Differential response to risperidone in schizophrenia patients by KCNH2Genotype and drug metabolizer status

Juliane Heide, Fengyu Zhang, Kristin Bigos, Stefan A. Mann, Vaughan J. Carr, Cynthia Shannon Weickert, Melissa J. Green, Daniel Weinberger, Jamie I. Vandenberg

Research output: Contribution to journalArticle

Abstract

Objective: Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channelsencoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effectsmaybeinfluencedby differential drug binding to Kv11.1 channel isoforms. Method: Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Results: Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and other atypical antipsychotics have similar potencies for the two isoforms. In the CATIE study (N=362), patients with genotypes associated with increased Kv11.1-3.1 expression (N=52) showed a better treatment response to risperidone compared with other drugs, but this association was dependent on metabolism status. Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7% of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes. Conclusions: These data support the hypothesis that Kv11.1 channels play a role in the therapeutic action of antipsychotic drugs, particularly risperidone, and further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients.

Original languageEnglish (US)
Pages (from-to)53-59
Number of pages7
JournalAmerican Journal of Psychiatry
Volume173
Issue number1
DOIs
StatePublished - Jan 1 2016

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Risperidone
Schizophrenia
Antipsychotic Agents
Protein Isoforms
Genotype
Pharmaceutical Preparations
Clinical Trials
Serotonin Receptors
Electrophysiology
Dopamine Receptors
Potassium
Therapeutics
Genes

ASJC Scopus subject areas

  • Psychiatry and Mental health

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Differential response to risperidone in schizophrenia patients by KCNH2Genotype and drug metabolizer status. / Heide, Juliane; Zhang, Fengyu; Bigos, Kristin; Mann, Stefan A.; Carr, Vaughan J.; Weickert, Cynthia Shannon; Green, Melissa J.; Weinberger, Daniel; Vandenberg, Jamie I.

In: American Journal of Psychiatry, Vol. 173, No. 1, 01.01.2016, p. 53-59.

Research output: Contribution to journalArticle

Heide, Juliane ; Zhang, Fengyu ; Bigos, Kristin ; Mann, Stefan A. ; Carr, Vaughan J. ; Weickert, Cynthia Shannon ; Green, Melissa J. ; Weinberger, Daniel ; Vandenberg, Jamie I. / Differential response to risperidone in schizophrenia patients by KCNH2Genotype and drug metabolizer status. In: American Journal of Psychiatry. 2016 ; Vol. 173, No. 1. pp. 53-59.
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abstract = "Objective: Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channelsencoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effectsmaybeinfluencedby differential drug binding to Kv11.1 channel isoforms. Method: Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Results: Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and other atypical antipsychotics have similar potencies for the two isoforms. In the CATIE study (N=362), patients with genotypes associated with increased Kv11.1-3.1 expression (N=52) showed a better treatment response to risperidone compared with other drugs, but this association was dependent on metabolism status. Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7{\%} of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes. Conclusions: These data support the hypothesis that Kv11.1 channels play a role in the therapeutic action of antipsychotic drugs, particularly risperidone, and further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients.",
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AU - Heide, Juliane

AU - Zhang, Fengyu

AU - Bigos, Kristin

AU - Mann, Stefan A.

AU - Carr, Vaughan J.

AU - Weickert, Cynthia Shannon

AU - Green, Melissa J.

AU - Weinberger, Daniel

AU - Vandenberg, Jamie I.

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AB - Objective: Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channelsencoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effectsmaybeinfluencedby differential drug binding to Kv11.1 channel isoforms. Method: Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Results: Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and other atypical antipsychotics have similar potencies for the two isoforms. In the CATIE study (N=362), patients with genotypes associated with increased Kv11.1-3.1 expression (N=52) showed a better treatment response to risperidone compared with other drugs, but this association was dependent on metabolism status. Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7% of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes. Conclusions: These data support the hypothesis that Kv11.1 channels play a role in the therapeutic action of antipsychotic drugs, particularly risperidone, and further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients.

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