Differential Response to Risperidone in Schizophrenia Patients by KCNH2 Genotype and Drug Metabolizer Status.
OBJECTIVE
Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channels encoded 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 effects may be influenced by differential drug binding to Kv11.1 channel isoforms.


METHODS
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.
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Juliane
J
Heide
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Fengyu
F
Zhang
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Kristin L
KL
Bigos
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Stefan A
SA
Mann
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Vaughan J
VJ
Carr
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Cynthia
C
Shannon Weickert
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Melissa J
MJ
Green
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Daniel R
DR
Weinberger
From the Victor Chang Cardiac Research Institute, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst; the Schizophrenia Research Institute, Darlinghurst; the Lieber Institute for Brain Development, Baltimore; the Department of Psychiatry and Behavioral Sciences, the Department of Neurology, the Department of Neuroscience, the Institute of Genetic Medicine, and the Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore; the School of Psychiatry, University of New South Wales, Randwick; the Research Unit for Schizophrenia Epidemiology, University of New South Wales, Darlinghurst; and Neuroscience Research Australia, Randwick.
Jamie I
JI
Vandenberg
D000328:Adult; D017398:Alternative Splicing; D014150:Antipsychotic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020033:Protein Isoforms; D018967:Risperidone / Q000378:metabolism / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D020033:Protein Isoforms; D018967:Risperidone