Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia

José A. Apud, Fengyu Zhang, Heather Decot, Kristin Bigos, Daniel Weinberger

Research output: Contribution to journalArticle

Abstract

Objective: Antidopaminergic drugs bind to hERG1 potassium channels encoded by the gene KCNH2, which accounts for the side effect of QT interval prolongation. KCNH2 has also been associated with schizophrenia risk, and risk alleles predict increased expression of a brain-selective isoform, KCNH2 3.1, that has unique physiological properties. The authors assessed whether genetic variation associated with KCNH2 3.1 expression influences the therapeutic effects of antipsychotic drugs. Method: The authors performed a pharmacogenetic analysis of antipsychotic treatment response in patients with schizophrenia using data from two independent studies: a National Institute of Mental Health (NIMH) double-blind, placebo-controlled inpatient crossover trial (N=54) and the multicenter outpatient Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study (N=364). The KCNH2 genotype that was previously associated with increased expression of KCNH2 3.1 in the brain was treated as a predictor variable. Treatment-associated changes in symptoms were evaluated in both groups with the Positive and Negative Syndrome Scale. The authors also analyzed time to discontinuation in the olanzapine arm of the CATIE study. Results: In the NIMH study, individuals who were homozygous for the KCNH2 3.1 increased expression-associated T allele of rs1036145 showed significant improvement in positive symptoms, general psychopathology, and thought disturbance, while patients with other genotypes showed little change. In the CATIE study, analogous significant genotypic effects were observed. Moreover, individuals who were homozygous for the T allele at rs1036145 were one-fifth as likely to discontinue olanzapine. Conclusions: These consistent findings in two markedly different treatment studies support the hypothesis that hERG1-mediated effects of antipsychotics may not be limited to their potential cardiovascular side effects but may also involve therapeutic actions related to the brain-specific 3.1 isoform of KCNH2.

Original languageEnglish (US)
Pages (from-to)725-734
Number of pages10
JournalAmerican Journal of Psychiatry
Volume169
Issue number7
DOIs
StatePublished - Jul 1 2012

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Antipsychotic Agents
Schizophrenia
Protein Isoforms
olanzapine
Brain
National Institute of Mental Health (U.S.)
Alleles
Clinical Trials
Therapeutics
Genotype
Potassium Channels
Therapeutic Uses
Psychopathology
Cross-Over Studies
Inpatients
Outpatients
Placebos
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia. / Apud, José A.; Zhang, Fengyu; Decot, Heather; Bigos, Kristin; Weinberger, Daniel.

In: American Journal of Psychiatry, Vol. 169, No. 7, 01.07.2012, p. 725-734.

Research output: Contribution to journalArticle

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abstract = "Objective: Antidopaminergic drugs bind to hERG1 potassium channels encoded by the gene KCNH2, which accounts for the side effect of QT interval prolongation. KCNH2 has also been associated with schizophrenia risk, and risk alleles predict increased expression of a brain-selective isoform, KCNH2 3.1, that has unique physiological properties. The authors assessed whether genetic variation associated with KCNH2 3.1 expression influences the therapeutic effects of antipsychotic drugs. Method: The authors performed a pharmacogenetic analysis of antipsychotic treatment response in patients with schizophrenia using data from two independent studies: a National Institute of Mental Health (NIMH) double-blind, placebo-controlled inpatient crossover trial (N=54) and the multicenter outpatient Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study (N=364). The KCNH2 genotype that was previously associated with increased expression of KCNH2 3.1 in the brain was treated as a predictor variable. Treatment-associated changes in symptoms were evaluated in both groups with the Positive and Negative Syndrome Scale. The authors also analyzed time to discontinuation in the olanzapine arm of the CATIE study. Results: In the NIMH study, individuals who were homozygous for the KCNH2 3.1 increased expression-associated T allele of rs1036145 showed significant improvement in positive symptoms, general psychopathology, and thought disturbance, while patients with other genotypes showed little change. In the CATIE study, analogous significant genotypic effects were observed. Moreover, individuals who were homozygous for the T allele at rs1036145 were one-fifth as likely to discontinue olanzapine. Conclusions: These consistent findings in two markedly different treatment studies support the hypothesis that hERG1-mediated effects of antipsychotics may not be limited to their potential cardiovascular side effects but may also involve therapeutic actions related to the brain-specific 3.1 isoform of KCNH2.",
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