By Rich Haridy

Over the last decade an idea that once sat on the fringes of mainstream science has slowly edged its way closer to the center. Since the 1980s researchers have identified a distinct association between inflammation and depression. Of course, alongside that research the biggest development in the field of psychiatry in the 1980s was the discovery of selective serotonin reuptake inhibitors, or SSRIs. Investigations into boosting or dampening the activity of certain neurotransmitters dominated psychiatric drug development over the 80s, 90s and 2000s but advocates for the inflammation hypothesis persisted.

A new metastudy from a team of Chinese scientists is attempting to find some clarity in the volumes of previously published research, collecting the results of 30 randomized controlled trials on the efficacy of different anti-inflammatory drugs treating depression. While this new metastudy does confidently conclude anti-inflammatory drugs do effectively improve symptoms of depression, another newly published study offers a strong counterpoint, suggesting the link between inflammation and depression is not directly causal but instead more indirect, and mediated by other factors such as poor sleep and obesity.

The big question still debated by many scientists today is whether depression is directly caused by neuroinflammation. Acute conditions we know are caused by neuroinflammation, such as traumatic brain injury or multiple sclerosis, are often associated with significantly higher rates of major depressive episodes.

A number of other autoimmune conditions identified by blood inflammatory markers, such as inflammatory bowel disease, are also known to correlate with depression and mood disorders. While it is fair to assume serious disease or brain injury can result in negative psychological effects, an interesting body of evidence has been growing to suggest causal mechanisms may connect inflammation and depression.

An influential 2015 study correlated enhanced microglial activity in the brain with acute depressive episodes, and a follow-up study more specifically linked that type of neuroinflammation to suicidal thoughts. Cambridge University neuroscientist Edward Bullimore perhaps presented the strongest case to date linking brain inflammation and depression in his 2018 book The Inflamed Mind: A Radical New Approach to Depression.

Bullimore’s thesis is that the entire field of psychiatry has been overly focused on SSRIs and neurotransmitters for several decades, ignoring the heterogeneous nature of depression and mood disorders. He suggests targeting inflammation may not help every depressed patient, but it certainly could help some, and the mono-focus of pharmaceutical development in psychiatry over the past few decades has limited a great deal of potential progress.

“I don’t think we’re talking about a scenario in future where every patient with symptoms of depression is going to be offered an anti-inflammatory drug,” Bullimore said to BBC News in 2016. “I don’t think that makes sense and frankly that sort of blockbuster one-size-fits-all approach to development of drugs for psychiatry has not been helpful to us in the past. We have to take a more personalized or stratified approach, not everyone that is depressed is depressed for the same reason.”

Many randomized controlled trials investigating the antidepressant effects of anti-inflammatory drugs have delivered conflicting results, so it still remains frustratingly unclear whether directly treating inflammation can improve symptoms of depression. A new metastudy has collected data from 30 separate trials to try and get some clarity over the efficacy of anti-inflammatory drugs treating depression.

The metastudy rolled together a number of different anti-inflammatory drugs into the one analysis, including non-steroidal anti-inflammatory drugs (NSAIDs), omega-3 fatty acids (omega-3 FAs), cytokine inhibitors, statins, corticosteroids, minocycline, pioglitazone, modafinil and N-acetylcysteine (NAC).

The overall conclusion of the metastudy was anti-inflammatory drugs demonstrate significant antidepressant effects compared to placebo. NSAIDs, omega-3 fatty acids, statins and minocyclines all showed the most significant antidepressant effects, and the results were notably stronger when administered in conjunction with standard antidepressant treatments.

This new metastudy, of course, has a number of caveats. Assessments of depression severity varied between many of trials included in the metastudy, limiting the ability to easily analyze efficacy, plus a few particular studies involved very small sample sizes. In particular, the research into statins and minocycline involved small cohorts, so the conclusions related to those drugs are limited.

“Our systematic review and meta-analysis suggests that anti-inflammatory agents exert an antidepressant effect in the treatment of MDD [major depressive disorder] and were generally safe with rates of adverse effects similar to those of placebo,” the researchers conclude in the new paper. “Adjunctive treatment shows a more remarkable effect with NSAIDs, omega-3 FAs, statins and minocyclines showing significant antidepressant effects for MDD.”

Although the link between depression and inflammation is growing, not everyone is convinced the relationship is causal. A team of researchers from The Netherlands has published a compelling new study attempting to home in on the possible mechanisms underpinning the association between inflammatory markers and depression.

The study set out to understand the covariates that could be influencing the observed relationship between inflammatory markers and depression. The conclusion of this impressively rigorous research is that depression is a significantly multifaceted condition, and is only linked to inflammation in very specific situations.

“Some specific depression symptoms appear to be related to increased inflammation, such as sleep problems,” explains one of the study’s authors, Eiko Fried.

The implication of the study is that inflammation is more directly associated with certain conditions that indirectly result in depressive symptoms. So, for example, inflammatory markers such as C-reactive protein (CRP) could be strongly linked to sleep problems, which then ultimately lead to symptoms of depression.

Fried suggests, “One depression is not the same as another and the treatment should not be the same for everyone.” He claims inflammation is only associated with depression in very specific scenarios, such as in conjunction with obesity or certain lifestyle factors. His study claims inflammation, or the certain inflammatory markers he studied, cannot be generally linked to depression, implying inflammation is not a direct causal factor in the onset of depression.

Interestingly, the one thing both advocates and detractors of the inflammation-depression hypothesis can agree on is the heterogenous nature of depression. Both Fried and Bullimore suggest more personalized treatment strategies must be the way of the future. So while the jury is certainly still out on whether treating inflammation can be directly beneficial for depression, we can be sure that depression in not a singular condition with just one particular cause.

The anti-inflammatory metastudy was published in the Journal of Neurology, Neurosurgery & Psychiatry.

The second new study on the topic was published in the journal Psychological Medicine.

Sources: BMJ, Leiden University