Jacqueline Le

Introduction: Major Depressive disorder (MDD) is a mood disorder characterized by sadness, isolation, and a loss of interest in parts of daily life. It occurs in women almost twice as often, and affects about 6% of the adult population worldwide. MDD is the 2^nd leading cause of disabilities and is a global health crisis. ^{1, 4} Currently, tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors or SNRI’s are key players. These generally work by inhibiting the reuptake of neurotransmitters into neurons, elongating the time that they are in the synapse, communicating with other cells. This works to strengthen neural circuits and improve mood; however, about half of patients have no response after their first antidepressant.² Research is shifting from a focus on these monoamine transmitters to a neurotrophic hypothesis, which focuses on growth factors like brain derived neurotrophic factor (BDNF) as a drug target due to its established role in brain development and neural plasticity maintenance.⁹ Studies have found that drugs currently used for different purposes may have therapeutic effects on MDD through increasing levels of depression. Other studies explore and confirm the role of the NMDA receptor and BNDF levels in MDD.^6,8 These findings point to BDNF as a promising new drug target with a few options already undergoing testing. Methods: One study took a library of 1280 compounds and explored effects on BDNF. Dissociated cortical neurons from Bdnf-luc mice embryos were isolated and grown in culture. At 13 days, the neurons were treated with each compound for 6 hours and a screening assay using Steady-Glo Luciferase Assay System was completed. The compounds that increased luciferase activity by >2-fold were considered active at inducing BDNF expression. RT-PCR was then used to measure changes in BDNF mRNA levels. The mechanism of action was investigated by also testing cyclooxygenase (COX) inhibitors and active metabolites of dipyrone (4-aminoantipyrine and 4-methylaminoantipyrine).⁶ Another study investigating ketamine used 53 patients in a random, placebo controlled study were infused with subanesthetic ketamine and BDNF levels were monitored at 100 minutes (2 hours) and 24 hours. Additionally, a whole brain regression was also performed to relate the change in BDNF with RSFC decreases at 2 hours. Three blood draws and fMRI scans were done with an MRS scan included, once before infusion, once at 2 hours, and once at 24 hours. ⁸  Results: Dipyrone, a COX inhibitor, was found to increase BDNF mRNA levels the most at 3 hours, and then at 6 hours. It is concluded that dipyrone likely indirectly induces neuronal activity, indicating the need for further investigation of the mechanism.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 works through trkB to start the signalling pathway. The unique 5’UTR of BDNF genes allows for the binding of Translin, ultimately taking BDNF and trkB to the dendrites and signal the upregulation and activation of NMDA-R which causes a glutamate surge that induces BDNF release. Overall these results strongly support the neurotrophic hypothesis that BDNF is key in hippocampal dysplasia and an increased susceptibility to mood disorders, and should be a larger target than the monoamine transmitters currently used. The exact mechanism of how BDNF effects the brain and how this pathway can be targeted is an area that needs continued research

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