Could inflammation be one cause of difficult-to-treat depression?
A small study of an arthritis drug offers an intriguing glimpse into the relationship between immunity, inflammation and mental health
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“Depression is often discussed primarily as a disorder of brain chemistry. This is understandable: commonly prescribed antidepressants influence signalling pathways involving serotonin, noradrenaline and dopamine, and these medicines can be extremely valuable.
However, depression is not a single, uniform biological condition. The same collection of symptoms may arise through several different – and frequently overlapping – mechanisms.
This article by Eleanor Hayward in The Times reports on an interesting proof-of-concept trial investigating whether inflammation may be an important driver of depressive symptoms in a particular subgroup of patients.
Researchers studied 30 adults with moderate-to-severe depression who had responded poorly to conventional antidepressant treatment and who also had persistent evidence of low-grade inflammation. Participants received either a single intravenous infusion of tocilizumab – an immunotherapy normally used for inflammatory conditions such as rheumatoid arthritis – or a saline placebo.
Tocilizumab blocks the receptor for interleukin-6, usually abbreviated to IL-6, an important inflammatory signalling protein.
After four weeks, 54 per cent of those receiving tocilizumab were classified as being in remission, compared with 31 per cent receiving placebo. Improvements were also observed across several measures, including fatigue, anxiety, overall depression severity and quality of life.
These findings are certainly interesting, but they should be interpreted cautiously. This was a very small and short trial and it was not sufficiently powered to establish statistical efficacy. Indeed, its primary outcome did not show a statistically significant difference between the groups. The researchers themselves describe the findings as proof of concept and appropriately call for a much larger randomised controlled trial.
The study therefore does not establish tocilizumab as a new routine treatment for depression. It does, however, strengthen an important principle: in some people, depression may be partly associated with immune and inflammatory dysregulation.
Depression viewed through the Seven Regulatory Systems
This is precisely why I believe complex health problems should be considered through my Integrated Regulatory Systems Framework™.
The seven regulatory systems are:
- Respiratory
- Neural
- Endocrine
- Immune and inflammatory
- Metabolic
- Musculoskeletal
- Circulatory
These systems do not operate independently. They communicate continuously, and dysregulation within one system can create additional regulatory load elsewhere.
In one person, depression may be predominantly associated with trauma, bereavement or adverse circumstances. In another, it may coexist with chronic pain, disrupted sleep, hormonal disturbance, metabolic dysfunction, nutritional insufficiency, persistent inflammation or altered autonomic regulation. Frequently, several of these factors are present simultaneously.
This does not make depression any less psychologically real. Nor does it mean that psychological support or antidepressant medication is unnecessary. It simply argues against assuming that every patient with depression has precisely the same underlying physiology.
The immune and inflammatory system
Approximately 30 per cent of people with depression may have evidence of low-grade systemic inflammation. Inflammatory cytokines can influence communication between the immune system and brain, altering neural activity, sleep, motivation, energy, appetite and mood.
Inflammation may also affect the way the body handles tryptophan. Tryptophan is an essential amino acid obtained from dietary protein and is required for serotonin synthesis. Under inflammatory conditions, more tryptophan may be directed through the kynurenine pathway rather than towards serotonin production.
This does not mean that depression can simply be corrected by eating more protein or taking tryptophan. The movement of tryptophan into the brain depends on several factors, including its concentration relative to other amino acids. Nevertheless, inadequate protein intake, restrictive diets, poor digestion or absorption, metabolic dysfunction and inflammatory activation may all influence the availability and metabolism of this important nutrient.
Nutrition and an anti-inflammatory dietary pattern
An anti-inflammatory dietary approach is not a replacement for psychiatric or psychological treatment, but it may help reduce part of the wider physiological burden.
In practical terms, this generally means emphasising:
- A wide variety of vegetables, fruit, herbs and spices
- Adequate high-quality protein
- Oily fish and other sources of omega-3 fatty acids
- Extra-virgin olive oil, nuts and seeds
- Fibre-rich foods that support the intestinal microbiome
- Minimally processed foods
- Stable blood-glucose regulation through balanced meals
It also means reducing excessive refined sugar, ultra-processed foods, repeatedly heated oils and excessive alcohol.
The objective is not to promote a fashionable ‘depression diet’. It is to support metabolic, immune, intestinal and neurological regulation while ensuring that the body has the raw materials required for normal neurotransmitter production.
Breathing, carbon dioxide and cellular oxygen delivery
The respiratory and circulatory systems also deserve consideration.
A person may have a normal oxygen saturation reading while still having inefficient oxygen delivery at tissue level. Carbon dioxide is not simply a waste gas. It helps regulate blood-vessel tone and assists the release of oxygen from haemoglobin into tissues through the Bohr effect.
Persistent overbreathing can lower carbon dioxide levels. This may contribute to cerebral vasoconstriction and symptoms such as light-headedness, fatigue, disturbed concentration, anxiety, altered bodily awareness and poor exercise tolerance. Some of these symptoms may overlap with, amplify or help maintain depressive and anxiety presentations.
Breathing retraining is not presented as a cure for severe depression. However, where dysfunctional breathing or chronic hyperventilation is demonstrable, improving nasal and diaphragmatic breathing and restoring more appropriate carbon-dioxide regulation may reduce respiratory and autonomic load.
The neural and musculoskeletal systems
Chronic pain, physical restriction, disturbed sleep and reduced activity can all influence mood. At the same time, prolonged psychological distress may increase muscular tension, pain sensitivity and autonomic arousal.
Appropriately selected osteopathic manipulative treatment may help address musculoskeletal dysfunction and, in some patients, influence autonomic regulation. Gentle treatment directed towards the thoracic cage, diaphragm, cervical region and wider mechanical system may support breathing mechanics, movement, circulation and relaxation.
This should be regarded as an adjunctive component of an integrated treatment plan – not as a stand-alone treatment for major depression.
Endocrine and metabolic contributors
Depressive symptoms may also be influenced by thyroid dysfunction, insulin resistance, unstable blood glucose, menopause, androgen deficiency, disturbed cortisol regulation, anaemia and nutritional deficiencies.
This is one reason why difficult-to-treat depression warrants thoughtful medical assessment rather than the automatic assumption that failure to respond to one antidepressant simply requires another antidepressant.
The purpose of investigation is not to search endlessly for abnormalities. It is to identify plausible, modifiable factors that may be increasing the person’s overall regulatory load.
What about supplementation?
Supplementation should be individualised and should complement – not replace – appropriate medical, psychiatric, psychological, nutritional and lifestyle care.
Depending upon the clinical history and relevant investigations, consideration might be given to nutrients such as:
- Omega-3 fatty acids
- Vitamin D
- Vitamin B12 and folate
- Iron, when deficiency is demonstrated
- Magnesium
- Zinc
Not everybody requires these supplements, and more is not necessarily better. Potential interactions must also be considered. In particular, tryptophan or 5-HTP should not be added casually to serotonergic antidepressant medication because of the risk of excessive serotonergic activity.
Is IL-6 testing necessary?
IL-6 is an expensive and comparatively specialised blood test. It is not commonly used in routine clinical practice, and its level can fluctuate considerably.
Importantly, this study found that baseline high-sensitivity C-reactive protein – hs-CRP – tracked treatment improvement more closely than IL-6 itself. Participants had persistent hs-CRP elevation confirmed on two separate tests, rather than relying upon a single result.
This is clinically relevant because hs-CRP is considerably more accessible and may eventually prove more useful as a practical screening marker. However, CRP is non-specific: it can rise because of infection, injury, obesity, dental disease, autoimmune activity and numerous other causes. An elevated result does not establish that inflammation is causing someone’s depression, nor does it indicate that immunotherapy is appropriate.
A move towards more personalised treatment
The real importance of this study is not that everyone with depression should receive an arthritis drug. Tocilizumab suppresses part of the immune response and carries meaningful risks; it requires specialist prescribing and monitoring.
The more important message is that treatment may become increasingly personalised according to the biology of the individual.
For patients with persistent depressive symptoms, particularly those who have not improved with conventional treatment, it may be helpful to consider whether immune activation, nutritional inadequacy, metabolic disturbance, hormonal dysfunction, chronic pain, disturbed breathing, poor sleep or autonomic dysregulation are contributing to the overall presentation.
The brain does not exist separately from the body. Mood emerges from the interaction of our psychology, circumstances, nervous system, immune system, hormones, metabolism, breathing, circulation and physical experience.
This small study does not provide a definitive new treatment. It does, however, support a broader and more integrated way of thinking about depression – one which seeks to understand why this particular person has developed these particular symptoms at this particular time.”
Clinical Disclaimer
This article is intended for educational and informational purposes only. It does not constitute medical advice and should not replace individual consultation with a qualified healthcare professional.
Main article
How an arthritis drug could treat severe depression
Scientists have discovered that targeting inflammation offers hope to the millions of people who see no improvement from standard antidepressants
Eleanor Hayward | The Times | 20 May 2026
An arthritis drug that treats inflammation in the body can help to treat severe depression, a breakthrough study has found.
The trial, led by the University of Bristol, involved 30 adults who had not responded to standard antidepressants, which work by altering levels of chemicals in the brain.
Half the participants were given tocilizumab, an immunotherapy drug that is used to treat severe rheumatoid arthritis and works by reducing or slowing inflammation.
Over four weeks, those on tocilizumab saw greater improvements in depression symptoms, fatigue, anxiety and quality of life than those on the placebo. Fifty-four per cent of people on the drug achieved depression remission, meaning they did not have any active depressive symptoms, compared with 31 per cent on the placebo.
The authors said the trial was an “important milestone” and demonstrated that anti-inflammatory drugs could be a promising treatment option for depression.
Nearly nine million people in the UK take antidepressants, but one in three people with depression do not respond to them. Antidepressants, including SSRI drugs, are based solely on increasing levels of certain chemicals in the brain, such as serotonin, norepinephrine and dopamine.
However, recent research shows that about a third of people with depression have signs of inflammation in their blood, indicating that their symptoms may be linked to an overactive immune system.
Other studies point to higher levels of inflammatory proteins called cytokines in people with depression, including interleukin 6 (IL-6), a cytokine that is a driver of inflammation in the body.
Tocilizumab, which is given as an injection and is commonly used to treat immune conditions including several types of arthritis, works by blocking the activity of the IL-6 protein, thereby reducing inflammation. This is the first study to show that it can help depression.
Éimear Foley, the study’s lead author, said: “Depression is estimated to affect around 10-20 per cent of people worldwide during their lifetime, yet for many patients current treatments do not work well enough. Our study moves us closer to more tailored depression care, where treatments are chosen to better fit a person’s biology. This will help us to provide the right treatment to the right patients at the right time.”
Professor Golam Khandaker, the study’s chief investigator, said: “This work represents an important milestone in the development of new treatments for depression, especially difficult-to-treat depression, which affects millions of people in the UK alone.
“This is one of the first randomised controlled trials to test immunotherapy for depression, the first to test IL-6R as the treatment target and the first to use a targeted approach to select patients most likely to benefit, and to show that it works.”
Several recent studies have proposed a “neuroinflammation theory of depression”, suggesting that proteins that drive inflammation in the body can get into the brain and affect brain cells. Research shows that people with diseases caused by chronic inflammation such as multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis are almost twice as likely to suffer anxiety and depression.
The trial results were published in JAMA Psychiatry. The next step will be to conduct a phase III randomised controlled trial that will provide definitive evidence to enable doctors to prescribe immunotherapy for depression.
Source note
Original article: Eleanor Hayward, “How an arthritis drug could treat severe depression”, The Times, 20 May 2026. Read the original Times article
Research paper: Foley ÉM, Turner N, Margelyte R, et al. Interleukin 6 as a Treatment Target for Depression: A Proof-of-Concept Randomized Clinical Trial. JAMA Psychiatry. Published online 20 May 2026. doi:10.1001/jamapsychiatry.2026.1053. Read the open-access research paper
The Times article is reproduced here from the text supplied for educational commentary. Copyright in the original newspaper article remains with Eleanor Hayward and The Times. The research paper is published open access under a CC BY licence.