An immune system imbalance can be a trigger for depression - study

Depression, recognized as the leading cause of disability worldwide, affects nearly one in six people over their lifetimes and is one of the most prevalent psychiatric disorders and a major source of human suffering. But is it caused when people endure traumatic and sad events or do biological mechanisms including neurotransmitters in the brain underlie this debilitating condition? Despite decades of research, much remains unknown about such processes.

Now, a new study by psychologists at the Hebrew University of Jerusalem highlights the link between inflammation and depression; this challenges traditional theories about neurotransmitters being involved.

An examination of decades of research suggests that immune system imbalances may trigger and sustain depressive symptoms, especially in high-risk groups. This research paves the way for personalized treatments targeting inflammation, offering new hope for those unresponsive to conventional therapies.

Prof. Raz Yirmiya, a pioneering psychologist researching inflammation and depression, has just published a comprehensive review in the journal Brain, Behavior, and Immunity under the title “The inflammatory underpinning of depression: An historical perspective.” It offers new insights that challenge long-held beliefs and open pathways toward personalized treatment.

Traditional theories of depression have focused on neurotransmitters like serotonin and norepinephrine, suggesting that a deficiency in these brain chemicals could lead to symptoms of depression. While widely accepted, these theories have failed to explain why a significant portion of patients fail to improve with conventional antidepressant medications.

Over the last 30 years, Yirmiya’s research, along with that of colleagues, has pointed to a different culprit – chronic inflammation.

“In many people, depression results from inflammatory processes,” stated Yirmiya, who was one of the first researchers to draw connections between immune system dysfunction and depression in the 1990s. In his latest review, he meticulously analyzed the 100 most-cited papers in the field, creating what he calls a “panoramic view” of the complex interactions between inflammation and depressive symptoms.

Research dating back to the 1980s has highlighted that depressed people often suffer from vulnerable immune functions. Surprisingly, certain immune-boosting treatments for cancer and hepatitis that induce an inflammatory response have been found to cause severe depressive symptoms in patients – offering a glimpse into the immune system’s role in mental health.

YIRMIYA’S OWN experiments further established a mechanistic link between inflammation and mood, showing that healthy individuals injected with low doses of immune-stimulating agents suffer from a temporary depressive state that can be prevented by either anti-inflammatory or conventional antidepressant treatments.

Two prior studies

Two large studies in the past, each including over 6,000 participants, showed that men with current or historical episodes of major depression were significantly more likely to have higher levels of CRP (c-reactive protein) made by the liver compared to their never-depressed counterparts.

Normally, you should have low levels of CRP in your blood, but the liver releases more CRP into your bloodstream if you have inflammation in your body. High levels of CRP may mean you have a serious health condition that causes inflammation.

The Hebrew University psychologist and his team have also shown that stress, which is often a major trigger for depression, can trigger inflammatory processes affecting the brain’s microglia cells, which are the representatives of the immune system in the brain.

Their recent findings reveal that stress-related inflammatory responses may initially activate microglia, but protracted stress eventually exhausts and damages them, thereby retaining or worsening depression. “This dynamic cycle of activation and degeneration of microglia mirrors the progression of depression itself,” Yirmiya added.

His study also highlights research that suggests specific groups, such as the elderly, those with physical illnesses, or those who suffered from early childhood adversity, and patients with treatment-resistant depression, are especially susceptible to inflammation-linked depression.

The findings stress the urgent need for anti-inflammatory treatments for certain patients and for microglia-boosting treatments for other patients. This shows that a personalized approach to treatment could be more effective than traditional, one-size-fits-all antidepressant therapy.

He concluded that “the research findings from the past 30 years underscore the critical role of the immune system in depression. Moving forward, a personalized medicine approach – tailoring treatment based on the patient’s specific inflammatory profile offers hope to millions of sufferers who find little relief in standard therapies. By embracing these advancements, we’re not just treating symptoms; we’re addressing the underlying causes.”

Through further investigation, he wants to inspire a new wave of treatments designed to replace despair with hope for those suffering from depression.