Abstract
BackgroundNeuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression.MethodsCytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22).ResultsPatients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = −0.67, P = 0.002).ConclusionsThis study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-d-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA-receptor agonist previously suggested to be implicated in the pathogenesis of depression, an effect that might have bearing for the good clinical outcome of ECT.
Highlights
Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression
Patients were clinically evaluated with Montgomery-Åsberg Depression Rating Scale (MADRS) before electroconvulsive therapy (ECT), and the median MADRS score for these patients was 37.0 (IQR 28.8–44.3)
Cytokines in patients with major depressive disorder (MDD) and healthy male volunteers Plasma levels of IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) were detected in 13 of the 14 healthy male volunteers and in all 19 unipolar depressed patients with an exception for IL10 and IL-6 that was not detected in one patient with MDD
Summary
Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. Major depressive disorder is a severe, life-threatening psychiatric illness, exposing the patient to direct risks, such as increased mortality due to cardiovascular disease, stroke, and alcohol abuse disorders. It is a leading cause of disability affecting millions of people worldwide and often causing chronic recurrent symptoms and profound socioeconomic burden [1]. With depression follows a high risk of suicidal behavior, including attempts and completed suicides. Increased concentrations of pro-inflammatory cytokines, chemokines, and acute-phase proteins have been observed in depressed patients. Increased circulating levels of interleukin (IL)-6 and C-reactive protein are the most frequently observed findings [8,9,10], and, increased central levels of IL-6 have been described [11, 12]
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