Blynn G. Bunney

Molecular Clock Genes in Man and Lower Animals: Possible Implications for Circadian Abnormalities in Depression

This paper reviews the recent discovery of clock genes that provide the mechanism for the regulation of circadian and seasonal rhythms in lower organisms and in humans and relates these clock genes to the circadian abnormalities in depression. (1) A subgroup of depressed patients have documented circadian abnormalities in mood, sleep, temperature and neuroendocrine secretion; (2) It is also suggested that seasonal affective disorder (SAD) patients may show an abnormality in their ability to shift their daily circadian rhythms in response to seasonal light changes; (3) The dramatic improvements in some depressions in response to three treatment modalities which manipulate circadian rhythms suggest that circadian abnormalities reported in patients may constitute a core component of the pathophysiology in depression; (4) Mutations in clock genes have been discovered that accelerate or delay circadian cycles; (5) It is hypothesized that 24-hour rhythm abnormalities in major depression and SAD may be due to altered clock genes.

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.

Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia.

Evidence is reviewed that one of the cognitive-affective parallel circuits in the brain, the dorsolateral prefrontal circuit, is compromised at the level of anatomical, neuropathological and transmitter-related molecules in a subgroup of schizophrenic patients. The dorsolateral prefrontal cortex (DLPFC) comprises a key structure in this circuit. Data supporting a compromised DLPFC includes cognitive deficits, decreased regional metabolism and blood flow activation; disruption of cortical subplate activity (inferred from maldistribution of neurons from the cortical subplate which are required for the orderly neuronal migration during the second trimester and for connectivity of the thalamocortical neurons); decrease in major components of the cortical inhibitory neurotransmitter system; and alterations in the molecules critical for NMDA-receptor mediated neural transmission. Thus a great deal of evidence accumulated over the last decade has definitively implicated the dorsolateral prefrontal cortex in the pathophysiology of schizophrenia. Emerging data also confirms neuropathology in the mediodorsal nucleus of the thalamus that projects to the DLPFC. There is currently a consensus that schizophrenia involves epigenetic factors interacting with genetic information in the cells to produce abnormal molecules which when they are associated with abnormal circuits such as the DLPFC, may result in abnormal behavior. Thus, abnormal cortical connections and or altered neurotransmitter related molecules in the DLPFC could explain some of the prominent frontal cognitive disruptions seen in schizophrenia.

Rapid and Sustained Antidepressant Response with Sleep Deprivation and Chronotherapy in Bipolar Disorder

BACKGROUND The development of a rapid-acting and sustainable treatment for bipolar disorder (BPD) depression has been a goal for decades. The most widely documented rapid-onset antidepressant therapy is sleep deprivation (SD), which acts within 24-48 hours in 40%-60% of depressed patients. Conventional antidepressants usually require 2-8 weeks to meet response criteria. The delay, which may prolong suffering and increase suicidal risk, underlines the urgency of alternative treatment strategies. This study evaluates the combined efficacy of three established circadian-related treatments (SD, bright light [BL]), sleep phase advance [SPA]) as adjunctive treatment to lithium and antidepressants. METHODS Forty-nine BPD patients were randomly assigned to a chronotherapeutic augmentation (CAT; SD+ BL+ SPA) or to a medication-only (MED) group. Clinical outcome was assessed using the Hamilton Rating Scale for Depression. RESULTS Significant decreases in depression in the CAT versus MED patients were seen within 48 hours of SD and were sustained over a 7-week period. CONCLUSIONS This is the first study to demonstrate the benefit of adding three noninvasive circadian-related interventions to SD in medicated patients to accelerate and sustain antidepressant responses and provides a strategy for the safe, fast-acting, and sustainable treatment of BPD.

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.

Decreasing striatal 6-FDOPA uptake with increasing duration of cocaine withdrawal

It has been hypothesized that a decrease in dopaminergic presynaptic activity during abstinence or withdrawal is related to relapse in cocaine-dependent subjects (Dackis and Gold 1985; Markou and Koob 1991). This study measured striatal 6-fluorodopa (6-FDOPA) uptake, an index of dopaminergic presynaptic activity, using positron emission tomography (PET) in 11 drug-free cocaine addicts compared to eight normal subjects. Middle abstinence cocaine addicts (n = 5, off cocaine 11–30 days) had significantly lower striatal 6-FDOPA uptake compared to normal controls or early abstinence cocaine addicts (n = 6, off cocaine 1–10 days). The cocaine-dependent subjects (n = 11) showed a significant negative correlation between days off cocaine and striatal 6-FDOPA uptake. The results suggest that during abstinence from cocaine there is a delayed decrease in dopamine terminal activity in the striatum.

Shifting attention in visual space: Tests of moving-spotlight models versus an activity-distribution model.

Participants were induced to concentrate preparatory attention at a central location, to identify a letter there, to identify a 2nd letter to the extreme left or right of a central horizontal range of 5 locations, and then to identify a 3rd letter at 1 of the central 5 locations. Analog and discrete versions of the moving-spotlight model predict that response times to the 3rd letter will be most rapid at the location of the 2nd letter, whereas an activity-distribution model predicts that the most rapid responses to the 3rd letter will be at the central location, where preparatory attention is strongest. The data from 3 experiments, taken together, are inconsistent with the moving-spotlight models and are consistent with the activity-distribution model.

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.

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

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.

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.