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Biol Psychiatry. 2017 Sep 1;82(5):351-360. doi: 10.1016/j.biopsych.2017.02.1176. Epub 2017 Mar 1.

A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex.

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Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, Irvine, California.
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California.
Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, Irvine, California. Electronic address:



Conventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder, an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressant strategies, low-dose ketamine (KT) and sleep deprivation (SD) therapies, dramatically reduce depressive symptoms within 24 hours in a subset of major depressive disorder patients. However, it is unknown whether they exert their actions through shared regulatory mechanisms. To address this question, we performed comparative transcriptomics analyses to identify candidate genes and relevant pathways common to KT and SD.


We used the forced swim test, a standardized behavioral approach to measure antidepressant-like activity of KT and SD. We investigated gene expression changes using high-density microarrays and pathway analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis) in KT- and SD-treated mice compared with saline-treated control male mice.


We show that KT and SD elicit common transcriptional responses implicating distinct elements of the circadian clock and processes involved in neuronal plasticity. There is an overlap of 64 genes whose expression is common in KT and SD. Specifically, there is downregulation of clock genes including Ciart, Per2, Npas4, Dbp, and Rorb in both KT- and SD-treated mice.


We demonstrate a potential involvement of the circadian clock in rapid antidepressant responses. These findings could open new research avenues to help design chronopharmacological strategies to treat major depressive disorder.


Anterior cingulate cortex; Circadian clock; Depression; Ketamine; Sleep deprivation; Transcriptome

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