Chlorpromazine dose for people with schizophrenia

Abstract

Chlorpromazine is one of the three antipsychotic drugs on the WHO Essential Drug List. It is used worldwide. The optimal dose has been the subject of evaluative research but summaries of this work are rare. To determine chlorpromazine dose response and dose adverse effect relationships for schizophrenia and schizophrenia-like psychoses. We searched the Cochrane Schizophrenia Group Trials Register (December 2008). References of all included studies were examined for further trials. All relevant randomised controlled trials (RCTs) comparing fixed doses of chlorpromazine for people with schizophrenia and reporting clinical outcomes. We extracted data independently. For dichotomous data we calculated fixed-effect relative risk (RR) and their 95% confidence intervals (CI). For continuous data, we calculated weighted mean differences (WMD) based on a fixed-effect model. We included four relevant studies (1012 participants) in this review. They are all hospital-based trials, have a duration of less than six months and are at moderate risk of bias. When low dose (</=400mg/day) was compared with medium dose (401-800 mg/day) mental state data were very few and difficult to interpret (n=22, 1 RCT, WMD 'withdrawal retardation' -2.00 CI -3.76 to -0.24). More people left for inefficacy of treatment in the low dose group (n=48, 1 RCT, RR 4.24 CI 0.24 to 74.01). In the short term, all measured extrapyramidal adverse effects tended to be lower in the low dose group (n=70, 2 RCTs, RR dystonia 0.20 CI 0.04 to 0.97). When low dose was compared with high (>800mg/day) data were taken from only one study (2gms chlorpromazine/day). Global state outcomes tended to favour the high dose group (n=416, 1 RCT, RR 'No clinically important improvement 1.12 CI 1.01 to 1.23). One case of death was reported in the high dose group (n=416, RR 0.33 CI 0.01 to 8.14) and a significantly greater number of people in the high dose group left early due to disabling adverse effects (n=416, RR 0.10 CI 0.04 to 0.27). Significantly less dystonia and unspecified extrapyramidal adverse effects were reported in the low dose group (n=416, dystonia RR 0.11 CI 0.02 to 0.45, unspecified extrapyramidal adverse effects RR 0.43 CI 0.32 to 0.59). People in both groups experienced akathisia (n=416, RR1.00 CI 0.55 to 1.83). The average dose of chlorpromazine given to people with schizophrenia has declined across time, but this has come about by long - and sometimes hard - experience rather than from direction from high-grade trial-based evidence. This progression towards gentler levels of dosing has taken six decades. We hope that, for modern compounds, data from relevant high-grade evaluative studies will be much more swiftly available to guide informed practice.