Association of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism With Reduced Hippocampal Volumes in Major Depression

Department of Psychiatry and Psychotherapy and Radiology, Ludwig-Maximilians University, Munich, Germany.
Archives of General Psychiatry (Impact Factor: 14.48). 04/2007; 64(4):410-6. DOI: 10.1001/archpsyc.64.4.410
Source: PubMed


Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity, which is believed to be altered in patients with major depression.
To examine the effect of the BDNF Val66Met polymorphism on hippocampal and amygdala volumes in patients with major depression and in healthy control subjects.
Cross-sectional comparison between patients and controls.
Inpatients with major depression from the Department of Psychiatry and Psychotherapy and healthy controls from the community were recruited.
The study population of 120 subjects included 60 patients with major depression and 60 healthy controls.
Using a combined strategy, hippocampal and amygdala volumes were estimated on high-resolution magnetic resonance images, and genotyping was performed for the BDNF Val66Met polymorphism.
Patients had significantly smaller hippocampal volumes compared with controls (P = .02). Significantly smaller hippocampal volumes were observed for patients and for controls carrying the Met-BDNF allele compared with subjects homozygous for the Val-BDNF allele (P = .006). With respect to amygdala volumes, no significant differences between patients and controls and no significant main effects for the BDNF Val66Met polymorphism were observed.
These genotype-related alterations suggest that Met-BDNF allele carriers might be at risk to develop smaller hippocampal volumes and may be susceptible to major depression. This study supports findings from animal studies that the hippocampus is involved in brain development and plasticity.

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Available from: Ronald Bottlender, Oct 27, 2014
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    • "As a result, participants were divided into three genotype groups: homozygous groups for methionine (bdnfmet66met) and valine alleles (bdnfval66val), and a heterozygous group carrying one methionine and one valine allele (bdnfval66met). Heterozygous individuals and subjects with two methionine alleles were combined into one group of methioninecarriers (bdnfval66met-or-bdnfmet66met), as has been done in previous functional magnetic resonance imaging (fMRI) studies investigating Val66Met polymorphism (Lau et al., 2010; Montag et al., 2008) since methionine homozygotes are infrequent (Shimizu et al., 2004), and having at least one methionine allele is associated with susceptibility to MDD (Frodl et al., 2007). After t procedure, four groups of participants were "
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    ABSTRACT: Rs6265 single nucleotide polymorphism, which influences brain-derived neurotrophic factor (BDNF) levels in the cortical and subcortical brain structures, may result in distinguished patterns of neural activation during a major depressive disorder (MDD) episode. Valine homozygotes with high levels of BDNF and methionine carriers with lower levels of BDNF may present specific neural correlates of MDD. In our study we have tested differences in blood oxygen level dependant (BOLD) signal between individuals with MDD and healthy controls for both allelic variants. Individuals with MDD (N=37) and healthy controls (N=39) were genotyped for rs6265 and compared separately in each allelic variant for BOLD response in a functional magnetic resonance imaging experiment examining appraisal of emotional scenes. The two allelic variants were also compared separately for both individuals with MDD and healthy controls. In the homozygous valine group MDD was associated with decreased neural activation in areas responsible for cognitive appraisal of emotional scenes. In the methionine group MDD was related to increased activation in subcortical regions responsible for visceral reaction to emotional stimuli. During an MDD episode methionine carriers showed more activation in areas associated with cognitive appraisal of emotional information in comparison to valine homozygotes. Small sample size of healthy controls carrying methionine (N=8). Our results suggest that allelic variations in the rs6265 gene lead to specific neural correlates of MDD which may be associated with different mechanisms of MDD in the two allelic groups. This may have potential importance for screening and treatment of patients. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jun 2015 · Journal of Affective Disorders
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    • "For both genes RT-PCR was performed on a TaqMan ABI PRISM s 7000 sequence detection system (Applied Biosystems) for allelic discrimination. Participants were classified into two groups: Val/Val and Met (Met/Met and Met/Val genotypes), on account of the dominant nature of the Met allele (Frodl et al., 2007). "
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    ABSTRACT: BACKGROUND: Whether the Brain Derived Neurotrophic Factor (BDNF) Val66Met polymorphism can predict antidepressant drug efficacy in depressed patients remains unclear, suggesting that it may depend on antidepressant classes. We assessed the impact of Val66Met polymorphism on antidepressant response and remission depending on antidepressant classes. METHODS: In a 6-month prospective, real-world setting, treatment study, 345 Caucasian depressed patients requiring a new or different drug treatment with a selective serotonin reuptake inhibitor (SSRI), a serotonin and noradrenalin reuptake inhibitor (SNRI) or a tricyclic antidepressant (TCA), were genotyped and assessed for response and remission. RESULTS: 231 (67%) patients were homozygous for the Val66 allele (Val/Val) and 114 (33%) were carriers of Met allele (Met). 152 (44.1%) patients were treated with SSRI, the others with SNRI/TCA. Both response and remission were explained by interactions between the Val66Met polymorphism and antidepressant drug classes (multivariate models adjusted for propensity-scores: p=0.02 and p=0.03 respectively). With SSRI, Val/Val patients had a higher response rate 3 months post-treatment than Met patients (68.1% versus 44%; adjusted-OR: 3.04, IC95% [1.05; 9.37], p=0.04). With SNRI/TCA, Val/Val patients had a lower remission rate 6 months post-treatment than Met patients (33.3% versus 60.9%, adjusted-OR: 0.27, IC95% [0.09; 0.76], p=0.02). LIMITATIONS: Limited sample size. CONCLUSIONS: This study argues for a personalized prescription of antidepressants in Caucasian patients with major depressive disorder, based on the BDNF Val66Met polymorphism: SSRI should be preferred for Val/Val patients and SNRI/TCA for Met patients. Further studies are required to confirm these data.
    Full-text · Article · Apr 2015 · Journal of Affective Disorders
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    • "For example, previous research points to the involvement of variation in BDNF Val 66 Met polymorphism in the pathophysiology of depression and anxiety disorders. Studies using magnetic resonance imaging found that Met 66 allele carriers with depression had smaller hippocampal volumes than Val 66 Val carriers (Frodl et al., 2007). Smaller hippocampal volume is also a general characteristic of major depression (Videbech and Ravnkilde, 2004). "
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    ABSTRACT: Smoking, especially nicotine dependence is associated with more severe symptoms of depression and anxiety disorders. However, the mechanisms underlying this association are unclear. We investigated the effect of brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism on the severity of depressive and anxiety symptoms in never-smokers, former smokers, non-dependent, and nicotine-dependent smokers with a current diagnosis of depression and/or anxiety. Patients with depressive or anxiety disorders and with available BDNF Val(66)Met polymorphism data (N=1271) were selected from Netherlands Study of Depression and Anxiety (NESDA). Dependent variables were severity of symptoms. Independent variables were smoking status and BDNF genotype. Age, sex, education, recent negative life events, alcohol use, body mass index, and physical activity were treated as covariates. After controlling for covariates, nicotine-dependent smokers had more severe depressive symptoms than non-dependent smokers, former and never-smokers. The latter three groups did not differ in severity of depression. In Val(66)Val carriers, nicotine-dependent smokers had more severe symptoms of depression and anxiety than the other three groups, which were comparable in symptom severity. In Met(66) carriers, there were no group differences on severity of depression and anxiety. Nicotine dependence was the strongest predictor of severity of symptoms only in Val(66)Val carriers. In patients with a current diagnosis of depression or anxiety, the relationship between nicotine dependence and symptom severity may be moderated by BDNF Val(66)Met. These results suggest that inherent genetic differences may be crucial for the worse behavioral outcome of nicotine, and that Val(66)Val carriers may benefit most in mental health from smoking cessation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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