The efficacies of clozapine and haloperidol in refractory schizophrenia are related to DTNBP1 variation.
OBJECTIVE
The prototypical atypical antipsychotic agent, clozapine, is more efficacious for refractory schizophrenia than the 'typical' antipsychotics, but the mechanism underlying this enhanced efficacy is still under investigation. Since 2002, at least 22 association studies have shown that the DTNBP1 can be associated with the risk for schizophrenia. We hypothesized that DTNBP1 might also influence the response to antipsychotic treatments. This study aimed to investigate the relationship between the DTNBP1 and the effects of clozapine and haloperidol on refractory schizophrenia.


METHODS
Patients with refractory schizophrenia were assigned to clozapine (n=85) or haloperidol (n=96) and followed for 3 months. Symptom improvement was evaluated by Positive and Negative Syndrome Scale score. Six markers at DTNBP1 and 38 ancestry-informative markers were genotyped in all participants. The relationships between the effects of antipsychotics and the diplotypes, haplotypes, genotypes, and alleles of DTNBP1 were tested by analysis of covariance, analysis of variance, and t-test.


RESULTS
Patients with diplotype ACCCTC/GTTGCC, genotypes T/T+T/C, or allele T of marker rs742105 (P1333) have better response to clozapine (0.005< or =P< or =0.049), and patients with diplotype ACCCTC/GCCGCC, genotype A/G, or allele A of marker rs909706 (P1583) have better response to haloperidol (0.007< or =P< or =0.080) in European-Americans, African-Americans, and/or the combined sample; European-American patients with diplotype ACCCTC/GCCGCC have worse response to clozapine on positive symptoms (P=0.011).


CONCLUSIONS
This study shows that the DTNBP1 gene modulates the effects of both the atypical antipsychotic clozapine and the typical antipsychotic haloperidol. Participants with different DTNBP1 diplotypes, haplotypes, genotypes, or alleles might have different responses to these antipsychotics.
Departments of Psychiatry, West Haven Campus, Connecticut, USA.
Lingjun
L
Zuo
Xingguang
X
Luo
John H
JH
Krystal
Joyce
J
Cramer
Dennis S
DS
Charney
Joel
J
Gelernter
D001741:Black or African American; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics*; D003024:Clozapine / Q000627:therapeutic use*; D004309:Double Bind Interaction; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D014644:Genetic Variation; D005838:Genotype; D006220:Haloperidol / Q000627:therapeutic use*; D006239:Haplotypes; D006801:Humans; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D044465:White People
D014150:Antipsychotic Agents; D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D003024:Clozapine; D006220:Haloperidol