Arteaga-Henriquez Gara, Burger Bianka, Weidinger Elif, Grosse Laura, Moll Natalie, Schuetze Gregor, Schwarz Markus, Wijkhuijs Annemarie, Op de Beeck Gommaar, Berghmans Raf, Versnel Marjan A, Arolt Volker, Müller Norbert, Drexhage Hemmo A
Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University, Munich, Germany; Department of Immunology, Erasmus Medical Center, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilian-University, Munich, Germany; Marion von Tessin Memory-Center, Munich, Germany.
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Apr 20;107:110226. doi: 10.1016/j.pnpbp.2020.110226. Epub 2020 Dec 18.
It is unclear how the tryptophan (TRP) breakdown pathway relates to the activated inflammatory state of patients with major depressive disorder (MDD). We determined in two different cohorts of patients with MDD (n = 281) and healthy controls (HCs) (n = 206) collected for the EU-MOODINFLAME project: We then correlated outcomes to each other, and to the clinical characteristics of patients. Both cohorts of patients differed clinically; patients of the Munich cohort (n = 50) were less overweight, less medicated, were less in the current episode and showed a higher HAM-D 17 score as compared with patients of the Muenster cohort (n = 231). An increased expression of ICCGs was found in the circulating monocytes of patients of both cohorts; this was in particular evident in the Munich cohort. In contrast, ISGs monocyte expression levels tended to be reduced (both cohorts). TRP serum levels were linked to the pro-inflammatory (ICCGs) monocyte state of patients; a decrease in TRP serum levels was found in the Munich cohort; TRP levels correlated negatively to patient's HAM-D 17 score. Contrary to what expected, KYN serum levels were not increased in patients (both cohorts); and an increased KYN/TRP ratio was only found in the Munich patients (who showed the lowest TRP serum levels). IDO-1 monocyte expression levels were decreased in patients (both cohorts) and negatively associated to their pro-inflammatory (ICCGs) monocyte state. Thus, a depletion of TRP via an ICCGs-inflammatory IDO activation is not likely in MDD. Downstream from KYN, and regarding compounds influencing glutamate receptors (GR), reduced serum levels of KYNA (NMDA-R antagonist), 3-HK (NMDA-R agonist), and XA (mGlu2/3 agonist) were found in patients of both cohorts; PIC serum levels (NMDA-R antagonist) were increased in patients of both cohorts. Reduced QUIN serum levels (NMDA-R agonist) were found in patients of the Muenster cohort,only. 3-HK levels correlated to the monocyte inflammatory ICCG state of patients. The ultimate effect on brain glutamate receptor triggering of this altered equilibrium between peripheral agonists and antagonists remains to be elucidated.
目前尚不清楚色氨酸（TRP）分解途径与重度抑郁症（MDD）患者的激活炎症状态之间的关系。我们在为欧盟-情绪炎症项目收集的两组不同的MDD患者（n = 281）和健康对照者（HCs）（n = 206）中进行了测定：然后我们将各项结果相互关联，并与患者的临床特征相关联。两组患者在临床上存在差异；与明斯特队列（n = 231）的患者相比，慕尼黑队列（n = 50）的患者超重程度较低、用药较少、处于当前发作期的比例较低，且汉密尔顿抑郁量表（HAM-D 17）评分较高。在两组患者的循环单核细胞中均发现吲哚胺2,3-双加氧酶诱导型（ICCGs）的表达增加；这在慕尼黑队列中尤为明显。相比之下，干扰素刺激基因（ISGs）单核细胞表达水平有降低的趋势（两组均如此）。TRP血清水平与患者的促炎（ICCGs）单核细胞状态相关；在慕尼黑队列中发现TRP血清水平降低；TRP水平与患者的HAM-D 17评分呈负相关。与预期相反，患者（两组）体内犬尿氨酸（KYN）血清水平并未升高；仅在慕尼黑患者（其TRP血清水平最低）中发现KYN/TRP比值升高。患者（两组）体内吲哚胺2,3-双加氧酶1（IDO-1）单核细胞表达水平降低，且与其促炎（ICCGs）单核细胞状态呈负相关。因此，在MDD中，通过ICCGs炎症性IDO激活导致TRP耗竭的可能性不大。在KYN的下游，关于影响谷氨酸受体（GR）的化合物，在两组患者中均发现犬尿喹啉酸（KYNA，NMDA-R拮抗剂）、3-羟基犬尿氨酸（3-HK，NMDA-R激动剂）和黄尿酸（XA，mGlu2/3激动剂）的血清水平降低；两组患者中吡啶甲酸（PIC，NMDA-R拮抗剂）的血清水平均升高。仅在明斯特队列的患者中发现喹啉酸（QUIN，NMDA-R激动剂）血清水平降低。3-HK水平与患者的单核细胞炎症ICCG状态相关。外周激动剂和拮抗剂之间这种平衡改变对脑谷氨酸受体触发的最终影响仍有待阐明。
