"Your immune system can quietly reroute brain chemistry." The post describes an enzyme switch, a fork in the road and a "neurotoxic" compound, and it has been shared widely. For once the chemistry is right. What the post leaves out is the human evidence, which is more interesting than the diagram, and more careful.
Tryptophan Has Two Roads
Tryptophan is an amino acid you get from food. A small fraction becomes serotonin. Most of it, even in a healthy body, goes down another road, the kynurenine pathway, which ends up making NAD+, a molecule every cell needs for energy. The first step on that road is controlled by two enzymes, IDO and TDO. Cortisol turns on TDO. Inflammatory signals such as interferons and TNF-alpha turn on IDO. So when the body is under chronic stress or low-grade inflammation, more tryptophan is pushed down the kynurenine road.
The popular version says this "starves" serotonin. That is probably too simple: the brain makes serotonin from a fraction of tryptophan so small that the diversion alone rarely explains a depression. The more likely culprit is what happens further down the road.
The Fork: Kynurenic Acid or Quinolinic Acid
Once kynurenine crosses into the brain, two cell types compete for it. Astrocytes turn it into kynurenic acid, which calms glutamate NMDA receptors and is broadly protective. Microglia, the brain's immune cells, turn it into quinolinic acid, which does the opposite: it activates NMDA receptors, promotes oxidative stress, and in cell cultures and animals it damages neurons. Inflammation tips the balance towards the microglial side. The post's green tick and warning sign are a fair summary of this fork.
What Human Studies Show
Two meta-analyses matter here. Ogyu and colleagues (2018) pooled 22 studies and found that people with depression have lower kynurenic acid and lower kynurenine, and that unmedicated patients have higher quinolinic acid. Marx and colleagues (2021) pooled 101 studies and 10,912 participants across depression, bipolar disorder and schizophrenia: tryptophan metabolism is shifted away from serotonin towards kynurenine in all three, and in mood disorders the shift leans towards quinolinic acid rather than the protective branch.
The cleanest natural experiment comes from medicine. When hepatitis C used to be treated with interferon-alpha, a strongly inflammatory drug, roughly a third of patients developed a clinical depression within weeks, and the size of their kynurenine shift predicted who would. Inflammation can cause depression in humans, not just in mice.
Why Some Antidepressants Fail
Here is the practical part. In 2013 Raison and colleagues gave infliximab, an antibody that blocks TNF-alpha, to people with treatment-resistant depression. Overall it did nothing better than placebo. But in the subgroup with elevated inflammation at baseline (C-reactive protein above 5 mg/L), it worked, and in those with low inflammation it did slightly worse than placebo. Later meta-analyses of anti-inflammatory add-ons show a modest average benefit that is likely concentrated in the inflamed subgroup. Around a quarter to a third of people with depression show this low-grade inflammation, and they tend to respond less well to standard antidepressants.
What It Does Not Say
Blood levels are a proxy: kynurenic acid barely crosses into the brain, and what happens in the brain is inferred. Most studies are cross-sectional, so cause and effect are hard to separate, and many patients take medication that changes these markers. "Neurotoxic" comes from cell cultures and animals; in humans, we have associations and plausible mechanisms, not proven neuron loss. And no, you should not take ibuprofen for your mood: the drugs in these trials are specific, prescribed, and only helped a minority.
What You Can Do
The levers that lower low-grade inflammation are the unglamorous ones. Exercise is the most interesting: trained muscle produces enzymes that convert kynurenine into kynurenic acid before it reaches the brain, which is one reason exercise protects against stress-induced depression in animal studies (Agudelo, 2014). Sleep debt, abdominal weight, alcohol, smoking and chronic stress all push the other way. If you have a depression that has not responded to two well-conducted treatments, asking your doctor for a CRP measurement is reasonable: it is cheap, and it changes the conversation.
If you are not sure where you stand, our free PHQ-9 depression screening takes three minutes and gives you a validated score to bring to a consultation. To go further on the same theme, read how chronic stress reshapes the brain, what the evidence says about magnesium and depression, and how the gut talks to the brain, a major source of the inflammatory signals discussed here.
Sources: Miller AH, Raison CL (2016). The role of inflammation in depression. Nature Reviews Immunology; Savitz J (2020). The kynurenine pathway: a finger in every pie. Molecular Psychiatry; Ogyu K, et al. (2018). Kynurenine pathway in depression: a systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews; Marx W, et al. (2021). The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies. Molecular Psychiatry; Raison CL, et al. (2013). A randomized controlled trial of the TNF antagonist infliximab for treatment-resistant depression. JAMA Psychiatry; Agudelo LZ, et al. (2014). Skeletal muscle PGC-1a1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell; Kohler-Forsberg O, et al. (2019). Efficacy of anti-inflammatory treatment on major depressive disorder. Acta Psychiatrica Scandinavica.