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Letters to the Editor   |    
Genetic Variation in KCNH2 and a Unique hERG Isoform in Patients With Schizophrenia: Efficacy-Safety Link
Barbara Warner, M.D.
Am J Psychiatry 2012;169:1318-1318. doi:10.1176/appi.ajp.2012.12070966
View Author and Article Information

Dr. Warner works for Novartis Pharmaceuticals.

Mendham, N.J.

Copyright © 2012 by the American Psychiatric Association

Accepted September , 2012.

To the Editor: Based on the results of an NIMH double-blind trial and the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, Apud et al. (1) have provided support for the hypothesis of Huffaker et al. (2) that a genetic variation in the hERG1 protein, the KCNH2 3.1 isoform, may be related to treatment response. Could this hypothesis be extended to personalized medicine to minimize the risk of dysrhythmias related to QTc prolongation by giving antipsychotics only to those who will benefit from them? Or better, could we de-risk compounds by developing more targeted drugs that only bind to brain KCNH2 3.1?

The patient samples in the NIMH (N=54) and the CATIE study (N=364) are too small to predict with any statistical certainty whether or not individuals with the KCNH2 3.1 isoform were more likely to experience QT/QTc prolongation and related events, since torsade de pointes is extremely rare (3). In phase 1 of the CATIE study (4), 0/231 QTc prolongation events were reported in the olanzapine group, 6/214 (3%) in the quetiapine group, 7/218 (3%) in the risperidone group, 2/172 (1%) in the perphenazine group, and 2/148 (1%) in the ziprasidone group; these values were not statistically different, and there were no instances of torsade de pointes. Citrome and Stroup (5) calculated the number needed to harm based on these data and found it was between 31.1 and 86. Were these patients with QTc prolongation treatment responders? Did they carry the isoform KCNH2 3.1?

Extending this inquiry, might it be valuable to perform genotyping on patients in antipsychotic drug clinical trials who experience QTc prolongation or its sequelae?

Apud  JA;  Zhang  F;  Decot  H;  Bigos  KL;  Weinberger  DR:  Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia.  Am J Psychiatry 2012; 169:725–734
[PubMed]
 
Huffaker  SJ;  Chen  J;  Nicodemus  KK;  Sambataro  F;  Yang  F;  Mattay  V;  Lipska  BK;  Hyde  TM;  Song  J;  Rujescu  D;  Giegling  I;  Mayilyan  K;  Proust  MJ;  Soghoyan  A;  Caforio  G;  Callicott  JH;  Bertolino  A;  Meyer-Lindenberg  A;  Chang  J;  Ji  Y;  Egan  MF;  Goldberg  TE;  Kleinman  JE;  Lu  B;  Weinberger  DR:  A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization, and risk of schizophrenia.  Nat Med 2009; 15:509–518
[CrossRef] | [PubMed]
 
Nielsen  J:  The safety of atypical antipsychotics: does QTc provide all the answers? Expert Opin Drug Saf 2011; 10:341–344
[CrossRef] | [PubMed]
 
Lieberman  JA;  Stroup  TS;  McEvoy  JP;  Swartz  MS;  Rosenheck  RA;  Perkins  DO;  Keefe  RSE;  Davis  SM;  Davis  CE;  Lebowitz  BD;  Severe  J;  Hsiao  JK;  Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators:  Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.  N Engl J Med 2005; 353:1209–1223
[CrossRef] | [PubMed]
 
Citrome  L;  Stroup  TS:  Schizophrenia, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), and number needed to treat: how can CATIE inform clinicians? Int J Clin Pract 2006; 60:933–940
[CrossRef] | [PubMed]
 
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References

Apud  JA;  Zhang  F;  Decot  H;  Bigos  KL;  Weinberger  DR:  Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia.  Am J Psychiatry 2012; 169:725–734
[PubMed]
 
Huffaker  SJ;  Chen  J;  Nicodemus  KK;  Sambataro  F;  Yang  F;  Mattay  V;  Lipska  BK;  Hyde  TM;  Song  J;  Rujescu  D;  Giegling  I;  Mayilyan  K;  Proust  MJ;  Soghoyan  A;  Caforio  G;  Callicott  JH;  Bertolino  A;  Meyer-Lindenberg  A;  Chang  J;  Ji  Y;  Egan  MF;  Goldberg  TE;  Kleinman  JE;  Lu  B;  Weinberger  DR:  A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization, and risk of schizophrenia.  Nat Med 2009; 15:509–518
[CrossRef] | [PubMed]
 
Nielsen  J:  The safety of atypical antipsychotics: does QTc provide all the answers? Expert Opin Drug Saf 2011; 10:341–344
[CrossRef] | [PubMed]
 
Lieberman  JA;  Stroup  TS;  McEvoy  JP;  Swartz  MS;  Rosenheck  RA;  Perkins  DO;  Keefe  RSE;  Davis  SM;  Davis  CE;  Lebowitz  BD;  Severe  J;  Hsiao  JK;  Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators:  Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.  N Engl J Med 2005; 353:1209–1223
[CrossRef] | [PubMed]
 
Citrome  L;  Stroup  TS:  Schizophrenia, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), and number needed to treat: how can CATIE inform clinicians? Int J Clin Pract 2006; 60:933–940
[CrossRef] | [PubMed]
 
References Container
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