Inflammation and depression are linked — but what keeps the immune system inflamed?
STUDY: Bindroo A et al, Brain, Behavior, and Immunity 2026; doi:10.1016/j.bbi.2026.106577
STUDY TYPE: Review
FUNDING: National Institute of Mental Health; National Institute of General Medical Sciences
Background
Inflammation is a normal immune response. It is supposed to be short-lived, but when it goes on too long it can cause depression. It wears down dopamine, causing low motivation and anhedonia. Around 24% of depressed patients have low-grade inflammation compared to 16% of controls. For treatment-resistant depression, the rate is 50%.
Why Inflammation Persists
Several factors can turn inflammation chronic, and most of them have to do with changes in modern life:
- Insomnia: Sleep restores immune function, and insomnia amplifies inflammation, as do disruptions of circadian rhythms such as light at night. A therapy for insomnia (CBT-i) reduces depression and inflammation.
- Stress: Early-life stress and trauma primes the immune system toward a more reactive, less self-resolving state, while ongoing stress activates inflammatory pathways through the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis (ie, stress hormones like cortisol)
- Sedentary living and energy-dense, ultra-processed foods cause inflammation
- Obesity: As fat cells grow, they outstrip their blood supply and die, leaving necrotic material that triggers an immune response
- Sanitation: As we take more antibiotics and spend less time in nature, we lose contact with microbes that regulated the immune response, including changes in the gut microbiome
- Infections: Viruses and other infections trigger chronic inflammatory responses that worsen mood and cognition, including like COVID, HIV, and HSV
Many of these are inter-linked. Stress worsens sleep, and insomnia worsens obesity and metabolic health, all of which raise the risk of infections.
Depression is three times more common in women, and inflammation may be part of the reason, as women have stronger immune responses than mend. Genetic factors are also involved. Genes that protect infants from infections by activating immunity may trigger over-reactive inflammation in later life.
Practice Implications
- I’ve highlighted links to lifestyle interventions above that treat depression and address causes of inflammation
- These are not “lightweight” interventions for mild depression. Some studies suggest they are more effective in more severe cases, and address the inflammatory pathways that keep antidepressants from working
- Learn more about the anti-inflammatory approach in Difficult to Treat Depression
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- Are you checking for inflammation in practice with an hs-CRP?
- Which approaches do you find more effective for patients with inflammation?
