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

Abstract

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment‐resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans

“…Ketamine treatment led to a rapid and significant reduction in immobility compared with the control saline treatment (Orozco‐Solis et al, ), consistent with the findings of several previous studies (Autry et al, ; Hines, Schmitt, Hines, Moss, & Haydon, ; Lopez‐Rodriguez, Kim, & Poland, ; Scheuing, Chiu, Liao, & Chuang, ). Further comparative transcriptomics analyses revealed that several key rhythmic genes (e.g., Ciart, Per2, Npas4, Dbp, and Rorb) were differentially expressed in the brain in response to ketamine treatment in mice (Orozco‐Solis et al, ). Several studies have demonstrated that ketamine enhanced rapid eye movement (REM) sleep and significantly increased levels of brain‐derived neurotrophic factor (BDNF), a synaptic protein correlated strongly with slow‐wave activity (SWA), to improve BDNF‐mediated synaptic plasticity and depressive symptoms (Ballard et al, ; Duncan et al, ; Evans et al, ; Monteggia & Zarate, ; Zarate & Machado‐Vieira, ).…”

“…Interestingly, some studies also have shown that circadian rhythms return to normal as depression symptoms remit (Avery, Shah, Eder, & Wildschiodtz, 1999;Hasler, Buysse, Kupfer, & Germain, 2010;Souetre et al, 1988;Troxel et al, 2012). A recent study from the University of California at Irvine involved transcriptome profiling to identify genes and pathways in relation to ketamine-associated alterations in circadian and sleep rhythms in mice (Orozco-Solis et al, 2017).…”

“…Interestingly, some studies also have shown that circadian rhythms return to normal as depression symptoms remit (Avery, Shah, Eder, & Wildschiodtz, ; Hasler, Buysse, Kupfer, & Germain, ; Souetre et al, ; Troxel et al, ). A recent study from the University of California at Irvine involved transcriptome profiling to identify genes and pathways in relation to ketamine‐associated alterations in circadian and sleep rhythms in mice (Orozco‐Solis et al, ). Ketamine treatment led to a rapid and significant reduction in immobility compared with the control saline treatment (Orozco‐Solis et al, ), consistent with the findings of several previous studies (Autry et al, ; Hines, Schmitt, Hines, Moss, & Haydon, ; Lopez‐Rodriguez, Kim, & Poland, ; Scheuing, Chiu, Liao, & Chuang, ).…”

“…A recent study from the University of California at Irvine involved transcriptome profiling to identify genes and pathways in relation to ketamine‐associated alterations in circadian and sleep rhythms in mice (Orozco‐Solis et al, ). Ketamine treatment led to a rapid and significant reduction in immobility compared with the control saline treatment (Orozco‐Solis et al, ), consistent with the findings of several previous studies (Autry et al, ; Hines, Schmitt, Hines, Moss, & Haydon, ; Lopez‐Rodriguez, Kim, & Poland, ; Scheuing, Chiu, Liao, & Chuang, ). Further comparative transcriptomics analyses revealed that several key rhythmic genes (e.g., Ciart, Per2, Npas4, Dbp, and Rorb) were differentially expressed in the brain in response to ketamine treatment in mice (Orozco‐Solis et al, ).…”

Circadian Misalignment and Bipolar Disorder

“…This may be due to the time required to normalize the whole-body circadian rhythm, which is the reason why antidepressants have a delayed therapeutic response. Recently, three antidepressant modalities have become the focus of research because of their very rapid antidepressant effect: sleep deprivation, electroconvulsive therapy, and ketamine therapy [19][20][21]. Previous evidence suggests that the mechanism underlying the antidepressant effect is a process in which the delayed circadian rhythm is restored to normal by treatment [22].…”