Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers

Poletti, Sara; Zanardi, Raffaella; Mandelli, Alessandra; Aggio, Veronica; Finardi, Annamaria; Lorenzi, Cristina; Borsellino, Giovanna; Carminati, Matteo; Manfredi, Elena; Tomasi, Enrico; Spadini, Sara; Colombo, Cristina; Drexhage, Hemmo A.; Furlan, Roberto; Benedetti, Francesco

doi:10.1016/j.bbi.2024.02.019

Cited by 7 publications

(4 citation statements)

References 84 publications

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“…Collectively, this highlights the robustness of our observations. In conclusion, our POC trial reports a striking concomitant Treg stimulation and clinical response in patients with bipolar depression that reinforces the notion that inflammation has a direct role in bipolar depression (Drexhage, 2018;Poletti et al, 2024). As the treatment is safe, as already reported in more than 25 other diseases (Raeber et al, 2023), our results warrant to pursue properly powered trial to demonstrate the therapeutic efficacy of IL-2LD in bipolar depression, and beyond in mood disorders in general.…”

Section: Discussionsupporting

confidence: 86%

“…It was then articulated in two parallel trials, one to be conducted in bipolar disorders at the Assistance Publique -Hôpitaux de Paris (DEPIL-2, ClinicalTrials.gov: NCT04133233) and one in both major depressive disorder (MDD) and BD at the Ospedale San Raffaele (IL-2REG; EudraCT N.: 2019-001696-36). IL-2REG was recently reported (Poletti et al, 2024) and here we present the outcomes of the DEPIL-2 trial. Design DEPIL-2 was a randomized, double-blind, placebo-controlled (2 active / 1 placebo), monocentre, proof-of-concept trial evaluating the tolerance and the efficacy of IL-2LD in patients with bipolar depression.…”

Section: Study Design Participants and Treatmentsmentioning

confidence: 98%

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Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Leboyer,

Foiselle,

Tchitchek

et al. 2024

Preprint

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Immune abnormalities including an insufficiency of regulatory T cells (Treg) and increased blood-based inflammatory markers have been observed in bipolar disorders (BD), particularly during depression. As Tregs are pivotal to control inflammation, Treg stimulation by low-dose IL-2 (IL-2LD) could have a therapeutic impact on bipolar depression. We performed a randomized, double-blind, placebo-controlled (2 active: 1 placebo) proof-of-concept trial of add-on IL-2LDin patients with bipolar depression. Patients received a placebo or IL-2LD(1MIU) once a day for 5 days, and then once a week for 4 weeks starting on week 2. The primary objective was to demonstrate a biological Treg response to IL-2LDassessed by fold increase in Treg percentage of CD4+ cells from baseline to day 5. Secondary objectives included safety assessment and mood improvement throughout the study period. This trial is registered with ClinicalTrials.gov, numberNCT04133233. Fourteen patients with bipolar depression were included, with 4 receiving placebo and 10 IL-2LD. Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2LDexpanding 1.17 [95% CI 1.01-1.34] vs 1.01 [95% CI 0.90 - 1.12] (p=0.0421) and activating Tregs. Secondary evaluation criteria were also met with significant improvements of depressive symptoms and global functioning from day-15 onwards in the IL-2LDtreated patients. The treatment was well-tolerated, with no serious adverse events related to treatment. This proof-of-concept trial shows that stimulating Tregs in patients with bipolar depression is safe and associated with clinical improvements. This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2LDas an adjunct treatment of major mood disorders.

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Section: Discussionsupporting

confidence: 86%

Section: Study Design Participants and Treatmentsmentioning

confidence: 98%

Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Leboyer,

Foiselle,

Tchitchek

et al. 2024

Preprint

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“…Also, inhibiting microglial activation with the broadly anti-inflammatory minocycline leads to better neuroplasticity and normalization of the kynurenine pathway in animal models of depression [ 153 , 154 ], whereas, in treatment-resistant patients with CRP > 3 [ 155 ] it has an antidepressant effect. In agreement with a different immune profile in MDD and BD, a recent study from our group showed how MDD and BD patients respond differently to an immune-modulatory treatment with low-dose IL-2: higher effect of treatment in BD; increase of CD4 + Naïve T cells and decrease in CD4 + Central Memory cells only in MDD [ 156 ]. These effects are in agreement with the different involvement of the IRS in the two disorders and support the usefulness of this perspective in clinical practice.…”

Section: Discussionsupporting

confidence: 61%

Inflammatory mediators in major depression and bipolar disorder

Poletti,

Mazza,

Benedetti

2024

Transl Psychiatry

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Major depressive disorder (MDD) and bipolar disorder (BD) are highly disabling illnesses defined by different psychopathological, neuroimaging, and cognitive profiles. In the last decades, immune dysregulation has received increasing attention as a central factor in the pathophysiology of these disorders. Several aspects of immune dysregulations have been investigated, including, low-grade inflammation cytokines, chemokines, cell populations, gene expression, and markers of both peripheral and central immune activation. Understanding the distinct immune profiles characterizing the two disorders is indeed of crucial importance for differential diagnosis and the implementation of personalized treatment strategies. In this paper, we reviewed the current literature on the dysregulation of the immune response system focusing our attention on studies using inflammatory markers to discriminate between MDD and BD. High heterogeneity characterized the available literature, reflecting the heterogeneity of the disorders. Common alterations in the immune response system include high pro-inflammatory cytokines such as IL-6 and TNF-α. On the contrary, a greater involvement of chemokines and markers associated with innate immunity has been reported in BD together with dynamic changes in T cells with differentiation defects during childhood which normalize in adulthood, whereas classic mediators of immune responses such as IL-4 and IL-10 are present in MDD together with signs of immune-senescence.

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“…The neutrophil to lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII; platelets x neutrophils/lymphocytes), easily calculated from white blood cell assays, are higher in patients with mood disorders, and associated with lower hippocampal volumes, and lower responses to antidepressant treatment [20,21]. In patients with higher baseline inflammatory biomarkers, new treatments affecting the immune system (including infliximab, minocycline, celecoxib, low-dose interleukin 2) can boost antidepressant response in patients not responding to conventional monoaminergic antidepressants [22][23][24][25], possibly depending on the basal levels of inflammation or on other not-yet-studied predictive factors [23,26,27], and thus raising the possibility of individually tailored immune modulation in patients with treatment-resistant depression (TRD) [28,29].…”

Section: Introductionmentioning

confidence: 99%

Higher Seasonal Variation of Systemic Inflammation in Bipolar Disorder

Dallaspezia,

Cardaci,

Mazza

et al. 2024

IJMS

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Seasonal rhythms affect the immune system. Evidence supports the involvement of immuno-inflammatory mechanisms in bipolar disorder (BD), with the neutrophil to lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII; platelets × neutrophils/lymphocytes) consistently reported to be higher in patients with BD than in HC, but seasonal rhythms of innate and adaptive immunity have never been studied. We retrospectively studied NLR and SII in 824 participants divided into three groups: 321 consecutively admitted inpatients affected by a major depressive episode in course of BD, and 255 consecutively admitted inpatients affected by obsessive–compulsive disorder (OCD; positive psychiatric control), and 248 healthy controls (HC). Patients with BD showed markedly higher markers of systemic inflammation in autumn and winter, but not in spring and summer, in respect to both HC and patients with OCD, thus suggesting a specific effect of season on inflammatory markers in BD, independent of a shared hospital setting and drug treatment. Given that systemic inflammation is emerging as a new marker and as target for treatment in depressive disorders, we suggest that seasonal rhythms should be considered for tailoring antidepressant immuno-modulatory treatments in a precision medicine approach.

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Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers

Cited by 7 publications

References 84 publications

Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Inflammatory mediators in major depression and bipolar disorder

Higher Seasonal Variation of Systemic Inflammation in Bipolar Disorder

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