Plasma Indoleamine-2,3-Dioxygenase (IDO) is Increased in Drug-Naï ve Major Depressed Patients and Treatment with Sertraline and Ketoprofen Normalizes IDO in Association with Pro-Inflammatory and Immune- Regulatory Cytokines.

BACKGROUND: Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of inflammatory and immune-regulatory cytokines and stimulation of indoleamine-2,3-dioxygenase (IDO). There is also evidence that anti-inflammatory drugs may have clinical efficacy in MDD. METHODS: This study examined a) IDO in association with interferon (IFN)-γ, Interleukin (IL)-4 and Transforming Growth Factor (TGF)-ß1 in 140 drug-naïve MDD patients and 40 normal controls; and b) the effects of an eight-week treatment of sertraline with or without ketoprofen (a nonsteroidal antiinflammatory drug) on the same biomarkers in 44 MDD patients. RESULTS: Baseline IDO, IFN-γ, TGF-ß1 and IL-4 were significantly higher in MDD patients as compared with controls. Treatment with sertraline with or without ketoprofen significantly reduced the baseline levels of all biomarkers to levels which were in the normal range (IDO, TGF-ß1, and IL-4) or still somewhat higher than in controls (IFN-γ). Ketoprofen add-on had a significantly greater effect on IDO as compared with placebo. The reductions in IDO, IL-4, and TGF-ß1 during treatment were significantly associated with those in the BDI-II. CONCLUSION: MDD is accompanied by activated immune-inflammatory pathways (including IDO) and the Compensatory Immune-Regulatory System (CIRS). The clinical efficacy of antidepressant treatment may be ascribed at least in part to decrements in IDO and the immune-inflammatory response. These treatments also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD while enhancing the CIRS.

Lowered zinc and copper levels in drug-naïve patients with major depression: Effects of antidepressants, ketoprofen and immune activation.

Objectives: The aim of the present work is to examine the effects of treatment with sertraline with and without ketoprofen on serum levels of zinc and copper in association with immune-inflammatory biomarkers in drug-naïve major depressed patients.Methods: We measured serum zinc and copper, interleukin (IL)-1ß, IL-4, IL-6, IL-18, interferon-γ, and transforming growth factor-ß1 in 40 controls and 133 depressed patients. The clinical efficacy of the treatment was measured using the Beck Depression Inventory-II (BDI-II) at baseline and 8 weeks later.Results: We found significantly reduced serum zinc and copper in association with upregulation of all cytokines, indicating activation of the immune-inflammatory responses system (IRS) and the compensatory immune regulatory system (CIRS). Treatment with sertraline significantly increased zinc and decreased copper. During treatment, there was a significant inverse association between serum zinc and immune activation. The improvement in the BDI-II during treatment was significantly associated with increments in serum zinc coupled with attenuation of the IRS/CIRS.Conclusions: Lower zinc is a hallmark of depression, while increments in serum zinc and attenuation of the immune-inflammatory response during treatment appear to play a role in the clinical efficacy of sertraline.

Total and ionized calcium and magnesium are significantly lowered in drug-naïve depressed patients: effects of antidepressants and associations with immune activation.

Major depressive disorder (MDD) is associated with alterations in calcium (Ca) and magnesium (Mg), as well as circulating pro- and anti-inflammatory cytokines. Anti-inflammatory drugs are commonly used as adjuvant treatments for MDD. However, no studies examined the effects of a combinatorial treatment with sertraline and ketoprofen, an anti-inflammatory drug, on Ca and Mg levels in MDD. The present study examined a) differences in both cations between drug-naïve MDD patients and controls, and b) the effects of sertraline and ketoprofen on Ca and Mg (both total and ionized). In the same patients, we also examined the associations between both cations and IL-1ß, IL-4, IL-6, IL-18, IFN-γ, TGF-ß1, zinc, and indoleamine 2,3-dioxygenase (IDO). Clinical improvement was assessed using the Beck Depression Inventory-II (BDI-II) at baseline and after follow up for 2 months. Serum Ca and Mg (total and ionized) were significantly lower in MDD patients as compared with controls, while treatment significantly increased calcium but decreased magnesium levels. There were significant and inverse correlations between the BDI-II scores from baseline to endpoint and Ca (both total and ionized), but not Mg, levels. The effects of calcium on the BDI-II score remained significant after considering the effects of zinc, IDO and an immune activation z unit-weighted composite score based on the sum of all cytokines. There was a significant and inverse association between this immune activation index and calcium levels from baseline to endpoint. In conclusion, lowered levels of both cations play a role in the pathophysiology of major depression. Antidepressant-induced increases in Ca are associated with clinical efficacy and attenuation of the immune response. The suppressant effect of antidepressants on Mg levels is probably a side effect of those drugs. New antidepressant treatments should be developed that increase the levels both Ca and Mg. Graphical abstract.