Key messages
• We do not know if people with non-responsive schizophrenia have better outcomes if they switch to a different antipsychotic medicine or continue with the same one because the evidence is very uncertain.
• The few studies which looked at this question differed markedly from each other in terms of the antipsychotics used, study duration and definitions of initial non-response.
• We need further large, well-conducted studies to shed light on this important topic.
What is schizophrenia?
Schizophrenia is a serious, long-term and disabling mental disorder. It affects how a person thinks, feels and behaves. About 1 in 100 people will experience schizophrenia at some point in their lives. Men and women are equally likely to develop the disorder over their lifetime, though men tend to be diagnosed earlier.
How is it treated?
Antipsychotic medication is the primary treatment for schizophrenia. Antipsychotics help manage the symptoms, including hallucinations, delusions, disorganised thinking and severe agitation, that people with schizophrenia experience.
However, many people with schizophrenia do not respond to their initial antipsychotic treatment (termed 'non-responsive' schizophrenia). In these situations, treatment options include: adding more antipsychotic medicines; adding other psychotropic agents (i.e. medicines for mental disorders other than antipsychotics, including mood stabilisers and antidepressants); increasing the dose of the initial medicine given, or switching to another antipsychotic drug. However, determining what is the best treatment remains unclear.
What did we want to find out?
This review examined whether switching to a different antipsychotic medicine, as opposed to continuing treatment with the same one, improved people's response rates, alleviated overall and specific symptoms of schizophrenia, and resulted in higher dropout rates or adverse effects (i.e. unwanted, harmful effects).
What did we do?
We searched for studies that examined switching antipsychotics compared to continuing the same antipsychotic in people with schizophrenia who did not respond to their initial treatment. We compared and summarised the study results and rated our confidence in the evidence, based on factors such as study methods and sample sizes.
What did we find?
We found only 10 studies that involved 997 people. Most of the studies were small; only three studies had more than 100 participants.
We found no differences between the two strategies (that is, between switching to a different antipsychotic versus continuing with the original antipsychotic) in our key outcomes, including response to the medicines, tolerability (measured as the number of people who left the studies early due to adverse effects), and quality of life. However, the evidence was very uncertain for most of our outcomes of interest.
What are the limitations of the evidence?
Our confidence in the evidence is limited, primarily due to the inclusion of only a small number of studies with few participants. Additionally, the studies varied widely in terms of the antipsychotics tested, the study designs and durations, and the definitions of non-response that the investigators used. Larger, well-designed studies are urgently needed to help healthcare professionals determine the best ways of treating people with non-responsive schizophrenia.
How current is this evidence?
The evidence is current to December 2022.
This review synthesises currently available RCT evidence on switching antipsychotics versus continuing the same antipsychotic in individuals with schizophrenia who did not respond to their initial treatment. Overall, the evidence remains highly uncertain regarding the effects of either strategy on efficacy and safety outcomes, and no definitive recommendations can currently be made. There is an urgent need for larger, well-designed trials to identify the optimal treatment strategy for these cases.
Many people with schizophrenia do not respond to an initially prescribed antipsychotic drug. In such cases, one treatment strategy could be to switch to a different antipsychotic drug.
To examine the effects of switching antipsychotic drugs in treating people with schizophrenia who have not responded to initial antipsychotic treatment.
We searched the Cochrane Schizophrenia Group Trials Register (to December 2022). We inspected the references of all included studies for further relevant trials.
We included all relevant randomised controlled trials (RCTs) comparing switching to a different antipsychotic drug rather than continuing treatment with the same antipsychotic drug for people with schizophrenia who did not respond to their initial antipsychotic treatment.
At least two review authors independently extracted data. The primary outcomes were: clinically relevant response as defined by study authors; tolerability (participants leaving the study early due to adverse effects); and quality of life assessed by the change score in the 36-Item Short Form survey. We analysed dichotomous data using the risk ratio (RR) and its 95% confidence interval (CI). We analysed continuous data using mean differences (MD) and corresponding 95% CI. We assessed the risk of bias of the included studies and used GRADE to evaluate the certainty of evidence for the following outcomes: clinically relevant response, tolerability (leaving the study early due to adverse effects), quality of life score change, acceptability (leaving the study early for any reason), general mental state (average change in general mental state scores), duration of hospitalisation, and number of participants experiencing at least one adverse effect.
We included 10 RCTs with 997 participants in the review. Nine studies used a parallel design, and one used a cross-over design. Seven studies were double-blind, two were single-blind and one did not provide any detail regarding blinding. All studies included people who were non-responsive to ongoing antipsychotic treatment. The minimum duration of the ongoing antipsychotic treatment ranged from three days to two years. The length of the comparison phase varied from two weeks to six months. The studies were published between 1993 and 2022. In about half of the studies, the methods of randomisation, allocation and blinding were poorly reported.
The evidence is very uncertain regarding the effect of switching antipsychotics on clinically relevant response (RR 1.25, 95% CI 0.77 to 2.03; I² = 43%; 7 studies, 693 participants), quality of life (MD -1.30, 95% CI -3.44 to 0.84; 1 study, 188 participants), Positive and Negative Syndrome Scale (PANSS) score change (MD -0.92, 95% CI -4.69 to 2.86; I² = 47%; 6 studies, 777 participants), duration of hospitalisation (in days) (MD 9.19, 95% CI -8.93 to 27.31; I² = 0%; 2 studies, 34 participants) and the number of people experiencing at least one adverse effect (RR 1.29, 95% CI 0.81 to 2.05; I² = 36%; 3 studies, 412 participants). Compared to continuing current treatment, switching antipsychotics may result in little to no difference in tolerability, defined as the number of participants leaving the study early due to adverse effects (RR 0.73, 95% CI 0.24 to 2.26; I² = 31%; 6 studies, 672 participants; low-certainty evidence) and leaving the study early for any reason (RR 0.91, 95% CI 0.71 to 1.17; I² = 0%; 6 studies, 672 participants; low-certainty evidence).