Many people are told, often very early in their journey, “You have depression.”
It’s said kindly, sometimes urgently, and usually with the hope that naming it will bring clarity or relief.
But for many patients, that label quietly does something else. It turns a set of symptoms into an identity. And it can close the door on a more important question:
Why is this happening?
Symptoms, not a fixed condition
Low mood, loss of motivation, emotional numbness, withdrawal, hopelessness, and fatigue are real experiences. They can be deeply painful and life-altering. But experiencing these symptoms does not mean someone is depression, or that their brain is broken.
It means the brain and body are responding to something.
In clinical practice, what we call “depression” is often better understood as a pattern of symptoms—a downstream expression of physiologic stress—rather than a standalone disease that appears in isolation.
The limits of the neurotransmitter story
For decades, depression has been explained primarily as a chemical imbalance—most often a deficiency of serotonin. That idea shaped treatment approaches, research funding, and public understanding.
What’s becoming increasingly clear, however, is that this explanation was never fully proven. Large-scale studies have failed to consistently show that people with depressive symptoms have lower serotonin levels than those without. More importantly, the neurotransmitter model doesn’t explain why depression so often appears alongside chronic illness, inflammation, infection, autoimmune disease, or prolonged physiologic stress.
The science hasn’t so much “disproved” neurotransmitters as it has placed them downstream.
What research has revealed instead
Over the past several decades, research has steadily shown that immune activation and inflammation can directly produce symptoms we label as depression.
When the immune system is activated—by infection, autoimmunity, toxins, or ongoing stress physiology—it releases inflammatory signals that affect the brain. These signals can alter motivation, pleasure, energy, sleep, and emotional tone. In fact, the cluster of behaviors seen during acute illness—withdrawal, low mood, fatigue, loss of appetite—closely mirrors depressive symptoms. This response is often referred to as sickness behavior, and it is driven by immune signaling, not psychology.
When immune activation becomes chronic, those same symptoms can persist long after the original trigger is gone.
Why depression often overlaps with fatigue and brain fog
Depressive symptoms rarely exist in isolation. They often travel with fatigue, cognitive slowing, poor concentration, sleep disruption, and loss of physical stamina.
This overlap is not coincidental. Inflammatory signaling affects energy production, mitochondrial function, and how the brain allocates effort and reward. When the system is under sustained immune strain, the brain shifts into a more conservative, withdrawn state.
From a physiologic perspective, this isn’t failure—it’s adaptation. The brain is responding to a body that no longer has excess resources to spare.
Looking upstream: what the symptoms are responding to
Within a root-cause framework, symptoms of depression often reflect one or more upstream drivers, such as:
- chronic or stealth infections
- autoimmune or inflammatory conditions
- biotoxin or mycotoxin exposure
- prolonged fight-or-flight physiology
- metabolic or mitochondrial stress
Each of these can alter immune signaling in ways that directly affect mood, motivation, and emotional resilience.
This is why simply treating depressive symptoms in isolation often falls short. The symptoms may soften temporarily, but they tend to return if the underlying drivers remain active.
Where medications fit—and where they don’t
Psychiatric medications can be helpful tools. They may reduce symptom intensity, restore function, or provide stability during particularly difficult periods. For some people, they are essential.
But medications that target neurotransmitters do not correct immune imbalance or chronic inflammation. They don’t address infections, toxins, or persistent stress physiology. When used alone, they often act as symptom modifiers, not root-cause solutions.
Understanding this distinction can be deeply relieving. It reframes medication use as a support—not a verdict that something is permanently wrong.
A different way to understand depression
Seen through an immune-informed lens, depression is not something a person has. It is something the system is doing in response to strain.
Low mood, withdrawal, and loss of motivation become signals—information pointing toward a body that has been under more stress than it can comfortably manage.
A grounded and hopeful conclusion
When symptoms of depression are approached as signals rather than identities, the conversation changes. The focus shifts from “What’s wrong with me?” to “What is my body responding to?”
As upstream drivers of immune dysfunction are identified and addressed, inflammatory signaling often quiets. Energy improves. Emotional range returns. Motivation gradually rebuilds. In many cases, depressive symptoms lessen or resolve—not because they were forced away, but because the conditions that created them changed.
Depression, in this framework, is not the end of the story. It’s part of the body’s language. And when that language is understood, it often leads to clearer, more durable paths toward healing.
References
- Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-457. doi:10.1016/j.biopsych.2009.09.033
- Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22-34. doi:10.1038/nri.2015.5
- Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199-229. doi:10.1016/j.neuroscience.2013.04.060
- Han KM, Ham BJ. How inflammation affects the brain in depression: a review. Psychiatry Investig. 2021;18(4):340-353. doi:10.30773/pi.2020.0301
- Lee CH, Giuliani F. The role of inflammation in depression and fatigue. Front Immunol. 2019;10:1696. doi:10.3389/fimmu.2019.01696
- Beurel E, Toups M, Nemeroff CB. The bidirectional relationship of depression and inflammation: double trouble. Neuron. 2020;107(2):234-256. doi:10.1016/j.neuron.2020.06.002
- Leonard BE. The concept of depression as a dysfunction of the immune system. Curr Immunol Rev. 2010;6(3):205-212. doi:10.2174/157339510791823835
- Poletti S, Leone G, Hoogenboezem TA, et al. Markers of neuroinflammation influence psychopathology and cognitive function in mood disorders. Transl Psychiatry. 2024;14:121. doi:10.1038/s41398-024-02921-z
- Köhler CA, Freitas TH, Maes M, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017;135(5):373-387. doi:10.1111/acps.12698
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56. doi:10.1038/nrn2297