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

doi:10.1016/j.biopsych.2012.10.033

Biological Psychiatry

Volume 73, Issue 11, 1 June 2013, Pages 1059-1063

https://doi.org/10.1016/j.biopsych.2012.10.033 Get rights and content

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.

Section snippets

Participants

A subset of the current sample has been reported in a previous study examining the serotonin transporter gene in relation to response to exposure therapy in PTSD (19). Eighty-two civilians with PTSD (24 who had survived motor vehicle accidents, 31 who had survived physical assaults) who were of white European ancestry and had completed an 8-week exposure-based cognitive behavior therapy (CBT) program at the Traumatic Stress Clinic (University of New South Wales, Australia) between January 2003

Demographic and Clinical Data

Demographic and clinical data are presented in Table 1. There were no significant differences between the Val/Val and Met carrier groups on age, time posttrauma, pretreatment depression scores, pretreatment PTSD severity, trauma type, or gender distribution. There were no significant differences in the distribution of 5HTT serotonergic transporter genotypes across the groups.

Treatment Response

Table 1 presents the mean PTSD severity (total CAPS scores) pretreatment and posttreatment, and Figure 1 illustrates the

Discussion

PTSD participants with the BDNF Met-66 low activity-dependent secretion allele displayed poorer response to exposure therapy than the Val/Val genotype group. The BDNF genotype was found to be a significant predictor of response to exposure therapy, above and beyond the effect of pretreatment PTSD severity, premorbid psychiatric history, and age. The regression analysis revealed that BDNF genotype contributed 14% of the variance in treatment response after controlling for these other significant

References (32)

M.R. Milad et al.
Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder
Biol Psychiatry
(2009)
M.F. Egan et al.
The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function
Cell
(2003)
A.L. Mahan et al.
Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder
Trends Neurosci
(2012)
R.A. Bryant et al.
Preliminary evidence of the short allele of the serotonin transporter gene predicting poor response to cognitive behavior therapy in posttraumatic stress disorder
Biol Psychiatry
(2010)
I.T. Kolassa et al.
The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism
Biol Psychiatry
(2010)
R.S. Duman et al.
A neurotrophic model for stress-related mood disorders
Biol Psychiatry
(2006)
L.M. Rattiner et al.
Brain-derived neurotrophic factor in amygdala-dependent learning
Neuroscientist
(2005)
J. Peters et al.
Induction of fear extinction with hippocampal-infralimbic BDNF
Science
(2010)
R. Kalisch et al.
Context-dependent human extinction memory is mediated by ventromedial prefrontal and hippocampal network
J Neurosci
(2006)
G.J. Quirk et al.
Neural mechanisms of extinction learning and retrieval
Neuropsychopharmacology
(2008)

F. Sotres-Bayon et al.

Dissociable roles for the ventromedial prefrontal cortex and amygdala in fear extinction: NR2B contribution

Cereb Cort

(2009)

F. Soliman et al.

A genetic variant BDNF polymorphism alters extinction learning in both mouse and human

Science

(2010)

S.A. Heldt et al.

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

Mol Psychiatry

(2007)

Z.Y. Chen et al.

Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior

Science

(2006)

T.B. Lonsdorf et al.

Amygdala-dependent fear conditioning in humans is modulated by the BDNFval66met polymorphism

Behav Neurosci

(2010)

D.C. Choi et al.

Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear

Proc Natl Acad Sci U S A

(2010)

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

Background

Methods

Results

Conclusions

Section snippets

Participants

Demographic and Clinical Data

Treatment Response

Discussion

Biol Psychiatry

Cell

Trends Neurosci

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Brain-derived neurotrophic factor in amygdala-dependent learning

Neuroscientist

Induction of fear extinction with hippocampal-infralimbic BDNF

Science

Context-dependent human extinction memory is mediated by ventromedial prefrontal and hippocampal network

J Neurosci

Neural mechanisms of extinction learning and retrieval

Neuropsychopharmacology

Dissociable roles for the ventromedial prefrontal cortex and amygdala in fear extinction: NR2B contribution

Cereb Cort

A genetic variant BDNF polymorphism alters extinction learning in both mouse and human

Science

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

Mol Psychiatry

Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior

Science

Amygdala-dependent fear conditioning in humans is modulated by the BDNFval66met polymorphism

Behav Neurosci

Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear

Proc Natl Acad Sci U S A

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