The phrase “treatment-resistant” gets handed to a lot of people who don’t deserve it.
In clinical practice it usually means just one thing: you’ve tried two or three antidepressants and none of them got you where you wanted to go. That’s the entire diagnostic threshold. But what it implies, to the person carrying it, is much heavier: “I’m broken in a way that doesn’t fix.”
After treating over 800 patients in my IV ketamine therapy practice, I want to make the case that “resistant” is the wrong word. Most of these patients aren’t resistant. They’re stuck — and what they’re stuck on is a specific biological mechanism with a name, a literature, and paths around it.
When an SSRI Stops Working, Your Brain Isn’t Out of Options
When an SSRI stops working, your brain hasn’t lost the ability to respond to treatment. It’s lost the ability to respond to that particular kind of treatment, on the serotonin layer.
The structural layer of the brain — where neuroplasticity and synaptic connections actually live — is a different lane entirely. Treatments that target it work through a completely different mechanism: glutamate, NMDA receptors, BDNF release. Real synaptic rewiring, measured in hours, not weeks.
Most of the people in my office don’t need to keep climbing the SSRI ladder. They need someone to tell them the ladder isn’t where the leverage is anymore.
A More Accurate Label: “Receptor-Downregulated”
If “treatment-resistant” is a label you’ve been carrying, consider trading it in for “receptor-downregulated.” It’s more accurate. It points to a different mechanism. And it points toward a different door.
Watch the video that walks through this in more depth. Or learn more about ketamine therapy at AlphaOmega Wellness.
— Dr. Dee Bonney, MD
Board-Certified ER Physician & Founder of AlphaOmega Wellness
Frequently Asked Questions
What does “treatment-resistant depression” actually mean?
Clinically, it usually means you’ve tried two or three antidepressants without reaching the relief you wanted. That’s the entire threshold — it does not mean your brain can’t respond to any treatment.
Why is “resistant” often the wrong word?
Most patients aren’t resistant to treatment — they’re stuck on the serotonin layer that SSRIs target. A more accurate description is “receptor-downregulated,” which points toward treatments that work on a different mechanism.
How does ketamine work differently from SSRIs?
SSRIs act on serotonin. Ketamine works on the structural layer of the brain through glutamate and NMDA receptors, triggering BDNF release and synaptic rewiring — changes measured in hours rather than weeks.