INTRODUCTION The response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels. METHODS The levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤ 7. RESULTS Response to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p= 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047). CONCLUSIONS In MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.

中文翻译：

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血浆血清素和犬尿氨酸途径代谢物水平与艾司西酞普兰和去甲文拉法辛治疗反应的关系

引言 重度抑郁症 (MDD) 患者对抗抑郁药治疗的反应已被证明受多种因素的影响，包括疾病严重程度和炎症。越来越多的证据表明，犬尿氨酸代谢途径在 MDD 患者中被炎症激活，并在抑郁症的病理生理学中发挥作用。据报道，抗抑郁药治疗也会影响犬尿氨酸途径代谢物水平。本研究调查了依他普仑与去甲文拉法辛的抗抑郁治疗结果与治疗前和治疗后血清素和犬尿氨酸途径代谢物水平变化之间的差异关联。方法 使用液相色谱-质谱法 (LC-MS) 对 161 名目前患有 MDD 的抑郁症患者在基线和用依他普仑或去甲文拉法辛治疗 8 周后测量血浆中血清素和犬尿氨酸途径代谢物的水平。治疗反应通常定义为汉密尔顿抑郁量表 21 项 (HAMD-21) 总分比基线降低至少 50%；缓解定义为治疗后 HAMD-21 评分≤ 7。 结果 对依他普仑治疗的反应与较高的基线血清素水平 (p = 0.022)、较低的基线犬尿氨酸 (Kyn)/色氨酸 (Trp) 比值 (p = 0.008) 相关）和较低的基线喹啉酸（QuinA）/色氨酸（Trp）比率（p = 0.047），表明炎症状态较低。在艾司西酞普兰治疗组中，通过 HAMD-21 评分相对于基线的百分比变化来衡量的抑郁症状的更大改善也与更高的基线血清素水平 (p = 0.033) 相关。此外，艾司西酞普兰治疗的缓解者显示治疗后犬尿氨酸 (KynA)/3-羟基犬尿氨酸 (3HK) 比率显着增加 (p = 0.015)。相比之下，对去甲文拉法辛治疗的反应与分析的任何代谢物无关。我们还证实了之前的一份报告，即与健康对照相比，MDD 患者的血浆血清素水平较低 (p = 0.004)，并且犬尿氨酸血浆水平与抑郁症状的严重程度呈负相关 (p = 0.047)。结论 在 MDD 患者中，依他普仑的抗抑郁反应与基线血清素水平呈正相关，与犬尿氨酸通路的激活呈负相关。这些结果似乎与之前的文献一致，表明炎症的生物标志物证据与对来自选择性 5-羟色胺再摄取抑制剂类的抗抑郁药的较低反应有关。此外，犬尿氨酸 (KynA)/3-羟基犬尿氨酸 (3HK) 比值的增加与依他普仑治疗下的完全缓解有关，该比值先前已被表征为神经保护指数。这些结果似乎与之前的文献一致，表明炎症的生物标志物证据与对来自选择性 5-羟色胺再摄取抑制剂类的抗抑郁药的较低反应有关。此外，犬尿氨酸 (KynA)/3-羟基犬尿氨酸 (3HK) 比值的增加与依他普仑治疗下的完全缓解有关，该比值先前已被表征为神经保护指数。这些结果似乎与之前的文献一致，表明炎症的生物标志物证据与对来自选择性 5-羟色胺再摄取抑制剂类的抗抑郁药的较低反应有关。此外，犬尿氨酸 (KynA)/3-羟基犬尿氨酸 (3HK) 比值的增加与依他普仑治疗下的完全缓解有关，该比值先前已被表征为神经保护指数。