Currently available antidepressants, at least in their initial action, exert their antidepressant effect by influencing monoamine levels in the brain. Despite increasing the monoamine levels within the first day, the clinical manifestation of the antidepressant effect may be delayed by days to weeks. Approximately one third of major depressed patients will have a 50% or more reduction in symptoms with the first agent prescribed. Although the total number of patients responding increases with subsequent medication trials, the proportionate response to each new drug is much less than to the original drug. This series of trials may take months to years. This scenario has led to the search for a medication that rapidly reduces depressive symptoms. Esketamine seems to fulfill those criteria.
The brain’s response to any medication is much more complex than increasing as certain neurotransmitter. Esketamine does not raise monoamine neurotransmitters. Instead, esketamine binds to the post-synaptic NMDA glutamate receptor blocking glutamate neurotransmission. There are a few other biochemical happenings at the receptor level that are necessary for this to effectively occur, but that is a bit in the weeds for this article. Another result of this binding is the activation of the mTOR pathway. This is a pathway that eventually leads to increased BDNF and increased synapse formation. Pay no attention to the acronyms, just know it’s a good thing to happen. Wikipedia can give you a fuller explanation. This is amazing in two ways. First, that protein formation (needed for the building of synapses) can be elicited and seen occurring within 2 hours of administration is remarkable. This occurs with typical antidepressants but may take weeks. Second, the BDNF increase and the onset of new synapse formation correlates with a decrease in depressive symptoms and suicidal ideations. A medication that can be administered intranasally in a psychiatrist’s office and reduce suicidal ideations and decrease depression within 2 hours is a large leap forward in psychiatric treatment.