Evidence
Alert

Anti-inflammatory drugs do not lift depression in bipolar disorder

Two drugs which are often used to treat inflammation failed  to help people with bipolar depression. Previous research has suggested that inflammation of the brain may be involved in some mental illnesses, including depression. It meant that drugs which block inflammation could potentially be a new way of treating depression.

But the first large clinical trial of two of these drugs, called minocycline and celecoxib, has produced disappointing results.  

People with bipolar disorder experience mood swings, extreme highs followed by extreme lows. There is a need for new treatments. But in this trial, neither minocycline nor celecoxib was more effective than a dummy pill (placebo) in treating bipolar depression.  

These negative results are a setback in the search for new treatments for mental illnesses. But they are also an example of the importance of publishing negative results. Other scientists will not waste resources testing these drugs in a similar setting.  

What’s the issue?

About one in 50 (2%) people have bipolar disorder and many do not respond well to existing treatments. The cause of the condition is unknown, but some research suggests that inflammation may be involved. It could be that an over-reaction of the body’s natural inflammatory response might change the way the brain functions.

That has led some scientists to suggest that anti-inflammatory drugs could help in bipolar disorder. Small trials have suggested that drugs (including minocycline and celecoxib) might relieve the symptoms of bipolar depression. But, until now, there has been no large randomised trial to confirm the effects. It was unknown whether these anti-inflammatory drugs would be effective.

What’s new?

The study examined the effect of the two drugs (given separately and together) on 266 people with bipolar depression in Pakistan. They were all receiving standard clinical care as outpatients and they took the drugs, or placebo, for 12 weeks. The severity of their depressive symptoms was measured.

The trial found neither drug was more effective than placebo. Results of blood tests suggested that some people in the study had raised levels of inflammation. Previous studies have suggested that people with raised levels of inflammation might be most likely to benefit from these drugs. 

But in this trial, even this group of  people did not benefit from the anti-inflammatory drugs. 

Why is this important?

Previous research has suggested that inflammation of the brain may be involved in psychiatric conditions. But this study found it will not be easy to translate that finding into new treatments, at least in bipolar depression.

It is important to test emerging ideas properly. Following these results, doctors, patients and their carers know that anti-inflammatory drugs unfortunately will not help relieve depression in bipolar disorder.

The study shows the benefits of publishing negative results. It is important that results showing a drug has no effect are brought to wide attention. This will stop other researchers wasting time carrying out an identical trial.

What’s next?

The results dampen enthusiasm for the emerging idea that treating inflammation could help people with psychiatric conditions. It had been thought that anti-inflammatory drugs might be effective new treatments for bipolar depression.

In the short term, the findings will discourage the use of minocycline and celecoxib to treat people with bipolar disorder. And they will count against any plans to carry out a similar clinical trial.

In the longer term, the results mean that scientists will have to re-examine exactly how inflammation of the brain relates to psychiatric conditions such as bipolar depression. This work may in future lead to further trials of new or existing drugs.

You may be interested to read

The full study: Husain MI, and others. Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial. Lancet Psychiatry 2020;7:515-527

A commentary on the study: Berk M, and others. Anti-inflammatory treatment of bipolar depression: promise and disappointment. Lancet Psychiatry 2020;7:467-468

Background on the associations between changes to the inflammatory response system and mood disorders: Jones BDM, and others. Inflammation as a treatment target in mood disorders: review. BJPsych Open. 2020;6:e60

Evidence from previous RCTs of anti-inflammatory treatments in mood disorders: Husain MI, and others. Anti-inflammatory treatments for mood disorders: Systematic review and meta-analysis. J Psychopharmacol. 2017;31:1137-1148

Funding

This research was funded by the Stanley Medical Research Institute (SMRI) and supported by the NIHR Biomedical Research Centre at South London, UK.

Commentaries

Study author

I was disappointed. I am a clinical scientist and I see people yearning for new treatments. I was surprised that changes we saw in patients’ inflammatory markers did not mediate their response to these drugs.

I think we know enough now to say these anti-inflammatory drugs should not be used in the clinic for bipolar depression. Doing another clinical trial in the same population is not likely to show anything different so it is important for funders to support more studies that aim to investigate how inflammation is associated with disease activity in bipolar disorder. As a scientific community, we need to take a step back and look closer at the mechanisms of this disease.

Ishrat Husain, Clinical Scientist and Staff Psychiatrist, Centre for Addiction and Mental Health, Toronto, Canada

Psychiatrist

The main impact will be on research into anti-inflammatory drugs for mood disorder. A negative finding of this sort in a well-designed study is an important check on current enthusiasm for the argument that inflammation plays a major part in the causation and expression of mood disorder. It suggests that there is no discernible effect at all in bipolar patients as a whole. However, the present study did not include a group of people with depression who also had particularly marked inflammatory disease. A group like that may be more likely to respond to anti-inflammatory drugs.

Guy Goodwin, Emeritus Professor of Psychiatry, University of Oxford

Conflicts of Interest

MIH receives salary support from COMPASS Pathways Limited. Other authors have received fees and research support from various pharmaceutical companies, none of which has a financial interest in this research.