Can Depression Be Treated With Anti-Inflammatory Drugs?

A news story highlights the interplay between the immune system and depression, but it provides this information without crucial context.

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In September 2017, British newspaper The Telegraph published a story suggesting that anti-inflammatory drugs could cure depression. The article, while interesting, misleads readers by overstating and presenting without context longstanding scientific work on the link between depression, inflammation, and the immune system.

The article’s thesis rests on a quote from a single scientist’s talk at a press conference, which the author uses to argue that that the link between depression and inflammation could potentially be exploited to develop a new treatment for clinical depression:

Depression could be treated using anti-inflammatory drugs, scientists now believe, after determining that it is a physical illness caused by a faulty immune system. […]

Current treatment is largely centered around restoring mood-boosting chemicals in the brain, such as serotonin, but experts now think an overactive immune system triggers inflammation throughout the entire body, sparking feelings of hopelessness, unhappiness and fatigue.

Right off the bat, the writer uses two exceedingly broad terms without caveat: “depression” and “anti-inflammatory drugs”. The unqualified use of these terms potentially suggest to the reader that a) clinical depression is exclusively a disorder related to inflammation and b) anti-inflammatories (any of them) can be a viable treatment for most if not all cases of depression.

Neither of these suggestions are true, however.

No Credible Scientists Have Argued that All Depression is Caused by Inflammation

Ed Bullmore, the Head of the Department of Psychiatry at the University of Cambridge and the primary scientist quoted in The Telegraph (who told us via e-mail that he was never contacted by the author of the story), told us that his talk focused on a specific type of anti-inflammatory drugs for a specific subset of people diagnosed with Major Depressive Disorder:

I repeatedly tried to make the point that we are not talking about all depression being related to inflammation but about a subgroup of patients with [Major Depressive Disorder], many of whom may be less responsive to conventional anti-depressants, and also patients with comorbid depressive symptoms associated with non-psychiatric disorders like RA [rheumatoid arthritis].

Indeed, the notion that inflammation is a sole or primary cause of any psychiatric disorder is not something that researchers are seriously arguing. Amit Etkin, a professor in the Department of Psychiatry and Behavioral Sciences at Stanford University, who researches the neurological basis for mood disorders, told us that there are some potential avenues that show promise, but that overall the research so far has been fairly inconclusive:

The role of the immune system in psychiatric disorders (including depression) is something that has been looked at for a long time. The most clear-cut data are for narcolepsy being due to an autoimmune attack on a specific small group of neurons deep in the brain. There is some evidence that conditions like schizophrenia can have as their root a maternal infection, which affects the developing fetus.

Similarly, one can develop something that looks like depression after a significant inflammatory disorder, and depression is a common co-morbid condition with certain inflammatory disorders. However, it is likely that the vast majority of depression has little to do with inflammation, even if some of it does.

Association is Not Evidence of Causation

That there is a robust association between inflammation and the symptom of depression is neither new, nor is it all that controversial. What this means is that a number of studies have documented that people with depression also exhibit markers for increased inflammation — and vice versa. Scientists, however, have not fully unravelled the relationship, which could be understood as both a causal agent for transient depression as well as a reaction to depression, as discussed in a 2013 review published in the journal JAMA Psychiatry:

First, inflammation may lead to depression. Some studies indicate that proinflammatory cytokines [specific chemicals that produce an inflammatory response] contribute to the development of depression by activation of [an enzyme that leads to decreased production of serotonin]. Decreased serotonin levels are an important factor in the pathogenesis of depression, as observed in the effect of SSRIs in treating depressive symptoms. […]

Second, depression may also lead to inflammation. Psychological stress activates the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system, which releases stress hormones. These hormones, together with cytokine release induced by stress, initiate the acute-phase response triggering inflammation.

The Telegraph piece conflates evidence for this association with evidence that anti-inflammatory drugs are the groundbreaking cure for depression we have all been waiting for. The only evidence the story provides for the efficacy of anti-inflammatory drugs for this purpose, however, is the existence of potential clinical trials and a quote from Bullmore:

Scientists at Cambridge and the Wellcome Trust are hoping to begin trials next year to test whether anti-inflammatory drugs could switch off depression.

“There is evidence to suggest it should work,” added Prof Bullmore.

Perhaps most irresponsibly, the article quotes Bullmore on the issue of vaccines — which produces an immune response and therefore inflammation — in a way that potentially suggests that vaccines can cause the kind of clinical depression normally addressed by antidepressants. This is not true, nor was it his intent.

“I meant to imply that vaccination could cause transient, mild depressive or dysphoric symptoms, not clinical depression,” Bullmore told us. Numerous studies have demonstrated that there is a relationship between triggering an immune response and the occurrence of depressive symptoms; it is part of a suite of physiological and neurological responses sometimes referred to as “sickness behavior“. This is different than the kind of depression one would treat pharmacologically.

The Anti-Inflammatories Discussed Are Specific, Powerful Drugs with Side Effects

None of this is to say there isn’t evidence that using anti-inflammatory medicine could “work” to alleviate depression. It is to say, however, that none of the evidence provided in the Telegraph’s reporting actually supported that assertion. Indeed, many scientists have been looking into the potential for inflammation-targeting drugs. “The best evidence to date is from meta-analytic studies of anti-inflammatory drugs in clinical trials for non-psychiatric disorders, like rheumatoid arthritis, where depressive symptoms are common,” Bullmore told us.

Michael Irwin, a professor at UCLA and director of their Norman Cousins Center for Psychoneuroimmunology, echoed this point, telling us via phone that the research has not been as much of a slam dunk as implied by The Telegraph:

The data on treating inflammation to reduce depression is, I think, very mixed. There have been large scale trials that have been done, psoriasis patients, for example, showing that the use of an anti-inflammatory medication to treat psoriasis was associated with decreases in depressive symptoms in their net population.

Another group […] showed that if you took patients with major depressive disorder and gave them an anti-inflammatory medication that blocks [TNF, an enzyme associated with inflammation] you could actually improve depression, but if you really look at that trial, what you find is that the overall result was negative. It didn’t improve the depression.

These discussions highlight problems with the second major generalization in the Telegraph story— the broad use of the term “anti-inflammatory drugs”. The class of drugs implicated by the Telegraph story are powerful anti-inflammatories that share little in common with over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) like Advil or Aleve, which readers may have interpreted the headline to be suggesting. “The evidence so far is stronger for anti-cytokine antibodies [which target the enzymes that produce inflammation] than for NSAIDs and other small molecules,” Bullmore told us.

According to Irwin, the actual drugs — such as anti-cytokine antibodies — that show potential are not as benign or as simple as one might think. “The bigger issue that I have is those medications are very powerful and they can increase the risk of infectious disease, increase the risk of cancers, and are incredibly expensive,” he said.

While the science discussed by the Telegraph in this article is real, it omits seriously important context and misrepresents decades-old research as a breaking development in a way that could provide false hope to those suffering from depression. The interplay between the immune system and the mind is increasingly well established, but that doesn’t mean that science has established anything close to a new treatment for depression as a result of this understanding.

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Knapton, Sarah.   “Depression Is a Physical Illness Which Could Be Treated With Anti-inflammatory Drugs, Scientists Suggest.”
    The Telegraph.   8 September 2017.

Glasser, R., et al.   “The Influence of Psychological Stress on the Immune Response to Vaccines.”
    Annals of the New York Academy of Sciences.   May 1998.

Slavich, G.M., and Irwin, M.R.   “From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression.”
    Psychological Bulletin.   May 2014.

Wium-Andersen, Marie Kim, et al.   “Elevated C-Reactive Protein Levels, Psychological Distress, and Depression in 73,131 Individuals”
    JAMA Psychiatry.   February 2013.

Brydon, Lena, et al.   “Peripheral Inflammation is Associated with Altered Substantia Nigra Activity and Psychomotor Slowing in Humans.”
    Biological Psychiatry.   1 June 2008.

Kappelmann, N, et al.   “Antidepressant Activity of Anti-cytokine Treatment: A Systematic Review and Meta-Analysis of Clinical Trials of Chronic Inflammatory Conditions.”
    Molecular Psychiatry.   18 October 2016.