The Reason Why Depression (and Anxiety) Occurs Following Inflammation


Inflammation causes depression. Treatment with pro-inflammatory cytokines or bacterial toxins called lipopolysaccharides always results in depression. Scientists call this a sickness behavior in people undergoing pathogenic infection. Anhedonia, melancholia, and fatigues are all hallmarks of both sickness behavior and major depression.

“Exposure to pro-inflammatory cytokines produces a sickness syndrome with symptoms that overlap considerably with those seen in depression,” pioneers in the field, Professors Charles L. Raison and Andrew H. Miller, wrote in a research review in Nature Reviews Immunology. “The onset of depression is often mistaken with the development of sickness, and symptoms associated with infections are often mistaken with the onset of depression.”

The question is: Why does inflammation induces depression?

Pro-inflammatory cytokines can reach the brain and disturb neurocircuits — e.g., dopamine, serotonin, etc. — responsible for human behavior and mental health. Even antidepressants that act on these neurocircuits work partly by lowering inflammation. The question is: Why does inflammation upset the brain neurocircuits? Why does inflammation induces depression? The answer partly lies in the behavioral adaptations to pathogens or infections.

Purpose 1: Energy Conservation

The first human, or any animals for that matter, have evolved alongside microbes. The body reacts to pathogens — i.e., microbes that could harm the host — via inflammation. Inflammation is like a gun firing at criminals, causing collateral damage along the way (such as nearby cars or healthy cells). That’s why wound healing is necessary after pathogen elimination. And these processes are energetically costly.

So, one reason why inflammation causes depression is to discourage physical activity — such as killing the motivation or inducing fatigue to get out of bed — to free up energy for clearing infection and wound healing. In other words, depression could be an energy-conserving behavior.

As Professors Raison and Miller described in a separate 2013 review, “The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D),” in Molecular Psychiatry: “This [energy-saving behavioral] state…has been widely considered to develop in the context of infection and/or tissue injury as a means of marshaling limited metabolic resources for the expensive tasks of immune activation, fever generation, and tissue repair.”

Purpose 2: Social Withdrawal

Pathogenic microbes are often contagious. Infected people can transmit the disease to others if they come close enough. As ancestral humans often live in groups, social withdrawal would lower the risk of infection in the tribe. The Covid-19 pandemic best illustrates this where people distance themselves to limit new cases.

Likewise, infected people are immunologically compromised. They are, thus, prone to pathogens from elsewhere that are usually not virulent enough to cause diseases in the healthy.

Another reason why depression follows inflammation is to encourage social withdrawal, which prevents others and oneself from getting infected, the 2013 Molecular Psychiatry review also suggested.

Purpose 3: Threat Alertness

Depression may also come with anxiety, agitation, and insomnia — i.e., the anxious depression subtype — which are traits of hypervigilance. Although it may contradict the energy conservation theory, it can be complementary. An infected person who is physically weak may also need to be more aware of potential environmental threats. And one way is to not sleep vulnerably.

For support, professors of the 2013 review cited several human experiments confirming that pro-inflammatory cytokines can disrupt neurocircuits in both the basal ganglia (i.e., to induce motor retardation and fatigue) and the dorsal anterior cingulate cortex (i.e., to induce alertness).

Besides, an irritable person often reacts angrily and rejects the care of others, contributing to social withdrawal. And while agitation increases movement, “agitated patients tend to restrict their geographic mobility by, for example, staying home,” Harvard psychiatrists wrote in “An Evolutionary Hypothesis of Depression and Its Symptoms, Adaptive Value, and Risk Factors.”

Modernity Evolutionary Mismatch

Major depression is a disease of modernity. One paradox is that the leading predictor of major depression is chronic psychological stress, not pathogens. Still, the two are linked. Mental stress could increase the leaking of microbial toxins from the gut, which exacerbates inflammation, as I detailed in a 2020 review in the Frontiers of Neuroscience.

In ancestral times, mammals perceive psychological stressors as signals of incoming threats. Escaping from a predator, engaging in human conflict, or competing for reproductive access might cause wounding. And microbial infection could happen via the wound. That’s one reason why psychological stress primes inflammation in the body.

Yet, almost anything in this age can be a psychological stressor — be it relationships, jobs, studies, racism, etc. People experiencing racism, for instance, have a distinct genetic profile characterized by pro-inflammatory and stress-responsive states, which I detailed in The Faculty.

“Stress perception and risk of subsequent wounding was reliable enough that evolution favored organisms that prepotently activated inflammatory systems in response to a wide array of environmental threats and challenges (including psychosocial stressors),” Professors Miller and Raison elaborated nicely in a 2016 review. “Even if this activation was often a false alarm.”

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MSc Biology | 9x first-author academic papers | 280+ articles on coronavirus | Independent science writer


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