Abstract Background Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology [1-3]. Based on reported immune cell abnormalities, we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2), a T-cell growth factor of proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naï ve CD4+ T cells [4-6], and possibly correcting the partial T cell defect observed in mood disorders [7, 8]. Aims & Objectives We performed a single-center, randomised, double-blind, placebo-controlled phase II trial in depressed patients with major depressive or bipolar disorder administering low-dose IL-2 (aldesleukin). The primary endpoint was the change in the relative concentration of peripheral blood Tregs (CD3+CD4+FoxP3+CD127loCD25hi Treg). Secondary endpoints were changes in Th1 and Th2, Naï ve T cells, Central memory T cells; safety and antidepressant efficacy of aldesleukin at day 36 (end of treatment) and at day 60 (end of follow up). Methods Thirty-six consecutively recruited inpatients at the Mood Disorder Unit at San Raffaele Hospital in Milan, Italy, were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). The treatment (either IL-2 or placebo) was administered daily for the first 5 days (induction phase) and weekly for the following 4 weeks (maintenance phase). Clinical evaluations (Montgomery-Å sberg Depression Rating Scale (MADRS), Inventory for Depressive Symptomatology Self-Rated (IDS-SR)) have been performed concurrently with each injection; blood samples have been collected at baseline, after 5 days and at week 60 and analysed through flow cytometry with a 28-color flow cytometry panel. Results Twenty-eight out of 36 enrolled patients, concluded the study (10 Placebo, 6 BD and 4 MDD) whereas all patients completed the induction phase. Low-dose IL-2 significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups as measured by a reduction in both MDRS and IDS-SR scores, and expanded the population of Treg, Th2, and Naive CD4+/CD8+ immune cell counts. Changes in cell counts were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. Discussion & Conclusion This is the first RCT evidence supporting the hypothesis that a treatment able to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response. Indeed, the main effect observed of IL-2 was to promote Tregs expansion and enhance response at 5 weeks of treatment preventing the subsequent relapse, thus promoting and consolidating improvement over time. References 1.Benedetti, F. and B. Vai, New biomarkers in mood disorders: Insights from immunopsychiatry and neuroimaging. European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology, 2023. 69: p. 56-57. 2.Benedetti, F., R. Zanardi, and M.G. Mazza, Antidepressant psychopharmacology: is inflammation a future target? International clinical psychopharmacology, 2022. 37(3): p. 79-81. 3.Branchi, I., et al., Brain-immune crosstalk in the treatment of major depressive disorder. European Neuropsychopharmacology, 2021. 45: p. 89-107. 4.Klatzmann, D. and A.K. Abbas, The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol, 2015. 15(5): p. 283-94. 5.Rosenzwajg, M., et al., Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Annals of the rheumatic diseases, 2019. 78(2): p. 209-217. 6.Graß hoff, H., et al., Low-dose IL-2 therapy in autoimmune and rheumatic diseases. Frontiers in immunology, 2021. 12: p. 648408. 7.Simon, M.S., et al., Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2021. 111: p. 110391. 8.Simon, M.S., et al., Premature T cell aging in major depression: A double hit by the state of disease and cytomegalovirus infection. Brain, Behavior, &Immunity-Health, 2023. 29: p. 100608.
更多
原文链接
分享
引用
