A BDNF Val66Met Polymorphism and Ketamine-induced Rapid Antidepressant Action

TO THE EDITOR Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) plays a key role in the patho-physiology 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. 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 ket-amine 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 ap-ical dendrites and decreases in apically targeted, ex-citatory postsynaptic currents in layer V pyramidal cells of the prefrontal cortex. Additionally, mice with the Met al-lele showed decreased spine density and diameter, as well as impaired synaptic formation/maturation (synaptogen-esis). Interestingly, no ketamine-induced antidepressant or synaptogenic effects were detected in Met/Met mice. These findings imply that expression of the BDNF Met al-lele results in basal synaptic deficits that block the syn-aptogenic 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 knockout mice showed that ketamine increases the level of BDNF in the hippocampus, and that ketamine-induced antidepre-ssant 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 tropomyo-sin-related kinase B receptor …