Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update

Sriretnakumar, Venuja; Huang, Eric; Müller, Daniel J.

doi:10.1517/17425255.2015.1075003

Cited by 34 publications

(28 citation statements)

References 99 publications

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“…Several serotonergic receptor type 2A ( 5-HT2A ) gene polymorphisms have been associated with response to clozapine,34 although these associations have not been universally replicated 27,35. Studies have demonstrated an association between clozapine efficacy and genetic variants in the serotonin receptor type 2A ( 5-HT2A ),34 type 2C ( 5-HT2C ),36 and type 6 ( 5-HT6 )37 and serotonin transporter ( 5-HTT ) genes,36 although these findings have not been consistently replicated 26–28.…”

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 99%

“…Meta-analysis has confirmed the need for replication studies of much larger sample sizes to detect real associations 25,27. Most pharmacogenomic studies in clozapine use have focused on candidate genes coding for specific enzymes believed to be involved in the absorption, distribution, metabolism, and/or excretion of antipsychotic medications 27,28,89.…”

Section: Challenges In Applying Pharmacogenomics In Trs and Future DImentioning

confidence: 99%

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Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

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Up to 30% of people with schizophrenia do not respond to two (or more) trials of dopaminergic antipsychotics. They are said to have treatment-resistant schizophrenia (TRS). Clozapine is still the only effective treatment for TRS, although it is underused in clinical practice. Initial use is delayed, it can be hard for patients to tolerate, and clinicians can be uncertain as to when to use it. What if, at the start of treatment, we could identify those patients likely to respond to clozapine – and those likely to suffer adverse effects? It is likely that clinicians would feel less inhibited about using it, allowing clozapine to be used earlier and more appropriately. Genetic testing holds out the tantalizing possibility of being able to do just this, and hence the vital importance of pharmacogenomic studies. These can potentially identify genetic markers for both tolerance of and vulnerability to clozapine. We aim to summarize progress so far, possible clinical applications, limitations to the evidence, and problems in applying these findings to the management of TRS. Pharmacogenomic studies of clozapine response and tolerability have produced conflicting results. These are due, at least in part, to significant differences in the patient groups studied. The use of clinical pharmacogenomic testing – to personalize clozapine treatment and identify patients at high risk of treatment failure or of adverse events – has moved closer over the last 20 years. However, to develop such testing that could be used clinically will require larger, multicenter, prospective studies.

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Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 99%

Section: Challenges In Applying Pharmacogenomics In Trs and Future DImentioning

confidence: 99%

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

View full text Add to dashboard Cite

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“…To date, pharmacogenetic research has emphasized the major neurotransmitter systems involved in the pharmacodynamics and pharmacokinetics of antipsychotics. While issues with consistency exist in the findings [67][68][69][70], many of these associations could still be important. Several reasons may underlie the inconsistent results, such as different duration of clozapine treatment among the studies, different inclusion criteria for clozapine responders [23], and different ethnicities [71][72][73][74].…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Clozapine as a Model for Antipsychotic Development

Mihaljević²,

et al. 2017

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Schizophrenia is a devastating illness that affects up to 1% of the population; it is characterized by a combination of positive symptoms, negative symptoms, and cognitive impairment. Currently, treatment consists of one class of medications known as antipsychotics, which include typical (first-generation) and atypical (second-generation) agents. Unfortunately, antipsychotic medications have limited efficacy, with up to a third of patients lacking a full response. Clozapine, the first atypical antipsychotic developed, is the only medication shown to be superior to all other antipsychotics. However, owing to several life-threatening side effects and required enrollment in a registry with routine blood monitoring, clozapine is greatly underutilized in the US. Developing a medication as efficacious as clozapine with limited side effects would likely become the first-line therapy for schizophrenia and related disorders. In this review, we discuss the history of clozapine, landmark studies, and its clinical advantages and disadvantages. We further discuss the hypotheses for clozapine's superior efficacy based on neuroreceptor binding, and the limitations of a receptor-based approach to antipsychotic development. We highlight some of the advances from pharmacogenetic studies on clozapine and then focus on studies of clozapine using unbiased approaches such as pharmacogenomics and gene expression profiling. Finally, we examine how these approaches could provide insights into clozapine's mechanism of action and side-effect profile, and lead to novel and improved therapeutics.

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“…Paradoxically, GWAS of drug response, including adverse reactions to a drug, composes less than 10% of the total number of published GWAS reports and has achieved genome-wide significant association with less than 300 SNPs, averaging 2 or less per study [47,48] . Despite this limitation, these studies have still provided valuable information on the mechanisms underlying drug distribution, efficacy and toxicology [49][50][51] . For example, hepatic CYP2C19 enzyme, a CYP450 superfamily member, regulates the metabolism of many drugs, including antidepressants [52,53] , and their genetic variants were detected to have a significant effect on the choice of appropriate types and doses of clinical anticoagulants.…”

Section: Perspective On the Application Of Full Genetic Model Gwas Tomentioning

confidence: 99%

Full genetic analysis for genome-wide association study of Fangji: a powerful approach for effectively dissecting the molecular architecture of personalized traditional Chinese medicine

2018

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Elucidation of the systems biology foundation underlying the effect of Fangji, which are multi-herbal traditional Chinese medicine (TCM) formulas, is one of the major aims in the field. The numerous bioactive ingredients of a Fangji deal with the multiple targets of a complex disease, which is influenced by a number of genes and their interactions with the environment. Genome-wide association study (GWAS) is an unbiased approach for dissecting the genetic variants underlying complex diseases and individual response to a given treatment. GWAS has great potential for the study of systems biology from the point of view of genomics, but the capacity using current analysis models is largely handicapped, as evidenced by missing heritability. Recent development of a full genetic model, in which gene-gene interactions (dominance and epistasis) and gene-environment interactions are all considered, has addressed these problems. This approach has been demonstrated to substantially increase model power, remarkably improving the detection of association of GWAS and the construction of the molecular architecture. This analysis does not require a very large sample size, which is often difficult to meet for a GWAS of treatment response. Furthermore, this analysis can integrate other omic information and allow for variations of Fangji, which is very promising for Fangjiomic study and detection of the sophisticated molecular architecture of the function of Fangji, as well as for the delineation of the systems biology of personalized medicine in TCM in an unbiased and comprehensive manner.

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Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update

Cited by 34 publications

References 99 publications

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Clozapine as a Model for Antipsychotic Development

Full genetic analysis for genome-wide association study of Fangji: a powerful approach for effectively dissecting the molecular architecture of personalized traditional Chinese medicine

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