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Chlorpromazine is one of the 3 listed medicines for treating psychotic disorders in the World Health Organization's Essential Drug List. It is used across the globe for the 1% of people who suffer from this illness. Chlorpromazine has many adverse effects, including a range of movement disorders and anticholinergic and antihistaminic effects. Higher doses cause more adverse effects, but the evidence for which dose gives best clinical response for least adverse effects has not been carefully summarized for decades.
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 randomized clinical trials (RCTs) were included as selection criteria.
We extracted data independently. For dichotomous data, we calculated relative risk (RR) and their 95% confidence intervals (CIs). For continuous data, we calculated weighted mean differences based on a fixed-effect model.
We included 4 relevant studies (1012 participants). They are all hospital-based trials and have a duration of less than 6 months. The trials compared chlorpromazine low dose (<400 mg/d) with medium dose (400–800 mg/d) and high dose (>800 mg/d). There were no convincing differences between low and medium doses for measures of mental state. These ratings were based on the results of one small trial (n=22). Compared with medium dose, chlorpromazine low dose results in less risk of short-term dystonia (n=70, 2 RCTs, RR = 0.20, 95% CI = 0.04 to 0.97) and disturbance in general state at medium term (n=54, 1 RCT, RR = 0.22, 95% CI = 0.08 to 0.60). When low dose is compared with high, the latter shows more clinically important improvement (n=416, 1 RCT, RR = 1.12, 95% CI = 1.01 to 1.23) but increased dystonia (n=416, 1 RCT, RR = 0.11, 95% CI = 0.02 to 0.45) and extrapyramidal adverse effects (n=416, 1 RCT, RR = 0.43, 95% CI = 0.32 to 0.59) (Figure 1). The low-dose group had less risk of a range of a range of adverse effects including in the cardiovascular system (n = 416, 1 RCT, RR = 0.32, 95% CI = 0.19 to 0.54) and central nervous system (n = 416, 1 RCT, RR = 0.17, 95% CI = 0.04 to 0.74). Also dermatologic problems (n = 416, 1 RCT, RR = 0.10, 95% CI = 0.04 to 0.22), the gastrointestinal system (n = 416, 1 RCT, RR = 0.36, 95% CI = 0.21 to 0.62) and for ocular problems (n = 416, 1 RCT, RR = 0.33, 95% CI = 0.22 to 0.50) were less common in this group. There were no comparisons of medium dose versus high. Full details are reported elsewhere.1
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 evidence. This progression toward gentler levels of dosing has taken 6 decades. We can hope that for modern compounds dose-ranging studies are more informative early on in the use of a new drug.