Depression isn’t just “feeling sad.” In fact, it changes the way the brain works, its structure, and even how cells grow there. In this article, we’ll explore key ways depression affects the brain, using trusted scientific studies. The explanations are simple and flow step‑by‑step, so it’s easy to follow.
1. Brain Chemicals: The Serotonin Story—and Its Limits
For many years, people believed depression was simply a "chemical imbalance," especially involving serotonin. Serotonin is a brain chemical that helps regulate mood. When people take medications called SSRIs (like fluoxetine or sertraline), these drugs keep serotonin active in the brain longer, which often lifts mood.
However, a 2022 review in Molecular Psychiatry found no solid proof that low serotonin actually causes depression . While serotonin helps, depression isn’t as simple as being low in one chemical.
That doesn’t deny SSRIs work for many people—just that depression is more complex than a single “low serotonin” issue. SSRIs may help by improving how brain cells grow and connect (what scientists call "neuroplasticity"), not just by adjusting one chemical.
2. Brain Structure and Function: What Scans Show Us
Doctors use MRIs to scan brains of people with major depression. These studies find that certain parts of the brain often change in people with depression:
The hippocampus, which helps with memory and learning, tends to become smaller.
The prefrontal cortex, which handles decision-making and self-control, often shows less activity.
The amygdala, which deals with emotions and fear, often becomes more active.
A review of many brain studies found that the default mode network—areas active during daydreaming or worry—shows signs of change: less structural integrity (meaning tissue is altered) paired with more activity or connections .
But interestingly, only four of fourteen high-quality studies showed a clear link between physical shrinkage and overactivity in those areas . So while we see changes, how they relate isn’t always clear.
3. Stress and the HPA Axis: How Worry Affects the Brain
Chronic stress plays a big role in depression. It activates the HPA axis—a chain reaction involving your brain and adrenal glands that releases stress hormones like cortisol.
High cortisol over time can:
Shrink the hippocampus.
Damage connections between brain cells.
Increase inflammation.
A review in Brain Sciences explains how ongoing stress leads to inflammation, messes with the HPA axis, and damages the brain’s plasticity (its ability to adapt). Another recent study confirms this, showing stress injures the tiny branches on nerve cells—limiting how well the brain can rewire itself .
4. Neurogenesis: When the Brain Stops Growing New Cells
Your brain continues growing new nerve cells (neurogenesis) in areas like the hippocampus, even as an adult. According to the "neurogenesis hypothesis," depression may slow or stop this growth
Animal studies from the early 2000s showed that antidepressants help restore cell growth in the hippocampus; stress and depression slow it down.
And in humans, scans show smaller hippocampal volume in people with depression—suggesting fewer new cells. This helps explain why depression often brings memory problems or difficulty learning.
5. Inflammation, Immune Response, and the Gut–Brain Link
Recent research shows that inflammation also affects the brain in depression. Stress, poor diet, or illness can trigger low-level, long-lasting inflammation. This inflammation releases chemicals that hurt nerve cells and limit brain flexibility.
Surprisingly, many experts now look at depression through the lens of the gut–brain axis—the idea that your gut bacteria influence your moods. Most serotonin is made in the gut, and unhealthy gut bacteria can prompt inflammation, disturb stress responses, and reduce brain plasticity . Some researchers are testing probiotics or special diets to help mental health.
6. Functional “Aging” of the Brain
Brain scans also show signs of accelerated aging in people with depression. A 2022 study using resting-state fMRI from a large group in China found that people with major depression had brains that looked, in function, about 4.4 years older than their actual age. That difference was bigger than what the general population shows, suggesting depression speeds up aging in brain networks.
7. Microstructure: Nerve Cells and Supporting Cells
Inside your brain, not only neurons (nerve cells), but also glial cells support nerve function. Recent studies highlight how depression damages glial cells—especially astrocytes and microglia.
A 2024 study in Signal Transduction and Targeted Therapy described how chronic stress changes glial cells and triggers immune activity in the brain. This weakens support for neurons and harms brain circuits involved in mood .
8. Epigenetics: How Experience Changes Gene Expression
Your experiences—especially stress—can shape how your genes work, a field called epigenetics.
Recent literature shows that stress alters chemical tags on DNA in brain areas like the hippocampus and nucleus accumbens. These tags control genes for mood and stress response. Such changes can last for years, raising the risk of depression again after an initial episode.
9. Thinking Patterns: Learned Helplessness Model
Psychological studies show that when people feel powerless, it can shift brain function.
Animal studies of “learned helplessness” mimic depression by giving animals uncontrollable stress. They show reduced activity in the prefrontal cortex and overactivity in stress hubs, reinforcing negative thought patterns.
10. Reversing the Changes: Therapy, Medication, Lifestyle
One hopeful takeaway: many brain changes can be reversed.
CBT (Cognitive Behavioral Therapy) helps stress control and emotion regulation. Brain studies show it increases activity in the prefrontal cortex and decreases emotional overactivity .
Antidepressants like SSRIs and newer options (e.g., ketamine) boost plasticity, restore neurogenesis, and help rebalance stress systems. They also reduce inflammation and repair glia.
Lifestyle improvements—exercise, healthy diet, good sleep—lower inflammation, boost BDNF (a brain growth protein), and improve stress response. Exercise increases VEGF and BDNF, helping hippocampus recovery . Dietary studies show inflammation from processed foods harms the brain, while whole-foods help .
Summary
Depression affects the brain in many connected ways:
It may disrupt brain chemicals—but not just serotonin.
It shrinks and over-drives key brain areas.
It damages the hippocampus and erases new cells.
It causes inflammation and harms supporting brain cells.
It changes gene expression through stress experiences.
It may cause the brain to age faster.
It alters thought-control networks like prefrontal cortex.
But there is also hope: therapy, medications, and lifestyle all promote healing. Many changes can be reversed, especially when treatment starts early.
While the brain’s complexity means no single magic cure exists, understanding how depression changes it opens the way to many paths of healing. Whether through medicine, talk therapy, or healthier life habits—depression doesn’t have to be a permanent condition.
References:
Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 28, 3243–3256 (2023). https://doi.org/10.1038/s41380-022-01661-0
Scheepens DS, van Waarde JA, Lok A, de Vries G, Denys DAJP, van Wingen GA. The Link Between Structural and Functional Brain Abnormalities in Depression: A Systematic Review of Multimodal Neuroimaging Studies . Front Psychiatry. 2020 Jun 3;11:485. doi: 10.3389/fpsyt.2020.00485. PMID: 32581868; PMCID: PMC7283615.
Remes O, Mendes JF, Templeton P. Biological, Psychological, and Social Determinants of Depression: A Review of Recent Literature. Brain Sci. 2021 Dec 10;11(12):1633. doi: 10.3390/brainsci11121633. PMID: 34942936; PMCID: PMC8699555.
Luo Y, Chen W, Qiu J, Jia T. Accelerated functional brain aging in major depressive disorder: evidence from a large scale fMRI analysis of Chinese participants. Transl Psychiatry. 2022 Sep 21;12(1):397. doi: 10.1038/s41398-022-02162-y. PMID: 36130921; PMCID: PMC9492670.
Cui, L., Li, S., Wang, S. et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Sig Transduct Target Ther 9, 30 (2024). https://doi.org/10.1038/s41392-024-01738-y
