A small trial suggests that IL-6 receptor blockade may help some patients with inflammation-related depression, but that signal now needs to be confirmed in larger, longer-term studies.
Brief report: Interleukin 6 as a therapeutic target for depression – a proof-of-concept randomized clinical trial
A recent proof-of-concept randomized controlled trial (RCT) published in JAMA PsychiatryResearchers investigated whether systemic interleukin-6 receptor (IL-6R) inhibition with the IL-6 receptor antagonist tocilizumab could improve depressive symptoms in patients with hard-to-treat depression associated with low-level inflammation.
Tocilizumab therapy was associated with a pattern of progressively greater improvements in depression severity, physical pain, anxiety, and fatigue over time. This treatment was numerically favorable in terms of remission and response rates. These changes were more correlated with early high-sensitivity C-reactive protein (hs-CRP) than with IL-6 levels.
This finding highlights the potential of IL-6/IL-6R pathway inhibition as a therapeutic target for inflammation-related depression. Such a strategy could eventually be combined with repeated HS-CRP testing, a simple, low-cost blood test for patient selection to predict treatment response and support broader access to precision-based care.
IL-6 is a well-known cytokine that can increase levels of inflammation in the body. Scientists have discovered large amounts of this molecule in blood samples from patients with difficult-to-treat depression. Blood-based markers such as hs-CRP are also elevated in conditions related to inflammation.
There is also growing evidence that inflammation may play a role in depression. Based on these findings, researchers tested several anti-inflammatory drugs to treat depression. However, most of these treatments have far-reaching effects. This makes it difficult to identify the specific pathways involved. High-quality clinical trials investigating whether targeting the IL-6/IL-6R pathway in patients can improve depressive symptoms remain limited.
About research
In this double-blind RCT, researchers explored IL-6 as a potential target for developing treatments for hard-to-treat depression that involves low-grade inflammation.
The study included 30 people diagnosed with moderate to severe depression using International Classification of Diseases, 10th Revision (ICD-10) codes. These participants also had mild inflammation with hs-CRP levels ≥0.30 mg/dL on two tests.
The study population had more somatic depressive symptoms as assessed using the Beck Depression Inventory II (BDI-II) scale, scores 7 or higher. Researchers recruited participants from primary and secondary care centers and self-referrals in the UK from October 2018 to June 2022.
The research team randomly divided participants into two groups, balancing gender and severity of depression. One group received a single intravenous infusion of 8.0 mg/kg tocilizumab (maximum dose: 800 mg per patient), n=14. The other group received saline infusion (placebo) (n=16). Researchers evaluated results at the start of the study and 1, 2, and 4 weeks after injection. The researchers used the BDI-II scale to assess the primary outcome, physical symptoms two weeks after the infusion, and the secondary outcome, depression severity.
The researchers evaluated the exploratory results using established measures. These include anxiety, fatigue, cognition, anhedonia, and health-related quality of life (HRQoL). They used the following scale: For anxiety, the State-Trait Anxiety Inventory (STAI). Multidimensional Fatigue Inventory (MFI) for fatigue. Cambridge Neuropsychological Test Automated Battery for Cognition (CANTAB). The Snaith-Hamilton Pleasure Scale (SHAPS) for anhedonia. EuroQol 5-dimensional 3-level (EQ-5D-3L) for HRQoL.
The team analyzed data from 2023 to 2025. Multivariable regression models were used for statistical analysis. We also calculated risk difference (RD) and number needed to treat (NNT) values to estimate remission rates and assess treatment response.
result
The average age of participants was 41 years. 80% were women. They were on antidepressants. More than half (57%) were using selective serotonin reuptake inhibitors (SSRIs). Tocilizumab therapy showed a pattern of gradual and significant improvements in depression severity, somatic symptoms, anxiety, and fatigue. The efficacy of remission rate and symptom level was also numerically improved. However, the prespecified primary endpoint, physical symptoms at day 14, showed little difference between the groups. After four weeks of infusion, researchers observed a remission rate of 54% vs. 31%, RD=0.2, NNT=5, and a response rate of 46% vs. 19%, RD=0.2, NNT=4 in the treatment and placebo groups. Although these findings favored tocilizumab numerically, the confidence interval did not include the effect. However, the drug failed to improve cognitive function.
Because the study included only a small number of participants, the researchers could not determine whether the results were statistically significant. Nevertheless, they considered that this treatment may have clinically meaningful benefits in reducing the severity of anxiety, fatigue, and depression, and improving overall well-being. This improvement addressed initial hs-CRP levels rather than IL-6 levels. These findings suggest that hs-CRP can more reliably predict response to immunotherapy. Tocilizumab was also well tolerated over 4 weeks in these patients. No one withdrew from the study or reported any serious adverse events.
conclusion
The findings suggest that blocking IL-6-associated inflammation may provide a new approach for patients with depression associated with chronic inflammation. Such treatments may particularly benefit patients who do not respond well to standard antidepressants. The study results also suggest that repeated hs-CRP testing may help identify patients most likely to benefit from IL-6-targeted therapy in future trials. Such efforts may ultimately help improve resource allocation and treatment outcomes, thereby reducing the burden of disease on individuals and health systems.
These treatments also have the potential to bring depression treatment a step closer to precision medicine by allowing doctors to choose treatments based on an individual’s biological profile. In the future, trials involving larger populations and longer follow-up periods should be conducted to validate these results and make them applicable to a broader population.
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