TY - JOUR
T1 - Whole blood transcriptional signatures associated with rapid antidepressant response to ketamine in patients with treatment resistant depression
AU - Cathomas, Flurin
AU - Bevilacqua, Laura
AU - Ramakrishnan, Aarthi
AU - Kronman, Hope
AU - Costi, Sara
AU - Schneider, Molly
AU - Chan, Kenny L.
AU - Li, Long
AU - Nestler, Eric J.
AU - Shen, Li
AU - Charney, Dennis S.
AU - Russo, Scott J.
AU - Murrough, James W.
N1 - Funding Information:
This work was supported by the Ehrenkranz Laboratory for Human Resilience, a component of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai and by a generous gift from the Gottesman Foundation to Mount Sinai. Additional support for this work is by a Postdoc.Mobility Fellowship of the Swiss National Science Foundation (FC), a Walter and Gertrud Siegenthaler Postdoctoral Fellowship and a Brain and Behavior Research Foundation NARSAD Young Investigator Award (FC), by the Kurt und Senta Herrmann Stiftung (FC) and by a Postdoctoral Fellowship from the Canadian Institutes of Health Research (KLC). The content is solely the responsibility of the authors and does not necessarily represent the views of the funding bodies.
Publisher Copyright:
© 2021, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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 processes. We thus 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 analyzed (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 showed 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. Response to ketamine was associated with a distinct transcriptional signature, however, we did not observe gene expression changes indicative of an anti-inflammatory effect. Future studies are needed to determine the role of the peripheral immune system in the antidepressant effect of ketamine.
AB - 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 processes. We thus 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 analyzed (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 showed 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. Response to ketamine was associated with a distinct transcriptional signature, however, we did not observe gene expression changes indicative of an anti-inflammatory effect. Future studies are needed to determine the role of the peripheral immune system in the antidepressant effect of ketamine.
UR - http://www.scopus.com/inward/record.url?scp=85122897124&partnerID=8YFLogxK
U2 - 10.1038/s41398-021-01712-0
DO - 10.1038/s41398-021-01712-0
M3 - Article
C2 - 35013133
AN - SCOPUS:85122897124
VL - 12
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
IS - 1
M1 - 12
ER -