Chlorpromazine versus placebo for schizophrenia

For previous plain language summary please see Appendix 3.

People with schizophrenia often hear voices or see things (hallucinations) and have strange beliefs (delusions). The main treatment for these symptoms of schizophrenia is antipsychotic drugs. Chlorpromazine was one of the first drugs discovered to be effective in the treatment of schizophrenia during the 1950s. It remains one of the most commonly used and inexpensive treatments even today. However, being an older drug (‘typical’ or first generation) it also has serious side effects, such as blurred vision, a dry mouth, tremors or uncontrollable shaking, depression, muscle stiffness and restlessness.

An update search was carried out in 2012 and the review now includes 55 studies that assess the effects of chlorpromazine in treating schizophrenia compared with no active treatment (‘dummy’ treatment or placebo). Evidence was, in the main, rated by the review authors as low quality. There is some evidence to suggest that chlorpromazine reduces relapse and improves people’s mental health, symptoms and functioning. However, the side effects of chlorpromazine are severe and debilitating. Chlorpromazine causes sleepiness and sedation. It also causes movement disorders (such as tremors and uncontrollable shaking), considerable weight gain and lowering of blood pressure with accompanying dizziness.

Chlorpromazine is low-cost and widely available. Despite its many side effects, chlorpromazine is likely to remain a benchmark drug and one of the most widely used treatments for schizophrenia worldwide.

It should be noted that the quality of evidence from the 55 included studies was low and in addition to this, 315 studies were excluded because of flaws in the reporting of information or data and in research design and methods. Larger, better conducted and reported trials should focus on important outcomes such as quality of life, levels of satisfaction, relapse, hospital discharge or admission and number of violent incidents.

Authors' conclusions: 

The results of this review confirm much that clinicians and recipients of care already know but aim to provide quantification to support clinical impression. Chlorpromazine's global position as a 'benchmark' treatment for psychoses is not threatened by the findings of this review. Chlorpromazine, in common use for half a century, is a well-established but imperfect treatment. Judicious use of this best available evidence should lead to improved evidence-based decision making by clinicians, carers and patients.

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Background: 

Chlorpromazine, formulated in the 1950s, remains a benchmark treatment for people with schizophrenia.

Objectives: 

To review the effects of chlorpromazine compared with placebo, for the treatment of schizophrenia.

Search strategy: 

We searched the Cochrane Schizophrenia Group’s Trials Register (15 May 2012). We also searched references of all identified studies for further trial citations. We contacted pharmaceutical companies and authors of trials for additional information.

Selection criteria: 

We included all randomised controlled trials (RCTs) comparing chlorpromazine with placebo for people with schizophrenia and non-affective serious/chronic mental illness irrespective of mode of diagnosis. Primary outcomes of interest were death, violent behaviours, overall improvement, relapse and satisfaction with care.

Data collection and analysis: 

We independently inspected citations and abstracts, ordered papers, re-inspected and quality assessed these. We analysed dichotomous data using risk ratio (RR) and estimated the 95% confidence interval (CI) around this. We excluded continuous data if more than 50% of participants were lost to follow-up. Where continuous data were included, we analysed this data using mean difference (MD) with a 95% confidence interval. We used a fixed-effect model.

Main results: 

We inspected over 1100 electronic records. The review currently includes 315 excluded studies and 55 included studies. The quality of the evidence is very low. We found chlorpromazine reduced the number of participants experiencing a relapse compared with placebo during six months to two years follow-up (n=512, 3 RCTs, RR 0.65 CI 0.47 to 0.90), but data were heterogeneous. No difference was found in relapse rates in the short, medium or long term over two years, although data were also heterogeneous. We found chlorpromazine provided a global improvement in a person's symptoms and functioning (n=1164, 14 RCTs, RR 0.71 CI 0.58 to 0.86). Fewer people allocated to chlorpromazine left trials early ( n=1831, 27 RCTs, RR 0.64 CI 0.53 to 0.78) compared with placebo. There are many adverse effects. Chlorpromazine is clearly sedating (n=1627, 23 RCTs, RR 2.79 CI 2.25 to 3.45), it increases a person's chances of experiencing acute movement disorders (n=942, 5 RCTs, RR 3.47 CI 1.50 to 8.03) and parkinsonism (n=1468, 15 RCTs, RR 2.11 CI 1.59 to 2.80). Akathisia did not occur more often in the chlorpromazine group than placebo. Chlorpromazine clearly causes a lowering of blood pressure with accompanying dizziness (n=1488, 18 RCTs, RR 2.38 CI 1.74 to 3.25) and considerable weight gain (n=165, 5 RCTs, RR 4.92 CI 2.32 to 10.43).

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