The Hidden Culprit Behind Depression
Research linking inflammation, our immune systems, and our mental health
For years, we’ve considered depression to be a wiring issue — a misfire of brain chemistry with a bit of serotonin shortage here and too much stress there. But a growing body of research is flipping that notion on its head, suggesting that inflammation — the same process that fights off colds, heals sprained ankles, and causes us to regret last night’s questionable takeout — might also be pulling the strings behind our mood swings. The idea that depression could be part brain, part immune system may sound bizarre, but there’s a lot of research supporting this theory. So, what exactly is going on beneath the surface?
Inflammation: Friend or Frenemy?
Inflammation is the body’s emergency response team — like an army of highly trained soldiers rushing in to defend against infection or heal injury. But what happens when this army overstays its welcome? Picture them not just fighting invaders but also ransacking the city. That’s chronic inflammation, and it could be culpable for our mood changes.
A meta-analysis of 82 studies found notable differences in levels of inflammatory molecules between people with depression and those without.1 With names that could be plucked from a sci-fi novel - Interleukin-6, tumour necrosis factor-alpha, and C-Reactive Protein — these inflammatory molecules were consistently elevated in those battling depression. Research has even found that higher levels of these molecules are associated with increased severity of depression and suicidality.2 These molecules are our bodies’ prime defenders, but when they hang around too long they can cause all sorts of problems, mental health included.
How Inflammation Toys with Our Moods
So, how does inflammation mess with our minds? Some inflammatory molecules, like cytokines, can sneak past the blood-brain barrier. Once inside the brain, these molecules activate specialised immune cells called microglia. Microglia are the brain’s tidy housekeepers, keeping things in order. But when inflammation ramps up they can go rogue, remodelling neural connections, and disrupting the delicate balance of neurotransmitters like serotonin and dopamine.3
Perhaps some of the most compelling evidence linking inflammation to depression comes from the autopsies of suicide victims. Numerous pathologists have found higher levels of activated microglia in the brains of suicide victims, implicating these neural housekeeper cells in exacerbating depressive symptoms.4
Think of it like a botched home renovation — with microglia tearing down walls that should have stayed up, and disrupting the electricity so the lights won’t stay on. That’s what chronic inflammation does to our brains, disrupting essential connections and leading to the emotional numbness and brain fog we associate with depression.
So Where’s All This Inflammation Coming From?
Enter Michael Berk and his team, who did a deep dive into the origins of this inflammation, and guess what? The evidence points straight to our modern lifestyles. A poor diet, lack of exercise, obesity, smoking, stress, and even gut issues can all send our immune systems into a frenzy.5
If our diet is packed with processed foods or we’ve been enjoying a bit too much sedentary bliss, we could be laying the groundwork for chronic inflammation. Stress, in particular, is a prime offender. Research shows that prolonged stress cranks up levels of pro-inflammatory molecules called cytokines, in both humans and animals. ⁵ The longer the stress drags on, the higher the inflammation, and the greater the risk of slipping into depression.
An Evolutionary Quirk?
But why would evolution saddle us with a system that can mess with our moods so dramatically? There’s a theory: during times of illness or injury, feeling low-energy and disinterested in life may have been a survival advantage. Running around and socialising while unwell wouldn’t have helped our early ancestors heal. Instead, “sickness behaviour” — that desire to shut down and withdraw — might have been nature’s way of ensuring we conserved energy and didn’t spread our germs to the tribe. It’s biology’s way of saying, “Stay in your cave; let your body recover.”
What Does This Mean for Treatment?
So, should we all start gobbling anti-inflammatories like candy? Not so fast. It turns out that common antidepressants, particularly SSRIs, have anti-neuroinflammatory effects of their own, which could explain why they work so well for some people.6 However, they’re far from a universal fix.
Emerging research suggests that people with elevated inflammatory molecules — like CRP or cytokines — might benefit from treatments specifically targeting inflammation, though more research is needed. ³ There’s also real potential for new, personalised treatments, where we custom-tailor immunotherapies based on individual immune profiles (especially with cutting-edge biologic drugs on the horizon). There’s a future where we’ll be spared the horrible trial-and-error approach of current antidepressant prescribing.
In the meantime, there are everyday ways to cool down the inflammatory fire. Regular exercise, a Mediterranean-style diet, and improved sleep habits have all been shown to reduce inflammation. ⁵ They’re not a magic bullet, but getting out for a brisk walk or trading that processed snack for some leafy greens can go a long way in improving both our mental and physical health. It turns out that modulating our own immune systems is within reach for most people.
Viewing depression through the lens of inflammation adds another piece to an intricate and incomplete puzzle, fitting alongside what we already know about brain chemistry. The complex interplay between the immune system, lifestyle, and mental health reminds us that we are, quite literally, a product of both mind and body. These 21st century medical advancements are incredibly exciting, and new immunotherapies are going to change medicine as we know it. Watch this space.
1.Köhler, C. A. et al. Peripheral cytokine and chemokine alterations in depression: A meta‐analysis of 82 studies. Acta Psychiatrica Scandinavica 135, 373–387 (2017).
Köhler-Forsberg, O. et al. Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression. Brain Behavior and Immunity 62, 344–350 (2017).
Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Reviews. Immunology 16, 22–34 (2015).
Torres-Platas, S. G., Cruceanu, C., Chen, G. G., Turecki, G. & Mechawar, N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun. 42, 50–59 (2014).
Rao, J. S., Harry, G. J., Rapoport, S. I. & Kim, H. W. Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol. Psychiatry 15, 384–392 (2010).
Steiner, J. et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J. Psychiatr. Res. 42, 151–157 (2008).
Berk, M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Medicine 11, (2013).
Dionisie, V., Filip, G. A., Manea, M. C., Manea, M. & Riga, S. The anti-inflammatory role of SSRI and SNRI in the treatment of depression: a review of human and rodent research studies. Inflammopharmacology 29, 75–90 (2020).