Why Depression Comes

Why Depression Comes is a question many people ask, looking for answers beyond the commonly understood factors. For a long time, medical professionals thought depression simply weakened the body's defenses, making people more vulnerable to sickness. But surprisingly, about two decades ago, scientists studying blood samples from individuals with depression started noticing something different: certain immune markers, specifically cytokines and T-cells, were present at higher levels, not lower as expected.

This unexpected finding began to build a stronger connection between inflammation in the body and the presence of depression. The link became even clearer when patients treated with certain immune-boosting medications, like interferon-alpha used for skin cancer or hepatitis C, frequently developed symptoms of depression. Further studies in healthy adults also showed that those with naturally higher levels of these inflammatory cytokines were more likely to experience depression later in life.

So, how does inflammation potentially cause depression? These cytokines, acting as signaling molecules, can travel to the brain in a couple of ways – either directly across the protective blood-brain barrier or by sending signals along nerve fibers from other parts of the body. Once in the brain, cytokines can interfere with crucial chemical messengers called neurotransmitters. These neurotransmitters, including serotonin, dopamine, and glutamate, play vital roles in regulating our mood, sleep patterns, appetite, learning, and memory – all functions often disrupted by depression. While a common theory suggests depression is caused by a lack of serotonin activity (and many antidepressants work by increasing it), research also shows cytokines can ramp up stress hormone signals in the brain, potentially making some individuals more susceptible to depression.

Given this evidence pointing towards inflammation, medical researchers were eager to see if anti-inflammatory drugs could offer a new way to treat depression. Early small studies between 2006 and 2012 in Europe and Iran explored this, finding that depressed adults who took anti-inflammatory medications like aspirin or Celecoxib alongside their antidepressant seemed to experience greater relief from symptoms like sadness and fatigue compared to those just taking an antidepressant.

However, Professor Andrew Miller, a psychiatry expert at Emory University, observed a critical missing piece in these early studies: they didn't consider whether the participants actually had high levels of inflammation to begin with. His team set out to investigate if anti-inflammatory drugs only benefited depressed patients with high inflammation, or if they helped everyone with depression.

In their study, they recruited 60 otherwise healthy adults diagnosed with depression, specifically excluding those with other illnesses that could cause inflammation. Participants were divided into two groups: one received a strong anti-inflammatory drug called Infliximab, and the other received a placebo. As might be expected, among the participants who had high levels of inflammation, those given Infliximab saw their depression symptoms lessen.

But the surprising discovery came when they analyzed the group with normal inflammation levels. The assumption had been that anti-inflammatory treatment for depression would be a one-size-fits-all solution. Instead, they found that participants in this normal inflammation group who received Infliximab were actually less likely to recover from depression compared to those who got the placebo.

This suggests a fascinating complexity: blocking inflammation in individuals without pre-existing high levels might actually be harmful. It introduces the intriguing idea that the brain might need a certain baseline level of inflammatory cytokines to function correctly. The study, published in 2013, significantly advanced our understanding, showing that inflammation's role in mental health is more nuanced than initially thought. It also helps explain why other research has hinted that anti-inflammatory drugs might sometimes worsen depression outcomes for certain people – like a more recent analysis of over 1,500 individuals that found those combining anti-inflammatories with antidepressants were less likely to overcome their depression.

For the past two decades, the prevailing view linked high levels of inflammation in the body and brain directly to depression. Professor Miller's work challenges this "one-size-fits-all" approach, suggesting it's now likely that both excessively high and potentially low levels of inflammation could play a role in why depression comes.

While Professor Miller's study didn't declare anti-inflammatory drugs a universal cure, it provides crucial clues on how to use them effectively for specific groups of depressed individuals. The key appears to be identifying those with elevated inflammation levels. A common blood test measuring C-reactive protein (CRP), an indicator of cytokine levels, is already used for other inflammatory conditions. Researchers are hopeful that CRP testing could be used to identify depressed individuals who might benefit most from anti-inflammatory medication, making pharmacological treatment potentially more precise than the current trial-and-error approach of trying different antidepressants until one works.

From a personal perspective, working with people experiencing depression has always highlighted to me that "depression" often feels like a broad term covering several similar yet distinct conditions – which could explain the difficulties in finding effective treatments for everyone. This research strongly supports that idea and hopefully paves the way for new research exploring more personalized treatment options for patients by looking "outside the box" of traditional approaches.

Professor Miller's original research can be found here:

Raison, C. L., Rutherford, R. E., Woolwine, B. J., Shuo, C., Schettler, P., Drake, D. F., Haroon E and Miller A H (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers JAMA Psychiatry 70(1): 31-41

Peter Mabbutt FBSCH FNCIP

Head of Academics

President of the BSCH