For decades, the “Monoamine Dogma” ruled psychiatry: the brain was a chemical soup, depression was a lack of serotonin, and the cure was simply “filling the tank.” But there was always a glitch in the matrix—why did it take weeks for pills to work if the chemistry changed in hours?

In this special 25th-anniversary episode, we review a retrospective paper from 2026 that traces the history of the “Neuroplastic Revolution.” We go back to the turning point: the accidental discovery that ketamine could stop depression in four hours, proving the problem wasn’t a lack of fuel, but broken wiring.

We unpack the science of structural repair: how ketamine blocks the “disappointment center” (the lateral habenula), wakes up the “construction foreman” (mTOR), and releases BDNF (Miracle-Gro for the brain) to physically regrow lost connections. We also look at the macro level, exploring how this “reboot” disrupts the Default Mode Network to stop the loop of rumination. Finally, we discuss where we are today in 2026: the age of Precision Psychiatry, where we stop guessing and start treating the specific biological cause—whether it’s inflammation, glutamate, or connectivity.

Reference:

Bulek, D., & BaDour, S. (2026). From monoamine deficits to multiscale plasticity: Twenty-five years of ketamine and the neurophysiology of depression. Journal of Neurophysiology. https://doi.org/10.1152/jn.00516.2025

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