Abstract
BackgroundMood disorders associate with peripheral markers of low-grade inflammation, among which circulating levels of interleukin-1β (IL-1β) consistently predict diagnosis and poor outcomes. Antidepressant chronotherapeutics (total sleep deprivation and light therapy, TSD+LT) prompts response in drug-resistant bipolar depression, but its effect on peripheral inflammation were never assessed. Here we explored the effects of TSD+LT on IL-1β signaling.MethodsWe studied the ratio between IL-1β and its receptor antagonist (IL-1β:IL1ra) in 33 healthy participants, and in 26 inpatients with a major depressive episode in course of Bipolar Disorder, before and after treatment with three cycles of repeated TSD+LT, interspersed with sleep recovery nights, administered during 1 week. Treatment effects of mood and on IL-1β:IL1ra were analyzed in the context of the Generalized Linear Model (GLM).ResultsAt baseline, patients had higher IL-1β, IL1ra, and IL-1β:IL1ra than controls. Treatment significantly decreased IL-1β:IL1ra, by decreasing IL-1β and increasing IL1ra, the effect being proportional to baseline levels and normalizing values. Patients with higher baseline levels showed the highest decrease in IL-1β:IL-1ra, which associated with the immediate antidepressant response at the first cycle; while patients with lower baseline values showed negligible changes in the IL-1β:IL-1ra, unrelated to treatment response.ConclusionWe observed a parallel change of inflammatory biomarkers and severity of depression after chronotherapeutics, suggesting that a reduction in inflammation associated with depression could contribute to the mechanism of action of TSD+LT, and warranting interest for controlled studies addressing the role of inflammation in the recovery from bipolar depression.
Highlights
The immune state of patients affected by a depressive episode during major depressive disorder (MDD) or bipolar disorder (BD) is likely to play a role both, in the pathogenesis of depression, and as a determinant of therapy outcome (Benedetti et al, 2020; Branchi et al, 2021)
In respect to antidepressant response, we studied the 1-week combination of chronotherapeutics and lithium, a model experimental antidepressant treatment, which allows to explore the multi-target neurobiological mechanisms of antidepressant effects at close time points (Gillin et al, 2001; Benedetti and Smeraldi, 2009)
We showed that TSD+LT causes an increase in stem cell factor (SCF), a neurotrophic factor involved in neuronmicroglia interactions fostering an anti-inflammatory milieu, proportional to treatment efficacy (Benedetti et al, 2016a)
Summary
The immune state of patients affected by a depressive episode during major depressive disorder (MDD) or bipolar disorder (BD) is likely to play a role both, in the pathogenesis of depression, and as a determinant of therapy outcome (Benedetti et al, 2020; Branchi et al, 2021). Known effects of TSD and LT, which can be associated with its antidepressant effects, include an enhancement in serotonergic, noradrenergic, and dopaminergic neurotransmission; a reduction in NMDA glutamatergic signaling; changes in brain cortico-limbic metabolism; and a phase-advance of the sleep-wake and activity-rest rhythm (Gillin et al, 2001; Adrien, 2002; Benedetti and Smeraldi, 2009; Benedetti, 2012; Wirz-Justice et al, 2013; Geoffroy and Palagini, 2020) Because of these multiple effects, combined TSD+LT can prompt response in more than one half of the treated patients, targeting suicidality and partially overcoming treatment resistance (Colombo et al, 2000; Benedetti et al, 2005, 2014), and we observed worse antidepressant response with higher baseline peripheral cytokines (Benedetti et al, 2002, 2017). We explored the effects of TSD+LT on IL-1β signaling
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