Allele-specific transcription factor binding across human brain regions offers mechanistic insight into eQTLs.

Transcription factors (TFs) regulate gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Because TF occupancy is driven in part by recognition of DNA sequence, genetic variation can influence TF-DNA associations and gene regulation. To identify variants that impact TF binding in human brain tissues, we assessed allele-specific binding (ASB) at heterozygous variants for 94 TFs in nine brain regions from two donors. Leveraging graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signals between alleles at heterozygous variants within each brain region and identified thousands of variants exhibiting ASB for at least one TF. ASB reproducibility was measured by comparisons between independent experiments both within and between donors. We found that rare alleles in the general population more frequently led to reduced TF binding, whereas common alleles had an equal likelihood of increasing or decreasing binding. Further, for ASB variants in predicted binding motifs, the favored allele tended to be the one with the stronger expected motif match, but this concordance was not observed within highly occupied sites. We also found that neuron-specific cis-regulatory elements (cCREs), in contrast with oligodendrocyte-specific cCREs, showed depletion of ASB variants. We identified 2670 ASB variants associated with evidence for allele-specific gene expression in the brain from GTEx data and observed increasing eQTL effect direction concordance as ASB significance increases. These results provide a valuable and unique resource for mechanistic analysis of cis-regulatory variation in human brain tissue.

Usage of Therapeutic Sleep Deprivation: A Survey in Psychiatric Hospitals in Austria, Germany, and Switzerland.

Objective: Therapeutic sleep deprivation (SD) is a nonpharmacological treatment that is used most often for depression. The aim of this study was to examine the pattern of use of SD in psychiatric hospitals in Austria, Germany, and Switzerland. Methods: A questionnaire about perceived usage of SD was sent by mail to all 511 psychiatric hospitals in the three countries. Nonresponders were asked to answer the questionnaire by phone. We achieved a response rate of 75.3%. Results: SD was recommended by 61.3% of all hospitals. Despite this degree of recommendation, nearly two thirds of the psychiatric hospitals had not treated a patient with SD during the last 12 months. Of the respondents, 59.5% considered SD to be indicated for major depressive disorder, 17.7% for bipolar depression, and 7.8% for other indications. SD was administered most frequently in inpatient settings and in combination with other therapies. Total SD (patients kept awake entire night) and partial late SD (patients kept awake in second half of night) were judged equally effective. Of the hospitals, 53.0% reported having seen hypomania and 13.2% manic episodes as side effects (rates do not represent actual incident rates). Conclusion: The lack of large controlled studies for SD with its different forms of treatment probably still hinders a broader use of the therapy. Therefore, further efforts should be undertaken to provide high-quality scientific evidence for the usage of SD.

Circadian patterns of gene expression in the human brain and disruption in major depressive disorder.

A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ("controls") and 34 patients with MDD. Our dataset covered ~12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h 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-ERBa), 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 the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain 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 suggests potentially important molecular targets for treatment of mood disorders.

Resilience to Chronic Stress Is Characterized by Circadian Brain-Liver Coordination.

Background: Chronic stress has a profound impact on circadian regulation of physiology. In turn, disruption of circadian rhythms increases the risk of developing both psychiatric and metabolic disorders. To explore the role of chronic stress in modulating the links between neural and metabolic rhythms, we characterized the circadian transcriptional regulation across different brain regions and the liver as well as serum metabolomics in mice exposed to chronic social defeat stress, a validated model for studying depressive-like behaviors. Methods: Male C57BL/6J mice underwent chronic social defeat stress, and subsequent social interaction screening identified distinct behavioral phenotypes associated with stress resilience and susceptibility. Stressed mice and their control littermates were sacrificed every 4 hours over the circadian cycle for comprehensive analyses of the circadian transcriptome in the hypothalamus, hippocampus, prefrontal cortex, and liver together with assessments of the circadian circulatory metabolome. Results: Our data demonstrate that stress adaptation was characterized by reprogramming of the brain as well as the hepatic circadian transcriptome. Stress resiliency was associated with an increase in cyclic transcription in the hypothalamus, hippocampus, and liver. Furthermore, cross-tissue analyses revealed that resilient mice had enhanced transcriptional coordination of circadian pathways between the brain and liver. Conversely, susceptibility to social stress resulted in a loss of cross-tissue coordination. Circadian serum metabolomic profiles corroborated the transcriptome data, highlighting that stress-resilient mice gained circadian rhythmicity of circulating metabolites, including bile acids and sphingomyelins. Conclusions: This study reveals that resilience to stress is characterized by enhanced metabolic rhythms and circadian brain-liver transcriptional coordination.

Chronic stress can have detrimental effects on both physical and mental health, often disrupting biological daily rhythms, known as circadian rhythms. To delve deeper into this phenomenon, we investigated how chronic stress affects circadian rhythms in the brain, liver, and blood metabolism of mice. Our study revealed that mice resilient to stress showed an increase in shared circadian biological processes between the liver and different brain regions together with enhanced rhythms in circulating metabolites. These findings propose an unprecedented link between stress adaptation and systemic circadian coordination and offer valuable insights into the mechanisms that underlie circadian disturbances seen in psychiatric disorders.

Multiomic profiling of transcription factor binding and function in human brain.

Transcription factors (TFs) orchestrate gene expression programs crucial for brain function, but we lack detailed information about TF binding in human brain tissue. We generated a multiomic resource (ChIP-seq, ATAC-seq, RNA-seq, DNA methylation) on bulk tissues and sorted nuclei from several postmortem brain regions, including binding maps for more than 100 TFs. We demonstrate improved measurements of TF activity, including motif recognition and gene expression modeling, upon identification and removal of high TF occupancy regions. Further, predictive TF binding models demonstrate a bias for these high-occupancy sites. Neuronal TFs SATB2 and TBR1 bind unique regions depleted for such sites and promote neuronal gene expression. Binding sites for TFs, including TBR1 and PKNOX1, are enriched for risk variants associated with neuropsychiatric disorders, predominantly in neurons. This work, titled BrainTF, is a powerful resource for future studies seeking to understand the roles of specific TFs in regulating gene expression in the human brain.

Allele biased transcription factor binding across human brain regions gives mechanistic insight into eQTLs.

Transcription Factors (TFs) influence gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Because genomic localization of TFs is in part driven by TF recognition of DNA sequence, variation in TF binding sites can disrupt TF-DNA associations and affect gene regulation. To identify variants that impact TF binding in human brain tissues, we quantified allele bias for 93 TFs analyzed with ChIP-seq experiments of multiple structural brain regions from two donors. Using graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signal between alleles at heterozygous variants within each tissue sample from each donor. Comparison of results from different brain regions within donors and the same regions between donors provided measures of allele bias reproducibility. We identified thousands of DNA variants that show reproducible bias in ChIP-seq for at least one TF. We found that alleles that are rarer in the general population were more likely than common alleles to exhibit large biases, and more frequently led to reduced TF binding. Combining ChIP-seq with RNA-seq, we identified TF-allele interaction biases with RNA bias in a phased allele linked to 6,709 eQTL variants identified in GTEx data, 3,309 of which were found in neural contexts. Our results provide insights into the effects of both common and rare variation on gene regulation in the brain. These findings can facilitate mechanistic understanding of cis-regulatory variation associated with biological traits, including disease.

Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer's disease-specific cis-regulatory elements.

Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer's disease (AD) and unaffected controls have been well documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq plus snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell type-specific transposase accessible regions enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as candidate transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Microglia links were globally enriched for heritability of AD risk and previously identified active regulatory regions.

Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia.

The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

Rapid-acting antidepressant strategies: mechanisms of action.

Current antidepressants are ineffective in many depressed patients. Thus there is an urgent need to develop treatment strategies which have significantly faster response, can be sustained and have minimal side-effects. This paper reviews clinical data, potential biomarkers, mechanisms of action and future research directions for two proven strategies that produce marked improvement in severe depressive symptoms within 48 h, ketamine and sleep deprivation therapy (SDT). These treatments provide unequivocal evidence that the depressive process can be rapidly reversed in a subgroup of patients. Seventeen ketamine studies in over 150 patients showed a rapid response. Low-dose intravenous ketamine produced mild psychotomimetic effects but response has not been effectively sustained. SDT has been investigated in over 60 studies with a 40-60% response rate within 48 h. Although SDT is often used in Europe to initiate a rapid response, it is less utilized within the USA, in part, because it has a short duration when administered alone. We review data concerning chronotherapeutic strategies of bright-light therapy (BLT) and sleep-phase advance (SPA) which successfully sustain the antidepressant efficacy of SDT. Evidence is further discussed that a significant group of mood disorders have abnormal circadian rhythms which are known to be controlled by clock genes. It is hypothesized that chronotherapeutic manipulations can reset clock genes and thus, abnormalities in circadian rhythms. Further findings are reviewed that ketamine, in addition to its role as an NMDA antagonist, can also alter circadian rhythms. Thus, ketamine may share a critical mechanism with SDT.

Rapid-acting antidepressants and the circadian clock.

A growing number of epidemiological and experimental studies has established that circadian disruption is strongly associated with psychiatric disorders, including major depressive disorder (MDD). This association is becoming increasingly relevant considering that modern lifestyles, social zeitgebers (time cues) and genetic variants contribute to disrupting circadian rhythms that may lead to psychiatric disorders. Circadian abnormalities associated with MDD include dysregulated rhythms of sleep, temperature, hormonal secretions, and mood which are modulated by the molecular clock. Rapid-acting antidepressants such as subanesthetic ketamine and sleep deprivation therapy can improve symptoms within 24 h in a subset of depressed patients, in striking contrast to conventional treatments, which generally require weeks for a full clinical response. Importantly, animal data show that sleep deprivation and ketamine have overlapping effects on clock gene expression. Furthermore, emerging data implicate the circadian system as a critical component involved in rapid antidepressant responses via several intracellular signaling pathways such as GSK3ß, mTOR, MAPK, and NOTCH to initiate synaptic plasticity. Future research on the relationship between depression and the circadian clock may contribute to the development of novel therapeutic strategies for depression-like symptoms. In this review we summarize recent evidence describing: (1) how the circadian clock is implicated in depression, (2) how clock genes may contribute to fast-acting antidepressants, and (3) the mechanistic links between the clock genes driving circadian rhythms and neuroplasticity.

Identification of potential blood biomarkers associated with suicide in major depressive disorder.

Suicides have increased to over 48,000 deaths yearly in the United States. Major depressive disorder (MDD) is the most common diagnosis among suicides, and identifying those at the highest risk for suicide is a pressing challenge. The objective of this study is to identify changes in gene expression associated with suicide in brain and blood for the development of biomarkers for suicide. Blood and brain were available for 45 subjects (53 blood samples and 69 dorsolateral prefrontal cortex (DLPFC) samples in total). Samples were collected from MDD patients who died by suicide (MDD-S), MDDs who died by other means (MDD-NS) and non-psychiatric controls. We analyzed gene expression using RNA and the NanoString platform. In blood, we identified 14 genes which significantly differentiated MDD-S versus MDD-NS. The top six genes differentially expressed in blood were: PER3, MTPAP, SLC25A26, CD19, SOX9, and GAR1. Additionally, four genes showed significant changes in brain and blood between MDD-S and MDD-NS; SOX9 was decreased and PER3 was increased in MDD-S in both tissues, while CD19 and TERF1 were increased in blood but decreased in DLPFC. To our knowledge, this is the first study to analyze matched blood and brain samples in a well-defined population of MDDs demonstrating significant differences in gene expression associated with completed suicide. Our results strongly suggest that blood gene expression is highly informative to understand molecular changes in suicide. Developing a suicide biomarker signature in blood could help health care professionals to identify subjects at high risk for suicide.

Homer1a Undergoes Bimodal Transcriptional Regulation by CREB and the Circadian Clock.

Accumulating evidence points to a significant link between disrupted circadian rhythms and neuronal disfunctions, though the molecular mechanisms underlying this connection are virtually unexplored. The transcript Homer1a, an immediate early gene related to postsynaptic signaling, has been demonstrated to exhibit robust circadian oscillation in the brain, which supports the hypothesis that Homer1a mediates the communication between circadian inputs and neuronal activity. Here, we determined how the circadian clock is implicated in Homer1a gene regulation by using circadian clock Bmal1-mutant mice either in the presence or absence of stress stimulation. The Homer1 gene generates multiple transcripts, but only the short variant Homer1a responds to acute stress with sleep deprivation (SD) in mice. Chromatin immunoprecipitation assays revealed that both transcription factor CREB and the circadian clock component BMAL1 bind to the Homer1 promoter in mouse brain. Importantly, circadian Homer1a gene expression is unaltered in the absence of BMAL1, while its immediate early response to SD relies on BMAL1. Deletion of Bmal1 results in attenuated CREB activity in mouse brain, which appears to contribute to decreased expression of Homer1a in response to SD. In conclusion, Homer1a undergoes bimodal control by the circadian clock and CREB.

A study of psychological pain in substance use disorder and its relationship to treatment outcome.

Substance Use Disorder (SUD) is a major public health concern affecting an estimated 22.5 million individuals in the United States. The primary aim of this study was to characterize psychological pain in a cohort of patients participating in outpatient treatment for SUD. A secondary aim was to determine the relationships between pre-treatment assessments of psychological pain, depression, anxiety and hopelessness with treatment retention time and completion rates. Data was analyzed from 289 patients enrolled in an outpatient community drug treatment clinic in Southern California, U.S. A previously determined threshold score on the Mee-Bunney Psychological Pain Assessment Scale (MBP) was utilized to group patients into high and low-moderate scoring subgroups. The higher pain group scored higher on measures of anxiety, hopelessness and depression compared to those in the low-moderate pain group. Additionally, patients scoring in the higher psychological pain group exhibited reduced retention times in treatment and more than two-fold increased odds of dropout relative to patients with lower pre-treatment levels of psychological pain. Among all assessments, the correlation between psychological pain and treatment retention time was strongest. To our knowledge, this is the first study to demonstrate that psychological pain is an important construct which correlates with relevant clinical outcomes in SUD. Furthermore, pre-treatment screening for psychological pain may help target higher-risk patients for clinical interventions aimed at improving treatment retention and completion rates.

Assessment of psychological pain in suicidal veterans.

Psychological pain is a relatively understudied and potentially important construct in the evaluation of suicidal risk. Psychological pain also referred to as 'mental pain' or 'psychache' can be defined as an adverse emotional reaction to a severe trauma (e.g., the loss of a child) or may be associated with an illness such as depression. When psychological pain levels reach intolerable levels, some individuals may view suicide as the only and final means of escape. To better understand psychological pain, we previously developed and validated a brief self-rating 10-item scale, Mee-Bunney Psychological Pain Assessment Scale [MBP] in depressed patients and non-psychiatric controls. Our results showed a significant increase in psychological pain in the depressed patients compared to controls. We also observed a significant linear correlation between psychological pain and suicidality in the depressed patient cohort. The current investigation extends our study of psychological pain to a diagnostically heterogeneous population of 57 US Veterans enrolled in a suicide prevention program. In addition to the MBP, we administered the Columbia Suicide Severity Rating Scale (C-SSRS), Beck Depression Inventory (BDI-II), Beck Hopelessness Scale (BHS), and the Barratt Impulsiveness Scale (BIS-11). Suicidal patients scoring above a predetermined threshold for high psychological pain also had significantly elevated scores on all the other assessments. Among all of the evaluations, psychological pain accounted for the most shared variance for suicidality (C-SSRS). Stepwise regression analyses showed that impulsiveness (BIS) and psychological pain (MBP) contributed more to suicidality than any of the other combined assessments. We followed patients for 15 months and identified a subgroup (24/57) with serious suicide events. Within this subgroup, 29% (7/24) had a serious suicidal event (determined by the lethality subscale of the C-SSRS), including one completed suicide. Our results build upon our earlier findings and recent literature supporting psychological pain as a potentially important construct. Systematically evaluating psychological pain along with additional measures of suicidality could improve risk assessment and more effectively guide clinical resource allocation toward prevention.

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

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.

Post-mortem molecular profiling of three psychiatric disorders.

BACKGROUND: Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. METHODS: We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. RESULTS: We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. CONCLUSIONS: We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling.

Psychological pain: a review of evidence.

This paper defines a symptom construct termed psychological pain and reviews clinical and neuroimaging evidence relevant to it. The psychological pain associated with severe depression is often perceived as worse than any physical pain that the individual has experienced and could be a critical component of suicidality that could be systematically assessed in potentially suicidal patients. Converging evidence from brain imaging studies suggests overlapping patterns of brain activation induced by both psychological pain and by physical pain. Future research on the role of psychological pain and its interaction with nociceptive pathways may provide novel clues to the understanding and treatment of depression and other psychiatric illnesses.

Microarray technology: a review of new strategies to discover candidate vulnerability genes in psychiatric disorders.

OBJECTIVE: An international effort is in progress to discover candidate genes and pathways associated with psychiatric disorders, including two of the most serious diseases, schizophrenia and mood disorders, through the use of new technology-microarrays. Instead of studying one gene at a time, microarrays provide the opportunity to analyze thousands of genes at once. METHOD: This article reviews the steps in this discovery process, including the acquisition and characterization of high-quality postmortem brain tissue, RNA extraction, and preparation and use of microarray technology. Two alternative microarray methods and factors affecting the quality of array data are reviewed. RESULTS: New analytical strategies are being developed to process the massive data sets generated by microarray studies and to define the significance of implicated genes. Array results must be validated by other methods, including in situ hybridization and real-time polymerase chain reaction. Identified genes can also be evaluated in terms of their chromosomal locations and possible overlap with regions of suggestive linkage or association identified with genome-wide linkage analysis in psychiatry and in terms of overlap with genes identified by microarray studies in animals administered psychoactive drugs. Microarray studies are only the first major step in the process. Further efforts in the investigation involve multiple strategies for studying function and gene structure, including transgenic and knockout animal studies. CONCLUSIONS: Microarrays present a methodology that can identify genes or pathways for new and unique potential drug targets, determine premorbid diagnosis, predict drug responsiveness for individual patients, and, eventually, initiate gene therapy and prevention strategies.

Mechanisms of rapid antidepressant effects of sleep deprivation therapy: clock genes and circadian rhythms.

A significant subset of both major depressive disorder and bipolar disorder patients rapidly (within 24 hours) and robustly improves with the chronotherapeutic intervention of sleep deprivation therapy (SDT). Major mood disorder patients are reported to have abnormal circadian rhythms including temperature, hormonal secretion, mood, and particularly sleep. These rhythms are modulated by the clock gene machinery and its products. It is hypothesized that SDT resets abnormal clock gene machinery, that relapse of depressive symptoms during recovery night sleep reactivates abnormal clock gene machinery, and that supplemental chronotherapies and medications can block relapse and help stabilize circadian-related improvement. The central circadian clock genes, BMAL1/CLOCK (NPAS2), bind to Enhancer Boxes to initiate the transcription of circadian genes, including the period genes (per1, per2, per3). It is suggested that a defect in BMAL1/CLOCK (NPAS2) or in the Enhancer Box binding contributes to altered circadian function associated, in part, with the period genes. The fact that chronotherapies, including SDT and sleep phase advance, are dramatically effective suggests that altered clock gene machinery may represent a core pathophysiological defect in a subset of mood disorder patients.

Assessment of psychological pain in major depressive episodes.

Severe psychological or mental pain is defined as an experience of unbearable torment which can be associated with a psychiatric illness (e.g., major depressive disorder) or a tragic loss such as the death of a child. A brief self-rating scale (Mee-Bunney Psychological Pain Assessment Scale [MBPPAS]) was developed to assess the intensity of psychological pain. The scale was used to measure psychological pain in 73 major depressive episode (MDE) patients and 96 non-psychiatric controls. In addition to the MBPPAS, all subjects completed four additional instruments: Suicidal Behavior Questionnaire (SBQ), Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), and the Brief Pain Inventory (BPI). Known-groups, content and convergent validity, and internal reliability of the scale were established. MDE and control subjects were ranked according to MBPPAS scores. A threshold was set at 32 representing 0.5 SD above the mean for MDEs. MDE subjects above the threshold of 32 had significantly higher SBQ scores than those below. A significant linear correlation between psychological pain and SBQ suicidality scores was observed. This is the first study to contrast psychological pain in controls and patients with MDE. Our results suggest that psychological pain is a useful and unique construct in patients with MDE that can be reliably assessed and may aid in the evaluation of suicidal risk.