BDNF play a key role in synaptic plasticity in the brain.It mediates long-term potentiation in the hippocampus (hence important in associative learning and memory consolidation process).BDNF is thought to be involved in extinction learning (i.e. a previously feared stimulus (conditioned stimulus) becomes associated with safety signals = inhibitory associative learning) as consolidation of such learning requires plasticity in certain brain areas. 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).The Methionine allele ( Met/Met or Val/Met) is associated with reduced activity dependent secretion of BDNF. Met allele carriers also fail in extinction learning.
Would patients with PTSD,(= extinction learning has failed in PTSD i.e. fearful memories stay alive), respond to treatment differently depending on BDNF genotype?
Kim L. Felmingham, Carol Dobson-Stone, Peter R. Schofield, Gregory J. Quirk, and Richard A. Bryant investigates this interesting question.
Adult patients with PTSD (motor vehicle accidents and physical assaults), who are not on any psychotropic medications,completed 8 weekly 90-minute individual CBT sessions. Genomic DNA was extracted from mouth swabs or via saliva samples.The BDNF Val66Met genotypes were determined by mass spectrometry analysis .The genotype frequencies of the 55 participants were 54.5% Val/Val (n = 30), 40% Val/Met (n = 22), and 5.5% Met/Met (n= 3). Because the rarity of the Met/Met genotype, Val/Met and Met/Met genotypes were grouped together for analyses. 55 patients completed the full treatment with 30 BDNF Val/Val homozygotes and 25 BDNF Met allele carriers.
No significant differences between the Val/Val and Met carrier groups on any background variables.
BDNF Met group showed a reduced response to exposure treatment with a 40% reduction in CAPS (Clinician administered PTSD Scale) score post treatment, whereas the Val/Val group showed a 62% reduction in CAPS score. BDNF genotype was found to be a significant predictor of response to exposure therapy ie BDNF Met-66 low activity dependent secretion allele displayed poorer response to exposure therapy than the Val/Val genotype group. BDNF genotype contributed 14% of the variance in treatment response after controlling for these other significant predictors.
There are two explanations emerging from this study.Low level BDNF could be predictive of poorer extinction learning and hence predict reduced efficacy of an extinction-based therapy. Other explanation is that BDNF interacts with the pathogenesis of PTSD to yield a disease subtype that is differentially responsive to subsequent exposure-based treatment.
The low-expression allele of the serotonin transporter gene was previously shown to be associated with poor treatment response in PTSD. This is the first study to show that the functional BDNF Val66Met polymorphism can predict the response to exposure-based therapy.
Comments: Small sample size and hence results should be considered as preliminary. Important research contributing to our understanding of genomic predictors of treatments.Findings have greater relevance for Asians ( where Met allele is abundant). Frequency among Caucasians is less than 20%.
In the accompanying commentary Mary-Anne Enoch suggests the need for investigating other gene pathways like COMT and genes within the GABA ergic and serotonergic systems.
Summary of the article:
Felmingham KL, Dobson-Stone C, Schofield PR, Quirk GJ, Bryant RA. Biol Psychiatry. 2013 Jun 1;73(11):1059-63.