Applicability of a genetic signature for enhanced iloperidone efficacy in the treatment of schizophrenia.
OBJECTIVE
To demonstrate how several polymorphisms previously associated with the efficacy of the novel antipsychotic iloperidone could be used together to predict clinical response and provide practical information for individualized treatment.


METHODS
This inpatient randomized, double-blind, placebo- and ziprasidone-controlled, 28-day study of the efficacy of iloperidone was conducted from November 2005 to September 2006. Likelihood ratios, predicted probabilities of response, and number needed to treat were calculated for patients with schizophrenia (DSM-IV criteria) using 6 genetic markers of iloperidone response as measured by change in the Positive and Negative Syndrome Scale-Total (PANSS-T) score. Data analysis was performed on 409 patients of various ethnic origins.


RESULTS
The 6-marker genotype combinations defined 4 groups of patients with distinct probabilities of response. More than 75% of iloperidone-treated patients in the group with the optimal genotype combinations showed a 20% or greater improvement, compared with 37% for patients with other genotypes. These patients had a significant response by the first week of treatment, which was earlier than for patients with other genotype combinations. The odds of responding to iloperidone treatment with at least 20% improvement ranged from 2.4 to 3.6 for patients with 1 of the 6 favorable single-marker genotypes. The odds increased to 9.5 or greater for patients with the most favorable 6-marker combinations. The difference in PANSS-T score improvement observed between the genotype groups was also seen for the positive, negative, and general psychopathology PANSS subscales. The relationship between treatment efficacy and genotype combinations was not observed for patients treated with ziprasidone.


CONCLUSIONS
These results illustrate the combined use of genetic markers to predict enhanced response to iloperidone and support the application of pharmacogenetics to differentiate medication options and improve individualized treatments for schizophrenia.


BACKGROUND
(ClinicalTrials.gov) Identifier: NCT00254202.
Volpi
Simona
S
Vanda Pharmaceuticals Inc, Rockville, MD 20850, USA.
Potkin
Steven G
SG
Malhotra
Anil K
AK
Licamele
Louis
L
Lavedan
Christian
C
D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011336:Probability; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D011594:Psychometrics; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D005819:Genetic Markers; D007555:Isoxazoles; D010879:Piperazines; D010880:Piperidines; D013844:Thiazoles; C092292:ziprasidone; C081732:iloperidone