Pharmacogenetics in schizophrenia: a review of clozapine studies

Kohlrausch, Fabiana B.

doi:10.1590/1516-4446-2012-0970

Cited by 24 publications

(27 citation statements)

References 161 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The direction of this association was further shown in a meta-analysis, although it was not found to be statistically significant 30. Genetic variants of the dopamine receptors type 2 and type 1 and dopamine transporter haplotypes have also been found to be associated with clozapine efficacy 26,33. Overall, these findings suggest that the dopaminergic system plays some part in mediating clozapine response.…”

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 88%

“…Overall, these findings suggest that the dopaminergic system plays some part in mediating clozapine response. However, a recent meta-analysis25 did not identify the previously reported association between dopamine genes DRD2 rs1799732 and DRD3 rs6280 and clozapine response 26,28. This study25 applied a stricter inclusion criteria than the previous meta-analysis,26 only including studies where clozapine was investigated alone (rather than with other antipsychotics).…”

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 96%

“…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. The most recent meta-analysis identified three genetic variants within serotonin genes associated with the response to clozapine: rs6313 and rs6314 within the 5-HTR2A gene and rs1062613 within the 5-HT3A gene 25…”

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 99%

See 2 more Smart Citations

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

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

View full text Add to dashboard Cite

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.

show abstract

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 88%

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 96%

Section: Pharmacogenomics and Clozapine Responsementioning

confidence: 99%

See 1 more Smart Citation

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

Lally¹,

Gaughran²,

Timms³

et al. 2016

PGPM

View full text Add to dashboard Cite

show abstract

“…The implications of a genetic test incorporating such variants would have far-reaching clinical applications; given the fact that early and effective treatment has been associated with favorable outcome [20,21]. To date, the majority of pharmacogenetic studies investigating CLZ response have focused on gene variants in dopamine and serotonin neurotransmitter pathways [reviewed in [22]].…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine

Taylor¹,

Tiwari²,

Lieberman

et al. 2016

Complex Psychiatry

View full text Add to dashboard Cite

Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. GRM2 (rs4067 and rs2518461), SLC1A2 (rs4354668, rs4534557, and rs2901534), SLC6A9 (rs12037805, rs1978195, and rs16831558), GRIA1 (rs2195450), and GAD1 (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy. Response was assessed following 6 months of CLZ monotherapy using change in Brief Psychiatric Rating Scale (BPRS) scores. Categorical and continuous response variables were analyzed using χ² tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed for SLC6A9, SLC1A2, GRM2, and GRIA1. Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene (SLC6A9) exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (p_uncorrected = 0.008, p_corrected = 0.08). To clarify the role of SLC6A9 in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.

show abstract

“…1,2 The main genes investigated are those that encode drug-metabolism enzymes 3 ; study of the expression of P-glycoprotein (P-gp), which contributes to the multidrug resistance phenotype, is a clear example (for a review, see Lopes-Rodrigues et al 4 ). P-gp is a transmembrane drug transporter encoded by the multidrug resistance 1 (MDR1) gene; it acts as an efflux pump that works in an adenosine triphosphate (ATP)-dependent fashion.…”

Section: Introductionmentioning

confidence: 99%

Association study between the MDR1 gene and clinical characteristics in schizophrenia

Tovilla-Zárate¹,

Vargas

Hernández

et al. 2014

Rev. Bras. Psiquiatr.

View full text Add to dashboard Cite

Objective: Schizophrenia is a complex psychiatric disorder, characterized by disturbed patterns of thought and affecting 0.3-2.0% of the world population. Previously, the multidrug resistance 1 (MDR1) gene has been associated with schizophrenia in treatment response studies in psychotic patients. The aim of this study was to determine the association between MDR1 gene polymorphisms and clinical characteristics in patients with schizophrenia. Methods: Positive and negative symptoms of schizophrenia were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in 158 Mexican patients with schizophrenia. Analyses of MDR1 gene polymorphisms were performed using TaqMan technology. A multivariate ANOVA was performed with MDR1 polymorphisms and gender as independent variables. Results: Males with the G/G genotype of MDR1 rs2032582 presented significantly higher levels of delusions (p = 0.02). When comparing female vs. male groups, the difference was statistically significant (p = 0.0003). Analyses of the MDR1 gene rs1045642 variant showed no significant differences. Conclusion: Our findings suggest that male carriers of the G allele of variant rs2032582 exhibit greater severity of delusions; however, these results should be taken as preliminary, and replication studies in other populations of different ethnic origins are required to confirm these findings.

show abstract

Pharmacogenetics in schizophrenia: a review of clozapine studies

Cited by 24 publications

References 161 publications

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

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

Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine

Association study between the MDR1 gene and clinical characteristics in schizophrenia

Contact Info

Product

Resources

About