Interleukin 2 improves response to treatment in patients with depression

Despite tremendous improvements in antidepressant psychopharmacology based on drugs that act directly on neurotransmitter function, one-third of patients with major depressive disorder (MDD) do not achieve complete symptomatic remission, and in individuals with ineffective initial treatment, many relapses are observed despite the continuation of apparently effective treatment, paving the way for treatment-resistant depression (TRD). The outcomes are even worse in Bipolar Disorder (BD), which has been associated with extremely low success rates of antidepressant medications. From this foundation came the need for continued research of pathogenetic mechanisms to meet the clinical needs for more targeted and effective antidepressant treatment for more patients.

Previous research has demonstrated that before depressive episodes occur in major depressive disorder (MDD) or bipolar disorder (BD), there is a systemic inflammatory response characterized by increased production of cytokines, changes in gene expression in circulating cells, and activation of microglia in the brain. This leads to disruption of the normal balance in neurotransmitter production and maintenance of neuronal synaptic function.

Literature also indicates that 30-50% of people with mood disorders have a clinically identifiable inflammatory state. Depression, particularly when resistant to traditional antidepressant therapies, is accompanied by an inflammatory state that invades the entire body. Indeed, depressed patients are more vulnerable to inflammatory and autoimmune diseases, and in turn, these diseases trigger depression even in those who have never suffered from them: the depression that affected Covid-19 survivors is an example.

Recent findings indicate that the inflammation observed is not an isolated event but rather a result of a broader immune system imbalance. This imbalance involves signs of aging in lymphocyte cells and their overactivation, leading to inflammation and autoimmune reactions. Therefore, the hypothesis suggests stimulating the regulatory aspects of the immune system, not by inhibiting its functions (as previously attempted with anti-inflammatory drugs and monoclonal antibodies), but by guiding its activity towards achieving a more optimal balance within the body's systems.

Interleukin-2 is a molecule, normally present in the body, with immunomodulatory functions that can influence the activity of T lymphocytes, stimulating the production of new cells and their regulatory functions on immunity and inflammation. This T-cell growth factor has demonstrated anti-inflammatory efficacy in other autoimmune diseases and is already in use on the market, albeit in formulations other than the microdoses used in this study.

The newly published study evaluated the safety, efficacy, and biological responses of low-dose Interleukin-2 (IL-2) in depressed patients with major depressive disorder (MDD) or bipolar disorder (BD). Thirty-six patients were recruited from the Mood Disorders Department of IRCCS Ospedale San Raffaele - Turro and were randomized in a 2:1 ratio to receive either interleukin-2 (12 MDD and 12 BD), or placebo (6 MDD and 6 BD).

The researchers thus defined an antidepressant boosting treatment with low-dose interleukin-2 (IL-2), combined with the traditional antidepressant therapies the patients were taking. Changes in interleukin-induced cell frequencies were rapidly obtained in the first five days of treatment, and predicted subsequent improvement in depression severity, with no major side effects. Proportional to T-cell stimulation, study participants showed an enhanced antidepressant response, even when suffering from the forms of depression resistant to traditional treatments.

The study thus confirmed that immune-inflammatory mechanisms represent promising targets for antidepressant pharmacology, and that correcting the imbalances between the inflammatory and regulatory components of our immune system may be a new therapeutic strategy for resistant depression.

"This is the first randomized control trial to support the hypothesis that treatment to strengthen the immune system, and specifically T cells, may be an effective way to correct the immune-inflammatory abnormalities associated with mood disorders and at the same time, enhance the antidepressant response," says Dr. Poletti.

"We think that our studies can already change clinical practice: indeed, we have shown with this research the therapeutic effects of low-dose Interleukin-2 without detecting any side effects. We hope that this evidence will now pave the way for a new way to intervene in treatment-resistant depression, hopefully igniting attention on to address the expected process of obtaining an indication for clinical use of this substance for depression," says Professor Benedetti.

"What’s the next step? We are already beginning to evaluate the effects of another antidepressant immunomodulator, minocycline, the effects of which on the brain we are studying with innovative PET and MRI techniques; we are also studying how the history of exposure to infectious diseases and adverse experiences may have contributed to the condition of immune dysfunction that we have verified in our study participants. Research is continuing, and we think that at some point in the future we will be able to identify people who, rather than having to endure depression for many months without benefit from available treatments, can be treated and healed right away by acting on the immune system," Professor Benedetti concludes.

The study was funded by the European Union H2020 Grant 754740 "MOODSTRATIFICATION".