The Brain-Derived Neurotrophic Factor Val66Met
Polymorphism Predicts Response to Exposure
Therapy in Posttraumatic Stress Disorder
Kim L. Felmingham, Carol Dobson-Stone, Peter R. Schofield, Gregory J. Quirk, and
Richard A. Bryant
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
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.
posttraumatic stress disorder, treatment predictor
potentiation in the hippocampus, and is thought to act as a
key biological mechanism underlying associative learning and
memory consolidation (1,2). Extinction learning is a form of
inhibitory associative learning, where a previously feared stimulus
(conditioned stimulus) becomes associated with safety signals.
Regions of the infralimbic prefrontal (IL PFC) cortex in rats, and
ventromedial prefrontal cortex (vmPFC) in humans are critical for
retention of extinction learning (2,3). Recall of extinction in
humans activates vmPFC and hippocampus (3,4). Consolidation
of extinction learning requires plasticity in the IL PFC, which
depends at least partially on protein synthesis (5,6).
Recent evidence suggests that BDNF plays a key role in extinction
learning (2,7). Rats that fail to learn extinction have reduced BDNF in
hippocampal afferents to the IL PFC; however, augmenting BDNF in
this network prevents extinction failure (2). Similarly, deletion of
hippocampal-dependent BDNF impairs extinction learning in rats (8).
rain-derived neurotrophic factor (BDNF) is a neurotrophin
with a key role in regulating protein synthesis and synaptic
plasticity in the brain (1,2). BDNF mediates long-term
BDNF is likely to be responsible for consolidating extinction memory
in IL PFC because direct infusion of BDNF into the IL PFC significantly
enhances extinction, as demonstrated by reduced conditioned
freezing relative to saline-infused rats (2). This effect is apparent on
the initial extinction trial, suggesting that extinction training is not an
essential mediator of this effect. Indeed, subsequent infusions of
BDNF into IL PFC facilitates extinction of conditioned fear responses
without any extinction training (2).
A single-nucleotide polymorphism in the gene encoding
human BDNF gives rise to a functional variant at codon 66 with
the substitution of the amino acid valine (Val) by methionine (Met)
(Val66Met:9). The Met allele (Met/Met or Val/Met genotype) has
been associated with reduced hippocampal function and poorer
episodic memory and results in reduced activity-dependent
secretion of BDNF (9). In genetic mouse models, insertion of the
Met allele has been shown to decrease the release of BDNF from
hippocampal neurons (10) and has been shown to impair
extinction learning in both mice and humans (7). A divergent
finding was reported by Lonsdorf and colleagues (11), who found
that the BDNF Met group displayed reduced extinction learning
during the first block of extinction trials, relative to the Val/Val
group. However, this may have been due to the poorer extinction
learning revealed during fear acquisition in the BDNF Met group
in this study. In addition, evidence suggests that BDNF has
differential effects on neural plasticity in prelimbic and infralimbic
prefrontal regions and amygdala networks during fear expression
and extinction (12,13). Importantly, Soliman et al. (7) found that
human Met allele carriers displayed reduced activity in vmPFC
regions and greater activity in amygdala during extinction learn-
ing than those with the Val/Val genotype (7). This suggests that
BDNF Met allele carriers fail to recruit inhibitory vmPFC networks
involved in extinction learning that act to inhibit amygdala fear-
based processing (7). Furthermore, epigenetic upregulation of the
BDNF promoter within the PFC, resulting in increased levels of
BDNF expression, correlates with fear extinction (14).
From the School of Psychology (KLF), University of Tasmania, Hobart;
School of Psychology (KLF, RAB), University of New South Wales;
Neuroscience Research Australia (CD-S, PRS), and School of Medical
Sciences (CD-S, PRS), University of New South Wales, Sydney, Australia;
and Departments of Psychiatry and Anatomy and Neurobiology (GJQ),
University of Puerto Rico School of Medicine, San Juan, Puerto Rico.
Address correspondence to Kim Felmingham, Ph.D., School of Psychology,
University of Tasmania, TAS 7005 Australia; E-mail: Kim.Felmingham@
Received Apr 30, 2012; revised and accepted Oct 16, 2012.
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& 2012 Society of Biological Psychiatry
Posttraumatic stress disorder (PTSD) is conceptualized as
failure of fear extinction learning, and patients with this disorder
display reduced activity in vmPFC regions implicated in extinction
(15–17). Exposure therapy for PTSD aims to facilitate extinction
learning (16), and successful exposure therapy in PTSD has been
associated with increased activity in vmPFC networks involved in
extinction and reduced activity in amygdala response to fearful
faces (17), as well as size of the rostral anterior cingulate cortex
(which is implicated in extinction learning (18). The only previous
study of genetic predictors of exposure therapy in patients with
PTSD found that the low-expression allele of the serotonin
transporter gene was associated with poor treatment response
(19). Carriers of this allele have been shown to acquire condi-
tioned startle responses more readily (20) and display decoupling
of the amygdala-prefrontal network, which is implicated in
extinction learning (21). This finding suggests that genetic
vulnerability to enhanced conditioning or impaired extinction
may influence response to exposure therapy. On the basis of the
role that BDNF plays in extinction, we examined the capacity of
the BDNF Val66Met polymorphism (mediating activity-dependent
BDNF secretion) to predict the response to exposure therapy in
PTSD. Specifically, given evidence that BDNF facilitates extinction
learning, we hypothesized that the BDNF Met allele would predict
poorer response to exposure therapy in PTSD.
Methods and Materials
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 expo-
sure-based cognitive behavior therapy (CBT) program at the
Traumatic Stress Clinic (University of New South Wales, Australia)
between January 2003 and August 2006 (19) were approached to
participate in the study. Fifty-five participants agreed to partici-
pate and provided DNA suitable for BDNF genotyping. Eighteen
participants had comorbid major depression (8 in the Val-Val
group, 10 in the Met group), and 5 reported comorbid substance
abuse. There were no significant differences in age, gender, time
since trauma, comorbid disorders, PTSD severity, or treatment
response between those who participated or those who refused
to participate in the study. Inclusion criteria were a DSM-IV
diagnosis of PTSD and age between 18 and 65 years. Exclusion
criteria included active suicidal intent or psychosis, severe
traumatic brain injury, personality disorder, taking psychotropic
medication, or cognitive impairment that prevented engaging in
CBT. Before obtaining informed consent, participants were
informed that the study was testing the relationship between
genetics and recovery from trauma, and participants were
reimbursed $20. After complete description of the study to the
subjects, written informed consent was obtained.
Diagnoses of PTSD were made by master’s level clinical
psychologists with the Clinician Administered PTSD Scale (CAPS)
(23). Participants then completed 8 weekly 90-minute individual
CBT sessions. A subset of these participants were drawn from
an arm of a previously reported randomized controlled trial of
CBT that comprised imaginal exposure combined with in vivo
exposure and cognitive restructuring (22). The first session
comprised psychoeducation, the subsequent six sessions com-
prised imaginal and in vivo exposure and cognitive restructuring,
and the final session comprised relapse prevention. Treatment
response was quantified using the CAPS at posttreatment (within
2 weeks of therapy cessation) by a clinical psychologist indepen-
dent from the study.
Genomic DNA was extracted from mouth swabs or via saliva
samples. The collection methodology shifted from mouth swabs
to saliva samples during the course of the study because of the
higher and more reliable yield of DNA provided by saliva
samples. Genomic DNA was extracted from mouth swabs using
a standard proteinase K digestion and chloroform extraction
procedure, and saliva samples were purified using the Oragene
DNA collection kit (DNA Genotek, Ottawa, Canada). The BDNF
Val66Met genotypes were determined using primer extension
followed by mass spectrometry analysis on the Sequenom
MassARRAY system (Sequenom, San Diego, California) by the
Australian Genome Research Facility (http://www.agrf.org.au).
The genotype frequencies of the 55 participants were 54.5%
Val/Val (n ¼ 30), 40% Val/Met (n ¼ 22), and 5.5% Met/Met (n ¼ 3),
which were in Hardy-Weinberg equilibrium (w2¼ .16, p ? .05).
We grouped Met allele carriers (Val/Met and Met/Met genotypes)
together for analyses because the rarity of the Met/Met genotype
prevents meaningful analysis. Posttreatment, all 55 patients had
completed the full treatment with 30 BDNF Val/Val homozygotes
and 25 BDNF Met allele carriers.
To examine the impact of BDNF genotype on response to
exposure treatment, a repeated-measures analysis of covariance
(ANCOVA) was conducted on total CAPS scores with BDNF Group
(Val/Val, Met) as the between factor, and Time (pretreatment,
posttreatment) as the within factor, and 5HTT serotonergic
tranporter genotype as a covariate. To determine if BDNF
genotype could predict response to exposure therapy, a hier-
archical multiple regression was conducted with CAPS posttreat-
ment data as the dependent variable, and age, pretreatment
PTSD severity (pretreatment CAPS scores), previous psychiatric
history, 5HTT serotonergic transporter genotype, and BDNF
genotype entered as predictors (in that order). Age, psychiatric
history, and 5HTT transporter genotype were included as pre-
dictors because these variables may mediate the effects of BDNF
and response to exposure treatment (19,24,25). An alpha value of
p ? .05 was used for all analyses.
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 distribu-
tion of 5HTT serotonergic transporter genotypes across the
Table 1 presents the mean PTSD severity (total CAPS scores)
pretreatment and posttreatment, and Figure 1 illustrates the
2BIOL PSYCHIATRY ]]]];]:]]]–]]]
K.L. Felmingham et al.
impact of BDNF genotype on treatment response. Figure 1
reveals that the BDNF Met group showed a reduced response
to exposure treatment with a 40% reduction in CAPS score
posttreatment, whereas the Val/Val group showed a 62% reduc-
tion in CAPS score. A repeated measures ANCOVA (controlling for
5HTT genotype) revealed a significant interaction between BDNF
and Time [F(1,52) ¼ 7.7, p ¼ .008, Z2p¼ .13] and a significant
effect of time [F(1,52) ¼ 9.8, p ¼ .003], but no significant main
effect of BDNF [F(1,52) ¼ 3.8, p ¼ .06]. Post hoc analyses of the
BDNF ? Time interaction revealed there were no significant
differences between Val/Val and Met groups pretreatment, but
the Met group had significantly higher CAPS scores than the Val/
Val group at posttreatment.
Hierarchical Multiple Regression
Findings from the hierarchical multiple regression are pre-
sented in Table 2. Age was a significant predictor of posttreat-
ment PTSD scores, whereas pretreatment CAPS severity, 5HTT
genotype, and previous psychiatric history were nonsignificant
predictors. BDNF genotype was a highly significant predictor of
posttreatment PTSD scores after controlling for pretreatment
PTSD participants with the BDNF Met-66 low activity-
dependent secretion allele displayed poorer response to expo-
sure 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 pretreat-
ment 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 predictors. One explanation for this
finding is that lower levels of BDNF predict poorer extinction
learning in the context of exposure therapy and hence predict
the efficacy of an extinction-based therapy. However, an impor-
tant alternative explanation to consider is that BDNF interacts
with the pathogenesis of PTSD to yield a disease subtype that is
differentially responsive to subsequent exposure-based treat-
ment. This latter possibility should receive additional investiga-
tion given that insufficient extinction may be critical to the
pathogenesis of PTSD. To our knowledge, this is the first study to
show that the functional BDNF Val66Met polymorphism predicts
response to exposure-based therapy. Our finding is in accord
with previous evidence in animals that BDNF depletion impairs
fear extinction (8) and that BDNF infusion into IL PFC facilitates
fear extinction (2). It is also consistent with recent evidence in
healthy control participants that the BDNF Met allele impairs
extinction in a fear conditioning/extinction paradigm (7).
Table 1. Demographic and Clinical Data for Participants with the BDNF Val/Val (n ¼ 30) and BDNF Met (n ¼ 25) genotypes
18 M/12 F
24 S/6 L
17 M/8 F
17 S/8 L
Quantitative variables are mean values, with standard deviation indicated in parentheses.
5HHT genotype, genotype on the serotonin transporter gene; BDI, Beck Depression Inventory; BDNF, brain-derived neurotrophic factor; CAPS,
Clinician Administered PTSD Scale; F, female; L, long allele on the serotonin transporter gene; M, male; MVA, motor vehicle accident; S, short allele on the
serotonin transporter gene.
aThe Met carrier group comprises those subjects with Val/Met or Met/Met genotypes.
bt statistic or w2statistic, as appropriate.
Figure 1. Effect of brain-derived neurotrophic factor genotype on
response to exposure treatment in posttraumatic stress disorder: pre-
treatment and posttreatment scores on the Clinician Administered PTSD
Scale for the Val/Val (n ¼ 30) and Met (n ¼ 25) groups. Error bars
Table 2. Hierarchical Multiple Regression Predicting Total CAPS Scores at
Pretreatment CAPS Total
5HTT serotonin transporter short allele carriers coded as 1, long allele
carriers coded as 2. Brain-derived neurotrophic factor (BDNF) Val/Val
carriers coded as 1, Met carriers as 0.
CAPS, Clinician Administered PTSD Scale.
aSignificant predictors (p ? .05).
K.L. Felmingham et al.
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Successful response to exposure therapy is associated with
increased functional brain activity in ventromedial prefrontal
regions (18). Availability of BDNF in hippocampal projections to
the IL medial PFC is critical for extinction memories (2), and BDNF
Met carriers display reduced activity in ventromedial prefrontal
regions and greater amygdala activity during extinction learning
(7). This suggests that lower levels of BDNF in hippocampal and
ventromedial prefrontal networks (resulting from the impaired
activity-dependent secretion of the BDNF Met allele) result in
reduced protein synthesis and neural plasticity in these pathways.
Consequently, there is expected to be relatively less change in
ventromedial prefrontal activity in response to exposure-based
therapy in PTSD patients with the Met allele. To test this
hypothesis, future studies should examine functional brain
responses associated with exposure-based therapy in PTSD
patients when stratified by BDNF Val66Met genotype.
We note that there is a need to consider the potential
interaction between BDNF and other functional polymorphisms
that have been associated with extinction learning. Although
our previous study of genetic prediction of CBT in PTSD found
that the low-expression allele of the serotonin transporter gene
predicted poorer response to exposure treatment (19), we did
not find an interactive effect of the serotonin transporter and
BDNF genotype on treatment response. However, we examined
the impact of BDNF immediately posttreatment to capture the
most direct measure of extinction learning. Because the effect of
the serotonin transporter gene was found at 6-month follow-up,
the relationship between the serotonin transporter gene and
BDNF should be examined at longer time frames posttreatment.
The COMTval158 is a methylation enzyme metabolizing mono-
aminergic neurotransmitter and has been linked to impover-
ished extinction learning (20). Of relevance to the current study
is evidence that the met/met genotype of COMT is associated
with PTSD severity in the context of low-intensity traumatic
experience (26). A recent study of exposure therapy for patients
with panic disorder found that patients with the Met/Met
genotype responded more poorly to therapy than those with
at least one Val allele (27). This finding is relevant in light of
proposals that panic disorder and PTSD may be mediated by
comparable neural circuitry that implicates conditioning and
extinction networks (28). Furthermore, findings from this study
and our current study support a widely held, but largely
untested, hypothesis that extinction is necessary for CBT
exposure treatment. Finally, BDNF binds to specific high-
affinity TrkB receptors; modulation of TrkB activation has been
shown to block the consolidation of fear extinction (29), and the
TrkB-NTRk2 polymorphism has been associated with stress-
related mood disorders (30,31) and obsessive-compulsive disorder
(32). Taken together, these convergent findings suggest that future
studies need to identify interactions of genotypes that are impli-
cated in extinction learning to determine the role that these
interactions play in how people respond to therapies that are
based on extinction learning and retention.
Despite the independent contribution of BDNF genotype to
treatment response, this finding needs important qualification.
The small samples sizes in this study highlight the need for
replication of the finding in larger groups. Future research should
also examine genetic predictors of treatment response in relation
to nontreatment control conditions to rule out any genetic
influences on spontaneous remission. We lacked the sample size
necessary to study any interaction of BDNF Val66Met genotype
with other potential genetic predictors, as well as other potential
factors, such as gender. Our sample was also limited to European
patients (future studies should use genetic confirmation of
ancestry), and it remains to be seen whether this pattern is
observed in other ethnic groups. We also did not operationally
measure extinction learning or retention, and thus the extent to
which we can attribute the differential response to exposure
therapy to extinction remains speculative.
These limitations notwithstanding, this preliminary study
presents novel evidence that response to exposure therapy in
PTSD is influenced by BDNF genotype. This finding converges
with animal and human evidence revealing that BDNF facilitates
extinction learning. It confirms predictions of Soliman et al. (7)
that the BDNF Val66Met polymorphism influences the efficacy of
extinction-based exposure therapy. This study highlights the
importance of identifying specific genotypes as potential pre-
dictor variables in clinical trials of exposure therapy in PTSD.
Evidence that genotypes influence response to CBT may provide
a platform for the eventual application of personalized medicine
to the treatment of PTSD.
This work was supported by a National Health Medical Research
Council Program Grant (400403) to RAB, a National Health Medical
Research Council Enabling grant (No. 480184) to PRS, and a
University of New South Wales Vice-Chancellors Post-doctoral
Fellowship to CD-S. We thank Kerrie Pierce for DNA sample
RAB, KLF, CD-S, and PRS report holding grants from the National
Health and Medical Research Council and Australian Research
Council. PRS reports paid speaker fees from Janssen unrelated to
this study and GJQ report no biomedical financial interests or
potential conflicts of interest.
1. Rattiner LM, Davis M, Ressler KJ (2005): Brain-derived neurotrophic
factor in amygdala-dependent learning. Neuroscientist 11:323.
2. Peters J, Dieppa-Perea L, Melendex LM, Quirk GJ (2010): Induction of
fear extinction with hippocampal-infralimbic BDNF. Science 328:
3. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan AM,
Handwerger K, Orr SP, Rauch SL (2009): Neurobiological basis of
failure to recall extinction memory in posttraumatic stress disorder.
Biol Psychiatry 66:1075–1082.
4. Kalisch R, Korenfeld E, Stephan KE, Weiskopf N, Seymour B, Dolan RJ
(2006): Context-dependent human extinction memory is mediated by
ventromedial prefrontal and hippocampal network. J Neurosci 26:
5. Quirk GJ, Mueller D (2008): Neural mechanisms of extinction learning
and retrieval. Neuropsychopharmacology 33:56–72.
6. Sotres-Bayon F, Diaz-Mataix L, Bush DE, LeDoux JE (2009): Dissociable
roles for the ventromedial prefrontal cortex and amygdala in fear
extinction: NR2B contribution. Cereb Cort 19:474–482.
7. Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, et al.
(2010): A genetic variant BDNF polymorphism alters extinction
learning in both mouse and human. Science 327:863–866.
8. Heldt SA, Stanek L, Chhatwal JP, Ressler KJ (2007): Hippocampus-
specific deletion of BDNF in adult mice impairs spatial memory and
extinction of aversive memories. Mol Psychiatry 12:656–670.
9. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino
A, et al. (2003): The BDNF val66met polymorphism affects activity-
dependent secretion of BDNF and human memory and hippocampal
function. Cell 112:257–269.
10. Chen ZY, Jing DQ, Bath KG, Ieraci A, Khan T, Siao CJ, et al. (2006):
Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related
behavior. Science 314:140–143.
11. Lonsdorf TB, Weike AI, Golkar A, Schalling M, Hamm AO, Ohman A
(2010): Amygdala-dependent fear conditioning in humans is modu-
lated by the BDNFval66met polymorphism. Behav Neurosci 124:9–15.
12. Choi DC, Maguschak KA, Ye K, Jang SW, Myers KM, Ressler KJ (2010):
Prelimbic cortical BDNF is required for memory of learned fear
4BIOL PSYCHIATRY ]]]];]:]]]–]]]
K.L. Felmingham et al.
but not extinction or innate fear. Proc Natl Acad Sci U S A 107: Download full-text
13. Mahan AL, Ressler KJ (2012): Fear conditioning, synaptic plasticity and
the amygdala: implications for posttraumatic stress disorder. Trends
14. Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M (2007):
Histone modifications around individual BDNF gene promoters in
prefrontal cortex are associated with extinction of conditioned fear.
Learn Mem 14:268–276.
15. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B,
et al. (2005): A functional magnetic resonance imaging study of
amygdala and medial prefrontal responses to overtly fearful faces in
posttraumatic stress disorder. Arch Gen Psychiatry 62:273–281.
16. Rothbaum BO, Davis M (2003): Applying learning principles to the
treatment of post-trauma reactions. Ann N Y Acad Sci 1008:112–121.
17. Felmingham KL, Kemp AH, Williams LM, Das P, Hughes G, Peduto A,
Bryant RA (2007): Anterior cingulate and amygdala changes after
cognitive behavioural therapy in posttraumatic stress disorder.
Psychol Sci 18:127–129.
18. Bryant RA, Felmingham KL, Whitford T, Kemp AH, Hughes G, Peduto
A, Williams LM (2008): Rostral anterior cingulate volume predicts
treatment response to cognitive behavior therapy in posttraumatic
stress disorder. J Psychiatry Neurosci 33:142–146.
19. Bryant RA, Felmingham KL, Falconer EM, PeBenito L, Dobson-Stone C,
Pierce KD, Schofield PR (2010): Preliminary evidence of the short allele
of the serotonin transporter gene predicting poor response to
cognitive behavior therapy in posttraumatic stress disorder. Biol
20. Lonsdorf TB, Weike AI, Nikamo P, Schalling M, Hamm AO, Ohman A
(2009): Genetic gating of human fear learning and extinction: Possible
implications for gene–environmental interactions in anxiety disorders.
Psychol Sci 20:198–206.
21. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz
KE, Kolachna BS, et al. (2005): 5-HTTLPR polymorphism impacts
human cingulate–amygdala interactions: A genetic susceptibility
mechanism for depression. Nat Neurosci 8:828–834.
22. Bryant RA, Moulds ML, Guthrie RM, Dang ST, Mastodomenico J, Nixon
RD, et al. (2008): A randomized controlled trial of exposure therapy
and cognitive restructuring for posttraumatic stress disorder. J Consult
Clin Psychol 76:695–703.
23. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Klauminzer G,
Charney DS (1990): A clinician rating scale for assessing current and
lifetime PTSD: The CAPS-1. Behav Ther 13:187–188.
24. Toth E, Gerstner R, Wilf-Rakoni A, Raizel H, Dar DE, Richter-Levin G,
Levit O, Zangen A (2008): Age-dependent effects of chronic stress
on brain plasticity and depressive behavior. J Neurochem 107:
25. Taliaz D, Loya A, Gersner R, Haramati S, Chen A, Zangen A (2011):
Resilience to chronic stress is mediated by hippocampal brain-derived
neurotrophic factor. J Neurosci 31:4475–4483.
26. GuthrieRM, BryantRA (2007):
trauma and subsequent posttraumatic stress. Psychosom Med 68:
27. Kolassa IT, Kolassa S, Ertl V, Papassotiropoulos A, De Quervain DJ
(2010): The risk of posttraumatic stress disorder after trauma depends
on traumatic load and the catechol-o-methyltransferase Val(158)Met
polymorphism. Biol Psychiatry 67:304–308.
28. Lonsdorf TB, Ruck C, Bergstrom J, Andersson G, Ohman A, Lindesfors
N, Schalling M (2010): The COMTval158met polymorphism is asso-
ciated with symptom relief during exposure-based cognitive-beha-
vioral treatment in panic disorder. BMC Psychiatry 10:99.
29. Shin LM, Liberzon I (2010): The neurocircuitry of fear, stress, and
anxiety disorders. Neuropsychopharmacology 35:169–191.
30. Rattiner LM, Davis M, French CT, Ressler KJ (2004): Brain-derived
neurotrophic factor and tyrosine kinase receptor B involvement in
amygdala-dependent fear conditioning. J Neurosci 24:4796–4806.
31. Kohli MA, Salyakina D, Pfennig A, Lucae S, Horstmann S, Menke A,
et al. (2010): Association of genetic variants in the neurotrophic
receptor encoding gene NTRK2 and a lifetime history of suicide
attempts in depressed patients. Arch Gen Psychiatry 67:348–359.
32. Duman RS, Monteggia LM (2006): A neurotrophic model for stress-
related mood disorders. Biol Psychiatry 59:1116–1127.
K.L. Felmingham et al.
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