Rethinking Depression: Beyond Chemical Imbalance

"Depression affects millions worldwide, yet its root cause has long remained elusive. Behind its lived experience lies a biological mystery. Why does the brain, an organ built to adapt and survive, sometimes disrupt its own careful harmony? For decades, the dominant story was simple: a "chemical imbalance," a shortage of serotonin or dopamine. That story is comforting in its clarity, yet incomplete. Antidepressants can ease symptoms, yet they do not explain why depression begins, or why it persists in some people and not others."

"They looked at more than 200,000 cells from a region of the brain central to decision-making and mood. In patients who died with major depression, certain regulatory doors were locked shut, others thrown wide open. Every cell carries the same DNA instruction manual, but not every page is open at once. Chromatin accessibility, whether a piece of DNA is "open" or "closed", decides which instructions can be read."

"Chromatin accessibility, whether a piece of DNA is "open" or "closed", decides which instructions can be read. And in depression, whole chapters of the manual appear to be rewritten. Neurons That Remember Stress The most striking changes appeared in certain excitatory neurons, which act as the brain's stress sensors. In animal models, silencing them blunts depression-like behaviors; activating them intensifies stress responses."

Chromatin accessibility was mapped in over 200,000 nuclei from a brain region central to mood and decision-making. Depression-associated changes appeared as some regulatory regions becoming more open and others closed, altering which genes can be read. Two cell types with the strongest alterations were deep-layer excitatory neurons that function as stress sensors and a gray-matter microglia subtype. Genetic variants linked to depression clustered near regulatory regions that influence nearby gene expression. These findings indicate cell-type-specific rewiring of gene regulatory programs in major depression rather than solely a neurotransmitter deficit.

Read at Psychology Today