Many people know what depression feels like, and most of us can also recognize the social withdrawal, changes in appetite, and other behaviors that depression causes.
Yet, our understanding of how depression unfolds in the brain is not nearly as well-evolved. One person’s depression might have a completely different underlying biological cause than another person with the same depressive symptoms.[1] This variation helps explain why treatments that work well for one person may not work for another.
But here’s the good news: Scientists have identified clear, measurable differences between what a healthy brain and a depressed brain look like and how they function. They have also found that treatment for depression brain recovery can help the brain return to its healthy state.[2]
By further developing our understanding of how biology and depression interact, current treatments for depression can be improved, and new treatments can be developed.
How Depression Affects the Brain at a Biological Level
Neuroimaging studies like MRIs have been useful for mapping the structural and functional neural characteristics responsible for the development of depression.[3],[4] These physical changes are objective and observable, similar to a blood test that a doctor uses to determine the cause of a physical ailment.
The key word here is “similar.” Though doctors can use blood tests to look for specific biological markers, mental health professionals still rely almost entirely on self-reporting and behavioral assessments to make their diagnoses.[4] This is why neuroscience is so important to the study of depression. As brain imaging technology continues to improve, clinicians may be able to use these tools to guide treatment decisions more precisely.
Depression is not the result of a single issue in one region of the brain. Instead, it’s a circuit problem.[4] These circuits are widely distributed throughout the brain, yet are integrated and interconnected. Therefore, multiple regions linked both functionally and structurally are responsible for the typical symptoms of depression.[3]
A good example of this is the corticolimbic brain regions. This network of circuits is responsible for everything from managing stress to controlling emotions to overseeing executive functioning. When this area is structurally deficient or experiences neurochemical deficits, depressive symptoms can result.[5] Understanding brain function in major depressive disorder requires examining how these interconnected systems work together.
Here’s another example: When you experience chronic anxiety and stress, the connections between nerve cells can break apart. As a result, communication between the affected cells is disrupted. The prevailing theory is that this breakdown of communication in the brain contributes directly to the biology of depression.[2]
The brain-based connection with depression goes deeper still. Years ago, researchers believed that depression caused a reduction in the brain’s neuroplasticity (its ability to form new neural pathways). However, modern research points to disruptions in neuroplasticity as a cause of depression, not just a side effect.[6] This shift in understanding has important implications for how we approach treatment.
Why Depression Is More Than a Mood Problem
It’s easy to think of depression in terms of its observable features. However, as discussed above, there are also clear brain changes in depression involving its function, structure, and chemistry.[3]
In fact, brain function in major depressive disorder is so complex that no single theory can explain it.[7] Current research suggests that the various subtypes of depression likely involve the same core brain pathways and regions, but that each type might be triggered differently.[5]
Depression involves many different brain systems, not just changes in mood, with cognitive, emotional, and physiological symptoms. Likewise, depression affects every corner of daily life, including work performance, sleep, appetite, and physical health.[5],[6]
The common notion that depression is just being really sad is simply not true. Given the complexity of this disorder, it’s easy to understand why the general understanding of it is so oversimplified. But scientists have gained an incredible amount of knowledge about the biology of depression in recent years, and the more we learn, the more likely the public will come to understand how complex depression truly is.
Depression and Brain Chemistry
Depression involves the action of numerous neurotransmitters. An electrical signal travels down a nerve cell’s axon, signals the release of the neurotransmitter, which then binds to receptors on neighboring neurons, and the process of reuptake clears out the remaining neurotransmitter from the space between the neurons.[1]
This process is how neurons communicate with one another. It’s also where antidepressants do their work. Most antidepressants increase the amount of neurotransmitters at the synapse, the gap between neurons.[1] The relationship between depression and neurotransmitters is central to understanding both the condition and its treatment.
The Role of Neurotransmitters in Depression
Four neurotransmitters are key to depression:
- Serotonin regulates appetite, mood, sleep, and pain inhibition. Certain antidepressants block the removal of serotonin from the synapse, thereby increasing its levels in the brain.[1]
- Norepinephrine is involved in energy, stress response, motivation, and alertness, as well as the brain’s reward system. Some antidepressants help increase the amount of norepinephrine to combat symptoms like low drive and fatigue.[1].[7]
- Dopamine is important for motivation, reward processing, and experiencing pleasure. When dopamine levels are low, symptoms such as anhedonia (the inability to feel joy) can arise. Increasing dopamine levels through medication and lifestyle changes can help reduce depressive symptoms.[5],[7]
- Glutamate, the brain’s main excitatory neurotransmitter, and GABA, the primary inhibitory neurotransmitter, also influence brain chemistry as it pertains to depression. Low glutamate or GABA levels are associated with depressive symptoms. Antidepressants can help regulate these levels.[1],[2],[7]
Why a Chemical Imbalance Doesn’t Tell the Whole Story
For years, scientists assumed that low levels of serotonin caused depression. This conclusion about depression and neurotransmitters was based on the observation that antidepressants that increased serotonin levels helped improve the mood of many depressed patients
The issue, though, is that up to 50 percent of patients taking serotonin-specific antidepressants saw no improvement in mood at all. What’s more, studies that reduced serotonin levels in people without depression did not reliably produce depressive symptoms.[7],[8] These findings challenged the depression brain chemistry imbalance theory that had dominated the field for decades.
Today, our understanding of depression is much deeper. For example, the story involves stress, too: Chronic stress reduces serotonin production and actively increases neurotoxic byproducts.[8] Furthermore, research shows that GABA, glutamate, brain inflammation, and other factors are also involved in the development of depression.5 This more complex picture helps explain why effective treatment often requires addressing multiple systems simultaneously.
So, depression isn’t the result of one chemical imbalance. It’s the result of multiple chemical systems all interacting with one another. Fixing one of these systems isn’t enough. Instead, effective treatment depends on which system (or systems) are disrupted in any given person.
Structural Changes in the Depressed Brain
Depression doesn’t just involve the neurotransmitters discussed above, nor does it simply change how you feel. Instead, it produces physical changes in your brain, like volume reductions in the hippocampus, an enlarged amygdala, thinning of the prefrontal cortex, and disruptions between neurons.[3],[4],[7]
Brain changes are linked to hallmark symptoms of depression. For example, a reduction in the size of the hippocampus is associated with the number of depressive episodes, their severity, and their duration.[3],[6] Meanwhile, the amygdala shows elevated activity in some depressed patients, which can lead to enlargement of the structure. This, in turn, is correlated with the intensity of depression, anxiety, intrusive thoughts, and rumination.[6]
The good news is that these and other structural changes aren’t permanent. With the appropriate treatment, many of them can be at least partially reversed.[6] So, while the answer to the question, “Can depression damage the brain?” is “yes,” the long-term effects of depression on the brain can be mitigated with early and effective treatment.[3],[7] This reversibility underscores the importance of seeking help sooner rather than later.
How Depression Impacts Memory and Focus
Depression is most often described in emotional terms: feelings of emptiness, a sense of hopelessness, and pervasive sadness. But for many people with depression, other symptoms are just as prevalent. The cognitive symptoms, such as the inability to make decisions or concentrate, can be just as debilitating. This is why many people with depression report difficulty functioning at work or school, even when their mood symptoms are relatively stable.
As a result, even simple tasks can feel overwhelming. Retaining information can be difficult. Brain fog can impair attention. The ability to process information can be severely compromised.[3],[4] Beyond that, the relationship between depression and cognitive impairment can be long-lasting: These effects can accumulate over time, and the longer depression goes untreated, the more severe the cognitive impairments tend to be.[3],[6]
Why the Biology of the Brain Is Important for Treatment
Examining the physical changes depression causes in the brain isn’t just important for science; it’s also important for treating depression. Neuroscience teaches us that depression should be treated as early as possible. If not, the brain can undergo significant structural and functional changes.[7]
For example, chronic depression can cause neurodegeneration, or the loss of functionality or structural integrity of neurons. Though this type of damage is most often associated with Parkinson’s disease and Alzheimer’s disease, the neurodegenerative hypothesis of depression states that inflammation and oxidative stress in the brain are key factors in the development of depressive symptoms.[3],[8]
The takeaway is this: Mental health professionals must take biology into account when treating depression. The biological perspective helps explain why some treatments work for some patients but not others, and why treatment for some patients takes longer.[3]
Clinicians can take this into account to develop the most effective treatment for their patients.
Mental Health Treatment for Depression: A Brain-Based Approach
A brain-based approach to treating depression is different from a symptom-first approach that’s been so prevalent over the years. The goal of a biological approach is to both relieve symptoms and restore the brain’s functionality.
Perhaps the best option for treating depression is a combination of treatments. Psychotherapy, for example, helps normalize amygdala activity, thereby reducing the likelihood that its structure enlarges and worsens symptoms.[3] Moreover, therapy generates changes in the brain distinct from those resulting from medication, further promoting a multi-modal approach to treatment.[3],[6] This is how therapy rewires the brain in depression, creating new neural pathways that support healthier thought patterns and emotional responses.
For example, combining cognitive-behavioral therapy and pharmacotherapy rewires neural circuits, helping the brain combat the negative structural and functional changes caused by depression.[3] Exercise has a similar effect: studies show that regular physical exercise promotes the development of new brain cells, particularly in the hippocampus.
[9] Antidepressants have the same effect, so combining the two offers improved outcomes.[1],[6]
Antidepressants and brain changes go well beyond promoting the growth of new brain cells, though. For example, they help normalize neurotransmitter levels between neurons, restore the size of the hippocampus, and bring hormone levels back to a healthy range.6,5 Some antidepressants help reduce inflammation in the brain, too. Research on this front could one day lead to specific treatments for depression based on each person’s biological profile.[8]
The long-term outlook for treating depression from a biological perspective is extremely promising. Targeted treatments that address symptom reduction, increase brain functionality, and address structural changes in the brain could make depression treatment far more effective for far more people.
Mental Health Treatment for Depression at Mission Connection
The research on depression is clear: The symptoms you experience have a biological basis, and that biology can change with the proper approach.
Devising the right approach requires patience and expertise. No two cases of depression are identical, which is all the more reason to work with a mental health provider that takes a personalized approach to care as opposed to a one-size-fits-all solution.
Recovery from depression isn’t just possible; it’s supported by years of research. Our brains have an incredible ability to adapt, rebuild, and heal, even after protracted depression. The most critical step, then, is to seek help and get the process of healing underway.
At Mission Connection, we understand that depression is a complex condition caused by many different factors. Whether you’re exploring treatment for the first time, looking to revisit your current treatment plan, or seeking support that goes beyond simply taking antidepressants, we’re here to help. Get started on your journey to recovery today.
References
- Harvard Health Publishing (2022). What causes depression? https://www.health.harvard.edu/mind-and-mood/what-causes-depression
- Yale Medicine (2021). How depression affects the brain. https://www.yalemedicine.org/news/neurobiology-depression
- Singh, M. K., & Gotlib, I. H. (2014). The neuroscience of depression: implications for assessment and intervention. https://doi.org/10.1016/j.brat.2014.08.008
- Zhang, F.-F. et al. (2018). Brain structure alterations in depression: psychoradiological evidence. https://doi.org/10.1111/cns.12835
- Filatova, E. V., Shadrina, M. I., & Slominsky, P. A. (2021). Major depression: one brain, one disease, one set of intertwined processes. https://doi.org/10.3390/cells10061283
- Trifu, S. C. et al. (2020). Brain changes in depression. https://doi.org/10.47162/RJME.61.2.06
- Hasler, G. (2010). Pathophysiology of depression: do we have any solid evidence of interest to clinicians? https://doi.org/10.1002/j.2051-5545.2010.tb00298.x
- Hall, S. et al. (2024). The neurodegenerative hypothesis of depression and the influence of antidepressant medications. https://doi.org/10.1016/j.ejphar.2024.176967
- Remes, O., Mendes, J. F., & Templeton, P. (2021). Biological, psychological, and social determinants of depression: a review of recent literature. https://doi.org/10.3390/brainsci11121633