Research indicates that an imbalance in the immune system can be a trigger for depression

Depression, recognized as the leading cause of disability worldwide, affects almost one in six people during their lifetime. Despite decades of research, much remains unknown about the biological mechanisms underlying this debilitating condition.

Professor Raz Yirmiya, a pioneering researcher in the field of inflammation and depression from the Department of Psychology at the Hebrew University of Jerusalem, recently published an extensive review Brain, behavior and immunitythat offers new insights that challenge long-held beliefs and open paths to personalized treatment.

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

“In many people, depression is the result of inflammatory processes,” explains Professor Yirmiya, who was one of the first researchers to draw links between immune system dysfunction and depression in the 1990s. In his latest review, he carefully analyzed the hundred most cited papers in this field, creating a “panoramic view” of the complex interactions between inflammation and depressive symptoms.

Research dating back to the 1980s has shown that depressed individuals often exhibit compromised immune function. Surprisingly, certain immune-boosting treatments for cancer and hepatitis, which induce an inflammatory response, appear to cause severe depressive symptoms in patients, providing insight into the role of the immune system 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 stimulants exhibit a temporary depressive state, which can be prevented by anti-inflammatory or conventional antidepressants.

Professor Yirmiya and colleagues have also shown that stress – often a major trigger for depression – can trigger inflammatory processes, which affect the brain's microglia cells, which are the brain's representatives of the immune system. Their recent findings show that stress-related inflammatory responses may initially activate microglia, but that long-term stress ultimately depletes and damages these microglia, perpetuating or exacerbating depression.

“This dynamic cycle of microglia activation and degeneration mirrors the progression of depression itself,” says Yirmiya.

The review also highlights studies suggesting that specific groups, such as the elderly, people with physical illnesses, people who suffered early childhood adversities and patients with treatment-resistant depression, are particularly susceptible to inflammation-related depression. The findings reveal the need for anti-inflammatory treatments for certain patients and microglia-stimulating treatments for others, suggesting that a personalized treatment approach may prove more effective than the traditional one-size-fits-all antidepressant therapy.

Professor Yirmiya concludes: 'Research results over the past thirty years underline the crucial role of the immune system in depression. In the future, a personalized medicine approach – tailoring treatment to the patient's specific inflammatory profile – offers hope to millions of patients who get little relief from standard therapies. By embracing these advances, we are not just treating the symptoms; we tackle the underlying causes.

This study not only sheds light on the origins of depression, but also sets the stage for future therapeutic approaches, especially those that target the immune system. Through further research, Professor Yirmiya aims to inspire a new wave of treatments designed to replace despair with hope for people suffering from depression.