Optimising Drug Treatment for Psychosis: Using What We’ve got Better – Role of Clozapine

Posted on:March 29, 2020

Last Updated: November 22, 2021

Time to read: 4 minutes

This article is based on the talk by Prof Oliver Howes at RCPsychIC 2019. Prof Howes is Group Head and Professor of Molecular Psychiatry. His clinical work is as Consultant Psychiatrist at The Institute of Psychiatry/ Maudsley Hospital.

Many literature sources state prevalence of around one-third of patients with schizophrenia are treatment-resistant. However, in general, clinical practice, this increases to over 50% of patients in the general community team, and of these, around half have never received clozapine.
A network meta-analysis of antipsychotics in treatment-resistance schizophrenia concluded that clozapine was not superior to other second-generation antipsychotics, which suggested that no single drug was superior [Samara et al. 2016]. However, caution is advised in interpreting network meta-analyses where indirect comparisons are used to provide a measure of how one drug compares with another.
The concept of treatment resistance needs to be better defined for clinical trials and better understood for accurate reporting of comparator studies. A new meta-analysis that focuses specifically on studies that fall within a proposed concept of treatment resistance regarding diagnosis, treatment, and response, reveals clozapine to be superior to other antipsychotics. [Mizuno et al, 2019]

Clozapine was superior to other antipsychotics in improving total symptoms in both TRS (g = 0.34; 95%CI, 0.13–0.56) and non-TRS (g = 0.20; 95%CI, 0.08–0.32) studies. Furthermore, clozapine was superior in improving positive symptoms in both study groups, but not for negative symptoms. These findings do not support a subtype of schizophrenia which respond specifically to clozapine. Clozapine is more effective than other antipsychotics irrespective of treatment-resistance, arguing for its use more generally in schizophrenia.

An important point to highlight is that the NICE guidelines for schizophrenia do not seem to have translated into clinical practice. Previous studies show a mean delay of 5 years before patients were started on clozapine [Taylor et al. 2003]. During this time, patients underwent several different treatments of antipsychotics and polypharmacy. A more recent study revealed not much has changed in the ten years since the NICE guidelines for schizophrenia.[Howes et al. 2012]
There is a question on whether a delay in starting clozapine matters. A naturalistic study confirms a high response rate (75%) to initial antipsychotic treatment in first-episode schizophrenia, but a much-reduced rate of <20% occurs with a second antipsychotic [Agid et al. 2011]. On switching to clozapine, response rates returned to 75%. These results support the idea that patients have a low chance of responding to a second antipsychotic after failure to respond to the first, and that clozapine should be started earlier.
The critical treatment window of clozapine in treatment-resistant schizophrenia is reported to be less than three years, while delay beyond three years is a predictor of poorer outcome.[Yoshimura et al. 2017]
Clozapine is also associated with around 50% lower mortality rate than other antipsychotics in patients with schizophrenia.[Vermeulen et al. 2019]
A nationwide register-based cohort study of 62,250 patients showed the cumulative mortality rates during maximum follow‐up of 20 years were 46.2% for no antipsychotic use, 25.7% for any antipsychotic use, and 15.6% for clozapine use. [Taipale H et al., 2020]
Even in patients where clozapine is discontinued for undefined reasons, clozapine (besides olanzapine) is the most effective and safest option. [Luykx J et al., 2020]
Challenges associated with starting clozapine in patients include a lack of resources and familiarity for the community team, but also patient refusal. The TREAT approach is a community team that provides assessment and support in treatment resistance. Starting patients on clozapine not only improves their outcome and reduces mortality, but it also reduces their resource use on the health service with fewer nurse visits and out-patient appointments needed.