Wednesday October 19 2016
Research has linked inflammation to depression
"Arthritis pills could help beat depression," The Sun reports. A review of studies suggests anti-cytokine drugs, currently used to treat inflammatory conditions such as rheumatoid arthritis, could have a role in treating depression.
Cytokines are proteins released by cells when the immune system is activated and are linked to inflammatory diseases such as rheumatoid arthritis and psoriasis.
Scientists think there may also be a link between levels of inflammation in the body and symptoms of depression as previous research has found some people with depression have high levels of cytokines.
Researchers decided to look at the effect the treatment had on people's symptoms of depression in studies designed to show improvements to physical symptoms of conditions such as arthritis and psoriasis.
They also wanted to see whether people only felt less depressed if their symptoms of arthritis or psoriasis were better.
They found 20 studies, seven of them comparing anti-cytokine drugs to a placebo. When they pooled the data, they found a small to moderate improvement in depression scores for people taking anti-cytokine drugs. This improvement was not linked to improvements in physical illness symptoms.
We now need to see studies designed to assess the effect of anti-cytokine drugs on people with depression, but no physical illness, to see whether these drugs are safe and effective as a treatment for depression.
It is important to stress that researchers were looking at specialised anti-inflammatory drugs, like infliximab, and not at more widely used anti-inflammatories like ibuprofen. The use of ibuprofen is not recommended for depression.
Where did the story come from?
The study was carried out by researchers from the University of Cambridge, University College London and the University of Texas.
There is no information about specific funding for the study, although the researchers had grants from organisations including the Wellcome Trust, Academy of Medical Sciences and Royal College of Psychiatrists.
The study was published in the peer-reviewed journal Molecular Psychiatry on an open-access basis, so it's free to read online.
The Sun and the Daily Mail cover the study fairly accurately, although neither point out that the effect of the treatment was small in terms of relieving symptoms of depression. However, both make it clear that we don't yet know if the drugs are safe and effective for people with depression.
What kind of research was this?
This is a systematic review which includes three meta-analyses of studies. Meta-analyses are a good way to pool the research in an area, although they are only as good as the individual studies included.
In this case:
- seven studies were randomised controlled trials (RCTs) comparing cytokine modulator drugs with placebo
- three were RCTs of cytokine modulator drugs added to other drugs
- 10 were either not randomised or not placebo-controlled
Only one of the studies looked primarily at the effect of the drugs on depression.
What did the research involve?
Researchers looked for studies of cytokine modulators which measured depression or depressive symptoms. They grouped the studies together and carried out separate meta-analyses of the three different types of study, looking at changes in depression scores between those who took cytokine modulators and those who did not.
They then looked at the RCTs to see whether the change in depression scores could be explained by changes in the physical illnesses being treated. They also carried out analyses to see whether severity of depression symptoms, length of study, sex and age of participants, affected the results.
They did various sensitivity analyses to check for major discrepancies between the study results (heterogeneity), and to see if any individual study had a big influence on the overall results.
What were the basic results?
Seven randomised controlled trials in 2,370 people showed that those taking cytokine modulator drugs had a "small to moderate" improvement in depression symptoms, compared to people who took placebo.
The results were expressed as a "standard mean difference" between symptoms scores of 0.40 (95% confidence interval [CI] 0.22 to 0.59).
However, these figures are hard to interpret as they are the result of combining results from six different depression symptom scoring scales. It's hard to know how clinically important this difference is. The researchers said there was a lot of difference between the degree of symptom improvement in the studies (heterogeneity).
The findings from RCTs comparing cytokine modulator drugs plus another drug to the other drug alone also showed a small to moderate improvement in depression scores. The same was true for non-RCT studies, which showed a bigger standard mean difference – although this was probably because they could not take account of the placebo effect.
Analysis showed no clear link between improvement in depression scores and improvement in physical symptoms. The main focus of the trials was treatment for psoriasis, Crohn's disease, atopic dermatitis, complex regional pain syndrome and rheumatoid arthritis.
Only one study, of 55 people, looked at depression as a primary outcome. This study looked solely at people for whom antidepressants hadn't previously worked. It showed no improvement in depression scores for people taking cytokine modulators, compared to those who took placebo.
Age and sex made no difference to people's likelihood of benefiting from the drugs. Those with more severe depression, however, seemed to benefit more.
How did the researchers interpret the results?
The researchers say their study showed "robust improvements in depressive symptoms after anti-cytokine therapy" with a "small to moderate size effect".
They say the results "suggest inflammatory cytokines may have a key role" in how depression comes about, and that "anti-cytokine drugs may be effective for some patients with depression".
They suggest the antidepressant effect of anti-cytokine drugs should be tested first among people with depression who haven't responded to antidepressants, and who have high levels of inflammatory proteins circulating in their blood.
This study suggests some useful paths for future research into depression, but is not robust enough to allow doctors to start using these drugs to treat people with depression.
Because all but one of the studies included in the review were primarily intended to assess the effect of the drug on another condition, we don't know if they were big enough to reliably assess the effect of the drugs on depression.
Depression symptoms were assessed as secondary outcomes and we need to see trials designed with depression as the primary focus, to get truly reliable results.
It's worth noting that, in all but one study, people were not diagnosed as having depression – the researchers just looked at their scores for depression symptoms. These scores might fall short of a depression diagnosis.
The idea that depression can be triggered by inflammatory proteins in the blood is interesting, and is supported by this study. A recent study looked at non-steroidal anti-inflammatory drugs (NSAIDs, for example ibuprofen) and also found some evidence that they may have an effect on depression.
Many people with depression (about one third) are not helped by usual antidepressant drugs, which alter levels of messenger chemicals in the brain. Treatments targeting inflammatory proteins – another possible cause of depression – might offer hope to some of these people.
Cytokine modulators, including adalimumab, etanercept and infliximab, are more often used for conditions such as rheumatoid arthritis and can have significant side effects. These include making people more vulnerable to infection, severe allergic reactions, cancer and auto-immune diseases. These side effects should make us cautious about using these drugs to treat depression until we know how effective they are.
It is always important to be sure that the potential benefit of a new treatment approach isn't outweighed by associated side effects and complications.
Treatments for depression are not always drug-based. Talking therapies and exercise are often a useful alternative or addition to drug treatments.
Read more about treatments for depression.