For decades, the clinical focus of treating Major Depressive Disorder has been on alleviating profound sadness. However, traditional monoaminergic antidepressants often fall short of treating anhedonia—the absolute absence of pleasure—and can even cause “emotional blunting” by placing an artificial ceiling on a patient’s dopamine-driven joy. In Episode 58, we explore a landmark 2026 systematic review by Faisal and colleagues that synthesizes 13 neuroimaging studies to show how ketamine acts not just as an antidepressant, but as a “pro-joy intervention.”

We break down the brain’s reward architecture into the “Engine” (primitive structures like the striatum and nucleus accumbens) and the “Steering Wheel” (the prefrontal cortex). Chronic depression causes the dendritic spines connecting these regions to wither, leaving the eng ...