Depression Decoded: Scientists Identify the Brain Cells Behind Mood Disorders

Leon Wirz
Oct 20
4 min read

Published in Nature Genetics, August 2025

Broad Institute of MIT and Harvard, McLean Hospital, Stanley Center for Psychiatric Research

Introduction

Depression is one of the world’s leading causes of disability, affecting more than 300 million people globally, and nearly one in five adults in Switzerland during their lifetime. Despite decades of research and widespread use of antidepressants, the underlying biology of depression has remained elusive.

Is it a chemical imbalance? A stress disorder? Or something deeper within the brain’s cellular machinery?

A new study published in Nature Genetics (October 2025) provides the clearest picture yet. Using single-cell genomic technology, scientists have identified the specific brain cell types (neurons and microglia) that are functionally altered in people with major depressive disorder (MDD).

The Core Discovery

The research team discovered that depression leaves distinct molecular “signatures” in the brain, particularly in neurons (the cells that transmit electrical signals) and microglia (the brain’s resident immune cells).

Neurons showed disruptions in genes linked to synaptic plasticity, the brain’s ability to adapt and form new connections. Microglia, by contrast, displayed changes related to inflammation and stress response.

Together, these findings suggest that depression is not merely a chemical disorder, but an epigenetic and immunological rewiring of the brain.

How the Study Was Conducted

Researchers from the Broad Institute, McLean Hospital, and the Stanley Center for Psychiatric Research analyzed post-mortem brain samples from hundreds of individuals with and without major depression.

They applied single-nucleus chromatin accessibility profiling (a cutting-edge sequencing method that maps how tightly DNA is packed in each cell), revealing which genes are turned “on” or “off.”

By comparing millions of cells across different brain regions, the team built a high-resolution atlas of chromatin states for each cell type and linked them to known depression-associated genetic variants from large-scale genome-wide association studies (GWAS).

Key Findings

Cell-Specific Vulnerability: Depression-associated genetic variants were most active in neurons and microglia, but not in astrocytes or oligodendrocytes.
Neuronal Plasticity Deficit: Genes regulating neuronal signaling and synaptic remodeling were consistently less accessible, indicating reduced brain adaptability.
Immune Activation: Microglial cells exhibited increased chromatin accessibility in inflammatory and stress-response genes, supporting the idea of neuroinflammation as a driver of depression.
Unified Model of Depression: The study integrates the “chemical imbalance” and “inflammatory” hypotheses into one: a multi-cellular systems disorder involving neural, immune, and epigenetic pathways.

Limitations of the Study

Post-mortem bias: Brain tissue was collected after death, which may not reflect dynamic changes during active disease.
Causality unknown: It remains unclear whether these epigenetic changes cause depression or result from it.
Sample diversity: Most samples were of European ancestry, limiting generalization to global populations.
Clinical translation: Identifying cell changes is only the first step — converting this into therapy will take years.

Relevance for Switzerland

In Switzerland, mental health costs exceed CHF 11 billion annually, including healthcare expenses and productivity losses. Current treatment approaches rely heavily on trial-and-error prescription, leading to long delays before finding effective therapy.

If Swiss psychiatric centers integrate single-cell and epigenetic diagnostics, patients could one day be classified by biological subtype — for example, “microglia-dominant depression” versus “synaptic-plasticity depression.”

Institutions like ETH Zürich, University of Zürich, and PSI Villigen already lead in single-cell and neuro-omics research. This makes Switzerland uniquely positioned to pioneer precision psychiatry as part of its national digital-health and personalized-medicine initiatives.

Potential Impacts of a Successful Therapy

For patients: More accurate diagnoses and faster-acting, personalized treatments.
For pharma: A new class of drugs targeting microglial inflammation or neuronal epigenetics could reshape the antidepressant market (currently worth USD 17 billion).
For insurers: Shorter treatment cycles could drastically reduce reimbursement costs for long-term psychotherapy or ineffective drug trials.
For employers: Improved workplace productivity and reduced burnout-related absences.

Risks

Over-medicalization: Genetic and epigenetic profiling could label individuals as “biologically depressed” even when symptoms are context-driven.
Data privacy: Psychiatric genomics involves highly sensitive data — requiring strict governance, especially under Swiss DSG and EU GDPR.
Pharma dependency: Precision psychiatry could deepen reliance on expensive, patent-protected drugs, widening treatment inequalities.

Overall Assessment

This study represents a milestone in neuroscience and psychiatry — the first to link depression risk genes to specific cell types and chromatin states. It validates decades of suspicion that depression is both a neural network disorder and an immune-epigenetic condition.

However, it also underlines how far psychiatry still lags behind oncology or cardiology in biological precision. Translating these insights into clinical tools will require large-scale collaboration, standardized data, and cautious ethical oversight.

What Comes Next

Longitudinal studies following living patients to track how epigenetic states change during therapy.
Drug development targeting microglial activation or chromatin regulators.
Integration into psychiatric genomics consortia in Europe, potentially involving Swiss partners under the SPHN (Swiss Personalized Health Network).
AI-based diagnostic tools using patient-derived molecular data to guide therapy choice.

Reference

Chawla, A., Cakmakci, D., Fiori, L.M. et al. Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression. Nat Genet 57, 1890–1904 (2025). Link