About a quarter of people with depression have blood test evidence of low-grade inflammation, and higher inflammatory markers have been linked, loosely, to poorer response to antidepressants. That has made inflammation one of the most discussed explanations for treatment-resistant depression. It remains a research finding, not a clinical test: a 2026 umbrella review concluded that the evidence does not yet support using inflammatory biomarkers to guide treatment decisions.
The link between inflammation and TMS is thinner still. A 2024 systematic review found 15 human studies that measured inflammatory markers around a course of TMS, most of them rated poor or moderate in quality and with inconsistent results, and no marker has been shown to predict who will respond. This article sets out what is established, what is preliminary, and what is reasonable to do with the information now.
What "inflammation" means in depression research
Researchers are not talking about infection or an inflamed joint. They mean small, persistent elevations in immune signaling molecules measured in blood. The most studied are C-reactive protein (CRP), a liver protein that rises with inflammation anywhere in the body, and the cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha).
By convention in this literature, a CRP above 3 mg/L counts as low-grade inflammation. CRP is not specific to the brain or to depression. In UK Biobank data, the association between depression and higher CRP shrank substantially after accounting for body mass index, smoking, health status and early-life adversity, although it did not disappear.
How common is it?
Two large sources give a consistent picture.
- A 2019 meta-analysis of 37 studies found CRP above 3 mg/L in 27% of people with depression, and above 1 mg/L in 58%. Compared with matched controls, the odds of low-grade inflammation were 1.46 times higher.
- In the UK Biobank (26,894 people with a lifetime diagnosis of major depression and 59,001 controls), average CRP was 2.4 mg/L versus 2.1 mg/L, and 21.2% versus 16.8% had levels above 3 mg/L.
Both things are true at once: inflammation is more common in depression, and most people with depression do not have it. The difference between groups is real but small, and many people without depression have a CRP above 3 mg/L. This is why the practice's own article on the subject calls the phrase "inflammation causes depression" too blunt to be true, and describes inflammation as one pathway and one potential subtype. That article, inflammation and depression: what we know so far, covers the biology in more depth.
Does inflammation make depression harder to treat?
The evidence points that way, without being strong enough to act on. A 2015 meta-analysis of 35 studies found that people who did not respond to treatment tended to have higher baseline inflammation on a composite measure, and that persistently elevated TNF-alpha was associated with treatment resistance.
The 2026 umbrella review, which covered eight meta-analyses, was more cautious. Lower baseline CRP was associated with better antidepressant response in some analyses, but findings were inconsistent and effect sizes generally small. For ECT, the pattern nominally ran the other way, with higher baseline CRP and IL-6 linked to greater improvement, though none of those associations survived statistical correction. If inflammation matters for treatment selection, it may matter differently for different treatments, and nobody yet knows the rules.
Trials that treated the inflammation
The sharpest test of the idea is to give an anti-inflammatory drug and see whether depression improves. The results are instructive mainly for how qualified they are.
| Trial | Design | Overall result | In people with raised CRP |
|---|---|---|---|
| Infliximab (Raison, 2013) | 60 outpatients with treatment-resistant depression; three infusions or placebo | No overall difference from placebo | Favored infliximab when baseline hs-CRP was above 5 mg/L; favored placebo at 5 mg/L or below |
| Minocycline (Nettis, 2021) | 39 patients with treatment-resistant depression and CRP of at least 1 mg/L; 4 weeks | No difference between arms | Largest improvement with minocycline when CRP was 3 mg/L or higher |
| Minocycline (MINO-TRD, 2022) | 173 patients randomized at 9 German university hospitals; 6 weeks | Not superior to placebo | Not selected by CRP |
A 2019 meta-analysis of 36 randomized trials of anti-inflammatory agents (including NSAIDs, cytokine inhibitors, statins and minocycline) found that, as add-ons, they improved depressive symptoms more than placebo. The same paper reported that every included study was at high risk of bias and noted a trend toward more infections.
The pooled result and the individual trials above do not fit neatly together. In the three trials in the table, anti-inflammatory treatment did not beat placebo overall. In the two that examined baseline CRP, it appeared to help a subgroup with clearly raised markers and did nothing, or in the infliximab trial did worse than placebo, when markers were not raised. The subgroup findings come from small numbers (13 and 9 patients in the high-CRP arms of the infliximab trial) and need confirmation. None of these drugs is approved for depression, and they should not be started for mood without a specific medical indication.
TMS and inflammation: what has been studied
Because TMS acts on brain circuits directly and bypasses the bloodstream, two questions follow. Does inflammation blunt the response to TMS? And does TMS change inflammation?
On the second question, a 2024 systematic review found 17 studies (15 in humans, 2 in animals). In animal models of depression, anti-inflammatory changes went along with behavioral improvement. In human studies of treatment-resistant depression that finding was not consistently replicated: several reported changes in blood inflammatory markers after TMS, but only two could link those changes to clinical response, and most studies were rated poor or moderate in quality.
On the first question there is very little. One 2022 pilot study of 30 patients with treatment-resistant depression, of whom only 10 received rTMS, reported higher baseline IL-6 and hs-CRP in non-responders across treatments and a fall in TNF-alpha over time in the rTMS group. A study that size can raise a hypothesis and nothing more. No guideline or FDA labeling uses inflammatory markers to select patients for TMS, and the established predictors of response are clinical; see who responds to TMS.
So the accurate statement is this: it is plausible that inflammation and brain stimulation interact, it is being studied, and there is currently no evidence that a high CRP should steer someone toward or away from TMS. How TMS works covers the mechanisms that are better supported.
Should you have a CRP test?
A high-sensitivity CRP is inexpensive and widely available, and there are sound medical reasons to check it, including cardiovascular risk assessment. As a guide to depression treatment its value is limited, for the reasons above. Three practical points:
- A single raised value means little. CRP rises with recent infection, injury, obesity and smoking, so a result should be repeated and interpreted with the rest of the medical picture.
- A clearly and persistently raised value is a reason to look for a cause, such as an inflammatory or metabolic condition, that deserves treatment in its own right.
- A normal value does not rule anything in or out for depression treatment, and a raised value is not a reason to delay an effective treatment.
CRP fits naturally into the wider medical review described in ruling out medical causes before TMS, alongside thyroid function, blood count and sleep.
What is reasonable to do now
The measures usually recommended for chronic low-grade inflammation are worth doing for depression and general health on other grounds: regular physical activity, adequate sleep, treatment of sleep apnea, a dietary pattern rich in plants and fish, not smoking, and management of weight and metabolic conditions. None has been shown to convert a TMS non-responder into a responder, and none should be presented as a treatment for resistant depression by itself. They are sensible companions to whatever primary treatment is chosen.
Dr. Lewis's practice describes its functional medicine approach as examining how inflammation, metabolism, hormones, nutrition, sleep and gut health may influence mental well-being, and includes hs-CRP among the inflammation markers on its lab panels. It also states that functional testing is optional and often investigational. Related reading on the site includes ways to reduce chronic inflammation, anti-inflammatory foods and depression, and the overview of functional medicine and psychiatry.
Where this leaves someone with treatment-resistant depression
Inflammation is a credible piece of the biology of depression and a poor basis, so far, for individual treatment decisions. If your depression has not responded to two or more medications, the options with the strongest evidence are the ones compared in every treatment-resistant depression option, and none of them requires an inflammatory marker to qualify. Attention to inflammation belongs alongside that plan, as part of looking after the whole person, and not in place of it. TMS in an integrative, precision psychiatry practice discusses how the two fit together.
The rest of this series is collected in the TMS guide, and the TMS service page explains how to start a conversation about whether TMS is an option.
Frequently asked questions
Does inflammation cause treatment-resistant depression?
It may contribute in some people. Raised inflammatory markers are more common in depression and have been linked to poorer antidepressant response, but the associations are small and inconsistent, and cause has not been established.
Does a high CRP mean TMS will not work for me?
There is no evidence for that. Only a few small studies have looked at inflammatory markers and TMS response, and none is strong enough to guide decisions.
Does TMS reduce inflammation?
Some studies have reported changes in blood inflammatory markers after TMS, but a 2024 systematic review found the results inconsistent and mostly unrelated to clinical improvement. It is an open research question.
Should I take an anti-inflammatory medication for depression?
Not on your own. Trials of anti-inflammatory drugs have been mixed and at high risk of bias, in some trials benefit appeared only in people with clearly raised markers, and the drugs carry their own risks. None is approved for depression.
What CRP level counts as inflammation in depression studies?
Most studies define low-grade inflammation as a CRP above 3 mg/L. That threshold comes from research convention and is not a diagnostic cut-off for depression.
Sources
- Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychological Medicine, 2019. pubmed.ncbi.nlm.nih.gov
- An umbrella review of inflammatory biomarkers and their relationship to treatment response in MDD. Neuroscience & Biobehavioral Reviews, 2026. pubmed.ncbi.nlm.nih.gov
- Association between rTMS-induced changes in inflammatory markers and improvement in psychiatric diseases: a systematic review. Annals of General Psychiatry, 2024. pubmed.ncbi.nlm.nih.gov
- Elevated C-Reactive Protein in Patients With Depression, Independent of Genetic, Health, and Psychosocial Factors: Results From the UK Biobank. American Journal of Psychiatry, 2021. pubmed.ncbi.nlm.nih.gov
- Inflammation and clinical response to treatment in depression: A meta-analysis. European Neuropsychopharmacology, 2015. pubmed.ncbi.nlm.nih.gov
- A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry, 2013. pubmed.ncbi.nlm.nih.gov
- Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial. Neuropsychopharmacology, 2021. pubmed.ncbi.nlm.nih.gov
- Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Network Open, 2022. pubmed.ncbi.nlm.nih.gov
- Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatrica Scandinavica, 2019. pubmed.ncbi.nlm.nih.gov
- A kynurenine pathway enzyme aminocarboxymuconate-semialdehyde decarboxylase may be involved in treatment-resistant depression, and baseline inflammation status of patients predicts treatment response: a pilot study. Journal of Neural Transmission, 2022. pubmed.ncbi.nlm.nih.gov
Educational information, not medical advice. Whether TMS or any treatment fits you is a decision to make with a psychiatrist who knows your history.
The information provided on this blog is for educational and informational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.
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