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expert reaction to systematic review and meta-analysis of RCTs on anti-inflammatory drugs for depression

Research, published in the Journal of Neurology Neurosurgery & Psychiatry, reports that anti-inflammatory drugs can be used to reduce depressive symptoms in patients with major depressive disorders.

 

Dr Sameer Jauhar, Honorary Consultant Psychiatrist and Research Fellow, Institute of Psychiatry Psychology & Neuroscience, King’s College London (IoPPN), said:

“The role of the immune system in the development of depression has been a relatively hot topic within the field of depression over the last few years. Some evidence suggests a role in depression that has not responded adequately to conventional treatments (treatment-resistant depression), depression in people who may have increased markers of inflammation, and in depression in general.

“This raises the question of whether-as seen in other areas of medicine, e.g. cancer-anti-inflammatory medications may help with depression symptoms.

“Therefore, at face value, a meta-analysis of anti-inflammatory treatments in depressive illness is welcomed.

“However, such an analysis is only as good as the studies that it is composed of, and in this case, there are a number of factors that temper any enthusiasm one may have for the findings and claims in the paper.

“A number of very different compounds are included in this analysis under the umbrella term, “anti-inflammatory”, and to my mind they are very different to each other, e.g. omega 3 fatty acids and modafinil. One of the reasons the authors may have had to do this is because the numbers of participants in studies of individual drugs is very low.

“Also, a number of these drugs have more effects on other biological systems which are quite distinct from the immune system, so I do not think lumping them together makes biological sense.

“A related concern-and one we see in a number of meta-analyses, is that a lot of initial studies are published which show an effect, in small patient samples. This is not a problem- science needs to start somewhere, but the preferred method of ascertaining whether a treatment is going to be effective (and safe) for the public is a large, well-powered randomised controlled trial, in a representative sample. These are underway in this field, but this meta-analysis lacks these, and therefore-though indicating that some drugs may help with depressive symptoms in a proportion of people with depression, in terms of changing practice all it points to is which drugs should be tested in large randomised controlled trials.

“This study is not going to-and should not-change clinical practice.”

 

Prof Ed Bullmore, Head of Department of Psychiatry, University of Cambridge, said:

“The press release accurately reflects the science. The paper uses rigorous statistical methods to combine results from 30 previously published trials, involving about 1600 people with depression. Based on this large amount of data, they find that anti-inflammatory agents “on average” have modest but robust anti-depressant benefits. Interestingly, anti-inflammatory agents had a stronger effect when they were taken together with a conventional anti-depressant drug, like an SSRI.

“It is consistent with several similar recent studies, that have also combined results from multiple anti-inflammatory drug trials, and consistently demonstrated anti-depressant benefits of anti-inflammatory treatment. So this work is not entirely unexpected but it adds useful new evidence of anti-depressant efficacy for a wide range of anti-inflammatory agents, including omega-3 fatty acids, statins, and NSAIDs like aspirin.   

“Not all the clinical trials included in this review are equally good quality and there is a high degree of variability in how each trial has been designed and conducted. The authors handled these issues carefully but the quality of any statistical review or meta-analysis of multiple clinical trials is limited by the quality and consistency of the published trials on which it is based. It is encouraging that there were no major safety issues associated with any of the anti-inflammatory agents tested, but it will take a bigger dataset to be sure that all of these agents would be safe for treatment of depression in real-life.

“This should encourage further consideration of ways in which we could use a range of anti-inflammatory interventions to help people with depression, perhaps especially people who are already taking a conventional anti-depressant drug with limited benefit. However, as the authors conclude, further trials will be needed to support licensing and medical prescription of these and other anti-inflammatory agents for depression. 

“Many of these agents or related drugs are available over the counter, without consulting a doctor, partly because they are known to be safe or their risks are well understood. This study suggests that someone who is depressed, and might already be taking anti-depressant medication, might have some benefit from trying a safe anti-inflammatory intervention as well. However, the study falls short of providing definitive evidence that any particular agent is an effective anti-depressant, or is likely to work well for everybody with depression. Even for over the counter drugs and food supplements, it is advisable to let your doctors know what you’re taking, especially if you’re already taking prescribed medication or you experience any side-effects.” 

 

Prof David Curtis, Retired Consultant Psychiatrist and Honorary Professor at UCL and QMUL, said:

“I’m afraid I don’t find the results of this study convincing at all. They have combined results from many small studies, but their analysis shows that there has been a marked degree of publication bias. This means that there has been a tendency to only publish studies which show positive results and to leave studies which show negative results unpublished. It then naturally follows that when one combines the published studies one sees an overall positive effect, but this is not necessarily real.

“Although inflammatory mechanisms may be involved in to some extent in depression, overall the evidence is quite patchy and anti-inflammatory medications are not regarded as being helpful.

“Another problem with this study is that they have considered a variety of treatments which most doctors would not actually classify as anti-inflammatory agents, including statins, diabetes treatments and omega-3 fatty acids.

“Finally, it is quite misleading to describe the use of anti-inflammatory agents as safe. The most effective anti-inflammatory agents used were NSAIDs and although problems are rare every year thousands of people die from the side effects of these medications, which are usually taken for chronic pain and are especially risky if taken for long periods of time. By contrast, anti-depressants do not generally have dangerous side effects. Given that one would need to take treatment for several months, I don’t see that it makes sense to advocate treating depressed patients with potentially dangerous medications with at best weak effects rather than just use anti-depressants, which are actually safe and effective.”

 

 

Prof Carmine Pariante, Professor of Biological Psychiatry and NIHR Senior Investigator Award at the Institute of Psychiatry Psychology & Neuroscience, King’s College London, and Consultant Perinatal Psychiatrist at South London and Maudsley NHS Trust, said:

“This study confirms and extends the results from previous, smaller meta-analyses. It confirms what we knew already: that anti-inflammatory medications help depression when added to an antidepressant and are reasonably safe. Across all studies, anti-inflammatory almost double the possibility of remission from depression, the most stringent criteria for efficacy of an antidepressant (RR=1.79). However, it also tells us something new, and worrying: that this strategy does not seem to work in women. The evidence is sound, as it is based on more than 30 studies, all randomised controlled trials, all of high or moderate quality, and totalling more than 1,600 patients. However, this meta-analysis does not attempt to address the most important question: how can we predict who will and who will not respond to this specific combination therapy? Should it be restricted only to those with increased inflammation, and if so, measured how? Now that we have established that this is an effective strategy, we need to understand how it works and for whom.”

 

‘Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomized controlled trials’ by Shuang Bai et al. was published in Journal of Neurology Neurosurgery & Psychiatry at 23:30 UK time on Monday 28th October. 

DOI: 10.1136/jnnp-2019-320912

 

Declared interests

Dr Sameer Jauhar: Sameer is Co-investigator on a research study in psychosis, funded by Alkermes. Sameer has not received fees for being a Co PI or any expenses for this.

King’s College, London, has received fees from Lundbeck for lectures Sameer Jauhar has given on psychosis.

Funding: National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London SJ is funded by a JMAS (John, Margaret, Alfred, and Stewart) Sim Fellowship from the Royal College of Physicians, Edinburgh.

Prof Ed Bullmore: I am employed full time by the University of Cambridge and I lead the Wellcome Trust consortium for neuroimmunology which includes UK universities and global pharma companies working together to investigate anti-inflammatory drug treatments for depression and Alzheimer’s disease.

Prof David Curtis: I have no conflict of interest.

Prof Carmine Pariante: Professor Pariante is conducting research on the effects of anti-inflammatory in depression, including a Phase 2 trial, funded by the Wellcome Trust, using a new anti-inflammatory by Johnson & Johnson.

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