The Role of Brain Derived Neurotrophic Factor on Major Depressive Disorder
Introduction: Major Depressive disorder (MDD) is a mood disorder characterized by sadness and loss of interest in daily life. It occurs in women almost twice as often, and affects about 6% of the adult population.1,4 Currently, monoamine transmitter therapies are used to strengthen neural circuits and improve mood, but half of patients are unresponsive, indicating the need for more effective therapies.2 Research is shifting towards brain derived neurotrophic factor (BDNF) as a target, since it increases neural plasticity.9 Studies have found that pre-existing drugs could improve MDD through increasing BDNF expression. Other studies explore the role of the glutamate N-methyl-D-aspartate receptor (NMDA) receptor on BNDF levels in MDD.6,8 These findings highlight BDNF inducing drugs as potential MDD pharmacotherapies. Methods: One study analyzed 1280 compounds and explored effects on BDNF to identify unknown BDNF inducers. Neurons from Bdnf-luc mice embryos were treated with different compounds and screened for BDNF expression. RT-PCR was then used to measure changes in BDNF mRNA levels.6 Another study investigated ketamine’s effect on increasing BDNF and MDD improvement. 53 patients in a random controlled study were infused with subanesthetic ketamine and BDNF levels were monitored at 2 and 24 hours through 3 blood draws. Whole brain regression was also performed to relate the change in BDNF with brain function.8 Results: Dipyrone was found to increase BDNF mRNA levels the most at 3 and 6 hours, concluding that dipyrone likely indirectly induces neuronal activity, potentially through glutamate signals. 6 BDNF levels were also found to be significantly increased after the infusion of ketamine at 2 hours and 24 hours. There is strong evidence that neuronal BDNF transmission is increased through a spike in glutamate transmission, indicating the NMDA receptor as a key drug target. Ketamine activates ionotropic glutamate receptors, leading to an induction of an activity-dependent release of BDNF in neurons.8 Conclusions: Studies have established that BDNF uses high affinity tyrosine kinase B receptors (trkB) to signal synapse formation and plasticity. The transport of BDNF and trkB to the dendrites signals the upregulation and activation of NMDA-R, causing a glutamate surge that induces BDNF release. These results support the neurotrophic hypothesis that BDNF is key in hippocampal development and should be a better target than current pharmacotherapies. The exact mechanism of BDNF function and how this pathway can be targeted needs further investigation.
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