Key messages
Reducing the dose of antipsychotics may be associated with a higher number of study participants relapsing and leaving the study early.
Very little information was available on quality of life, functioning, and side effects.
Introduction to the review topic
Schizophrenia is a severe disease that needs treatment with medication (antipsychotics). Use of antipsychotics is connected with side effects, and it appears that these side effects may be worse with higher doses. On the other hand, the dose needs to be high enough to have an effect on the symptoms.
What did we want to find out?
We wanted to know if reducing the dose of antipsychotics is better than keeping the same dose, in order to improve:
- quality of life;
- number of participants readmitted to hospital;
- number of participants leaving the study early because of side effects;
- functioning;
- relapse;
- number of participants leaving the study early for any reason;
- number of participants with at least one side effect.
What did we do?
We searched for studies that examined reducing the dose of antipsychotics compared with keeping the same dose in people with schizophrenia.
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 25 studies involving a total of 2721 participants with schizophrenia. Twenty-two studies (2635 participants) provided data for the analyses. The studies lasted between 12 weeks and 2 years. They were conducted all over the world, including in the USA, the UK, Europe, and Asia. Fourteen studies were sponsored by public institutions, five by pharmaceutical companies, two by public institutions and pharmaceutical companies jointly, and four studies did not provide clear information on funding.
We found that dose reduction:
- probably has little to no effect on quality of life;
- makes no difference in readmission to hospital, but we are very uncertain about the results;
- probably increases the number of participants leaving the study early due to side effects;
- has little to no effect on functioning;
- may increase the number of participants with a relapse;
- probably increases the number of participants leaving the study early for any reason;
- probably has little to no effect on the number of participants with at least one side effect.
What are the limitations of the evidence?
We are mainly confident or moderately confident in our results.
Regarding readmission to hospital, we are not confident in the evidence because it is possible that study participants were aware of which treatment they were getting. Moreover, the studies were done in different types of people or used different ways of reducing the dose.
Regarding relapse, we have little confidence in the evidence because it is possible that study participants were aware of which treatment they were getting. Moreover, the studies were done in different types of people or used different ways of reducing the dose.
How up-to-date is the evidence?
The evidence is current to February 2021.
This review synthesised the latest evidence on the reduction of antipsychotic doses for stable individuals with schizophrenia. There was no difference between dose reduction and continuation groups in quality of life, functioning, and number of participants with at least one adverse effect. However, there was a higher risk for relapse and dropouts, and potentially for rehospitalisations, with dose reduction. Of note, the majority of the trials focused on relapse prevention rather potential beneficial outcomes on quality of life, functioning, and adverse effects, and in some studies there was rapid and substantial reduction of doses. Further well-designed RCTs are therefore needed to provide more definitive answers.
Antipsychotic drugs are the mainstay treatment for schizophrenia, yet they are associated with diverse and potentially dose-related side effects which can reduce quality of life. For this reason, the lowest possible doses of antipsychotics are generally recommended, but higher doses are often used in clinical practice. It is still unclear if and how antipsychotic doses could be reduced safely in order to minimise the adverse-effect burden without increasing the risk of relapse.
To assess the efficacy and safety of reducing antipsychotic dose compared to continuing the current dose for people with schizophrenia.
We conducted a systematic search on 10 February 2021 at the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, ISRCTN, and WHO ICTRP. We also inspected the reference lists of included studies and previous reviews.
We included randomised controlled trials (RCTs) comparing any dose reduction against continuation in people with schizophrenia or related disorders who were stabilised on their current antipsychotic treatment.
At least two review authors independently screened relevant records for inclusion, extracted data from eligible studies, and assessed the risk of bias using RoB 2. We contacted study authors for missing data and additional information. Our primary outcomes were clinically important change in quality of life, rehospitalisations and dropouts due to adverse effects; key secondary outcomes were clinically important change in functioning, relapse, dropouts for any reason, and at least one adverse effect. We also examined scales measuring symptoms, quality of life, and functioning as well as a comprehensive list of specific adverse effects. We pooled outcomes at the endpoint preferably closest to one year. We evaluated the certainty of the evidence using the GRADE approach.
We included 25 RCTs, of which 22 studies provided data with 2635 participants (average age 38.4 years old). The median study sample size was 60 participants (ranging from 18 to 466 participants) and length was 37 weeks (ranging from 12 weeks to 2 years). There were variations in the dose reduction strategies in terms of speed of reduction (i.e. gradual in about half of the studies (within 2 to 16 weeks) and abrupt in the other half), and in terms of degree of reduction (i.e. median planned reduction of 66% of the dose up to complete withdrawal in three studies). We assessed risk of bias across outcomes predominantly as some concerns or high risk.
No study reported data on the number of participants with a clinically important change in quality of life or functioning, and only eight studies reported continuous data on scales measuring quality of life or functioning. There was no difference between dose reduction and continuation on scales measuring quality of life (standardised mean difference (SMD) −0.01, 95% confidence interval (CI) −0.17 to 0.15, 6 RCTs, n = 719, I2 = 0%, moderate certainty evidence) and scales measuring functioning (SMD 0.03, 95% CI −0.10 to 0.17, 6 RCTs, n = 966, I2 = 0%, high certainty evidence).
Dose reduction in comparison to continuation may increase the risk of rehospitalisation based on data from eight studies with estimable effect sizes; however, the 95% CI does not exclude the possibility of no difference (risk ratio (RR) 1.53, 95% CI 0.84 to 2.81, 8 RCTs, n = 1413, I2 = 59% (moderate heterogeneity), very low certainty evidence). Similarly, dose reduction increased the risk of relapse based on data from 20 studies (RR 2.16, 95% CI 1.52 to 3.06, 20 RCTs, n = 2481, I2 = 70% (substantial heterogeneity), low certainty evidence).
More participants in the dose reduction group in comparison to the continuation group left the study early due to adverse effects (RR 2.20, 95% CI 1.39 to 3.49, 6 RCTs with estimable effect sizes, n = 1079, I2 = 0%, moderate certainty evidence) and for any reason (RR 1.38, 95% CI 1.05 to 1.81, 12 RCTs, n = 1551, I2 = 48% (moderate heterogeneity), moderate certainty evidence).
Lastly, there was no difference between the dose reduction and continuation groups in the number of participants with at least one adverse effect based on data from four studies with estimable effect sizes (RR 1.03, 95% CI 0.94 to 1.12, 5 RCTs, n = 998 (4 RCTs, n = 980 with estimable effect sizes), I2 = 0%, moderate certainty evidence).