidol to a person with uncomplicated acute schizophrenia, and if people with schizophrenia were equally reticent to take greater doses. Further research is needed regarding the efficacy and tolerability of the >1.5-3.0 mg/day dose range.