Depression and anxiety caused by chronic stress can arise from a variety of causes; poverty, physical, mental or sexual abuse, neglect, parental divorce, disabilities, and bullying, to name some. All of the above result in stress, anxiety, pain and feelings of low self-worth. It is these feelings that morph into depression and anxiety, beginning as early as the late teens and continue thereafter. This causes a change in brain chemistry brought on by stress, with subsequent changes in brain anatomy that are difficult to repair.

Traditional antidepressants target three neurotransmitters; serotonin, dopamine and norepinephrine which together, they represent about 15% of the brain’s neurotransmitters. While the exact mechanism of action of ketamine is not well known, we do know that it works on many different levels. Ketamine targets the glutamate system, which is the most abundant excitatory neurotransmitter released by nerve cells in the brain. It plays a major role in learning and memory. It is via the glutamate system and two important receptors, NMDA and AMPA receptors, that ketamine works to relieve depression and anxiety. Ketamine appears to increase the release of glutamate from the presynaptic neuron into the synaptic cleft. Ketamine then preferentially blocks glutamate at the NMDA receptors of the postsynaptic cell but does not block glutamate binding to adjacent AMPA receptors. The net effect is to increase AMPA activation. The effect is magnified by the way ketamine induces the neuron to make additional AMPA receptors and move them into the membrane of the synapse area.

By increasing the level of glutamate transmission while also shifting the balance of glutamate activation from NMDA to AMPA receptors, ketamine rapidly upregulates the production and release of BDNF (brain-derived neurotrophic factor). BDNF is a protein that helps promote the growth, maintenance, and survival of neurons — it is called fertilizer for the brain. BDNF enhances neuroplasticity. At the same time, ketamine stimulates another pathway called mTOR (mammalian target of rapamycin), which regulates many processes involved in cell growth, including synthesizing the proteins needed for long-term memory. The combination of increased BDNF production and mTOR stimulation improves synaptic connectivity in the prefrontal cortex and hippocampus, key areas of the brain associated with emotional regulation, and reverses the synaptic damage that occurs in these areas when the brain is subjected to chronic stress. Animal models show us that the repair can begin in a matter of hours after the administration of ketamine. Symptoms of depression and anxiety  improve when the damaged neurons can repair and regrow their connections with other neurons.