Anti-inflammatory drug tocilizumab shows promise for difficult-to-treat depression

Immunotherapy could be a promising new treatment option for patients with difficult-to-treat depression. This is a key finding from a University of Bristol-led pilot randomised controlled clinical trial, published in JAMA Psychiatry today [20 May]. 

Researchers investigated, for the first time, whether tocilizumab, an existing anti-inflammatory drug commonly used to treat immune conditions such as rheumatoid arthritis, could improve symptoms of depression in people who have not responded to standard antidepressant treatments.

While the pilot trial involved a small number of people (30 participants with moderate-to-severe depression), it provides early evidence that, compared with the saltwater placebo, tocilizumab may reduce depression symptoms, fatigue, anxiety and increase overall quality of life. 

Current drug treatments for depression are solely based on targeting chemicals in the brain, such as serotonin, norepinephrine, and dopamine. However, around one in three people with depression do not get better with these treatments.

Recent research shows that about one-in-three people with depression have signs of inflammation in their blood, indicating that, for some, their symptoms may be linked to an overactive immune system. Other studies point to higher levels of certain inflammatory proteins, called cytokines, in depression, including interleukin 6 (IL-6), a cytokine that plays a key role in body's inflammatory response.

Earlier work by the team using Mendelian randomisation further supports the idea that inflammation, particularly the cytokine IL-6, may contribute to depression. This genetic technique allows researchers to identify causal factors for disease by teasing apart correlation from causation making use of the underlying genetic differences within large populations. Studies using Mendelian randomisation, along with other study designs like longitudinal cohort studies, together provide triangulated evidence all pointing towards the IL-6 inflammation pathway as one of the key causes of depression.

Researchers wanted to see whether symptoms could improve in people with inflammation-related depression by blocking the IL-6 pathway, thus lowering inflammation levels. To test this, they conducted a small four-week pilot randomised controlled trial of thirty people with moderate-to-severe depression who had not responded well to standard antidepressants and who showed signs of low-grade inflammation in two separate blood tests taken two weeks apart. Participants were randomly assigned to receive either tocilizumab (14 people) or a placebo (16 people) and were followed over four weeks to record any effects.

While the results showed little statistical evidence for significant difference between two group, as expected for a small study, participants who received tocilizumab seemed to experience greater improvements over time across several measures as compared to those given a placebo, including overall depression severity, fatigue, state anxiety, and quality of life. Furthermore, the tocilizumab group was more likely to achieve depression remission compared to placebo group (54% vs 31%), which equates to a Number Needed to Treat (NNT) of 5, meaning an additional 5 patients will need to be treated to make one patient better. For comparison, the NNT for SSRIs – the most common first-line antidepressant for patients with moderate-to-severe depression – is about 7.

Golam Khandakar, Professor of Psychiatry and Immunology from the MRC Integrative Epidemiology Unit (MRC IEU) at the University of Bristol and NIHR Biomedical Research Centre: Bristol (NIHR BRC: Bristol), and the study's senior author and 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."

Dr Éimear Foley, Senior Research Associate in Immunopsychiatry at Bristol's MRC IEU and the NIHR BRC: Bristol, and the study's lead author, added:  "Depression is estimated to affect around 10-20% 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."

One participant who took part in this study said: "I was happy to take part. Without research, advancements in medicine cannot be made."

The next step will be to conduct a large-scale phase III randomised control trial that will provide definitive evidence to enable doctors to prescribe immunotherapy for depression.

The double-blind proof-of-concept randomised controlled trial involved a group of 30 participants recruited via the University of Cambridge and the Cambridgeshire and Peterborough NHS Foundation Trust. Participants were followed up for four weeks after treatment. The research was funded by Wellcome. The research received additional funding from the NIHR BRC: Bristol, NIHR BRC: Cambridge, and BMA Foundation J Moulton grant.