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Factors associated with response to clozapine in schizophrenia: a review.

ABSTRACT: Clozapine has been serving as the gold standard medication for patients with treatment-resistant schizophrenia who failed to respond to other antipsychotics. However, factors affecting response to this medication have not been comprehensively reviewed recently.In order to find factors associated with response to clozapine in schizophrenia, a literature search was conducted using PubMed through January 2011 with keywords of clozapine, response, and schizophrenia. Cross-referencing of relevant articles was also performed. Factors were arbitrarily classified into the following: demographic/clinical, oral dosage/pharmacokinetic, biochemical, (electro)physiological, genetic, imaging, and combinations.A synthesis from 280 articles indicated that demographic and clinical variables such as high baseline symptoms and low premorbid functioning have not been particularly useful in predicting response to clozapine. Pharmacokinetic evidence points to a threshold clozapine level of 350 ng/ml but in a context of significant inter- as well as intra-individual variability. Pharmacokinetic perspectives appear to have more implication in special situations including poor response, suspected toxicity and nonadherence. A number of laboratory-based studies have reported on many potential candidates for response prediction to clozapine, however, reproducibility, specificity, robustness of the findings, as well as clinical feasibility and cost-effectiveness all pose a significant practical challenge, in relation with the fact that pathophysiological bases of treatment resistance in schizophrenia largely remain to be elucidated.No unequivocal factors to clozapine response were found despite a relatively rich body of the literature, which calls for more works on this important topic. Clozapine level of 350 ng/ml appears to be useful in case of nonresponse.

SUBMITTER: Suzuki T

PROVIDER: S-EPMC5044555 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Factors associated with response to clozapine in schizophrenia: a review.

Suzuki Takefumi T Uchida Hiroyuki H Watanabe Koichiro K Kashima Haruo H

Psychopharmacology bulletin 20110101 1

<h4>Background</h4>Clozapine has been serving as the gold standard medication for patients with treatment-resistant schizophrenia who failed to respond to other antipsychotics. However, factors affecting response to this medication have not been comprehensively reviewed recently.<h4>Methods</h4>In order to find factors associated with response to clozapine in schizophrenia, a literature search was conducted using PubMed through January 2011 with keywords of clozapine, response, and schizophrenia ...[more]

PMID: 22506438

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Project description:Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.

Project description:Abstract Background: Schizophrenia is a lifelong debilitating mental illness often characterized by hallucinations, delusions, and disorganized thought and behavior. Currently, antipsychotic medications serve as the best treatment option for schizophrenia, but clinical responses to antipsychotic medications are highly variable. Therefore, the demand for reliable biological predictors is high. A glutamate and N-methyl-d-asparate (NMDA) receptor hypofunction model based on pharmacologic and genetic studies have been suggested as an approach to study the pharmacogenetics of antipsychotic medications. Previous studies have shown clozapine (CLZ) displaces NMDAR antagonists and enhances NMDAR mediated neurotransmission. Previously, our group (Taylor et al, 2016) investigated 8 SNPs in the NMDAR subunit gene GRIN2B with response to CLZ and one marker (rs1072388) was nominally significant. Taylor et al (in press) more recently found the glycine transporter 1 gene (SLC6A9, rs16831558) exhibited an allele dose-dependent improvement in the positive symptoms of CC-homozygotes compared to T-allele carriers (Puncorrected = .008, Pcorrected = .08). In our current study, we examined the GRIN2A receptor gene that was genome-wide significant in the GWAS of schizophrenia by Ripke et al (2014). A SNP marker from GRIN2A (rs992266789) and one from the glutamate receptor ionotropic delta 2 (GRID2, rs1875705) were selected for our association study of CLZ treatment response. Methods: We investigated rs9922678 and rs1875705 in relation to CLZ treatment response in a prospective study consisting of 170 Caucasian patients treated with CLZ for 6 months. Treatment response was evaluated using the 18-item Brief Psychiatric Rating Scale (BPRS), using either responder vs nonresponder status or continuous change scores. Baseline score was included as a covariate. All statistical analyses were performed using IBM SPSS. Results: No significant association was observed for rs9922678 and rs1875705 with BPRS total score and responder vs nonresponder status under genotypic, allelic, and additive models. Conclusion: Although no significant results were obtained from our current study, there is still strong neurobiological evidence suggesting involvement of the glutamate system in CLZ action. Additional glutamate system genes and multiple markers should be investigated. Further studies with greater sample size are required before firm conclusions can be drawn. In addition, it would be helpful to investigate other phenotypes such as cognition and tardive dyskinesia because glutamate neurotransmission also plays a role in these areas.

Dataset Information

Factors associated with response to clozapine in schizophrenia: a review.

Publications

Factors associated with response to clozapine in schizophrenia: a review.

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