The Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Prediction of Neural Risk for Alzheimer Disease (original) (raw)

2011, Archives of General Psychiatry

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine shows rapid antidepressant efficacy-within 1 hour-in individuals with treatment-resistant major depressive disorder (MDD) (1,2) and bipolar disorder (3). This rapid antidepressant effect is in stark contrast to the lag typically associated with traditional monoamine-modulating medications, which require weeks to become effective. Ongoing studies are investigating the cellular and molecular mechanisms underlying ketamine's beneficial effects (4,5), with a view to both expanding our understanding of affective disorders and developing effective, viable, and rapid-acting treatments. A recent series of elegant animal studies suggest that increased brain-derived neurotrophic factor (BDNF) function is a necessary component of the antidepressant response of ketamine and other NMDA antagonists (5). BDNF is critical to neuronal plasticity (6) and thought to be strongly associated with the pathophysiology of affective disorders (7). In a recent issue of Biological Psychiatry, Liu and colleagues (8) compared the role of the Val66Met (rs6265) single nucleotide polymorphism (SNP), a putatively functional polymorphism within the first exon of BDNF, and ketamine response. BDNF knock-in mice (Val/Val, Val/Met, Met/Met) had differing levels of prefrontal cortex synaptogenesis after drug administration on the basis of this single polymorphism. Homozygous Val/Val mice exhibited a stronger neural response than Met carriers, with homozygous Met/Met carriers