variant brain-derived neurotrophic factor val66met endophenotypes: implications for posttraumatic...

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Psychiatric and Neurologic Aspects of War

Variant brain-derived neurotrophic factor Val66Metendophenotypes: implications for posttraumaticstress disorder

Helena Frielingsdorf,1,2 Kevin G. Bath,1,2,3 Fatima Soliman,1,2 JoAnn DiFede,2 B. J. Casey,1,2

and Francis S. Lee2

1The Sackler Institute for Developmental Psychobiology, Weill Medical College of Cornell University, New York, New York.2Department of Psychiatry, Weill Medical College of Cornell University, New York, New York 3Department of Neuroscience,Brown University, Providence, Rhode Island

Address for correspondence: Helena Frielingsdorf or Francis S. Lee, Department of Psychiatry, Weill Cornell Medical College,1300 York Avenue, Box 244, New York, New York 10065. [email protected] or [email protected]

Recently, a common single nucleotide polymorphism (SNP) has been identified in the gene encoding brain-derivedneurotrophic factor (BDNF). The variant BDNFMet has been shown to have decreased activity-dependent BDNFsecretion from neurons and to lead to impairments in specific forms of learning and altered susceptibility to stress. Amouse model containing BDNFMet has also been linked to increased anxiety-like behavior. In a translational study,mice and human carriers of the BDNFMet allele were compared in their ability to extinguish a learned fear memory.Both showed slower suppression of the learned fear response. In humans, the neural correlates of this behaviorwere validated using fMRI. As anxiety and fear extinction lie at the core of symptoms and therapeutic approachesto posttraumatic stress disorder (PTSD), we propose that BDNF genotype and neuroimaging may be useful asbiomarkers to provide guidance for more customized therapeutic directions. The aim of this paper is to review theavailable knowledge on the BDNF Val66Met SNP, with emphasis on anxiety- and fear-related endophenotypes andits potential implications for PTSD.

Keywords: BDNF; Val66Met; anxiety; PTSD; fear extinction

Introduction

Brain-derived neurotrophic factor (BDNF), a mem-ber of the neurotrophin family of polypeptidegrowth factors, is widely expressed in the developingand adult mammalian brain and has been identifiedas a key regulator of neuronal development withinthe central nervous system.1,2 In recent years, BDNFhas been implicated in the development and treat-ment of a number of psychiatric disorders, includ-ing depression, anxiety, and eating disorders. In thisreview, we will focus on a recently identified sin-gle nucleotide polymorphism (SNP) that has beenidentified in the gene encoding BDNF. We specifi-cally examine its role in the development of emo-tional and cognitive disorders. We will then expandupon this wealth of recent work to provide an argu-

ment for the potential role for this BDNF variant inadditional forms of psychiatric disorders with theirroots in emotional dysregulation, specifically post-traumatic stress disorder (PTSD).

BDNF is synthesized as a precursor protein(proBDNF) that is proteolytically cleaved to gen-erate mature BDNF.3 Throughout life, BDNF in-fluences the proliferation, differentiation, morphol-ogy, and functional activity of neuronal cells. BDNFaction is dictated by its binding to either of twofunctionally different classes of cell surface re-ceptors, the TrkB receptor tyrosine kinase or thep75 neurotrophin receptor (p75NTR), a memberof the tumor necrosis factor receptor super fam-ily.1 ProBDNF is preferentially bound by p75NTR,whereas mature BDNF preferentially binds to theTrkB receptor.4,5 BDNF binding to the TrkB receptor

doi: 10.1111/j.1749-6632.2010.05722.x150 Ann. N.Y. Acad. Sci. 1208 (2010) 150–157 c© 2010 Association for Research in Nervous and Mental Disease.

Frielingsdorf et al. BDNF Val66Met and PTSD

produces neurotrophic responses through rapid ac-tivation of the PI-3 kinase, Ras/MAPK, and PLC-�pathways, thus influencing transcriptional events af-fecting the cell-cycle, neurite outgrowth, and synap-tic plasticity.6–9 ProBDNF binding to the p75NTR

gives rise to an increase in JNK (c-Jun N-terminalkinase) and NF-�B (nuclear factor �B), which trig-gers apoptosis, axonal retraction, or the pruning ofdendritic spines.10

As mentioned, an SNP in the gene encodingBDNF has recently been identified. This SNP re-sults in an amino acid change from a valine (Val)to a methionine (Met) at position 66 (Val66Met)in the prodomain of BDNF (BDNFMet). Thus far,this SNP in the BDNF gene has only been foundin humans. The frequency of the BDNFMet allele isrelatively common and is ethnically stratified. Ap-proximately, 50% of Asians, 30% of Caucasians, and4% of African Americans carry at least one BDNFMet

allele.11,12 In Asian and Caucasian populations, theincidence of homozygous BDNFMet allele carriers isaround 20% and 4%, respectively.13

Impact of BDNF Val66Met on BDNFavailabilityThe molecular and cellular effects of BDNFVal66Met have been studied using a number ofmodel systems, including cell culture and animalsmodels. The initial work was carried out in in vitrocell culture systems. Transfection of BDNFMet intoneurons does not alter total levels of BDNF.14,15

This was shown in neuronal cultures from micein which BDNFMet was genetically knocked intothe endogenous BDNF locus. Specifically, BDNFMet

was less efficiently trafficked to neuronal processesand 20–30% less BDNF was released under depo-larizing conditions in cells from hetero- and ho-mozygous BDNFMet carriers, respectively.14 A num-ber of groups hypothesized that BDNFMet couldlead to less efficient sorting of BDNF into secre-tory granules. Subsequently, it was demonstratedthat BDNFMet bound less efficiently to the proteinsortilin, a molecule implicated both in the traffick-ing of BDNF in the biosynthetic pathway and as acoreceptor with p75NTR that binds proBDNF.5,16

Impact of BDNF Val66Met on neuronalsurvival and morphologyAs mentioned previously, BDNF plays a significantrole in the development of neuronal cells. To studythe potential role of BDNF Val66Met on neuronal

development, we and another lab developed linesof mice in which the BDNF Val66Met allele wasgenetically knocked into mice in a targeted fash-ion. In our lab, the endogenous mouse BDNF genewas replaced with a modified version of the mouseBDNF gene containing the Val66Met SNP.14 In a sec-ond lab, Cao and colleagues developed a mouse inwhich the human version of the BDNF gene contain-ing the Val66Met SNP was genetically knocked intothe mouse genome.17 To study the impact of BDNFVal66Met on neuronal birth, we carried out a seriesof studies in which we tracked rates of proliferationof new cells within the subventricular zone and theireventual migration and survival within the olfac-tory bulb (OB) in wild-type and BDNFMet homozy-gous mice. Interestingly, we found that BDNFMet ledto a significant reduction in the survival of newlyborn cells in the OB, suggesting that altered BDNFavailability as a result of the Val66Met SNP couldlead to a reduction in the birth of new cells in theadult brain.18 In a separate series of studies, Caoand colleagues demonstrated that, during develop-ment, BDNFMet alters the ability of axons to survivewithin the developing olfactory system, indicativeof potentially significant effects on axonal develop-ment throughout the brain.17 Finally, using Golgiimpregnation, we have demonstrated that the com-plexity of dendritic arbors of neurons in the hip-pocampus is significantly less elaborate in BDNFMet

homozygous mice compared to wild-type mice.14

This reduction in dendritic complexity mirrors thatof mice that have been exposed to chronic stressregimens.19 In these same BDNFMet mice, we foundthat in the hippocampus, a BDNF rich region, therewas a significant reduction in volume. These datareplicated findings from human imaging studies inwhich BDNFMet carriers were found to have reducedhippocampal volume compared to age- and sex-matched controls.

BDNF Val66Met leads to altered neuronalfunctionBDNF has been implicated in the electrical plas-ticity of neurons, specifically in the processesof long-term potentiation (LTP) and long-termdepression (LTD). In a recent series of experi-ments, we examined whether and how the BDNFVal66Met polymorphism affects hippocampal neu-rotransmission and synaptic plasticity using micehomozygous for the BDNFMet allele. We found

Ann. N.Y. Acad. Sci. 1208 (2010) 150–157 c© 2010 Association for Research in Nervous and Mental Disease. 151

BDNF Val66Met and PTSD Frielingsdorf et al.

that both young and adult BDNFMet homozy-gous mice exhibited a decrease in TBS (theta-burst stimulation)-induced LTP at the CA3-CA1synapses. We also observed a decrease in N-methyl-D-aspartate (NMDA) receptor-dependent LTD inthese mice. These data suggest that in humanBDNFMet carriers, electrophysiological processes as-sociated with memory function could be disruptedas a result of the BDNF Val66Met SNP.20

BDNF Val66Met is associated with alteredhippocampal memory functionBDNFMet has been associated with alterations inhippocampal plasticity and morphology. In a studyof human schizophrenic patients and age-matchedcontrols, Egan and colleagues demonstrated thatBDNFMet allele carriers have impairments in anepisodic memory task.15 Subsequently, these find-ings were in part replicated by Dempster et al.21

using a healthy control group. This same task, whentested using functional magnetic resonance imaging(fMRI), demonstrated that BDNFMet homozygousindividuals had reduced hippocampal activationcompared with controls and had a gene-dose-dependent reduction in n-acetyl aspartate, an in-tracellular marker of neuronal activity, indicatingpotential hippocampal dysregulation. These find-ings were later confirmed in another fMRI study bythe same group.22 They found again that BDNFMet

carriers showed a relative decrease in hippocampalactivation during encoding and retrieval of a declar-ative memory task. The BDNFMet allele carriers alsomade more errors on a retrieval memory task. Aseparate group in Australia found a similar decreasein hippocampal gray matter in BDNFMet carriersand also found that BDNFMet homozygous indi-viduals make more errors on a verbal recall task.23

Finally, in a fMRI study, Sambataro and colleaguesfound that BDNFMet allele carriers show a steeperdecline in age-related hippocampal activation dur-ing a declarative memory task.24

To get a clearer picture of the potential effects ofthe BDNFMet allele on memory function, we usedour knockin BDNF Val66Met mouse model. Thismanipulation allows us to assay memory functionon genetically homogenous background as well ascontrol many of the potential environmental factorsthat may impact gene function and neural develop-ment. Using a contextual fear-conditioning task, wetested mice on their ability to recall and generate

a fear response to a context in which they previ-ously received a series of three footshocks. This taskhas previously been shown to rely on the hippocam-pus. We found that contextual fear memory was sig-nificantly impaired in BDNFMet homozygous mice.These data provide additional convergent evidencefor a role for BDNF Val66Met and alterations inhippocampal memory function.14

BDNF Val66Met and affective disordersHuman studies attempting to link the Val66MetSNP with affective/anxiety disorders have resultedin mixed results. A 2008 meta-analysis focusing onthe Val66Met polymorphism and anxiety-relatedtraits reported no significant association betweenthe SNP and anxiety disorder or with harm avoid-ance, a trait that is thought to be closely associ-ated with anxiety and depression.25 They found thathealthy BDNFMet carrying subjects had significantlylower neuroticism scores than noncarriers. How-ever, in these studies the sample and effect sizeswere small. Another recent meta-analysis found nooverall association between carrying the BDNFMet

allele and diagnosis with major depressive disor-der (MDD),26 an effect that remained when strati-fied for ethnicity (Caucasian or Asian). Interestingly,when gender was taken into account, male homozy-gous carriers of the BDNFMet allele were signifi-cantly more likely to be diagnosed with MDD thannoncarriers. These results are consistent with an-other recent study in which BDNFMet homozygoussubjects exhibited significantly increased anxiety-related traits (e.g., harm avoidance, fear of un-certainty, and anticipatory worry) compared withnoncarriers.27

Other studies have begun to investigate the re-sponse to stress in BDNFMet allele carriers. In onesuch study, an interaction between early life stressand Val66Met status was found for measures ofanxiety and depression.23 Individuals carrying theBDNFMet allele who had been exposed to earlylife stress were found to have reduced hippocam-pal volume compared to noncarriers. The size ofthe hippocampi of these subjects was correlatedwith reduced lateral prefrontal cortex (PFC) vol-ume and higher depression scores. The interactionbetween BDNF genotype and early life stress also in-directly predicted higher scores on neuroticism andanxiety, albeit with modest effect sizes. In a sepa-rate study of healthy twins with either high or low

152 Ann. N.Y. Acad. Sci. 1208 (2010) 150–157 c© 2010 Association for Research in Nervous and Mental Disease.


familial risk for affective disorder, an interactionwas found between risk level and stress response.Individuals in the high-risk group and carrying theBDNFMet allele were found to have higher levelsof evening cortisol, suggesting that familial risk ofaffective disorders in combination with carrying theBDNFMet allele may impact stress responsiveness.28

This finding is consistent with another recent studyof subjects admitted with major depression in whichBDNFMet homozygous individuals were found tohave a greater hypothalamus-pituitary-adrenal re-sponse to dexamethasone challenge compared withBDNFMet heterozygotes and noncarriers.29

Because of its relative scarcity in the population,most human studies have difficulties reaching sta-tistical power for groups of BDNFMet homozygoussubjects. In the mouse model, this problem can beavoided. In the studies by Chen et al.14 only ho-mozygous BDNFMet/Met mice showed significantlyincreased anxiety-related behavior. The reported be-haviors included less spontaneous exploratory be-havior of the center of the open field and less timeand fewer entries into the open arms of the ele-vated plus maze compared with littermate controlBDNFVal/Val mice. Furthermore, the BDNFMet/Met

mice had greater latency to consume sweetenedmilk in the novelty-induced hypophagia task, atest that is regarded especially sensitive to chronicantidepressant-induced modulation of anxiety-likebehavior.30 Interestingly, the BDNFMet/Met mice didnot respond with decreased anxiety-like behavior tochronic (21 days) treatment with the selective sero-tonin reuptake inhibitor (SSRI) fluoxetine. In theexperiments performed by Chen et al.,14 only maleBDNFMet mice were used; however, the finding ofincreased anxiety-related behavior in the open fieldtask has also been replicated in female BDNFMet/Met

mice.31

BDNF Val66Met and fear-related behaviorModels of fear memory assess the response to fear-ful or neutral stimuli. The most commonly usedfear conditioning, Pavlovian classical conditioning,consists of a form of learning in which a neutralstimulus and/or context is associated with an aver-sive one, resulting in a fear response to the originallyneutral stimulus/context. The term fear extinctionis used to describe the process of gradual attenua-tion of a fear response to that stimulus after it is nolonger associated with danger.

As already mentioned, Chen et al.14 showed thatcontextual fear memory (i.e., fear response to theenvironment, where the aversive stimulus was deliv-ered) was attenuated in homozygous BDNFMet/Met

mice. However, in that same study, they noted nodifference between genotypes for cued-dependentfear memory.14

The first association between the Val66Met poly-morphism and ability to extinguish fearful memo-ries in the Val66Met transgenic mouse model wasdescribed by Yu et al.,32 using a conditioned tasteaversion task, in which mice were conditioned toassociate sucrose water with LiCl-induced nausea.The authors reported no effect of genotype on theacquisition or retention of the aversive memory.However, mice homozygous for the BDNFMet alleleshowed a marked decrease in the rate of extinctionfor this learned aversion. The slower extinction inBDNFMet homozygous mice was accompanied withlower levels of c-Fos expression in the ventromedialPFC (vmPFC), an area implicated in the extinctionof aversive memories.33–35 In addition, compared towild-type, littermate controls, naı̈ve BDNFMet ho-mozygous mice had diminished dendritic arboriza-tion as well as a 17% volume reduction of thevmPFC. Finally, the authors found that the impair-ment in fear extinction could be rescued by a sin-gle injection of the partial NMDA-receptor agonistd-cycloserine (DCS) during extinction training. Ina cohort of healthy human subjects, Hajcak et al.36

studied the relationship between the BDNFMet alleleand generalization of fear conditioned startle usinga paradigm similar to that originally developed byLissek et al.37 In this study, a paradigm where thedanger and safety cues consisted of rectangles of dif-ferent sizes and the aversive stimulus, a mild shock tothe triceps was always paired with the middle-sizedrectangle. It was found that BDNFMet allele carriersshowed a specific deficit in the startle response to themedium-sized rectangle (danger cue) but not to therectangle most similar in size. However, the samplesize was small (44 noncarriers, and 10 BDNFMet het-erozyotes and three BDNFMet homozygous carriersgrouped together). In another study investigatingfear potentiated startle, where a picture was pairedwith a mild shock to the ankle, the authors reportedthat BDNFMet allele carriers showed a reduced star-tle response to the aversive stimulus in late acqui-sition and early extinction blocks, but no effect onskin conductance. Again, the sample size was small



(39 noncarriers, and seven BDNFMet heterozygotesand two BDNFMet homozygotes).

In a recent translational study, we found thathuman BDNFMet allele carriers have intact fearconditioning but impairments in the extinction ofa learned fear response, as measured by skin con-ductance.38 This finding was replicated in a par-allel study conducted in BDNF Val66Met knockinmice. In mice that were conditioned to anticipatea mild footshock following a tone, BDNFMet micefailed to suppress the learned fear response overthe course of 30 extinction trials. This impairmentwas dose-dependent, such that mice homozygousfor BDNFMet were significantly slower than het-erozygous mice. The parallel human experimentsinvolved 36 healthy young adults (noncarriers) and36 BDNFMet allele carriers (31 heterozygotes andfive BDNF homozygotes). While undergoing fMRI,participants were fear conditioned by presentationof two different colored squares, one of which waspaired with an aversive sound. Once an associationwas formed, extinction was carried out by multi-ple presentations of both squares in the absenceof the aversive sound. The BDNFMet human sub-jects were found to have decreased activation of thevmPFC compared with noncarriers, a finding con-sistent with a failure to effectively engage circuitryimplicated in fear extinction. This was consistentwith findings in BDNFMet mice, in which lower lev-els of c-Fos were found in the vmPFC of BDNFMet

mice following extinction training.

Discussion: relevance for PTSD

PTSD is a condition characterized by increased anx-iety as well as a reduced ability to extinguish fear-ful memories after exposure to one or more trau-matic events. There is also a significant comorbid-ity with MDD. To date, only one publication pro-vides data on a possible link between Val66Met sta-tus and PTSD. In that study, no overrepresentationof BDNFMet allele carriers was seen in a cohort of96 war veterans diagnosed with PTSD.39 However,this result was inconclusive because of low statis-tical power, and further studies are warranted. Inthe largest study focusing on the acquisition of fear-related behavior, neither humans nor mice carryingthe BDNFMet allele showed any difference in the abil-ity to learn to generate a conditioned fear response toa cue.38 BDNFMet mice had decreased expression of

a contextual fear memory,14 which in theory couldpartially be a protective factor for the developmentof PTSD symptoms. However, that protective effectwould likely be overshadowed by the impaired orslowed ability to extinguish fearful memories.

We concluded, based on the currently availableliterature, that the variant BDNF Val66Met poly-morphism does not consistently confer an increasedoverall risk for affective- or anxiety-related disordersor traits. The only correlation found in a large meta-analysis suggested that males homozygous for theBDNFMet allele have an increased risk of developingMDD.26

Although most of the human studies to date havenot found a conclusive relationship between a sin-gle BDNFMet allele and anxiety-related traits, it isstill unclear whether the same is true for homozy-gous BDNFMet allele carriers. This is in part dueto low statistical power given the low percentageof homozygous individuals in the population. Bycontrast, the mouse model clearly indicates thereis a dose–response relationship between the num-ber of alleles and anxiety-related behavior.14 Hence,the mouse model provides robust evidence for ananxiety-like endophenotype that has been replicatedin both male and female homozygous mice. In sup-port of these findings, a recent study on healthy vol-unteers with a large number of homozygotes foundthat only homozygote carriers of the BDNFMet al-lele scored significantly higher on measures of anx-iety compared to noncarriers. This effect replicatedacross both sexes.27

Both human and rodent BDNFMet allele carriers,after being exposed to an aversive event, are slowerto show an attenuated response to a cue that haspreviously been associated with that aversive event,even after that cue no longer represents danger, thatis, impaired fear extinction.32,38 The study by Soli-man et al.38 found a significant impairment in fearextinction in heterozygous BDNFVal/Met individu-als. In addition to the behavioral findings, Solimanet al.38 also show that BDNFMet allele carriers recruitthe amygdala and vmPFC differently than noncar-riers. This is a similar pattern of increased amygdalaactivation and decreased medial PFC (mPFC) acti-vation to what has been observed in fMRI studiesof PTSD patients.40,41 In addition, the relative ex-tent of decrease in amygdala activation during fearextinction has been correlated with the degree ofextinction success in healthy volunteers.35



Extinction of fearful memories is thought to bebrought on by the formation of a new memory,one that associates the stimulus previously pairedwith a fearful event with one that signals safety. Thisis in contrast to the notion that fear extinction isin fact an erasure of the original memory. Recentfindings suggest that BDNF availability in the in-fralimbic mPFC from hippocampal projections iscritical for the formation of such new memories.42

It is therefore conceivable that the reduced activity-dependent secretion of BDNF associated with theBDNFMet allele leads to decreased synaptic plasticityin the mPFC and thereby deficiency in the formationof the new memory required for fear extinction.

There is a significant need for new therapeuticdirections for many psychiatric disorders. In addi-tion to new therapies, a lot would be gained if theuse of currently available pharmacological and psy-chotherapeutic therapies could be more effectivelyused. In the case of PTSD, a recent meta-analysisshowed that, on average, 80% of PTSD patientsimproved by 70% using different therapeutic ap-proaches.43 With today’s diagnostic tools, it is verydifficult to predict who will benefit the most from aparticular therapy. Furthermore, many patients gothrough a painful “trial and error” phase before themost effective therapeutic combination for that par-ticular individual is established. Hence, biomarkersthat predict treatment response would be very ben-eficial.

In the mouse model, adult BDNFMet mice showblunted alteration in anxiety-like behaviors afterchronic SSRI treatment,14 the most commonly usedpharmacological treatment for PTSD. The recentstudy by Soliman et al.38 also validates that both hu-mans and mice carrying the Met allele are worse at,or at least take longer, to extinguish fearful memo-ries. This finding implies that they may not respondas readily to exposure therapy, which is one of thebest documented and most widely used psychother-apeutic approaches for PTSD.44 The fact that expo-sure therapy relies on intact ability to extinguishfearful memories suggests that it could be informa-tive to genotype PTSD patients with regard to BDNFVal66Met in order to be able to offer modified or al-ternative treatment strategies.

Therapies aimed at normalizing BDNF functioncould be divided into at least two different cate-gories: (i) therapies aimed at normalizing BDNFsecretion during development in order to rescue

structural changes caused by BDNF Val66Met and(ii) therapies aimed at normalizing BDNF secretionin adult life in order to ensure intact moment tomoment BDNF-dependent synaptic plasticity andrelated functions. Drug discovery strategies to in-crease BDNF release from synapses or to prolongthe half-life of secreted BDNF may improve ther-apeutic responses for humans with this commonBDNF polymorphism.

Alternatively, therapies that do not involve BDNFsignaling could be used to circumvent the deficit inBDNF signaling as well as the decreased responseseen after SSRI treatment. As BDNF Val66Met statusis suggested to be associated with an impaired abilityto extinguish fearful memories, therapies aimed atenhancing fear extinction could be extremely useful.DCS, a partial NMDA receptor agonist, has emergedas one of the most promising pharmacological ther-apies aimed at enhancing fear extinction, that is,the efficacy of exposure therapy.45,46 Several studiesreport beneficial effects of DCS administered be-fore early sessions of exposure therapy for patientsdiagnosed with acrophobia and social phobia.46,47

Clinical studies evaluating the effects of DCS in en-hancing exposure therapy for PTSD are currentlyunder way. As NMDA receptors are necessary forBDNF-induced fear extinction,42 it is plausible thatNMDA receptor modulation could be an efficientmeans of bypassing the deficit in fear extinctionsupposedly caused by disrupted BDNF secretion inBDNFMet allele carriers. In the mouse model, Yuet al.32 demonstrated that one dose of DCS at acritical time during fear extinction can rescue theimpairment associated with the Val66Met status.Future studies are needed to confirm whether expo-sure therapy combined with NMDA receptor mod-ulators could be of similar value for PTSD patientscarrying the BDNFMet allele.

Propranolol, a nonselective �-blocker, has alsobeen proposed to attenuate subsequent fear re-sponse when administered directly after retrieval ofa previously experienced traumatic event.48 How-ever, preliminary results from clinical trials us-ing propranolol in the immediate aftermath of atraumatic event to prevent development of PTSDhave failed to show a significant effect of the treat-ment.49,50

Recent findings from both rodent and humanstudies also suggest that fear memories can be dis-rupted without the use of any drugs by performing



fear extinction during reconsolidation within a lim-ited time window after reexposure to a cue that pre-dicts the aversive event,51,52 an approach that maybe beneficial in BDNFMet allele carriers.

In conclusion, several new therapies are emergingthat may be used alone or in concert for PTSD pa-tients who do not successfully respond to SSRI andconventional exposure therapy alone. Further stud-ies are needed to clarify whether Val66Met geno-type confers an increased risk for the developmentof affective disorders, including PTSD. Independentof that, recent studies suggest that BDNF genotypebased therapy could be applicable for PTSD as wellas other affective- and anxiety-related disorders. Thestudy by Soliman et al.38 also implicates that, asidefrom genotype, behavioral tests of extinction capac-ity and neuroimaging could also serve as biomark-ers to direct more personalized psychiatric treat-ment. Future studies on patient cohorts will eluci-date whether these biomarkers prove to be useful ina clinical setting.

Acknowledgments

We acknowledge support from the Swedish BrainFoundation (H.F.), the Gylling family (H.F.),NIH Grants MH079513 (B.J.C., F.S.L.), MH060478(B.J.C.), NS052819 (F.S.L.), GM07739 (F.S.), andUnited Negro College Fund–Merck Graduate Sci-ence Research Dissertation Fellowship (F.S.), Bur-roughs Wellcome Foundation (F.S.L.), and the In-ternational Mental Health Research Organization(F.S.L).

Conflicts of interest

The authors declare no conflicts of interest.

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