TO THE EDITOR
Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology of major depression, as well as the therapeutic action of antidepressants.1,2) Serum levels of BDNF in drug naïve patients with major depression are significantly lower than those in normal controls. Additionally, serum levels of BDNF in drug naïve patients can be returned to control levels with antidepressant treatment,3) suggesting that serum BDNF may be a biomarker for major depression. This finding is supported by a meta-analysis study.4)
A single nucleotide Val66Met polymorphism is located within the BDNF precursor proBDNF, but not the mature BDNF protein. This polymorphism is associated with cognition (e.g., episodic memory and extinction learning) and hippocampal volume in humans.5,6) Knowing that ketamine is the most effective drug for treating refractory depression, I read with interest the article by Liu et al.7) that described the role of this BDNF Val66Met polymorphism in ketamine-induced synaptogenic and antidepressant responses in mice. Using knock-in mice with the BDNF Val66Met mutation,6,8) the authors found that mice with the Met allele displayed constitutive atrophy of distal apical dendrites and decreases in apically targeted, excitatory postsynaptic currents in layer V pyramidal cells of the prefrontal cortex. Additionally, mice with the Met allele showed decreased spine density and diameter, as well as impaired synaptic formation/maturation (synaptogenesis). Interestingly, no ketamine-induced antidepressant or synaptogenic effects were detected in Met/Met mice. These findings imply that expression of the BDNF Met allele results in basal synaptic deficits that block the synaptogenic and antidepressant actions of ketamine. The authors concluded that the therapeutic response to ketamine may be attenuated or blocked in patients with depression if they carry the Met allele.
A recent study using conditional BDNF gene knock-out mice showed that ketamine increases the level of BDNF in the hippocampus, and that ketamine-induced antidepressant effects are absent in BDNF null mice,9) again, suggesting a role for BDNF in the ketamine mechanism of action. Originally, Chen et al.8) reported no differences in the levels of BDNF between the brains of mice with the Met allele and those in wild-type (Val/Val) mice, although the hippocampal volume of mice with the Met allele was significantly lower than in wild-type mice. Furthermore, mice carrying the Met allele showed anxiety-related rather than depressive behavior.8,10) Mature BDNF and proBDNF activate two distinct receptors, the tropomyosin-related kinase B receptor and the p75 neurotropin receptor (p75NTR), respectively.2,10) Therefore, it is likely that disturbances in p75NTR signaling, mediated by proBDNF with a Met allele, may result in a lack of synaptogenic and antidepressant effect of ketamine in mice, although a further study will be needed to examine this in more detail.
The Met allele occurs at a 40-50% frequency within the Asian population, which is significantly higher than the 20-30% frequency seen in Caucasian populations.11,12) This would indicate an ethnic-based difference in the distribution for this polymorphism.11) Given the role of the Met allele in susceptibility to stress-related major depression,12) these results imply a higher prevalence of depression in Asian populations compared with Caucasian populations. However, this is not the case, indicating the involvement of other genetic and environmental factors, along with BDNF, in disease pathogenesis.
In conclusion, proBDNF proteins carrying the Val and Met polymorphism may be present in the serum of subjects with a BDNF Val66Met mutation. Therefore, it would be of great interest to determine whether proBDNF proteins with either the Val or Met amino acid or mature BDNF could be used as novel biomarkers for major depression.2) In addition, it may be of interest to examine whether patients who are resistant to the rapid antidepressant effects of ketamine carry the Met allele.
References
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