Abstract
Background: Clozapine is the recommended antipsychotic for treatment-resistant schizophrenia (TRS) but there is significant variability between patients in the degree to which clozapine will improve symptoms. The biological basis of this variability is unknown. Although clozapine has efficacy in TRS, it can elicit adverse effects and initiation is often delayed. Identification of predictive biomarkers of clozapine response may aid initiation of clozapine treatment, as well as understanding of its mechanism of action. In this article we systematically review prospective or genetic studies of biological predictors of response to clozapine.Methods: We searched the PubMed database until 20th January 2018 for studies investigating “clozapine” AND (“response” OR “outcome”) AND “schizophrenia.” Inclusion required that studies examined a biological variable in relation to symptomatic response to clozapine. For all studies except genetic-studies, inclusion required that biological variables were measured before clozapine initiation.Results: Ninety-eight studies met the eligibility criteria and were included in the review, including neuroimaging, blood-based, cerebrospinal fluid (CSF)-based, and genetic predictors. The majority (70) are genetic studies, collectively investigating 379 different gene variants, however only three genetic variants (DRD3 Ser9Gly, HTR2A His452Tyr, and C825T GNB3) have independently replicated significant findings. Of the non-genetic variables, the most consistent predictors of a good response to clozapine are higher prefrontal cortical structural integrity and activity, and a lower ratio of the dopamine and serotonin metabolites, homovanillic acid (HVA): 5-hydroxyindoleacetic acid (5-HIAA) in CSF.Conclusions: Recommendations include that future studies should ensure adequate clozapine trial length and clozapine plasma concentrations, and may include multivariate models to increase predictive accuracy.
Highlights
One third of patients with schizophrenia do not respond to standard antipsychotic treatment and are classified as having treatment resistant schizophrenia (TRS) (1)
If tests could be developed to help clinicians predict in advance whether or not a given patient is likely to respond to clozapine, this could substantially reduce the delay before clozapine initiation, and clozapine could be selectively employed in the subset of patients in whom it is likely to be effective
The search was performed in the PubMed database on 20th January 2018 using the keywords “clozapine” AND (“response” OR “outcome”) AND “schizophrenia.” The search was limited to the titles and abstracts of the papers, with additional filters set to human studies and English language
Summary
One third of patients with schizophrenia do not respond to standard antipsychotic treatment and are classified as having treatment resistant schizophrenia (TRS) (1). Clozapine has efficacy in reducing symptoms in patients who have not responded to other antipsychotics (2–4), but carries risk of serious side effects and requires regular blood monitoring. Clozapine will still fail to improve symptoms in 40 to 70% of TRS patients (2, 5), and currently this can only be determined through a trial of clozapine treatment. For these reasons patients and clinicians are often reluctant to initiate clozapine treatment. Clozapine is the recommended antipsychotic for treatment-resistant schizophrenia (TRS) but there is significant variability between patients in the degree to which clozapine will improve symptoms. In this article we systematically review prospective or genetic studies of biological predictors of response to clozapine
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