Question: In adults with treatment resistant schizophrenia (with or without mild learning disabilities), how effective are antipsychotic combinations, compared to any other intervention, in improving patient outcomes?


Plain language summary

Research evidence suggests that combining antipsychotic medications may have some benefit to those with treatment resistant schizophrenia; however this evidence available is weak with no clear indication as to which combinations are most effective. More rigorous controlled studies need to be carried out before any definite conclusions or recommendations can be made. No studies were identified looking at combination antipsychotics for patients with treatment resistant schizophrenia and a learning disability.

Clinical and research implications

No definite clinical implications may be made based on the evidence included in this BEST summary. There is weak evidence to suggest that various combined treatments may show some improved outcomes in patients with clozapine-resistant schizophrenia compared with placebo, but there is no strong evidence to suggest which combination strategies are superior to others. There is consensus among all of the included reviews/studies that more high quality randomised controlled trials, with adequate sample sizes, are needed before firms recommendations can be made about clozapine augmentation strategies.  One of the review authors also suggested that these trials should also measure global outcomes such as 'healthy days', 'social functioning', 'satisfaction with treatment', 'ability to live and work in the community', and compliance.

What do guidelines say?

The Scottish Intercollegiate Guidelines Network (SIGN) recommends that a trial of clozapine augmentation with a second SGA (Second Generation Antipsychotic) should be considered for service users whose symptoms have not responded adequately to clozapine alone, despite dose optimisation. Treatment should be continued for a minimum of ten weeks.

  "5.7.2 Clozapine augmentation with another antipsychotic: A systematic review identified six small RCTs (n=252) of clozapine augmentation. Trials were mainly short term with the longest being 12 weeks. Response was defined as a greater than 20% improvement in PANSS or BPRS scores. Augmentation of clozapine with an antipsychotic (aripiprazole, risperidone or sulpiride) improved symptoms particularly in those receiving treatment for longer than ten weeks. A meta-analysis of double blinded randomised controlled trials of clozapine augmentation identified 10 studies examining augmentation with antipsychotics. In a small study (n=28) of sulpiride augmentation there was a significant effect with respect to BPRS/PANNS (SMD 0.83, 95% CI 0.07 to 1.59). Meta-analysis of augmentation with other antipsychotics resulted in no statistically significant effects.112 These findings are in agreement with previous reviews, many of which encompassed less rigorous open label studies"


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To view the Cochrane review, click the link under Related Documents  below.

For related SIGN guidelines, follow the links below

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BEST Question 589.pdf