Depression: A Disease of the Whole Body

Major depression is one of the most common mood disorders, affecting about 280 million people worldwide. In Italy, at least 20% of people experience a depressive episode at some point in their lives, and 5% of the population suffers from recurrent major depression, a form of the disease that follows seasonal patterns.

Depression is not just a disease of the brain but involves the entire body. Research over the past 15 years has highlighted that, in some cases, it may be linked to a malfunctioning immune system that ages prematurely.

This premature aging of immune cells leads to changes in the type and quantity of cytokines produced—molecules that mediate the inflammatory response.

“This creates a persistent inflammatory state that involves and weakens the entire body and, at the brain level, results in reduced production of serotonin and other neurotransmitters important for emotional and cognitive regulation,” explains Benedetti.

This persistent inflammation can increase the incidence of conditions such as metabolic syndromes and cardiovascular dysfunctions among depressed patients, contributing to a decline in quality of life.

Since depression is accompanied by a generalized inflammatory state in the body, one possible therapy could involve modulating this abnormal response to restore the normal functioning of the immune system. In particular, simply taking an anti-inflammatory drug is not enough to hope for a cure. The path to potential treatment lies in modulating the inflammatory response rather than shutting it down entirely.

“We don’t want to block the immune system’s action, as it is naturally designed to defend us against diseases, but we aim to restore its homeostasis, that is, its physiological balance and functioning,” Benedetti continues.

This is the direction of the work being conducted by the professor’s group, which last May published a clinical study on the efficacy and safety of a treatment using interleukin-2 in the journal Brain, Behavior, and Immunity.
The study showed that administering low doses of this cytokine improved patients’ responses to existing antidepressant drugs by promoting the proliferation of T lymphocytes, a specific population of immune cells.

Not All Depressions Are the Same

Despite promising results, the road to an immunomodulation treatment that resolves depression remains long. This is because the inflammatory profiles of the disease are unique to each patient and depend on their genetics as well as their individual history.

The research led by the professor aims to map the disease profile in individual patients to personalize treatment strategies.

“However, this targeted profiling is complicated by the vast number of genetic and environmental variables that contribute to the disease, which are difficult for humans to manage,” explains the professor. In this context, the use of artificial intelligence tools for analyzing large datasets could help define categories of patients with specific disease profiles. “But we are only at the beginning of this new research perspective,” Benedetti concludes.

Today, compared to the past, mental health is gaining more attention in public discourse, although judgment and blame toward those suffering from depression remain deeply ingrained.

This is especially true for certain social groups, such as women, who are disproportionately affected by depression compared to men, particularly women who become mothers.

Postnatal Depression

Specifically, peripartum or postnatal depression, which encompasses depressive episodes occurring around the time of childbirth, remains under-researched. This is primarily due to societal and cultural perceptions of motherhood as the ultimate aspiration and achievement for women.

“As a result, women experience peripartum depression with an immense sense of guilt and often hesitate to speak about it. Yet, in my unit, we have estimated that at least 15% of women who become mothers suffer from it.

Recently, we published preliminary data linking the likelihood of experiencing peripartum depressive episodes to a genetic predisposition to hormonal fluctuations, which are in turn associated with alterations in the basal ganglia. These ancient brain regions are deeply involved in regulating emotions and motivation,” concludes the professor.

Feelings of guilt, stigma, fear of the very idea of suffering, and the complexity of the illness are all aspects to consider when discussing depression. Speaking openly about it, giving a voice to and acknowledging the existential suffering of affected patients, is essential to supporting them on their journey to recovery.