Jacqueline Le

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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