“Those who suffer from depression are not simply “sad” or “lazy”, but are afflicted by an inexpressible existential pain that paralyzes motivation and enjoyment of any pleasure. Depression is not only a brain disease, but afflicts the entire body”, says Professor Francesco Benedetti, Director of the Psychiatry and Clinical Psychobiology Unit at IRCCS San Raffaele Hospital and Professor of Psychiatry at Vita-Salute San Raffaele University. We interviewed the Professor about the research activity of his Unit on the biological basis of mood disorders, such as bipolar disorder and major depression.

Depression is a disease of the entire body

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

Depression is not only a brain disease but involves the whole body. Research over the last fifteen years has highlighted that, in some cases, depression could be linked to a malfunction of the immune system, which ages prematurely. This aging of immune cells could in fact lead to a change in the type and quantity of cytokines, which are molecules mediating the inflammatory response. “This generates a persistent inflammatory state, which involves and weakens the entire body and which, at the brain level, is reflected in a decreased production of serotonin and other neurotransmitters that are crucial for emotional and cognitive control,” explains Benedetti.

This persistent inflammation can favor the increased incidence of diseases such as metabolic syndromes and cardiovascular dysfunctions among depressed patients, thus worsening the quality of life.

Modulating inflammation to treat depression

Since depression is accompanied by a generalized inflammatory state of the body, possible therapies aim at modulating this abnormal response, to restore the normal functioning of the immune system. Modulating, rather than switching off the inflammatory response, could be a promising treatment. “We don't want to block the action of the immune system, which is naturally designed to defend us from diseases, but we want to restore its homeostasis, i.e. physiological balance and functioning,” continues Benedetti. 

This is the research direction followed by the professor’s group. Last May, his team published a clinical study on the efficacy and safety of a treatment with interleukin 2 in the journal Brain, Behavior, and Immunity. The study showed that administration of low doses of this cytokine improved patients' response to antidepressant drugs already in use, promoting proliferation of a specific population of immune cells, namely, T-lymphocytes.

 

Not all depressions are the same

Despite these promising results, the path to an immunomodulatory treatment that would resolve depression is still long, since inflammatory profiles of the disease are unique to each patient and depend on their genetics as well as their individual history. 

The research of the Unit directed by Professor Benedetti aims at outlining the disease profile in individual patients, to personalize treatment strategies. “This targeted profiling, however, is complicated by a very high number of genetic and environmental variables, which are difficult for a human being to manage, that contribute to the disease ,” explains the Professor. In this context, the use of artificial intelligence tools for the analysis of large amounts of data could help define categories of patients with specific disease profiles, "but we are only at the beginning of this new research perspective", concludes Benedetti.

 

Depression is female

Nowadays, mental health is gaining more attention in the public discourse, as compared to the past, despite judgment and blame for those suffering from depression are still entrenched. 

This is especially true for some social categories, such as women, who are affected by depression at a higher rate than men, and especially women who become mothers. 

In particular, peripartum depression, i.e. the set of depressive episodes that occur in the period of time around childbirth, is still little studied. This is due the social and cultural vision of becoming a mother as the highest aspiration and fulfillment for a woman. “The result is that women experience peripartum depression with enormous guilt and tend to avoid talking about it. Yet, in my Unit we have estimated that at least 15% of women who become mothers suffer from it. Recently, we have published preliminary data relating the probability of experiencing peripartum depressive episodes with a genetic predisposition to hormonal fluctuations, which are in turn associated with alterations of the basal ganglia. The latter are evolutionarily very ancient brain areas, involved in the regulation of emotions and motivation", concludes the Professor. 

Sense of guilt, stigma, fear of the mere idea of ​​suffering and the complexity of the illness are all aspects to take into consideration when talking about depression. Talking about the disease without judgements, giving voice and recognize the existential suffering of affected patients is necessary to accompany them through the recovery process.