Among subjects in the CATIE trial of antipsychotic effectiveness, a large U.S. study of schizophrenia treatment, 74 genes were associated with treatment failure as defined by antipsychotic discontinuation (1). Some of the identified genes code for proteins relevant to schizophrenia research, including brain-derived neurotrophic factor (BDNF). The role of BDNF in the pathophysiology of psychosis was reviewed by Nurjono et al., who highlighted research showing correlation of serum BDNF and positive symptoms, and reduction of BDNF-related mRNA in the hippocampus and frontal lobe of schizophrenia patients (2). Furthermore, certain single-nucleotide polymorphisms (SNPs) of the BDNF gene, including Val66Met, correlate with aspects of the disease.
Using the 74 candidate genes from CATIE as a point of departure, Zhang et al. compared SNP frequency in 89 patients on clozapine, who represented a treatment-resistant cohort, to SNP frequency in 190 patients not on clozapine (3). The mean age of subjects was 38.8 years and all were Caucasian. The only SNPs significantly associated with clozapine therapy were located on the BDNF gene. The minor alleles of three BDNF SNPs showed a dose-response such that homozygotes had the greatest likelihood of clozapine therapy and heterozygotes had an intermediate likelihood compared with major allele homozygotes, who had the lowest likelihood of clozapine therapy.
The minor allele of the Val66Met polymorphism results in BDNF with methionine instead of valine at codon 66. In prior research in patients with schizophrenia, the met allele was associated with reduced frontal gray matter, larger lateral ventricles, and impaired short-term episodic memory. Men with schizophrenia who were homozygous for the met allele developed psychosis earlier than heterozygotes or major-allele homozygotes (2).
Studies in Asians and Caucasians found that the BDNF met allele is not associated with increased risk for schizophrenia (1). However, in the presence of schizophrenia, available research indicates that the met allele is associated with a more severe and possibly treatment-resistant form of the disease. Zhang et al. suggest that the mechanism may be related to reduced synaptic plasticity and hippocampal dysfunction, phenotypic expressions of the met allele in healthy humans. Further research in people with schizophrenia who are met carriers may help elucidate the origins of treatment resistance and the pharmacogenetics of clozapine.
1. Nurjono M, Lee J, Chong SA. A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci. 2012;10:61-70. Full text
2. Need AC, Keefe RS, Ge D, et al. Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis. Eur J Hum Genet. 2009;17:946–957. Full text
3. Zhang JP, Lencz T, Geisler S, Derosse P, Bromet EJ, Malhotra AK. Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia. Schizophr Res. 2013 Feb 19. doi:pii: S0920-9964(13)00058-3. 10.1016/j.schres.2013.01.020 [Epub ahead of print]. Abstract