title: BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression.
abstract: OBJECTIVE
  Brain-derived neurotrophic factor (BDNF) is associated with antidepressant response on the cellular level, in animal models, and in clinical studies. A common variant in the BDNF gene results in a substitution of a methionine (Met) for a valine at the amino acid position 66. Previous studies reported that the Met variant results in enhanced response to antidepressant medications. These findings may be at odds with studies indicating that on a cellular level the Met variant impairs the secretion of BDNF.
  
  
  METHODS
  We examined the effects of BDNF single nucleotide polymorphisms (SNPs) in response to the antidepressants paroxetine and mirtazapine in a sample of 246 geriatric patients with major depression, treated in a double-blind, randomized, 8-week clinical trial. We also examined the effects of genetic variation at the BDNF-related loci neurotrophic tyrosine kinase receptor 2, cyclic AMP responsive element binding protein 1 (CREB1), and CREB binding protein. A total of 53 SNPs were genotyped.
  
  
  RESULTS
  BDNF genetic variation had a significant effect on the efficacy of paroxetine, with patients carrying the Met allele showing impaired response. SNPs at the CREB1 locus, which encodes a transcription factor important in BDNF signaling, also predicted response to paroxetine. Furthermore, we found a significant gene-gene interaction between BDNF and CREB1 that affected response to paroxetine. Because BDNF has been associated with cognitive function, we tested the effects of BDNF SNPs on change in a wide variety of cognitive tests over the 8-week trial, but there were no significant effects of genotype on cognition.
  
  
  CONCLUSIONS
  These results provide new evidence for the importance of the BDNF pathway in antidepressant response in geriatric patients. The negative effect of the Met66 allele on antidepressant outcomes is consistent with basic science findings indicating a negative effect of this variant on BDNF activity in the brain. Further, the effect of BDNF genetic variation on antidepressant treatment is modified by variation in the gene encoding the downstream effector CREB1.
authors.affiliation: Neuroscience Research Laboratories, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA. gmurphy@stanford.edu
authors.forename: Greer M
authors.initials: GM
authors.lastname: Murphy
authors.forename: Jane E
authors.initials: JE
authors.lastname: Sarginson
authors.forename: Heather S
authors.initials: HS
authors.lastname: Ryan
authors.forename: Ruth
authors.initials: R
authors.lastname: O'Hara
authors.forename: Alan F
authors.initials: AF
authors.lastname: Schatzberg
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
mesh_terms: D000368:Aged; D000483:Alleles; D000928:Antidepressive Agents / Q000627:therapeutic use*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D003863:Depression / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025341:Principal Component Analysis; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C579455:BDNF protein, human