Immune system imbalance may be a trigger for the development of depression

Recognized as the leading cause of disability worldwide, depression affects nearly one in six people during their lifetime. Despite decades of research, the biological mechanisms underlying this debilitating condition remain largely unknown.

Professor Raz Yirmiya, a pioneer in inflammation and depression research from the Department of Psychology at the Hebrew University of Jerusalem, recently published a comprehensive review in the journal Brain, Behavior, and Immunity, offering new insights that challenge long-held beliefs and open the way to personalized treatments.

Traditional theories of depression focus on neurotransmitters such as serotonin and norepinephrine, suggesting that a deficiency of these brain chemicals can lead to depressive symptoms. Although these theories are widely accepted, they cannot explain why a significant proportion of patients do not respond to conventional antidepressants. Over the past 30 years, research by Professor Yirmiya and others has pointed to another culprit: chronic inflammation in both the body and the brain.

“In many people, depression is a result of inflammatory processes,” explains Professor Yirmiya, who was one of the first researchers to establish the link between immune system dysfunction and depression in the 1990s. In his latest review, he carefully analysed 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 shown that people with depression often have weakened immune systems. Surprisingly, some cancer and hepatitis treatments that increase the inflammatory response lead to greater depressive symptoms in patients, providing insight into the role of the immune system in mental health.

Yirmiya's own experiments established a mechanistic link between inflammation and mood, showing that healthy people given low doses of immunomodulatory agents experienced a transient depressive state that could be prevented by either anti-inflammatory or traditional antidepressants.

Professor Yirmiya and his colleagues also showed that stress, one of the main factors that causes depression, can trigger inflammatory processes by affecting microglia cells, which are the immune system’s representatives in the brain. Recent studies show that inflammatory responses caused by stress initially activate microglia, but that prolonged stress depletes and damages them over time, maintaining or worsening depression.

"This dynamic cycling of microglial activation and degeneration reflects the very progression of depression," Yirmiya notes.

The review also highlights studies that show that certain groups, such as older adults, those with physical illnesses, those who experienced childhood adversity, and those with treatment-resistant depression, are particularly susceptible to inflammation-related depression. These findings highlight the need for anti-inflammatory drugs in some patients and microglia-enhancing treatments in others, suggesting that a personalized approach to treatment may be more effective than traditional one-size-fits-all antidepressant therapy.

Professor Yirmiya concludes: “Research over the past three decades has highlighted the critical role of the immune system in the development of depression. In the future, the approach to personalised medicine – tailoring treatment to the patient’s inflammatory profile – offers hope to the millions of people who find no relief from standard therapy. By embracing these advances, we are not simply treating symptoms, but addressing their underlying causes.”

This research not only sheds light on the origins of depression, but also opens up prospects for future therapeutic approaches, particularly those targeting the immune system. Professor Yirmiya aims to inspire a new wave of treatments that will replace despair with hope for those suffering from depression.