Key takeaways

• Depression is a biological condition with measurable long-term effects on brain structure, including regions responsible for memory, decision-making, and emotional regulation.
• Beyond the brain, chronic depression may be linked to increased risk of cardiovascular disease, metabolic disruption, and accelerated cognitive decline, though associations vary across individuals.
• Neuroplasticity gives the brain a remarkable capacity to reorganize and heal, and rapid treatment may help limit further decline.
• SAINT® for depression has achieved a 79% remission rate in clinical trials¹, helping people reach recovery in days rather than weeks.

Depression is far more than a shift in mood. At its core, major depressive disorder (MDD) is a complex condition shaped by genetics, neurobiology, and lived experiences resulting in dysfunction in neural circuits in the brain. 

Like many chronic health conditions, the long-term effects of depression can compound over time if left untreated or inadequately managed.

Research has helped scientists better understand how prolonged depressive episodes can reshape the brain, alter cognitive capacity and make the body more vulnerable to other health conditions. The effects of depression, in other words, are not purely emotional; they extend into the very architecture of how your brain and body function.

Understanding how depression affects the brain and body isn’t cause for alarm. It is meant to underscore the importance of timely, effective treatment and to highlight the encouraging reality that modern neuroscience now offers alternative pathways to rapid, meaningful recovery for those suffering from depression.

The Physical Impact: How Long-Term Depression Can Affect the Brain

The brain changes in response to experience, stress, and illness, particularly when episodes are prolonged or recurrent. Neuroimaging studies² have identified several patterns of structural change worth understanding.

The hippocampus

The hippocampus plays a central role in memory formation, spatial navigation, and learning. It is also one of the regions of the brain most sensitive to prolonged stress and its associated hormones.

The hippocampus can show reduced volume and altered activity in people living with MDD³., Elevated cortisol levels,a stress hormone often elevated during depressive episodes.Cortisol may be associated with reduced hippocampal subfield volumes, though studies have remained inconclusive regarding the main driver.

It is important to note that the relationship between cortisol and hippocampal volume in depression is still a preliminary area of research, and findings across studies are not entirely consistent. What the body of evidence does suggest is that prolonged stress responses, common in chronic depression, may, over time, affect the health and function of this memory-critical region.

The prefrontal cortex (PFC)

The prefrontal cortex is the seat of executive function, the mental processes that allow you to plan ahead, make decisions, regulate impulses, and adapt your behavior to new information. For those experiencing major depressive disorder, there may be abnormalities in this region.

A 2024 study published in Psychiatry Research: Neuroimaging found significant atrophy in key regions of the prefrontal cortex in patients with MDD compared to healthy controls, with findings linked to both depression severity and episode frequency.⁴ A separate review in PMC highlighted that volumetric reductions in the medial prefrontal cortex are among the documented neural abnormalities associated with MDD, with these changes tied to markers of illness progression, including longer illness duration, greater number of episodes, and treatment resistance.⁵

Research has specifically linked changes in this frontal brain area to difficulties with attention, planning, and the ability to shift course when something isn’t working—struggles that many people with depression will recognize from their own experience.⁶

Neural connectivity

Depression can not only alter individual brain structures; it can also disrupt the communication pathways between them. The brain operates through a dense web of interconnected circuits, and mood regulation depends on the coordinated activity of multiple regions.

Depression can disrupt these communication channels. Research has identified aberrant connectivity between limbic structures (involved in emotional processing) and prefrontal regions (involved in regulating those emotions), creating a kind of short-circuit in the brain’s mood-regulating network.⁶ When these pathways are impaired, the brain loses some of its ability to dampen negative emotional responses or generate motivation, which may help explain why depression can feel so persistent and all-encompassing.

The Mental Impact: The Cognitive Side Effects of Long-Term Depression

Many people living with depression describe something beyond sadness. It is a mental fog, a frustrating slowness of thought, and a sense that their mind is working against them. These experiences are very real and have a neurological basis.

Executive dysfunction

Executive dysfunction refers to difficulty with higher-order thinking tasks: planning, multitasking, problem-solving, and prioritizing competing demands. For someone managing a career, a household, or relationships, this can feel profoundly debilitating.

Research has shown links between impairments in attention, working memory, and performance monitoring in people with major depressive disorder to changes in prefrontal circuits, specifically those governing behavioral adjustment and self-evaluation.⁸ In practical terms, this can translate to tasks that once felt automatic, like organizing a project, drafting a message, or following a multi-step conversation, may require considerably more mental effort.

Brain fog and information processing

Slowed cognitive processing, or “brain fog,” is a frequently reported side effect of depression. Information that once registered quickly may now be difficult to retain. Decisions that once felt straightforward can suddenly feel overwhelming and paralyzing. These mental blockers are not due to some character flaw or lack of effort, but rather genuine changes in the brain’s ability to route and process information.

This cognitive friction is closely tied to the structural and connectivity changes discussed above. When the prefrontal cortex is under strain and neural communication is disrupted, the brain has to work harder to complete tasks it might otherwise handle with ease.

Memory impairment

Given the hippocampus’s role in memory, it is perhaps unsurprising that many people with depression struggle with memory, particularly the formation of new memories and the recall of positive experiences.

Studies have found that people with major depressive disorder tend to show multiple impairments in verbal memory, new learning, visual memory, and delayed recall compared to healthy individuals.² This is not simply a matter of being distracted or disengaged; it can reflect real functional changes in the brain regions responsible for memory encoding and retrieval. 

The Role of Neuroplasticity in Brain Health

There is an important counterpoint to the research we’ve looked at so far: the brain is not static. Neuroplasticity—the brain’s inherent ability to reorganize itself, form new neural connections, and adapt in response to new experiences or stimuli—means that many of the changes associated with depression may be responsive to treatment.

Neuroplasticity is the mechanism by which the brain can recover from injury, build new cognitive pathways, and reestablish healthier patterns of connectivity. It is also the biological foundation on which effective depression treatments work, helping the brain “relearn” more functional ways of regulating mood and cognition.

However, neuroplasticity has its limits, and timing matters. Waiting weeks or months for a conventional treatment to take effect or cycling through medications that ultimately fail to work can leave the brain in a prolonged state of stress.⁵ This is not inevitable for every individual, but it reinforces why prompt, effective treatment carries real value for long-term brain health.

The Mind-Body Connection

Depression does not confine its effects to the brain. Chronic depressive illness can also place stress on other systems in the body. The associations outlined below vary in strength across research literature, and individual factors always play a role, but the patterns are consistent enough to take seriously.

Increased risk of chronic disease

Research has examined the relationship between long-term depression and a range of physical health conditions:

• Cardiovascular disease and stroke. Chronic depression can place ongoing stress on the cardiovascular system, especially for individuals who already have other cardiovascular conditions. Depression has been associated with increased heart rate, elevated blood pressure, and reduced heart rate variability, all of which can strain the heart over time. A meta-analysis of 17 studies involving more than one million participants found that depression could be associated with higher risks of both fatal and non-fatal cardiovascular events in individuals with type 2 diabetes.⁹ 
• Type 2 diabetes. Depression and type 2 diabetes are frequently comorbid, and the relationship between them appears to be bidirectional. The metabolic changes associated with depression can interfere with how the body processes insulin. In clinical populations, the presence of depression has been associated with increased risk of macrovascular complications and poorer diabetes management outcomes.⁹
• Osteoporosis. Chronic depression has been linked in some studies to lower bone mineral density, potentially increasing the risk of fractures with age. Elevated cortisol, reduced physical activity, and nutritional factors associated with depression may all contribute to this effect, though the research in this area is still developing.¹⁰ 
• Alzheimer’s disease and cognitive decline. Perhaps one of the most studied long-term risks is the association between depression and dementia. Preliminary research suggests that depression may be associated with a greater risk of developing dementia later in life, though it is worth noting that the nature of this relationship is still debated.¹¹ Researchers continue to examine evidence to determine whether depression is a risk factor for dementia, an early symptom of neurodegeneration, or both.

Abnormal stress response

Depression often traps the body in a state of prolonged physiological stress by dysregulating the Hypothalamic-Pituitary-Adrenal (HPA) axis. This mechanism—the body’s central stress response system—can become overactive in patients with MDD, resulting in a continuous surge of cortisol. Over time, this sustained hormonal imbalance can suppress immune function, making it significantly harder for the body to fight off infections, recover from injury, and manage inflammatory challenges effectively.

Chronic pain and inflammation

Many people with long-term depression also report unexplained physical symptoms: persistent aches, frequent headaches, and digestive discomfort.¹² These are not simply psychological in origin. Depression and chronic pain share overlapping neural circuits, which may explain why the two can be experienced together.

The cycle of self-care

One of the more insidious effects of depression is what might be called the self-care gap. The exhaustion, low motivation, and cognitive impairment that accompany MDD often make it genuinely difficult to maintain the routines that protect physical health: regular exercise, a balanced diet, consistent sleep, and medical check-ups. Over time, this gap can allow minor health issues to go unchecked, compounding the physical toll of the illness itself.

How SAINT for Depression Can Help With the Long-Term Effects of Depression

The purpose of exploring the potential long-term effects of depression is not an invitation to despair. In fact, it is meant to show how essential it is to seek better, faster treatment—even when things haven’t worked out in the past. This is precisely where SAINT for depression comes in.

SAINT is an FDA-cleared, precision neuromodulation treatment for adults with MDD who have not achieved satisfactory improvement from prior antidepressant medications. Rather than targeting depression broadly, SAINT targets the specific neural circuits most disrupted by the condition.

Precision via fMRI

Before treatment begins, each patient undergoes a functional MRI (fMRI) brain scan. Healthcare professionals analyze this scan to map the individual’s unique neural architecture, identify the specific area of the brain affected, and target it for treatment. This personalized targeting means that stimulation is delivered exactly where each patient’s brain needs it most, removing the guesswork inherent in standard TMS approaches.

Rapid remission

SAINT uses accelerated intermittent Theta Burst Stimulation (aiTBS), a concentrated series of magnetic pulses delivered in 10 sessions per day over five consecutive days. This condensed treatment is designed to induce rapid neuroplasticity, helping the brain quickly rebuild healthier patterns of communication.

A 2022 double-blind, randomized controlled trial found that 79% of participants achieved remission following five days of treatment.¹ In another study, researchers found that, on average, participants reached remission in just 2.6 days.¹³ For someone whose brain has been under the strain of chronic depression, this speed can be critical.

A non-invasive bridge to wellness

SAINT requires no anesthesia, no surgery, and no medication changes. Patients remain fully awake and alert throughout each session and can typically drive themselves to and from appointments. For adults who have tried antidepressants without adequate relief, SAINT offers a science-backed, non-systemic alternative that may support the brain’s own capacity to recover.

Reclaiming your cognitive health

Depression is a biological condition, and the brain has a remarkable capacity to heal when given the right conditions and the right stimulus. Neuroplasticity is real, and it is the foundation of recovery. The question is not whether the brain can change, but rather how quickly and how effectively treatment can support that process.

If you or someone you care for has been living with depression, a conversation with a verified SAINT provider may be a meaningful next step. Understanding the long-term effects of depression is the first step. Acting on that understanding is where recovery begins.

Ready to explore rapid remission?

SAINT for depression is FDA-cleared for adults 22 and older with major depressive disorder who have not responded to prior antidepressant medications. Find a verified SAINT provider near you to learn whether this personalized treatment is right for your brain health.

FAQs

¹ Cole, E. J., et al. (2022). Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. The American Journal of Psychiatry, 179(2), 132–141. https://doi.org/10.1176/appi.ajp.2021.20101429

² Dai, L., Zhou, H., Xu, X., & Zuo, Z. (2019). Brain structural and functional changes in patients with major depressive disorder: a literature review. PeerJ, 7, e8170. https://doi.org/10.7717/peerj.8170 

³ Belleau, E. L., Treadway, M. T., & Pizzagalli, D. A. (2019). The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology. Biological psychiatry, 85(6), 443–453. https://doi.org/10.1016/j.biopsych.2018.09.031 

⁴ Kokce, A., Can, M. Ş., Karaca, O., Ozcan, E., & Kuş, İ. (2024). Atlas-based structural analysis of prefrontal cortex atrophy in major depressive disorder: Correlations with severity and episode frequency. Psychiatry research. Neuroimaging, 344, 111885. https://doi.org/10.1016/j.pscychresns.2024.111885 

 ⁵ Gerhard, D. M., & Bhagya Shree, S. R. (2019). The impact of stress and major depressive disorder on hippocampal and medial prefrontal cortex morphology. Biological Psychiatry, 85(6), 443–453. https://pmc.ncbi.nlm.nih.gov/articles/PMC6380948/

⁶ Zhi, D., Calhoun, V. D., Lv, L., Ma, X., Ke, Q., Fu, Z., Du, Y., Yang, Y., Yang, X., Pan, M., Qi, S., Jiang, R., Yu, Q., & Sui, J. (2018). Aberrant Dynamic Functional Network Connectivity and Graph Properties in Major Depressive Disorder. Frontiers in psychiatry, 9, 339. https://doi.org/10.3389/fpsyt.2018.00339 

⁷ Gotlib, I. H., et al. (2014). Cortical thickness in youth with major depressive disorder. BMC Psychiatry, 14, 60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994552/

⁸ Pizzagalli, D. A., & Roberts, A. C. (2022). Prefrontal cortex and depression. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 47(1), 225–246. https://doi.org/10.1038/s41386-021-01101-7 

⁹ Huang, C., et al. (2022). Comorbidity of type 2 diabetes mellitus and depression: clinical evidence and rationale for the exacerbation of cardiovascular disease. Frontiers in Cardiovascular Medicine, 9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960118/

¹⁰ Gebara, M. A., Shea, M. L., Lipsey, K. L., Teitelbaum, S. L., Civitelli, R., Müller, D. J., Reynolds, C. F., 3rd, Mulsant, B. H., & Lenze, E. J. (2014). Depression, antidepressants, and bone health in older adults: a systematic review. Journal of the American Geriatrics Society, 62(8), 1434–1441. https://doi.org/10.1111/jgs.12945 

¹¹ Diniz, B. S., et al. (2013). Depression and risk of developing dementia. Current Psychiatry Reports, 15(9), 384. https://pmc.ncbi.nlm.nih.gov/articles/PMC3327554/

¹² Trivedi M. H. (2004). The link between depression and physical symptoms. Primary care companion to the Journal of clinical psychiatry, 6(Suppl 1), 12–16.

¹³ Cole, E. J., et al. (2020). Stanford Accelerated Intelligent Neuromodulation Therapy for treatment-resistant depression. The American Journal of Psychiatry, 177(8), 716–726. https://doi.org/10.1176/appi.ajp.2019.19070720

About the Author

Jessica Hawkins, Senior Director of Clinical Affairs, brings more than 20 years of experience leading complex translational clinical research trials across a broad range of therapeutic areas and study designs, spanning both medical device and pharmaceutical development. Her career encompasses Phase II through Phase IV investigations, with deep expertise in regulatory compliance, GCP, and the operational rigor required to bring emerging therapies from bench to bedside. Known for her ability to build and inspire high-performing clinical teams, Jessica has a proven track record of advancing trials with precision, care, and an unwavering commitment to patient safety and data integrity.