The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Predicts Response to Exposure Therapy in Posttraumatic Stress Disorder.

School of Psychology (KLF), University of Tasmania, Hobart
Biological psychiatry (Impact Factor: 9.47). 01/2013; DOI: 10.1016/j.biopsych.2012.10.033
Source: PubMed

ABSTRACT BACKGROUND: The most effective treatment for posttraumatic stress disorder (PTSD) is exposure therapy, which aims to facilitate extinction of conditioned fear. Recent evidence suggests that brain-derived neurotrophic factor (BDNF) facilitates extinction learning. This study assessed whether the Met-66 allele of BDNF, which results in lower activity-dependent secretion, predicts poor response to exposure therapy in PTSD. METHODS: Fifty-five patients with PTSD underwent an 8-week exposure-based cognitive behavior therapy program and provided mouth swabs or saliva to extract genomic DNA to determine their BDNF Val66Met genotype (30 patients with the Val/Val BDNF allele, 25 patients with the Met-66 allele). We examined whether BDNF genotype predicted reduction in PTSD severity following exposure therapy. RESULTS: Analyses revealed poorer response to exposure therapy in the PTSD patients with the Met-66 allele of BDNF compared with patients with the Val/Val allele. Pretreatment Clinician Administered PTSD Scale severity and BDNF Val66Met polymorphism predicted response to exposure therapy using hierarchical regression. CONCLUSIONS: This study provides the first evidence that the BDNF Val66Met genotype predicts response to cognitive behavior therapy in PTSD and is in accord with evidence that BDNF facilitates extinction learning.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper highlights recent human neuroimaging and cross-species developmental and genetic studies that examine how fear regulation varies by age and the individual, especially during the period of adolescence, when there is a peak in the prevalence of anxiety disorders. The findings have significant implications for understanding who may be at risk for anxiety disorders and for whom, and when, an exposure-based therapy may be most effective. We provide proof of concept for targeting treatment to the individual as a function of age and genetics, inferred from mouse and human studies, and suggest optimization of treatment for nonresponders. © 2015 New York Academy of Sciences.
    Annals of the New York Academy of Sciences 03/2015; DOI:10.1111/nyas.12746 · 4.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The value of common polymorphisms in guiding clinical psychiatry is limited by the complex polygenic architecture of psychiatric disorders. Common polymorphisms have too small an effect on risk for psychiatric disorders as defined by clinical phenomenology to guide clinical practice. To identify polymorphic effects that are large and reliable enough to serve as biomarkers requires detailed analysis of a polymorphism's biology across levels of complexity from molecule to cell to circuit and behavior. Emphasis on behavioral domains rather than clinical diagnosis, as proposed in the Research Domain Criteria framework, facilitates the use of mouse models that recapitulate human polymorphisms because effects on equivalent phenotypes can be translated across species and integrated across levels of analysis. A knockin mouse model of a common polymorphism in the brain-derived neurotrophic factor gene (BDNF) provides examples of how such a vertically integrated translational approach can identify robust genotype-phenotype relationships that have relevance to psychiatric practice. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Biological Psychiatry 01/2015; DOI:10.1016/j.biopsych.2014.12.020 · 9.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Social-stress mouse model, based on the resident-intruder paradigm was used to simulate features of human post-traumatic stress disorder (PTSD). The model involved exposure of an intruder (subject) mouse to a resident aggressor mouse followed by exposure to trauma reminders with rest periods. C57BL/6 mice exposed to SJL aggressor mice exhibited behaviors suggested as PTSD-in-mouse phenotypes: intermittent freezing, reduced locomotion, avoidance of the aggressor-associated cue and apparent startled jumping. Brain tissues (amygdala, hippocampus, medial prefrontal cortex, septal region, corpus striatum and ventral striatum) from subject (aggressor exposed: Agg-E) and control C57BL/6 mice were collected at one, 10 and 42 days post aggressor exposure sessions. Transcripts in these brain regions were assayed using Agilent’s mouse genome-wide arrays. Results Pathways and biological processes associated with differentially regulated genes were mainly those thought to be involved in fear-related behavioral responses and neuronal signaling. Expression-based assessments of activation patterns showed increased activations of pathways related to anxiety disorders (hyperactivity and fear responses), impaired cognition, mood disorders, circadian rhythm disruption, and impaired territorial and aggressive behaviors. In amygdala, activations of these pathways were more pronounced at earlier time-points, with some attenuation after longer rest periods. In hippocampus and medial prefrontal cortex, activation patterns were observed at later time points. Signaling pathways associated with PTSD-comorbid conditions, such as diabetes, metabolic disorder, inflammation and cardiac infarction, were also significantly enriched. In contrast, signaling processes related to neurogenesis and synaptic plasticity were inhibited. Conclusions Our data suggests activations of behavioral responses associated with anxiety disorders as well as inhibition of neuronal signaling pathways important for neurogenesis, cognition and extinction of fear memory. These pathways along with comorbid-related signaling pathways indicate the pervasive and multisystem effects of aggressor exposure in mice, potentially mirroring the pathologic conditions of PTSD patients. Electronic supplementary material The online version of this article (doi:10.1186/s13041-015-0104-3) contains supplementary material, which is available to authorized users.
    Molecular Brain 02/2015; 8(1). DOI:10.1186/s13041-015-0104-3 · 4.35 Impact Factor