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Brain-Derived Neurotrophic Factor Polymorphism as a Genetic Risk for Depression? A Short Review of the Literature
Burak Yuluğ; Erol Ozan; Ertugrul Kilic
The Journal of Neuropsychiatry and Clinical Neurosciences 2010;22:123.e5-123.e6.

To the Editor: Brain-derived neurotrophic factor (BDNF) is a small dimeric neuroprotective protein and a member of the neurotrophin family which is widely expressed in the mammalian adult brain. It plays a critical role in the development, maintenance, and proliferation of peripheral (PNS) and central (CNS) nervous systems.1 The evidence regarding the antiapoptotic effect of BDNF through the mitochondrial membrane stabilization via the cell survival proteins is rapidly replicating (i.e., B cell lymphoma protein).1

Recent studies indicated that functional polymorphism of the BDNF gene, which includes a substitution of a valine for a methionine amino acid at the codon 66 (val66met), plays an important role in a predisposition to depression and cognitive deficits.

Regarding the data that the BDNF is a stress response neurotrophic factor reversing the devastating effect of stress on the limbic structures (i.e., atrophy and cell loss), as well as increasing evidence regarding limbic atrophy as a risk factor even in healthy individuals for depression, it can be hypothesized that BDNF plays a critical role in the development of depression.2,3 However, in light of previous findings indicating that limbic atrophy is related to cognitive dysfunction, it is possible that psychiatric patients who have limbic atrophy are more prone to show memory impairment.

Recent studies showed that BDNF val66met polymorphism has a negative impact on hippocampal volumes in patients with major depression and healthy individuals.3 These memory deficits during depression have been linked with BDNF polymorphism, whereas "met-carrier" humans who carry the methionine variant (val/met + met/met) exhibit abnormal hippocampal activity during episodic memory performance.4 Furthermore, studies indicating a significant association between the BDNF val66met polymorphism and depression severity are also rapidly replicating.3 In this respect, we have previously shown that there is a strong link between the BDNF polymorphism, depression severity, and the serum BDNF levels in depressed patients.5

These interesting findings suggested by neuroimaging studies indicate that reduced gray matter volume in the hippocampus and in the dorsolateral prefrontal cortex is implicated in mood regulation and cognitive performance.4,6 This is in accordance with recent studies showing that BDNF polymorphism can increase the risk for rapid cycling bipolar disorder and impairs the working memory performance in individuals with bipolar disorder and schizophrenia.7

Taken together, these studies indicate that BDNF val66met polymorphism is a significant genetic factor that affects the prefrontal and hippocampal function, which in turn not only has a negative impact on cognitive performance but may also increase the risk for developing depression.

In light of the evidence indicating impaired secretion of BDNF in individuals with the met66 allele, we hypothesize that these individuals are less able to adapt to stress which results not only in the altered structure or function of the hippocampus but also in the increased risk of depression. This opens a new window which should be evaluated with further experiments in the field of psychobiology research.

.
Peng CH, Chiou SH, Chen SJ, et al: Neuroprotection by imipramine against lipopolysaccharide-induced apoptosis in hippocampus-derived neural stem cells mediated by activation of BDNF and the MAPK pathway. Eur Neuropsychopharmacol 2008; 18:128—140
 
.
Heuser I, Lammers CH: Stress and the brain. Neurobiol Aging 2003; 24:69—76
 
.
Frodl T, Schüle C, Schmitt G, et al: Association of the brain-derived neurotrophic factor val66met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 2007; 64:410—416
 
.
Egan MF, Kojima M, Callicott JH, et al: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112:257—269
 
.
Yulay B, Ozan E, Aydin N, Kirpinar I: Brain-derived neurotrophic polymorphism: more than a prognostic factor during depression? J Neuropsychiatry Clin Neurosci 2009; 21:471—472
 
.
Pesawas L, Verchinski BA, Mattay VS, et al: The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neuroscience 2004; 24:10099—10102
 
.
Rybakowski JK, Borkowska A, Skibinska M, et al: Illness-specific association of val66met BDNF polymorphism with performance on Wisconsin Card Sorting Test in bipolar mood disorder. Mol Psychiatry 2006; 11:122—124
 
+

References

.
Peng CH, Chiou SH, Chen SJ, et al: Neuroprotection by imipramine against lipopolysaccharide-induced apoptosis in hippocampus-derived neural stem cells mediated by activation of BDNF and the MAPK pathway. Eur Neuropsychopharmacol 2008; 18:128—140
 
.
Heuser I, Lammers CH: Stress and the brain. Neurobiol Aging 2003; 24:69—76
 
.
Frodl T, Schüle C, Schmitt G, et al: Association of the brain-derived neurotrophic factor val66met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 2007; 64:410—416
 
.
Egan MF, Kojima M, Callicott JH, et al: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112:257—269
 
.
Yulay B, Ozan E, Aydin N, Kirpinar I: Brain-derived neurotrophic polymorphism: more than a prognostic factor during depression? J Neuropsychiatry Clin Neurosci 2009; 21:471—472
 
.
Pesawas L, Verchinski BA, Mattay VS, et al: The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neuroscience 2004; 24:10099—10102
 
.
Rybakowski JK, Borkowska A, Skibinska M, et al: Illness-specific association of val66met BDNF polymorphism with performance on Wisconsin Card Sorting Test in bipolar mood disorder. Mol Psychiatry 2006; 11:122—124
 
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