By Cecile LeBron, MD
Understanding the exact mechanism of how ketamine alleviates depression, anxiety, or PTSD remains a mystery. While several theories exist, no one can claim to have the complete picture. In this post, we’ll explore some of these hypotheses at a molecular level and simplify the discussion to explain how ketamine interacts with your brain, particularly through the Default Mode Network (DMN).
Note: The theories discussed here are sourced from “Ketamine for Treatment-Resistant Depression: The First Decade of Progress” by Sanjay J. Mathew and Carlos A. Zarate Jr.
Table of Contents
Molecular Mechanism of Action
Default Mode Network Effects
Mechanism of Action
Low-dose IV ketamine has shown rapid and lasting benefits for various mental health disorders, but its exact mechanism of action remains unknown. Several reproducible hypotheses provide compelling evidence for its effectiveness in treating these conditions.
Actions at the Molecular Level
Ketamine binds to numerous receptors in the body, but the most significant ones are NMDA and AMPA receptors. When ketamine binds to the NMDA receptor, its effects vary based on the binding location in the brain. This binding increases the production of the neurotransmitter glutamate.
Downstream Effects
The increase in glutamate activates the AMPA receptor, which may be the primary reason for Ketamine antidepressant and antianxiety effects. This activation triggers a signaling cascade that initiates the rapamycin (mTOR) pathway, increasing brain-derived neurotrophic factor (BDNF) and enhancing dendritic spine density, crucial for brain cell communication.
Signaling Pathways
By boosting dendritic spine density through this signaling pathway, ketamine enhances neuroplasticity, and the brain ability to grow, communicate, and adapt.
Other Hypotheses
Some experts argue that the rapid onset of antidepressant and antianxiety effects is due to the increase in dendritic spines, not just the blockade of NMDA receptors or stimulation of AMPA receptors. Other receptors, such as sigma-1, norepinephrine transporter (NET), m-opioid, and serotonin transporter (SERT), might also play a role.
Default Mode Network (DMN)
Ketamine affects the Default Mode Network (DMN), which can be thought of as the brain's "auto-pilot." The DMN activates when not engaged in tasks, such as daydreaming or reminiscing. For those with depression, anxiety, or PTSD, this "auto-pilot" can become overwhelming, generating persistent negative thoughts and ruminations.
A Practical Example
Imagine being an NBA player on the court. The game consists of high-action periods (playing the game) and breaks (resting on the bench). Playing represents the brain focusing on the external world, while breaks represent the DMN, a time for reflection and strategy.
What Happens When You Get Stuck?
Now, imagine being stuck in "bench mode" even while on the court. Instead of engaging in the game, you're consumed by past mistakes, future concerns, and self-doubt, preventing you from fully participating. This scenario mirrors the experience of someone with severe depression, anxiety, or PTSD, where their brain keeps them in "default mode," filled with negative ruminations and feelings of worthlessness or guilt.
The Good News
Clinical trials have shown that low-dose IV ketamine reduces activity in the DMN, allowing individuals to break free from "bench mode" and engage fully with life. We believe that low-dose IV ketamine can help you reclaim your best self and live life to the fullest.
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