Abstract
Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [g = 0.31; 95% confidence interval (CI) 0.06-0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted.
Highlights
One-third of patients with schizophrenia display suboptimal response to two trials of non-clozapine antipsychotic medication and are termed treatment resistant (Elkis, 2007; Howes et al, 2017)
This is pertinent given evidence that (1) the majority of treatment-resistant patients have a suboptimal response to antipsychotic medication from illness onset (Lally et al, 2016); (2) when patients fail to reach remission after a first antipsychotic trial, switching to a second non-clozapine antipsychotic does not increase the likelihood of remission (Kahn et al, 2018) and (3) duration of inadequate treatment, and thereby active symptoms, is associated with poorer long-term outcomes (Marshall et al, 2005)
A PubMed search restricted to titles and abstracts was conducted on 20 March 2020 using search terms ‘schizophrenia’ or ‘treatment-resistant schizophrenia’ or ‘treatment-refractory schizophrenia’ and ‘clozapine’ and ‘response’ or ‘outcome’, with filters set to English language studies on human participants
Summary
One-third of patients with schizophrenia display suboptimal response to two trials of non-clozapine antipsychotic medication and are termed treatment resistant (Elkis, 2007; Howes et al, 2017). Understanding the factors associated with variability in clozapine response could help to optimise clinical treatment algorithms This is pertinent given evidence that (1) the majority of treatment-resistant patients have a suboptimal response to antipsychotic medication from illness onset (Lally et al, 2016); (2) when patients fail to reach remission after a first antipsychotic trial, switching to a second non-clozapine antipsychotic does not increase the likelihood of remission (Kahn et al, 2018) and (3) duration of inadequate treatment, and thereby active symptoms, is associated with poorer long-term outcomes (Marshall et al, 2005)
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