Ketamine and depression - M. Korostyński


MOLECULAR MARKERS OF ANTIDEPRESSIVE EFFECTS OF KETAMINE


In clinical trials, the NMDA receptor antagonist ketamine was found to act as an antidepressant with rapid and persisting effects, even in otherwise treatment-refractory cases. Identification of the mechanisms underlying ketamine’s antidepressant action may enable the development of novel drugs, with similar clinical properties but lacking undesirable psychotomimetic effects.


Figure 1. High-throughput next-generation sequencer (Ion Proton) at the Laboratory of Genomics IP PAS.




This instrument was used to analyze drug-effects of gene expression in the mouse brain. Measurement of RNAs abundance levels was done at the level of the whole-transcriptome.

Screening for genes involved in the effects of NMDA antagonists has been performed at several time points  (1, 2, 4 and 8 h) following acute administration of ketamine, memantine, and phencyclidine in mice. Gene expression alterations were analyzed in striatum and hippocampus by applying whole-genome microarray profiling. We identified 52 transcripts with altered expression in response to treatment with NMDA receptor antagonists. Functional analysis indicated links that connect expression of the regulated genes to the intracellular signaling pathways related to MAPK, IL-6, and metabolism of insulin. Moreover, to obtain a more detailed molecular profile of ketamine, its transcriptional effects were further analyzed using next-generation sequencing. Consequently, ketamine-regulated expression of specific gene isoforms was detected. On top of that, gene expression alterations induced by the selected NMDA antagonists were compared to the molecular profiles of psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids.


Figure 2. Molecular classification of ketamine in a comparison to several psychotropic drugs with diverse mechanisms of pharmacological action.


The profile of gene expression alterations induced by ketamine was compared to the effects of antidepressants, antipsychotics, anxiolytics, psychostimulants, and opioids. Bioinformatics analyses were done by using hierarchical clusterization (diagram on the left side), PCA (middle) and heatmap (right side).

 

The comparison with other psychotropic drugs revealed that the molecular effects of ketamine are most similar to memantine, and phencyclidine. Based on the expression profile, the NMDA antagonist was placed among fluoxetine, tianeptine, as well as opioids and ethanol. The identified patterns of gene expression alterations in the brain provided novel molecular classification of ketamine. The transcriptional profile of ketamine reflects its multi-target pharmacological nature and reveals similarities between the effects of ketamine and monoaminergic antidepressants. This effect together with NMDA receptors blockade may explain the mechanisms of ketamine’s rapid antidepressant action observed in clinics.


Michał Korostyński PhD

Department of Molecular Neuropharmacology

www: http://if-pan.krakow.pl/en/departments/department-of-molecular-neuropharmacology/

e-mail: michkor@if-pan.krakow.pl


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