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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.

SUBMITTER: Bunney BG

PROVIDER: S-EPMC4765913 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.

Bunney B G BG Li J Z JZ Walsh D M DM Stein R R Vawter M P MP Cartagena P P Barchas J D JD Schatzberg A F AF Myers R M RM Watson S J SJ Akil H H Bunney W E WE

Molecular psychiatry 20141104 1

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 a ...[more]

PMID: 25349171

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:A cardinal symptom of Major Depressive Disorder (MDD) is the disruption of circadian patterns. Yet, to date, there is no direct evidence of circadian clock dysregulation in the brains of MDD patients. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain was difficult to characterize. Here we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-hour cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ('Controls') and 34 MDD patients. Our dataset covered ~12,000 transcripts in the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (AnCg), hippocampus (HC), amygdala (AMY), nucleus accumbens (NAcc) and cerebellum (CB). Several hundred transcripts in each region showed 24-hour cyclic patterns in Controls, and >100 transcripts exhibited consistent rhythmicity and phase-synchrony across regions. Among the top ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERB), DBP, BHLHE40(DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in MDD brains, due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This is the first transcriptome-wide analysis of cyclic patterns in the human brain and demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggest novel molecular targets for treatment of mood disorders. Sample collection, including human subject recruitment and characterization, tissue dissection, and RNA extraction, was described previously (see Evans 2003 Neurobiol Dis 14:240-250, Li 2004 Biol Psychiatry 55:346-352). RNA samples for different regions came from the same set of brains from 86 control subjects. Sample size varied by region: AnCg (n=70 controls), DLPFC (n=83), CB (n=51), AMY (n=32), HC (n=63) and NAcc (n=66). Many of the samples were run on two or more chips, resulting in the following chip counts for each region: AnCg = 124, DLPFC = 161, CB = 79, AMY = 62, HC = 108 and NaCC = 136. We ran each sample on at least two microarrays using the Affymetrix U133-A or U133Plus-v2 GeneChips, however, we only used the U133A part of the U133Plus-v2 GeneChip in our analysis. We applied RMA (Robust Multi-array Analysis) (see Irizarry 2003 Biostatistics 4:249-264, Irizarry 2003 Nucleic Acids Res 31:e15) to summarize probe set expression levels, using a custom Chip Definition File, resulting in expression data for 11,911 ENTREZ transcripts. Microarray data for each region were analyzed separately. All downstream analyses were performed in R. Details of the data processing, including data cleaning and normalization, are located in the Supplementary Materials (section 1). After data filtering, 1,424 microarrays remained, corresponding to 776 unique RNA samples in six regions.

Project description:Major depressive disorder (MDD) is a complex mental disorder featured by an increased focus on the self and emotion dysregulation whose interaction remains unclear, though. At the same time, various studies observed abnormal representation of global fMRI brain activity in specifically those regions, e.g., cortical midline structure (CMS) in MDD that are associated with the self. Are the self and its impact on emotion regulation related to global brain activity unevenly represented in CMS relative to non-CMS? Addressing this yet open question is the main goal of our study. We here investigate post-acute treatment responder MDD and healthy controls in fMRI during an emotion task involving both attention and reappraisal of negative and neutral stimuli. We first demonstrate abnormal emotion regulation with increased negative emotion severity on the behavioral level. Next, focusing on a recently established three-layer topography of self, we show increased representation of global fMRI brain activity in specifically those regions mediating the mental (CMS) and exteroceptive (Right temporo-parietal junction and mPFC) self in post-acute MDD during the emotion task. Applying a complex statistical model, namely multinomial regression analyses, we show that increased global infra-slow neural activity in the regions of the mental and exteroceptive self modulates the behavioral measures of specifically negative emotion regulation (emotion attention and reappraisal/suppression). Together, we demonstrate increased representation of global brain activity in regions of the mental and exteroceptive self, including their modulation of negative emotion dysregulation in specifically the infra-slow frequency range (0.01 to 0.1 Hz) of post-acute MDD. These findings support the assumption that the global infra-slow neural basis of the increased self-focus in MDD may take on the role as basic disturbance in that it generates the abnormal regulation of negative emotions.

Dataset Information

Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.

Publications

Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.

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