Back in the days when we were all cave-dwelling hunters and gatherers, there was no diagnostic manual to identify Major Depressive Disorder (MDD). There were, however, still symptoms of depression: fatigue, appetite and sleep changes, social withdrawal and so on. These symptoms of depression (coincidentally?) overlap with symptoms of sickness behaviour. When you are ill, your body responds by limiting energy output (more sleep, withdrawal) and if you are lucky, your partner or family respond with blankets and comforting soup.
In modern times, sickness behaviour symptoms can be considered in the context of MDD. In particular, somatic symptoms of depression (e.g., fatigue, appetite changes) have been associated with activation of the immune system, namely low-grade inflammation. This low-grade inflammation can be present even in the absence of a clear infection, and is associated with fatigue, energy conservation (overeating, oversleeping), and anhedonia in depression (Zwiep et al., 2026).
About 30% of depressed individuals have low-grade inflammation, which is often measured with C-reactive protein (CRP) or Interleukin-6 (IL-6; Osimo et al., 2019). This is not a coincidence; research suggests that depression and inflammation are associated (Kohler-Forsberg et al., 2019; Lai et al., 2023; Su et al., 2019). However, there is still a lot to learn about how this might be used in treatment, including which intervention should be given to whom, in which context it works, for how long a treatment should last, and what the long-term effects might be.
To this effect, Foley and colleagues (2026) conducted a proof-of-concept trial that targeted the IL-6/IL-6 receptor pathway, which is a specific inflammatory mechanism that has been associated with somatic symptoms of depression, including fatigue (Foley et al., 2024). They wanted to discover if it is an appropriate treatment target for depression, and what might be needed in a larger trial.
Just under a third of individuals with depression experience low-grade inflammation. Foley and colleagues (2026) wanted to know if targeting this inflammation could improve depressive symptoms.
Methods
In this proof-of-concept randomised controlled trial (RCT), the effect of one intravenous infusion of tocilizumab (8mg/kg body weight) was compared to a placebo (saline) infusion in depressed patients. Tocilizumab is a common medication used to treat conditions like rheumatoid arthritis and juvenile idiopathic arthritis, and works by blocking IL-6 signalling, which helps reduce inflammation in the body. The study was registered at ClinicalTrials.gov and the authors published the study protocol (Khandaker et al., 2018).
Participants were selected for persistent low-grade inflammation (CRP ≥ 3mg/l on two separate tests, without any infection or immune-related condition), non-response to antidepressant treatment, specific inflammation-related somatic symptoms of depression, and had to meet the diagnostic criteria for MDD (following ICD-10). These participants were measured at baseline and after 7, 14 and 28 days of the tocilizumab/placebo intervention. The primary outcome was somatic symptoms of depression measured with the Beck Depression Inventory II (BDI-II). Secondary and exploratory outcomes included depression severity, fatigue, anhedonia, anxiety, quality of life, and cognition.
Results
Twenty-nine participants took part in the trial, with 13 receiving the tocilizumab infusion. The average age of the participants was 41 years old and 80% of the participants were female. As expected, tocilizumab successfully lowered levels of CRP below clinical cut-offs, and increased circulating IL-6 levels. This suggests that the treatment worked as intended.
Primary outcome
At 14-days post-infusion, there was no difference in somatic symptom scores of depression between the tocilizumab group and the placebo group (-0.12, 95% CI [-2.51 to 2.28]), suggesting little effect of the treatment.
Secondary outcomes
Results on the secondary outcomes suggest a trend toward greater reductions in depression severity in the tocilizumab group compared to placebo, although confidence intervals indicate great uncertainty and results were not statistically significant (-2.10, 95% CI [-9.18 to 4.98]).
A similar pattern was observed for response (50% decrease in symptoms) and remission from depression; a trend but no statistically significant difference.
There were also no clear effects for anhedonia or cognition.
The tocilizumab group did show a stronger, but non-significant, trend toward improvement in different domains of fatigue, including physical (B = -0.71, 95% CI -2.04 to 0.63) fatigue and total fatigue (B = -4.69, 95% CI -9.63 to 0.25) over time. Importantly, higher baseline CRP corresponded to greater treatment effects.
No serious adverse events occurred during the trial.
A single infusion of tocilizumab was sufficient to clear the body of inflammation. However, there were no significant differences in reported depression outcomes between the intervention and placebo groups.
Conclusions
In conclusion, this proof-of-concept RCT demonstrated that tocilizumab appears to be safe and potentially promising in targeting inflammation in depression, with strong trends toward reducing fatigue and other depressive symptoms.
Furthermore, baseline CRP might predict treatment response of anti-inflammatory interventions in depression, highlighting an interesting avenue of further study.
However, even though most outcomes favoured tocilizumab treatment over placebo, the effects were not significant and should be interpreted with caution. Helpfully, the authors have calculated the sample sizes required for future fully-powered RCTs, which are available in the supplementary materials of the published paper.
Most outcomes favoured tocilizumab, but effects were not significant. This trial is an exciting first step in the journey towards better understanding the impact of treating inflammation in individuals with depression.
Strengths and limitations
In this proof-of-concept study, Foley et al. (2026) have made an important step in personalising depression treatment. By ensuring their clinical sample had high inflammation, the proposed IL-6/IL-6R mechanism could be measured and targeted. This represents a very important and often overlooked strategy for clinical trials; after all, you never know whether your umbrella works if you never tested it in the rain.
Another strength is in their primary outcome selection. Instead of a general, non-specific depression outcome, the authors selected the primary outcome related to the targeted mechanism of the intervention. After all, we (should) judge the umbrella by its ability to keep our head dry, not whether we avoid every single raindrop.
A final strength is the inclusion of people with lived experience in designing the study, ensuring the research stays grounded in what actually matters to those it aims to help. Including people with lived experience makes designing interventions more appropriate and thereby more effective.
To quote Mental Elf blogger Céline Wessa, who wrote about the future of anti-inflammatory treatments for depression and personalising treatment:
Future studies need to: recruit biologically enriched samples, demonstrate target engagement, prioritise mechanistically relevant outcomes.
The present study followed exactly this direction, representing an important step in personalising depression treatment.
However, this study also has important limitations:
- Due to the small sample size, the analyses were underpowered, and the true effect of the intervention remains unclear. Where the estimates point into the direction of an effect of tocilizumab, the confidence intervals indicate uncertainty, meaning we cannot be fully confident in interpreting this.
- Furthermore, as the duration of the trial was 4 weeks, long-term changes in depression status due to relief of chronic inflammation could not be picked up. The biological mechanisms and resulting symptoms develop over time, and probably needs some time to recover too (Miller & Raison, 2023).
- Finally, the study population was defined as difficult-to-treat, as in they had not responded to antidepressant medication. While ambitious and can be considered both a strength and weakness of a study, a difficult-to-treat population is of course more difficult to treat (and thus more difficult to find strong effects of treatment).
As for my final umbrella remark, this one was only tested in the heaviest storm without knowing if it holds up against lighter rainfall. As such, future research should aim to treat depression with inflammation, also in less-difficult-to-treat populations.
A good umbrella keeps your head dry in the rain, just as this clinical trial targeted the mechanism they knew to be involved in somatic symptoms of depression.
Implications for practice
Inflammation in depression is associated with treatment resistance and higher risk of developing comorbid disorders, including obesity and type 2 diabetes (Penninx et al., 2013; Strawbridge et al., 2015; Vreijling et al., 2024). As we have seen in the current study, treating the inflammation with tocilizumab can have beneficial effects, but the evidence is simply too uncertain at this point. We need more research to understand for whom and when this treatment is suitable.
The potential is there – after all, it lowered CRP below clinical levels. Moreover, it only took a single infusion. As this single infusion seems effective and practical for decreasing inflammation and improving fatigue scores, it could potentially be leveraged as a mono-symptom intervention, or as intervention for symptoms or symptom clusters related to inflammation (Zwiep et al., 2026).
Maybe, and my apologies for trailing off a bit, not every treatment needs to be able to treat everything? If fatigue or appetite or sleep problems are central to a person’s depression, maybe a treatment targeting a single symptom can be sufficient? Either way, the effect of tocilizumab on CRP and IL-6 in depression warrants more research, in more people, with longer follow-up, and additional assessment of inflammation-related symptoms. The role of the IL-6/IL-6R pathway in depression also requires further investigation.
The results are not sufficient to support clinical implementation, but they point us to an important next step: larger and longer trials that retain a mechanistic focus and select participants based on biological and phenotypic signs of inflammation.
To conclude, targeting inflammation may not be the answer for everyone – but for some, it could change everything.
This proof-of-concept trials indicates that targeting the IL-6/IL-6R pathway could be a promising treatment for depression, but larger and longer trials are needed to increase confidence in the findings.
Statement of interests
Joël Zwiep has no conflicts of interest to declare. Éimear Foley, the lead author of this paper and one of The Mental Elf’s blog coordinators, reviewed a draft of this blog to check for accuracy, but made no edits to the opinions, interpretations or critical appraisal.
Edited by
Dr Nina Higson-Sweeney.
Links
Primary paper
Éimear M. Foley, Nicholas Turner, Ruta Margelyte, Hannah J. Jones, Muzaffer Kaser, Glyn Lewis, Peter B. Jones, Golam M. Khandaker (2026). Interleukin 6 as a treatment target for depression: A proof-of-concept randomised controlled trial. JAMA Psychiatry.
Other references
Foley, É. M., Slaney, C., Donnelly, N. A., Kaser, M., Ziegler, L., & Khandaker, G. M. (2024). A novel biomarker of interleukin 6 activity and clinical and cognitive outcomes in depression. Psychoneuroendocrinology, 164, 107008. https://doi.org/https://doi.org/10.1016/j.psyneuen.2024.107008
Khandaker, G. M., Oltean, B. P., Kaser, M., Dibben, C. R. M., Ramana, R., Jadon, D. R., Dantzer, R., Coles, A. J., Lewis, G., & Jones, P. B. (2018). Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation. BMJ Open, 8(9), e025333. https://doi.org/10.1136/bmjopen-2018-025333
Kohler-Forsberg, O., C, N. L., Hjorthoj, C., Nordentoft, M., Mors, O., & Benros, M. E. (2019). Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand, 139(5), 404–419. https://doi.org/10.1111/acps.13016
Lai, J. Y., Ho, J. X., Kow, A. S. F., Liang, G., Tham, C. L., Ho, Y.-C., & Lee, M. T. (2023). Interferon therapy and its association with depressive disorders – A review [Review]. Frontiers in Immunology, Volume 14 – 2023. https://doi.org/10.3389/fimmu.2023.1048592
Miller, A. H., & Raison, C. L. (2023). Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies. Mol Psychiatry, 28(1), 68–75. https://doi.org/10.1038/s41380-022-01887-y
Osimo, E. F., Baxter, L. J., Lewis, G., Jones, P. B., & Khandaker, G. M. (2019). Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med, 49(12), 1958–1970. https://doi.org/10.1017/S0033291719001454
Penninx, B. W. J. H., Milaneschi, Y., Lamers, F., & Vogelzangs, N. (2013). Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Medicine, 11(1), 129. https://doi.org/10.1186/1741-7015-11-129
Strawbridge, R., Arnone, D., Danese, A., Papadopoulos, A., Herane Vives, A., & Cleare, A. J. (2015). Inflammation and clinical response to treatment in depression: A meta-analysis. European Neuropsychopharmacology, 25(10), 1532–1543. https://doi.org/https://doi.org/10.1016/j.euroneuro.2015.06.007
Su, K.-P., Lai, H.-C., Peng, C.-Y., Su, W.-P., Chang, J. P.-C., & Pariante, C. M. (2019). Interferon-alpha-induced depression: Comparisons between early- and late-onset subgroups and with patients with major depressive disorder. Brain, Behavior, and Immunity, 80, 512–518. https://doi.org/https://doi.org/10.1016/j.bbi.2019.04.032
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Wassa, C. (2026). Anti-inflammatories for depression: targeting the right patients matters. The Mental Elf. https://www.nationalelfservice.net/mental-health/depression/anti-inflammatories-depression-targeting-right-patients-matters/
Zwiep, J. C., Lamers, F., Vinkers, C. H., van der Wee, N. J. A., Penninx, B. W. J. H., Nawijn, L., & Milaneschi, Y. (2026). Inflammation, metabolic dysregulation, and depression profiles related to anhedonia and atypical, energy-related symptoms. Brain, Behavior, and Immunity, 132, 106240. https://doi.org/https://doi.org/10.1016/j.bbi.2025.106240
