title: Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.
abstract: Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.
authors.affiliation: Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, Irvine, CA, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Bunney
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, Irvine, CA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Walsh
authors.affiliation: Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, Irvine, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Stein
authors.affiliation: Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, Irvine, CA, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Vawter
authors.affiliation: Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, Irvine, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Cartagena
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Barchas
authors.affiliation: Department of Psychiatry, Stanford University, Palo Alto, CA, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Schatzberg
authors.affiliation: HudsonAlpha, Institute for Biotechnology, Huntsville, AL, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Department of Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Watson
authors.affiliation: Department of Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Akil
authors.affiliation: Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, Irvine, CA, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Bunney
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D056926:CLOCK Proteins / Q000235:genetics*; D021081:Chronobiology Disorders / Q000150:complications* / Q000235:genetics*; D003865:Major Depressive Disorder / Q000209:etiology / Q000235:genetics / Q000628:therapy; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D006179:Gyrus Cinguli / Q000378:metabolism; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use; D012892:Sleep Deprivation
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D056926:CLOCK Proteins