Schizophrenia is a serious mental illness which, for some people can become a long term problem. The usual first line treatment for schizophrenia is antipsychotic medication. However, because of the adverse effects these drugs can have, over time those taking them try to find a dose where they are gaining the most therapeutic benefit for the least amount of medication and doctors will often support them to do this. Conversely, for those whose illness does not respond well to medication, high doses are often used. This can cause severe adverse effects and can set up a cycle where individuals gain some benefit from the medication, develop side effects, then stop taking it and relapse. Therefore it would be helpful to find the optimum dose of each antipsychotic for different groups of people.
This review compares different doses of the antipsychotic risperidone, a drug introduced in the early 1990s and widely prescribed. Eleven trials were found comparing data for 2498 people. They were all under 12 weeks in length. Some looked at people in the first episode of schizophrenia or in an acute relapse, while others looked at those with a chronic long-term illness. For the purposes of this review doses of risperidone were divided into the following daily doses, ultra-low (less than 2mg), low (2mg - just less than 4mg), standard lower (4mg - just less than 6mg), standard higher (6mg - just less than 10mg) and high (10mg or more).
In the low and ultra low groups, there were a significant number of people leaving the study because of insufficient response, while those in the high dose group were more likely to leave the study for ‘any reason’ or ‘adverse event’. There were no significant differences between the standard lower and standard higher groups in improvement in general, or mental state, but both of these were better than an ultra low dose and gave less adverse effects than a high dose. There was some evidence to show that those in their first episode also respond well to a low dose. There were no good data on service use or quality of life. If further trials are conducted comparing different doses of risperidone, they should concentrate on specific groups of people, for example those in first episode or those with a chronic illness living in the community.
(Plain language summary prepared for this review by Janey Antoniou of RETHINK, UK www.rethink.org
There is still lack of strong evidence for an optimal dose for clinical practice. The quality of trials suggests that an over estimate of effect is likely and we think this is most probably for the mid-range doses. One such dose (standard-lower dose range, 4-<6 mg/day) does seem optimal for clinical response and adverse effects. Weak evidence suggests that low doses (≧2-<4 mg/day) may be of value for people in their first episode of illness. High doses (≧10 mg/day) did not confer any advantage over any other dose ranges and caused more adverse effects, especially for movement disorders. Ultra low dose (<2 mg/day) seemed useless. We advise the use of dosages from low dose to standard-lower dose for different kinds of individual patients. Future trials should focus on specific populations, e.g. those in their first episode, with acute exacerbation, in relapse or refractory to treatment, and should also test the optimal dose of risperidone over a longer period of time and in the community.
Risperidone is a widely used antipsychotic drug for people with schizophrenia. It is important to get a balance between gaining the most positive effects for the least negative outcomes. The optimal dose of risperidone is the focus of this review.
To determine risperidone dose response relationships for schizophrenia and schizophrenia-like psychoses.
We searched the Cochrane Schizophrenia Groups Trials Register (July 2008) for all relevant references.
All relevant randomised controlled clinical trials (RCTs).
Two review authors independently extracted data and resolved disagreement by discussion with a third member of the team. When insufficient data were provided, we contacted the study authors. For homogenous dichotomous data we calculated fixed-effect relative risk (RR) and 95% confidence intervals (CI) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (MD).
A consistent finding when risperidone ultra low doses (<2 mg/day) were compared with other doses (short-term data) was that more people left early because of insufficient response (n=456, 1 RCT, RR when compared with standard-low (≧4-<6 mg/day) 12.48 CI 1.43 to 4.30). The insufficient response for this low dose is reflected in measures of mental state. When low doses (≧2-<4 mg/day) are used and compared with standard-higher doses (≧6-<10 mg/day) and the high dose range (≧10 mg/day), more people left early because of insufficient response (≧4-<6 mg/day: n=173, 2 RCTs, RR 4.05 CI 1.09 to 15.07; ≧10 mg/day: n=173, 2 RCTs, RR 1.92 CI 1.36 to 2.70). For the outcome of 'no clinically important improvement' results favour standard-higher doses (n=272, 2 RCTs, RR 2.26 CI 0.81 to 6.34). When low doses are compared with other higher doses, we found no differences in terms of cardiovascular, CNS, endocrine or gastrointestinal adverse effects. Unspecified EPS were more frequent with the higher doses (≧10 mg: n=262, 2 RCTs, RR 0.45 CI 0.24 to 0.84). One trial did find that endpoint scores on PANSS significantly favoured a low dose when compared with ≧4-6 mg/day (n=124, 1 RCT, MD -12.40 CI -17.01 to -7.79). When ≧4-<6 mg/day is compared with high doses, less people left early (n=677, 1 RCT, RR leaving any reason 0.74 CI 0.54 to 1.00; n=677, 1 RCT, RR due to adverse effects 0.56 CI 0.32 to 0.97). ≧4-<6 mg/day was no worse than ≧6-<10 mg/day for 'no clinically important improvement' (n=39, 1 RCT, RR on CGI-I 0.79 CI 0.29 to 2.17). People allocated ≧4-<6 mg/day had more movement disorders than those on a low dose (n=124 1 RCT, RR 2.28 CI 1.67 to 3.11). When ≧6-<10 mg/day is compared with standard-lower doses and a high dose range, there is no significant difference in terms of proportions leaving early. ≧6-<10 mg/day is better than a low dose for 'no clinical important improvement' (n=172, 2 RCTs, RR 0.76 CI 0.61 to 0.94). Overall ≧6-<10 mg/day caused less problems especially in EPS when compared with ≧10mg/day (n=261, 2 RCTs, RR unspecified EPS 0.56 CI 0.31 to 0.99). When a high dose was compared with a low dose less people left early (n=70, 1 RCT, RR 0.43 CI 0.26 to 0.71) but not when compared with a standard-lower dose (n=677, 1 RCT, RR leaving due to adverse event 1.78 CI 1.03 to 3.09). ≧10 mg/day was better than a low dose in terms of 'no clinical important improvement' (n=257, 2 RCTs, RR 0.64 CI 0.50 to 0.82), but worse than a standard-higher dose (≧6-<10 mg/day: n=255, 2 RCTs, RR 1.22 CI 1.00 to 1.51). ≧10 mg/day caused more unspecified EPS adverse effects and any drug for adverse events when compared with a standard-higher dose and with a low dose.