An arthritis drug primarily used to treat rheumatoid arthritis may offer a new treatment avenue for people with difficult-to-depression, according to early research from the University of Bristol. The medication, tocilizumab, is an anti-inflammatory drug that blocks a specific immune pathway, and investigators have for the first time tested whether it can alleviate symptoms in patients who do not respond to standard antidepressant therapies.
The inflammation link
Current drug treatments for depression predominantly target brain chemicals such as serotonin, norepinephrine and dopamine. Yet approximately one in three individuals finds no relief from these conventional approaches – a problem that has driven researchers to explore alternative biological mechanisms. A growing body of evidence points to inflammation as a key factor in a significant proportion of depression cases. Studies have found that roughly a third of people with depression exhibit signs of inflammation in their blood, suggesting their condition may be linked to an overactive immune system.
Scientists have identified higher levels of inflammatory proteins called cytokines in individuals with depression, particularly a cytokine known as interleukin 6 (IL-6). A large-scale study from King’s College London reported that people with depression have higher levels of inflammation regardless of other factors. Further genetic evidence, known as Mendelian randomisation studies, conducted by the Bristol team has indicated that IL-6 may causally contribute to depression – genetically predicted higher IL-6 activity is associated with an increased risk of depressive symptoms. The same group has also shown that counts of certain immune cells, such as B cells and T cells, are elevated in individuals with depression compared with healthy controls, suggesting a role for both innate and adaptive immune responses.
Tocilizumab works by blocking the IL-6 receptor (IL-6R), thereby inhibiting inflammatory signals. This targeted approach aims to address the inflammatory component of depression rather than altering brain chemistry alone.
Study results
The Bristol team conducted a pilot, randomised controlled trial involving 30 participants with moderate-to-severe depression who had not responded to standard treatments. Participants were split into two groups: half received tocilizumab and the rest a placebo, administered over four weeks.
Although the small sample size meant that statistical significance was limited, the participants who received tocilizumab showed greater improvements over time compared with those given a placebo. Early evidence suggests the drug reduced depressive symptoms, fatigue and anxiety, and improved overall quality of life. In terms of remission, 54% of those treated with tocilizumab achieved depression remission, compared with 31% in the placebo group. This translates to a Number Needed to Treat (NNT) of five – meaning five patients need to be treated for one to benefit – which compares favourably with the NNT of approximately seven for selective serotonin reuptake inhibitors (SSRIs), the most common first-line antidepressants.
Senior author Professor Golam Khandaker, from the University of Bristol’s MRC Integrative Epidemiology Unit, 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.”
Lead author Dr Eimear Foley, a Senior Research Associate in Immunopsychiatry at Bristol, added: “Depression is estimated to affect around 10% to 20% 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.”
Tocilizumab is already licensed in the UK for conditions such as rheumatoid arthritis, but studies indicate that existing RA drugs do not significantly alleviate depression in RA patients. The drug has been subject to cost-effectiveness assessments for RA; in 2010 the National Institute for Health and Care Excellence (NICE) provisionally ruled it out on cost grounds for England and Wales, though it was recommended in Scotland. More recent analyses suggest that the addition of tocilizumab to RA treatment sequences can be cost-effective, particularly with the advent of biosimilars, which are projected to lead to significant savings and expanded access. The estimated annual cost per patient for tocilizumab in RA has been cited at around £9,000–£10,500. Common side effects include cough, sore throat, headache, dizziness, high blood pressure, increased cholesterol and skin rashes; the drug can also increase the risk of infections such as upper respiratory tract infections, shingles and pneumonia, and serious but rare cases of drug-induced liver injury have been reported.
The researchers now plan to conduct a large-scale phase III randomised controlled trial that would provide definitive evidence to enable doctors to prescribe immunotherapy for depression. The study, titled ‘Interleukin 6 as a treatment target for depression: a proof-of-concept randomised clinical trial’, is published in the journal JAMA Psychiatry.