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

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Flurin Cathomas ◽  
Laura Bevilacqua ◽  
Aarthi Ramakrishnan ◽  
Hope Kronman ◽  
Sara Costi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glutamate Receptor ◽  
Whole Blood ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Gene ◽  
Gene Expression Signature ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Transcriptional Profiles ◽  
Resistant Depression

AbstractKetamine 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.

60 GENE EXPRESSION AND KETAMINE RESPONSE IN SUBJECTS WITH TREATMENT RESISTANT DEPRESSION

2019 ◽  
Vol 29 ◽  
pp. S93
Author(s):  
Mohazzab-Hosseinian Sahra ◽  
Mehdi Pirooznia ◽  
Peter Zandi ◽  
Fernando Goes
Keyword(s):  
Gene Expression ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

scholarly journals Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing

2021 ◽  
Author(s):  
Chiara Fabbri ◽  
Oliver Pain ◽  
Saskia P. Hagenaars ◽  
Cathryn M. Lewis ◽  
Alessandro Serretti
Keyword(s):  
Gene Expression ◽  
Weight Gain ◽  
Association Study ◽  
Pearson Correlation ◽  
Drug Repurposing ◽  
Heat Shock Protein 90 ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Symptom Patterns

AbstractMajor depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.

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