Whole blood transcriptional signatures associated with rapid antidepressant response to ketamine in patients with treatment resistant depression.. Whole blood transcriptional signatures associated with rapid antidepressant response to ketamine in patients with treatment resistant depression.

Ketamine has rapid and sustained antidepressant effects in patients with treatment resistant depression (TRD). However, the underlying mechanisms of action are not well understood. There is increasing evidence that TRD is associated with a pro-inflammatory state and that ketamine may inhibit inflammatory cytokine production. We investigated whole blood transcriptional profiles related to TRD and gene expression changes associated with treatment response to ketamine. Whole blood was collected at baseline (21 healthy controls [HC], 26 patients with TRD) and then again in patients with TRD 24 hours following a single intravenous infusion of ketamine (0.5 mg/kg). We performed RNA-sequencing and compared a) baseline transcriptional profiles between patients with TRD and HC, b) responders vs. non-responders before ketamine treatment, and c) gene expression signatures associated with clinical improvement. At baseline, patients with TRD compared to HC were characterized by a gene expression signature indicative of interferon signaling pathway activation. Prior to ketamine administration, the metabotropic glutamate receptor gene GRM2 and the ionotropic glutamate receptor gene GRIN2D were upregulated in responders compared to non-responders. Ketamine response was associated with the downregulation of multiple genes coding for pro-inflammatory cytokines, the predicted inhibition of several interferon signaling associated upstream regulators and the downregulation of Indoleamine 2,3-Dioxygenase 1 (IDO1). The current study indicates that response to ketamine may be associated with up-regulation of glutamate receptors at baseline, and linked to transcriptional changes indicative of an anti-inflammatory response following ketamine. One specific anti-inflammatory mechanism might be the downregulation of IDO1 via inhibition of the interferon pathway. Overall design: RNA-sequencing was done on human MDD and control subjects to compare a) baseline transcriptional profiles between patients with Treatment Resistant Depression (TRD) and Human Controls (HC), b) responders vs. non-responders before ketamine treatment, and c) gene expression signatures associated with clinical improvement.

氯胺酮对难治性抑郁症（Treatment Resistant Depression, TRD）患者具有快速且持久的抗抑郁效应，但其潜在作用机制尚未得到充分阐明。越来越多的证据表明，难治性抑郁症与促炎状态相关，且氯胺酮可抑制炎症细胞因子的产生。本研究旨在探究与难治性抑郁症相关的全血转录组谱，以及与氯胺酮治疗应答相关的基因表达变化。研究人员采集了基线状态下的全血样本，涉及21名健康对照者（Healthy Controls, HC）与26名难治性抑郁症患者，并在难治性抑郁症患者接受单次静脉输注氯胺酮（0.5 mg/kg）后的24小时，再次采集其全血样本。随后开展RNA测序（RNA-sequencing），并进行三组对比分析：a）难治性抑郁症患者与健康对照者的基线转录组谱；b）氯胺酮治疗前的应答者与无应答者；c）与临床改善相关的基因表达特征。基线状态下，与健康对照者相比，难治性抑郁症患者的基因表达特征提示干扰素信号通路处于激活状态。在氯胺酮给药前，应答者体内的代谢型谷氨酸受体基因GRM2与离子型谷氨酸受体基因GRIN2D的表达水平显著高于无应答者。氯胺酮治疗应答与多个促炎细胞因子编码基因的下调、多个干扰素信号相关上游调控因子的预测性抑制，以及吲哚胺2,3-双加氧酶1（Indoleamine 2,3-Dioxygenase 1, IDO1）的下调密切相关。本研究表明，对氯胺酮的治疗应答可能与基线状态下谷氨酸受体的上调存在关联，同时与氯胺酮给药后体现抗炎反应的转录组变化相关。其中一种潜在的特异性抗炎机制可能是通过抑制干扰素通路，下调IDO1的表达。整体实验设计：本研究对人类重度抑郁症（Major Depressive Disorder, MDD）患者及对照受试者开展RNA测序，以完成以下三组对比：a）难治性抑郁症患者与健康对照者的基线转录组谱；b）氯胺酮治疗前的应答者与无应答者；c）与临床改善相关的基因表达特征。