The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression

Hwang, Jen‐Ping; Tsai, Shih‐Jen; Hong, Chen‐Jee; Yang, Chen-Hong; Lirng, Jiing‐Feng; Yang, Yamin

doi:10.1016/j.neurobiolaging.2005.10.013

Cited by 229 publications

(186 citation statements)

References 23 publications

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“…The BDNF G196A SNP has been studied for its possible association with Alzheimer's disease and depression, but reports are contradictory [25][26][27][28][29]. In the present study we found no association between this SNP and diabetes or obesity.…”

Section: Discussioncontrasting

confidence: 75%

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

et al. 2006

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Aims/hypothesis Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer's disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. Subjects and methods We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic-euglycaemic clamp.Results Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Conclusions/interpretation Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.

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Section: Discussioncontrasting

confidence: 75%

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

et al. 2006

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“…102 Increased Met allele expression in 110 depressed elderly Chinese subjects. 103 Met allele associated with expression of suicidal and psychotic symptoms in 154 depressed Japanese subjects. 104 Mice homozygous for the BDNF Met allele exhibit a decrease in biologically relevant BDNF release, an increase in anxiety-like behaviour and an attenuated anxiolytic response to chronic fluoxetine.…”

Section: Resultsmentioning

confidence: 99%

“…However, the conclusion that it is an increase in Met as opposed to Val expression which is associated with depression vulnerability, argues directly against the hypothesized 'protective' role of Met, as proposed by Sen et al 92 This has also been reported in a number of human studies, with the Met allele most associated with increased risk avoidance behaviour (a measure of anxious temperament) 102 and showing greatest expression in individuals suffering from anxiety disorders and depression. 102,103 It has also been reported that Met expression is not associated with the development of depression per se, but with clinical features such as psychosis and suicidal behaviour. 104 However, others have found no such associations (Table 4).…”

Section: Evidence Formentioning

confidence: 99%

Is it time to reassess the BDNF hypothesis of depression?

2007

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The brain-derived neurotrophic factor (BDNF) hypothesis of depression postulates that a loss of BDNF is directly involved in the pathophysiology of depression, and that its restoration may underlie the therapeutic efficacy of antidepressant treatment. While this theory has received considerable experimental support, an increasing number of studies have generated evidence which is not only inconsistent, but also directly contradicts the hypothesis. This article provides a critical review of the clinical and preclinical studies which have been responsible for this controversy, outlining pharmacological, behavioural and genetic evidence which demonstrates the contrasting role of BDNF in regulating mood and antidepressant effects throughout the brain. I will also review key studies, both human and animal, which have investigated the association of a BDNF single-nucleotide polymorphism (Val66Met) with depression pathogenesis, and detail the number of inconsistencies which also afflict this novel area of BDNF research. The article will conclude by discussing why now is a critical time to reassess the original BDNF hypothesis of depression, and look towards the formation of new models that can provide a more valid account of the complex relationships between growth factors, mood disorders and their treatment.

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“…Male BDNF Val66Met carriers have been shown to be at increased risk to develop depression, an effect that has recently been confirmed by the largest meta-analysis to date (Verhagen et al, 2010). In addition, carriers of the BDNF Val66Met SNP that develop depression often demonstrate more severe symptoms than individuals who are non-carriers (Hwang et al, 2006;Iga et al, 2007;Sarchiapone et al, 2008;Verhagen et al, 2010). Despite these findings, significant questions remain regarding the mechanisms underlying BDNF's contribution to the development of affective disorders and the potential role of this SNP in treatment response (Tsai et al, 2010).…”

Section: Introductionmentioning

confidence: 86%

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Bath

Jing

Dincheva

et al. 2012

Neuropsychopharmacol

155

114

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Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRIinduced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF Val/Val ) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF Met/Met ). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.

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The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression

Cited by 229 publications

References 23 publications

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Is it time to reassess the BDNF hypothesis of depression?

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

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