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    Circadian skin temperature rhythms, circadian activity rhythms and sleep in individuals with self-reported depressive symptoms. Lorenz Noah,Spada Janek,Sander Christian,Riedel-Heller Steffie G,Hegerl Ulrich Journal of psychiatric research BACKGROUND:Disturbed circadian rhythms have been associated with depression. New body-worn devices allow the objective recording of circadian parameters such as physical activity, skin temperature and sleep. The objective of this study was to investigate whether circadian skin temperature and circadian activity rhythms are altered in depressed individuals. METHODS:Data on skin temperature, physical activity and sleep were available for 1610 subjects from a population-based cohort study. In a matching process two groups were formed for analysis: 121 participants with pronounced depression symptoms (CES-D Score > 21) and n = 121 matched non-depressed controls (CES-D Score < 15). Circadian rhythms were investigated by analyzing non-parametric rhythm indicators of 24-h skin temperature and physical activity data. Sleep timing, continuity and quantity were calculated from actigraphy. RESULTS:No differences between the groups were found when all participants were considered. After excluding antidepressant medicated participants, the depression group was found to have a lower skin temperature amplitude t(208) = 2.45, p = .015 and a less stable skin temperature rhythm t(208) = 2.40, p = .017. The amplitude predicted the group status (beta = -5.529, p = .016). No effects were found for activity or sleep. CONCLUSION:The results indicate that skin-temperature rhythms are blunted in unmedicated depressed individuals. This could be a promising non-invasive marker for further analysis. 10.1016/j.jpsychires.2019.06.022
    Regulation of Circadian Genes by the MAPK Pathway: Implications for Rapid Antidepressant Action. Wang Xin-Ling,Yuan Kai,Zhang Wen,Li Su-Xia,Gao George Fu,Lu Lin Neuroscience bulletin Accumulating evidence suggests that the circadian rhythm plays a critical role in mood regulation, and circadian disturbances are often found in patients with major depressive disorder (MDD). The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is involved in mediating entrainment of the circadian system. Furthermore, the MAPK/ERK signaling pathway has been shown to be involved in the pathogenesis of MDD and the rapid onset of action of antidepressant therapies, both pharmaceutical and non-pharmaceutical. This review provides an overview of the involvement of the MAPK/ERK pathway in modulating the circadian system in the rapid action of antidepressant therapies. This pathway holds much promise for the development of novel, rapid-onset-of-action therapeutics for MDD. 10.1007/s12264-019-00358-9
    Circadian rhythm of plasma melatonin in endogenous depression. Nair N P,Hariharasubramanian N,Pilapil C Progress in neuro-psychopharmacology & biological psychiatry The circadian rhythm of plasma melatonin was investigated in normal men 18-30 years (N = 5), normal men 50-70 years (N = 5) and in six patients with endogenous depression. The environmental photoperiod was 11 hours. The subjects and patients were indoors with lights on from 07:00 until 23:00 hours. Blood samples were obtained every 4 hours over a 24 hour period, with additional sampling at 22:00 and 02:00 hours. Plasma melatonin was estimated by radioimmunoassay compared to both groups of controls. In the depressed patients, the levels of melatonin were low throughout the 24 hour period. The depressives had a delayed onset of the dark phase of the rhythm. The patients also showed peak melatonin levels occurring earlier than in the controls. Circadian rhythm of melatonin and therefore of its pacemaker may be altered in endogenous depression.
    Reduced neuroinflammation and enhanced neurogenesis following chronic agomelatine treatment in rats undergoing chronic constant light. Atanasova Dimitrinka,Lazarov Nikolai,Stoyanov Dimo S,Spassov Radoslav H,Tonchev Anton B,Tchekalarova Jana Neuropharmacology Experimental studies have revealed the involvement of neuroinflammation mediated by activated microglia in the pathophysiology of depression, suggesting a novel target for treatment. The atypical antidepressant Agomelatine (Ago) has an advantage compared to the classical antidepressants due to its chronobiotic activity and unique pharmacological profile as a selective agonist at the melatonin receptors and an antagonist at the 5HT receptors. We have recently revealed that Ago can exert a potent antidepressant effect in rats exposed to a chronic constant light (CCL). In the present study, we hypothesized that the anti-inflammatory activity of this melatonin analog on activated neuroglia in specific brain structures might contribute to its antidepressant effect in this model. Chronic Ago treatment (40 mg/kg, i.p. for 21 days) was executed during the last 3 weeks of a 6-week period of CCL exposure in rats. The CCL-vehicle-treated rats showed a profound neuroinflammation characterized by microgliosis and astrogliosis in the hippocampus, basolateral amygdala (BL) and partly in the piriform cortex (Pir) confirmed by immunohistochemistry. With the exception of the Pir, the CCL regime was accompanied by neuronal damage, identified by Nissl staining, in the hippocampus and basolateral amygdala and impaired neurogenesis with reduced dendritic complexity of hippocampal neuroprogenitor cells detected by doublecortin-positive cells in the dentate gyrus (DG) subgranular zone compared to the control group. Ago reversed the gliosis in a region-specific manner and partially restored the suppressed DG neurogenesis. Ago failed to produce neuroprotection in CCL exposed rats. The present results suggest that the beneficial effects of Ago represent an important mechanism underlying its antidepressant effect in models characterized by impaired circadian rhythms. 10.1016/j.neuropharm.2021.108706
    Neuroendocrine profiles in mood disorders. Linkowski Paul The international journal of neuropsychopharmacology The study of neuroendocrine abnormalities in major mental illness, such as the unipolar and bipolar affective syndromes, has been the focus of interest in the past few years. The neuroendocrine window into the brain has been considered as a fruitful and promising approach to the study of mental disorders, as suggested by studies of some neuroendocrine challenge tests in depression that demonstrated their potential use as biological markers. The modern approach to hormonal dynamics focuses on the circadian and pulsatile profiles that truly represent physiological modulation and tests the hypothesis that an abnormality in circadian rhythms is present in affective illness. From the fundamental point of view, such studies performed using a frequent sampling interval over the 24-h cycle aim to clarify the control and significance of the temporal sleep and wake fluctuations of neuroendocrine system activities. Twenty-four-hour hypersecretion of cortisol, diurnal hypersecretion of growth hormone, and normal 24-h levels of prolactin have been reported in careful chronobiological studies of depressed patients, along with sleep recordings. In addition, a nocturnal quiescent period, and a subsequent increase towards the morning maximum, have been consistently found in a subset of depressed patients suffering from endogenous depression. After successful treatment with antidepressants, most of these abnormalities (with the exception of those found in the prolactin study) tend to correct. The normalization of the timing of hormonal secretion was accompanied by a correction of sleep abnormalities and in particular, a lengthening of the REM latencies. Normalization of cortisol secretion was associated with a decrease in the magnitude of episodic cortisol pulses whereas normalization of growth hormone secretion was due to a diminished number of secretory pulses. In conclusion, a disorder of circadian time-keeping seems to characterize acute episodes of major endogenous depression in some patients. This abnormality as well as the associated increases in adrenocorticotropic and somatotropic activities seem to be a state-, rather than trait-dependent phenomenon. 10.1017/S1461145703003407
    Molecular Regulation of the Melatonin Biosynthesis Pathway in Unipolar and Bipolar Depression. Dmitrzak-Weglarz Monika,Banach Ewa,Bilska Karolina,Narozna Beata,Szczepankiewicz Aleksandra,Reszka Edyta,Jablonska Ewa,Kapelski Paweł,Skibinska Maria,Pawlak Joanna Frontiers in pharmacology Melatonin is a neurohormone that maintains the circadian rhythms of the body. By regulating the secretion of other hormones and neurotransmitters, it acts as a pleiotropic modulator that affects, for example, reproductive, immune, cardiovascular, sleep, and wake systems and mood. Thus, synthetic melatonin has become an essential component in the treatment of depressive disorders. Although we know the pathway of melatonin action in the brain, we lack comprehensive cross-sectional studies on the periphery of depressed patients. This study aimed to comprehensively analyze the differences between healthy control subjects ( = 84) and unipolar and bipolar depression patients ( = 94), including an analysis of the melatonin pathway at the level of the genes and serum biomarkers. An innovative approach is a pilot study based on gene expression profiling carried out on clinical and cell culture models using agomelatine and melatonin. We confirmed the melatonin biosynthesis pathway's molecular regulation dysfunctions, with a specific pattern for unipolar and bipolar depression, at the AANAT gene, its polymorphisms (rs8150 and rs3760138), and examined the serum biomarkers (serotonin, AANAT, ASMT, and melatonin). The biological pathway analysis uncovered pathways and genes that were uniquely altered after agomelatine treatment in a clinical model and melatonin treatment in a cell culture model. In both models, we confirmed the immunomodulatory effect of melatonin agents in depression. 10.3389/fphar.2021.666541
    We are in the dark here: induction of depression- and anxiety-like behaviours in the diurnal fat sand rat, by short daylight or melatonin injections. Ashkenazy Tal,Einat Haim,Kronfeld-Schor Noga The international journal of neuropsychopharmacology Circadian rhythms are considered an important factor in the aetiology, expression and treatment of major affective disorders, including seasonal affective disorder (SAD). However, data on the effects of daylight length manipulation or melatonin administration are complex. It has been suggested that since diurnal and nocturnal mammals differ significantly in their physiological and behavioural responses to daylight, diurnal rodents offer a preferable model of disorders related to circadian rhythms in the diurnal human. We previously found that diurnal fat sand rats maintained under short daylight (SD), show depression-like behaviour in the forced swim test (FST). The present study was designed to test additional behaviours related to affective disorders and study the involvement of melatonin in these behaviours. Sand rats were divided into short-daylight (SD, 5 h light:19 h dark) and long-daylight (LD, 12 h light:12 h dark) groups, and received 100 microg melatonin or vehicle administration for 3 wk (5 h and 8.5 h after light onset in the LD room). Animals were then tested for reward-seeking behaviour (saccharin consumption), anxiety (elevated plus-maze), aggression (resident-intruder test), and depression-like behaviour (FST). SD or melatonin administration resulted in a depressed/anxious-like behavioural phenotype including reduced reward seeking, increased anxiety, decreased aggression and decreased activity in the FST, supporting the notion that in a diurnal animal, reduced light results in a variety of behavioural changes that may model depression and anxiety; and that melatonin may be a significant factor in these changes. We suggest that the sand rat may offer an excellent model species to explore the interactions between daylight, affective behaviour and the related underlying mechanisms. 10.1017/S1461145708009115
    Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. Boivin D B Journal of psychiatry & neuroscience : JPN Recent evidence shows that the temporal alignment between the sleep-wake cycle and the circadian pacemaker affects self-assessment of mood in healthy subjects. Despite the differences in affective state between healthy subjects and patients with psychiatric disorders, these results have implications for analyzing diurnal variation of mood in unipolar and bipolar affective disorders and sleep disturbances in other major psychiatric conditions such as chronic schizophrenia. In a good proportion of patients with depression, mood often improves over the course of the day; an extension of waking often has an antidepressant effect. Sleep deprivation has been described as a treatment for depression for more than 30 years, and approximately 50% to 60% of patients with depression respond to this approach, especially those patients who report that their mood improves over the course of the day. The mechanisms by which sleep deprivation exerts its antidepressant effects are still controversial, but a reduction in rapid eye movement sleep (REM sleep), sleep pressure and slow-wave sleep (SWS), or a circadian phase disturbance, have been proposed. Although several studies support each of these hypotheses, none is sufficient to explain all observations reported to date. Unfortunately, the disturbed sleep-wake cycle or behavioural activities of depressed patients often explain several of the abnormalities reported in the diurnal rhythms of these patients. Thus, protocols that specifically manipulate the sleep-wake cycle to unmask the expression of the endogenous circadian pacemaker are greatly needed. In chronic schizophrenia, significant disturbances in sleep continuity, REM sleep, and SWS have been consistently reported. These disturbances are different from those observed in depression, especially with regard to REM sleep. Circadian phase abnormalities in schizophrenic patients have also been reported. Future research is expected to clarify the nature of these abnormalities.
    Lithium and circadian patterns of melatonin in the retina, hypothalamus, pineal and serum. Seggie J,Werstiuk E S,Grota L Progress in neuro-psychopharmacology & biological psychiatry Lithium, a widely used substance for treatment of manic-depressive illness has been reported to alter the phase relationship of a variety of circadian rhythms which have been implicated in the aetiology of depression and manic-depressive disorder. Although its mechanism of action is not understood, the theraputic action of lithium has been related to its ability to alter circadian rhythms. Chronic lithium administration to rats resulted in lithium levels comparable to the human theraputic range. These lithium levels affected a broad range of biological variables by significantly modifying their circadian pattern of variation, notably during the dark period of an alternating 12h light/12h dark schedule. These included water intake, body weight, retina weight and pineal, serum, retina and hypothalamic melatonin measures. Retinal lithium levels were significantly higher than serum lithium levels and retinal melatonin levels were reduced by lithium. The data are interpreted as suggesting that lithium may exert its theraputic effects by influencing melatonin levels at several locations along the retinal-hypothalamic-pineal pathway, resulting in a modulation of the potential cue value of this physiological stimulus for synchronization of circadian rhythms. Such an effect of lithium could have important chronobiological implications for circadian rhythms which use light and dark as a phase cue.
    Chronobiological theories of mood disorder. Zaki Nevin F W,Spence David Warren,BaHammam Ahmed S,Pandi-Perumal Seithikurippu R,Cardinali Daniel P,Brown Gregory M European archives of psychiatry and clinical neuroscience Major depressive disorder (MDD) remains the most prevalent mental disorder and a leading cause of disability, affecting approximately 100 million adults worldwide. The disorder is characterized by a constellation of symptoms affecting mood, anxiety, neurochemical balance, sleep patterns, and circadian and/or seasonal rhythm entrainment. However, the mechanisms underlying the association between chronobiological parameters and depression remain unknown. A PubMed search was conducted to review articles from 1979 to the present, using the following search terms: "chronobiology," "mood," "sleep," and "circadian rhythms." We aimed to synthesize the literature investigating chronobiological theories of mood disorders. Current treatments primarily include tricyclic antidepressants and selective serotonin reuptake inhibitors, which are known to increase extracellular concentrations of monoamine neurotransmitters. However, these antidepressants do not treat the sleep disturbances or circadian and/or seasonal rhythm dysfunctions associated with depressive disorders. Several theories associating sleep and circadian rhythm disturbances with depression have been proposed. Current evidence supports the existence of associations between these, but the direction of causality remains elusive. Given the existence of chronobiological disturbances in depression and evidence regarding their treatment in improving depression, a chronobiological approach, including timely use of light and melatonin agonists, could complement the treatment of MDD. 10.1007/s00406-017-0835-5
    Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats. Mairesse Jerome,Silletti Viviana,Laloux Charlotte,Zuena Anna Rita,Giovine Angela,Consolazione Michol,van Camp Gilles,Malagodi Marithe,Gaetani Silvana,Cianci Silvia,Catalani Assia,Mennuni Gioacchino,Mazzetta Alessandro,van Reeth Olivier,Gabriel Cecilia,Mocaër Elisabeth,Nicoletti Ferdinando,Morley-Fletcher Sara,Maccari Stefania The international journal of neuropsychopharmacology Agomelatine is a novel antidepressant acting as an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist. Because of its peculiar pharmacological profile, this drug caters the potential to correct the abnormalities of circadian rhythms associated with mood disorders, including abnormalities of the sleep/wake cycle. Here, we examined the effect of chronic agomelatine treatment on sleep architecture and circadian rhythms of motor activity using the rat model of prenatal restraint stress (PRS) as a putative 'aetiological' model of depression. PRS was delivered to the mothers during the last 10 d of pregnancy. The adult progeny ('PRS rats') showed a reduced duration of slow wave sleep, an increased duration of rapid eye movement (REM) sleep, an increased number of REM sleep events and an increase in motor activity before the beginning of the dark phase of the light/dark cycle. In addition, adult PRS rats showed an increased expression of the transcript of the primary response gene, c-Fos, in the hippocampus just prior to the beginning of the dark phase. All these changes were reversed by a chronic oral treatment with agomelatine (2000 ppm in the diet). The effect of agomelatine on sleep was largely attenuated by treatment with the MT1/MT2 melatonin receptor antagonist, S22153, which caused PRS-like sleep disturbances on its own. These data provide the first evidence that agomelatine corrects sleep architecture and restores circadian homeostasis in a preclinical model of depression and supports the value of agomelatine as a novel antidepressant that resynchronizes circadian rhythms under pathological conditions. 10.1017/S1461145711001970
    The circadian basis of mood disorders: recent developments and treatment implications. Monteleone Palmiero,Maj Mario European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology In humans, most physiological and behavioural functions demonstrate a circadian rhythmicity, which is essential to adequately cope with dramatic fluctuations occurring in the external environment. Therefore, it is intuitive that alterations in the endogenous machinery regulating circadian oscillations may lead to physical and mental symptoms and morbidities. Mood disorders, especially unipolar depression and seasonal affective disorder, have been linked to circadian rhythm abnormalities. This paper provides a brief description of the molecular and genetic mechanisms regulating the endogenous clock system and reviews selected studies describing circadian abnormalities in patients with depression. Evidence is emerging that a disruption of the normal circadian rhythmicity occurs at least in a subgroup of depressed patients and that interventions able to resynchronize the human circadian system, including sleep deprivation, light therapy and drugs specifically acting on the endogenous clock system, have proven antidepressant effects. It seems likely that, in the future, the knowledge coming from the exploration of molecular and genetic mechanisms involved in the physiology of the circadian clock system will be fruitful for a deeper understanding of the etiopathogenesis of mood disorders and the development of more effective therapeutic strategies. 10.1016/j.euroneuro.2008.06.007
    Circadian abnormalities, molecular clock genes and chronobiological treatments in depression. Bunney Jennifer N,Potkin Steven G British medical bulletin BACKGROUND:A long-standing challenge in the treatment of depression is the development of a rapidly acting antidepressant. Conventional antidepressants typically require 2-8 weeks for clinical remission. In contrast, chronobiological interventions such as sleep deprivation treatment dramatically reduce depressive symptoms within 24-48 h in 40-60% of depressed subjects. It is hypothesized that fast-acting treatments for depression may alter circadian rhythms through chronobiological mechanisms relevant to clock gene function. SOURCES OF DATA:A bibliographic review using Entrez PubMed with Boolean search terms 'circadian' and 'depressive' identified more than 1000 clinical papers published over a 40-year period (1966-present). AREAS OF AGREEMENT:A large body of clinical data reports that sleep, temperature, hormone and mood changes in depression are consistent with disturbances in circadian-related processes. AREAS OF CONTROVERSY:Consensus has not been achieved in terms of defining underlying chronobiological mechanisms for optimal methods to produce rapid and sustained antidepressant responses to circadian interventions. GROWING POINTS:Chronobiological augmentation using combinations of sleep deprivation with light therapy and/or sleep phase advance in medicated patients supports a clinical strategy for accelerating and sustaining antidepressant responses. AREAS TIMELY FOR DEVELOPING RESEARCH:Advances in technology including improved assays for clock gene expression will facilitate exploring the role of clock genes and may lead to new rapidly acting antidepressant strategies and potential novel drug targets. 10.1093/bmb/ldn019
    Circadian rhythms and treatment implications in depression. Monteleone Palmiero,Martiadis Vassilis,Maj Mario Progress in neuro-psychopharmacology & biological psychiatry In humans almost all physiological and behavioural functions occur on a rhythmic basis. Therefore the possibility that delays, advances or desynchronizations of circadian rhythms may play a role in the pathophysiology of psychiatric disorders is an interesting field of research. In particular mood disorders such as seasonal affective disorder and major depression have been linked to circadian rhythms alterations. Furthermore, the antidepressant efficacy of both pharmacological and non-pharmacological strategies affecting endogenous circadian rhythms, such as new antidepressant medications, light-therapy and sleep deprivation, is consistent with the idea that circadian alterations may represent a core component of depression, at least in a subgroup of depressed patients. This paper briefly describes the molecular and genetic mechanisms regulating the endogenous clock system, and reviews the literature supporting the relationships between depression, antidepressant treatments and changes in circadian rhythms. 10.1016/j.pnpbp.2010.07.028
    Circadian rhythms and sleep in bipolar disorder. Bipolar disorders OBJECTIVE:Biological rhythm pathways are highlighted in a number of etiological models of bipolar disorder, and the management of circadian instability appears in consensus treatment guidelines. There are, however, significant conceptual and empirical limitations on our understanding of a hypothesised link between circadian, sleep, and emotion regulation processes in bipolar disorder. The aim of this article is to articulate the limits of scientific knowledge in relation to this hypothesis. METHODS:A critical evaluation of various literatures was undertaken. The basic science of circadian and sleep processes, their involvement in normal emotion regulation, and the types of evidence suggesting circadian/sleep involvement in bipolar disorder are reviewed. RESULTS:Multiple lines of evidence suggest that circadian and sleep-wake processes are causally involved in bipolar disorder. These processes demonstrably interact with other neurobiological pathways known to be important in bipolar disorder, but are unique in that they are open to behavioural manipulation. CONCLUSION:Further research into biological rhythm pathways to bipolar disorder is warranted. Person-environment feedback loops are fundamental to circadian adaptation, and models of circadian pathogenesis (and treatment) should recognize this complexity. 10.1111/j.1399-5618.2010.00843.x
    The prospective impact of sleep duration on depression and mania. Perlman Carol A,Johnson Sheri L,Mellman Thomas A Bipolar disorders OBJECTIVE:Many patients report sleeping less than 6 h per night during episodes of depression and mania. This type of sleep deficit may also be a risk factor for subsequent mood episodes; however, the long-term impact of sleep deficit remains unclear. The current study is among few longitudinal studies to assess the prospective effect of sleep deficit on depression and mania. METHODS:A subsample of 54 individuals from a longitudinal study of bipolar I disorder was selected. Participants entered the study during a mood episode. Baseline symptom data were collected at month 4 to allow for recovery from the initial episode, sleep was assessed at month 6, and follow-up symptom data were obtained during months 7-12. RESULTS:Sleep deficit predicted depressive symptoms across the 6-month follow-up but not mania. CONCLUSIONS:It is likely that the impact of sleep deficit on mania was probably missed because assessments covered a full month. Monitoring sleep duration may help predict depression in bipolar disorder and provide an opportunity for targeting intervention. 10.1111/j.1399-5618.2006.00330.x
    Depression in sleep disturbance: A review on a bidirectional relationship, mechanisms and treatment. Fang Hong,Tu Sheng,Sheng Jifang,Shao Anwen Journal of cellular and molecular medicine Sleep disturbance is the most prominent symptom in depressive patients and was formerly regarded as a main secondary manifestation of depression. However, many longitudinal studies have identified insomnia as an independent risk factor for the development of emerging or recurrent depression among young, middle-aged and older adults. This bidirectional association between sleep disturbance and depression has created a new perspective that sleep problems are no longer an epiphenomenon of depression but a predictive prodromal symptom. In this review, we highlight the treatment of sleep disturbance before, during and after depression, which probably plays an important role in improving outcomes and preventing the recurrence of depression. In clinical practice, pharmacological therapies, including hypnotics and antidepressants, and non-pharmacological therapies are typically applied. A better understanding of the pathophysiological mechanisms between sleep disturbance and depression can help psychiatrists better manage this comorbidity. 10.1111/jcmm.14170
    Psoriatic arthritis: exploring the occurrence of sleep disturbances, fatigue, and depression and their correlates. Haugeberg Glenn,Hoff Mari,Kavanaugh Arthur,Michelsen Brigitte Arthritis research & therapy INTRODUCTION:Sleep disturbances, fatigue, and anxiety/depression in psoriatic arthritis (PsA) may be influenced by skin and musculoskeletal manifestations. All of these in turn affect the psychosocial impact of disease. The objective was to explore the occurrence of sleep disturbances, fatigue, and anxiety/depression in psoriatic arthritis (PsA) patients, and their correlates. METHODS:A broad data collection was performed in 137 Norwegian PsA outpatient clinic patients including demographics, disease activity measures for both skin and musculoskeletal involvement, and patient-reported outcome measures. Sleep disturbances and fatigue were defined present if the numeric rating scale (0-10) score was ≥ 5. Anxiety/depression was assessed using a questionnaire (1-3; 1 defined as no anxiety/depression). Descriptive statistics was applied, and associations were explored using univariate and adjusted linear regression analysis. RESULTS:The mean age was 52.3 years, PsA disease duration 8.8 years; 49.6% were men and 54.8% were currently employed/working. The prevalence of sleep disturbances was 38.0%, fatigue 44.5%, and anxiety/depression 38.0%. In adjusted analysis, pain, fatigue, and higher mHAQ were associated with sleep disturbances. Sleep disturbances, pain, and anxiety/depression were associated with fatigue, whereas only fatigue was associated with anxiety/depression. CONCLUSIONS:The prevalence of sleep disturbances, fatigue, and anxiety/depression was frequently reported by PsA patients. No measures reflecting skin involvement or objective measures of musculoskeletal involvement were independently associated with sleep disturbances, fatigue, or anxiety/depression. Our data suggest that patients' perceptions of musculoskeletal involvement (pain or mHAQ) play an important role causing sleep disturbances and fatigue, whereas fatigue in PsA patients is strongly associated with anxiety/depression. 10.1186/s13075-020-02294-w
    Sleep disorders as core symptoms of depression. Nutt David,Wilson Sue,Paterson Louise Dialogues in clinical neuroscience Links between sleep and depression are strong. About three quarters of depressed patients have insomnia symptoms, and hypersomnia is present in about 40% of young depressed adults and 10% of older patients, with a preponderance in females. The symptoms cause huge distress, have a major impact on quality of life, and are a strong risk factor for suicide. As well as the subjective experience of sleep symptoms, there are well-documented changes in objective sleep architecture in depression. Mechanisms of sleep regulation and how they might be disturbed in depression are discussed. The sleep symptoms are often unresolved by treatment, and confer a greater risk of relapse and recurrence. Epidemiological studies have pointed out that insomnia in nondepressed subjects is a risk factor for later development of depression. There is therefore a need for more successful management of sleep disturbance in depression, in order to improve quality of life in these patients and reduce an important factor in depressive relapse and recurrence.
    Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Franzen Peter L,Buysse Daniel J Dialogues in clinical neuroscience The majority of individuals with depression experience sleep disturbances. Depression is also over-represented among populations with a variety of sleep disorders. Although sleep disturbances are typical features of depression, such symptoms sometimes appear prior to an episode of depression. The bidirectional associations between sleep disturbance (especially insomnia) and depression increase the difficulty of differentiating cause-and-effect relationships between them. Longitudinal studies have consistently identified insomnia as a risk factor for the development of a new-onset or recurrent depression, and this association has been identified in young, middle-aged, and older adults. Studies have also observed that the combination of insomnia and depression influences the trajectory of depression, increasing episode severity and duration as well as relapse rates. Fortunately, recent studies have demonstrated that both pharmacological and nonpharmacological interventions for insomnia may favorably reduce and possibly prevent depression. Together, these findings suggest that sleep-related symptoms that are present before, during, andlor after a depressive episode are potentially modifiable factors that may play an important role in achieving and maintaining depression remission.
    Depression and sleep: pathophysiology and treatment. Thase Michael E Dialogues in clinical neuroscience This review examines the relationship between sleep and depression. Most depressive disorders are characterized by subjective sleep disturbances, and the regulation of sleep is intricately linked to the same mechanisms that are implicated in the pathophysiology of depression. After briefly reviewing the physiology and topography of normal sleep, the disturbances revealed in studies of sleep in depression using polysomnographic recordings and neuroimaging assessments are discussed. Next, treatment implications of the disturbances are reviewed at both clinical and neurobiologic levels. Most antidepressant medications suppress rapid eye movement (REM) sleep, although this effect is neither necessary nor sufficient for clinical efficacy. Effects on patients' difficulties initiating and maintaining sleep are more specific to particular types of antidepressants. Ideally, an effective antidepressant will result in normalization of disturbed sleep in concert with resolution of the depressive syndrome, although few interventions actually restore decreased slow-wave sleep. Antidepressants that block central histamine 1 and serotonin 2 tend to have stronger effects on sleep maintenance, but are also prone to elicit complaints of daytime sedation. Adjunctive treatment with sedative hypnotic medications--primarily potent, shorter-acting benzodiazepine and gamma-aminobutyric acid (GABA A)-selective compounds such as zolpidem--are often used to treat associated insomnia more rapidly. Cognitive behavioral therapy and other nonpharmacologic strategies are also helpful.
    Circadian rhythms and depression: human psychopathology and animal models. Kronfeld-Schor Noga,Einat Haim Neuropharmacology Most organisms (including humans) developed daily rhythms in almost every aspect of their body. It is not surprising that rhythms are also related to affect in health and disease. In the present review we present data that demonstrate the evidence for significant interactions between circadian rhythms and affect from both human studies and animal models research. A number of lines of evidence obtained from human and from animal models research clearly demonstrate relationships between depression and circadian rhythms including (1) daily patterns of depression; (2) seasonal affective disorder; (3) connections between circadian clock genes and depression; (4) relationship between sleep disorders and depression; (5) the antidepressant effect of sleep deprivation; (6) the antidepressant effect of bright light exposure; and (7) the effects of antidepressant drugs on sleep and circadian rhythms. The integration of data suggests that the relationships between the circadian system and depression are well established but the underlying biology of the interactions is far from being understood. We suggest that an important factor hindering research into the underlying mechanisms is the lack of good animal models and we propose that additional efforts in that area should be made. One step in that direction could be the attempt to develop models utilizing diurnal animals which might have a better homology to humans with regard to their circadian rhythms. This article is part of a Special Issue entitled 'Anxiety and Depression'. 10.1016/j.neuropharm.2011.08.020
    Effects of circadian disruption on mental and physical health. Karatsoreos Ilia N Current neurology and neuroscience reports Circadian (daily) rhythms in physiology and behavior are phylogenetically ancient and are present in almost all plants and animals. In mammals, these rhythms are generated by a master circadian clock in the suprachiasmatic nucleus of the hypothalamus, which in turn synchronizes "peripheral oscillators" throughout the brain and body in almost all cell types and organ systems. Although circadian rhythms are phylogenetically ancient, modern industrialized society and the ubiquity of electric lighting has resulted in a fundamental alteration in the relationship between an individual's endogenous circadian rhythmicity and the external environment. The ramifications of this desynchronization for mental and physical health are not fully understood, although numerous lines of evidence are emerging that link defects in circadian timing with negative health outcomes. This article explores the function of the circadian system, the effects of disrupted clocks on the brain and body, and how these effects impact mental and physical health. 10.1007/s11910-012-0252-0
    Circadian rhythm disruption and mental health. Walker William H,Walton James C,DeVries A Courtney,Nelson Randy J Translational psychiatry Circadian rhythms are internal manifestations of the solar day that permit adaptations to predictable environmental temporal changes. These ~24-h rhythms are controlled by molecular clockworks within the brain that are reset daily to precisely 24 h by exposure to the light-dark cycle. Information from the master clock in the mammalian hypothalamus conveys temporal information to the entire body via humoral and neural communication. A bidirectional relationship exists between mood disorders and circadian rhythms. Mood disorders are often associated with disrupted circadian clock-controlled responses, such as sleep and cortisol secretion, whereas disruption of circadian rhythms via jet lag, night-shift work, or exposure to artificial light at night, can precipitate or exacerbate affective symptoms in susceptible individuals. Evidence suggests strong associations between circadian rhythms and mental health, but only recently have studies begun to discover the direct interactions between the circadian system and mood regulation. This review provides an overview of disrupted circadian rhythms and the relationship to behavioral health and psychiatry. The focus of this review is delineating the role of disruption of circadian rhythms on mood disorders using human night shift studies, as well as jet lag studies to identify links. We also review animal models of disrupted circadian rhythms on affective responses. Lastly, we propose low-cost behavioral and lifestyle changes to improve circadian rhythms and presumably behavioral health. 10.1038/s41398-020-0694-0
    Seasonal effects on human striatal presynaptic dopamine synthesis. Eisenberg Daniel P,Kohn Philip D,Baller Erica B,Bronstein Joel A,Masdeu Joseph C,Berman Karen F The Journal of neuroscience : the official journal of the Society for Neuroscience Past studies in rodents have demonstrated circannual variation in central dopaminergic activity as well as a host of compelling interactions between melatonin--a scotoperiod-responsive neurohormone closely tied to seasonal adaptation--and dopamine in the striatum and in midbrain neuronal populations with striatal projections. In humans, seasonal effects have been described for dopaminergic markers in CSF and postmortem brain, and there exists a range of affective, psychotic, and substance abuse disorders that have been associated with both seasonal symptomatic fluctuations and dopamine neurotransmission abnormalities. Together, these data indirectly suggest a potentially crucial link between circannual biorhythms and central dopamine systems. However, seasonal effects on dopamine function in the living, healthy human brain have never been tested. For this study, 86 healthy adults underwent (18)F-DOPA positron emission tomography scanning, each at a different time throughout the year. Striatal regions of interest (ROIs) were evaluated for differences in presynaptic dopamine synthesis, measured by the kinetic rate constant, K(i), between fall-winter and spring-summer scans. Analyses comparing ROI average K(i) values showed significantly greater putamen (18)F-DOPA K(i) in the fall-winter relative to the spring-summer group (p = 0.038). Analyses comparing voxelwise K(i) values confirmed this finding and evidenced intrastriatal localization of seasonal effects to the caudal putamen (p < 0.05, false-discovery rate corrected), a region that receives dopaminergic input predominantly from the substantia nigra. These data are the first to directly demonstrate a seasonal effect on striatal presynaptic dopamine synthesis and merit future research aimed at elucidating underlying mechanisms and implications for neuropsychiatric disease and new treatment approaches. 10.1523/JNEUROSCI.1953-10.2010
    Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder. Etain Bruno,Dumaine Anne,Bellivier Frank,Pagan Cécile,Francelle Laetitia,Goubran-Botros Hany,Moreno Sarah,Deshommes Jasmine,Moustafa Khaled,Le Dudal Katia,Mathieu Flavie,Henry Chantal,Kahn Jean-Pierre,Launay Jean-Marie,Mühleisen Thomas W,Cichon Sven,Bourgeron Thomas,Leboyer Marion,Jamain Stéphane Human molecular genetics Patients affected by bipolar disorder (BD) frequently report abnormalities in sleep/wake cycles. In addition, they showed abnormal oscillating melatonin secretion, a key regulator of circadian rhythms and sleep patterns. The acetylserotonin O-methyltransferase (ASMT) is a key enzyme of the melatonin biosynthesis and has recently been associated with psychiatric disorders such as autism spectrum disorders and depression. In this paper, we analysed rare and common variants of ASMT in patients with BD and unaffected control subjects and performed functional analysis of these variants by assaying the ASMT activity in their B-lymphoblastoid cell lines. We sequenced the coding and the regulatory regions of the gene in a discovery sample of 345 patients with BD and 220 controls. We performed an association study on this discovery sample using common variants located in the promoter region and showed that rs4446909 was significantly associated with BD (P= 0.01) and associated with a lower mRNA level (P< 10(-4)) and a lower enzymatic activity (P< 0.05) of ASMT. A replication study and a meta-analysis using 480 independent patients with BD and 672 controls confirmed the significant association between rs4446909 and BD (P= 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P= 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P= 0.01). In this study, we determined how rare and common variations in ASMT might play a role in BD vulnerability and suggest a general role of melatonin as susceptibility factor for BD. 10.1093/hmg/dds227
    Light therapy for bipolar disorder: a case series in women. Sit Dorothy,Wisner Katherine L,Hanusa Barbara H,Stull Stacy,Terman Michael Bipolar disorders OBJECTIVES:To perform a dose-ranging safety and efficacy study of bright light therapy for depression in women with bipolar disorder (BD). METHODS:Nine women with DSM-IV BD I or II in the depressed phase were exposed to 50 lux (illuminance at the receiving surface) red light for two weeks, after which they received 7,000 lux light therapy for two-week epochs of 15, 30 and 45 min daily. The Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and the Mania Rating Scale were used to assess mood symptoms. Four patients received morning light and five patients received midday light. RESULTS:Three of the four subjects treated with morning light developed mixed states. The fourth subject achieved a full, sustained response. To decrease the risk of inducing mixed episodes, we changed the time of light exposure to midday. Of the five women who received midday light therapy, two achieved full response and two showed early improvement but required a dose increase to sustain response. One woman remained depressed with 45 min of midday light but responded fully to a switch to morning light, 30 min daily. CONCLUSIONS:Women with bipolar illness are highly sensitive to morning bright light treatment; the induction of mixed states is a substantial risk. Initiating treatment with a brief duration (15 min) of midday light for bipolar depression is advisable. 10.1111/j.1399-5618.2007.00451.x
    Daily ratings of mood and sleep duration over 3.3 years are associated with the lunar illumination cycle in a rapid cycling bipolar patient. Burgess Helen J,Han Peisong,Bertram Holli,McInnis Melvin G Bipolar disorders 10.1111/bdi.13080
    Constant darkness induces IL-6-dependent depression-like behavior through the NF-κB signaling pathway. Monje Francisco J,Cabatic Maureen,Divisch Isabella,Kim Eun-Jung,Herkner Kurt R,Binder Bernd R,Pollak Daniela D The Journal of neuroscience : the official journal of the Society for Neuroscience Substantial experimental evidence indicates a major role for the circadian system in mood disorders. Additionally, proinflammatory cytokines have been proposed to be involved in the pathogenesis of depression. However, the molecular elements determining the functional interplay between these two systems in depression have not been described as yet. Here we investigate whether long-term light deprivation in the constant darkness (DD) paradigm affects depression-like behavior in mice and concomitantly modulates the levels of proinflammatory cytokines. We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-κB pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-κB signaling. Moreover, NF-κB activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF-κB, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression. We here first describe some of the molecular elements bridging chronobiological and inflammatory processes in the constant darkness mouse model of depression. 10.1523/JNEUROSCI.1537-11.2011
    Bedroom Light Exposure at Night and the Incidence of Depressive Symptoms: A Longitudinal Study of the HEIJO-KYO Cohort. Obayashi Kenji,Saeki Keigo,Kurumatani Norio American journal of epidemiology Previous studies have indicated that minimal exposure to light at night (LAN) increases depression risk, even at 5 lux, in nocturnal and diurnal mammals. Although such low-level LAN may affect human circadian physiology, the association between exposure to LAN and depressive symptoms remains uncertain. In the present study, bedroom light intensity was measured objectively, and depressive symptoms were assessed, during 2010-2014 in Nara, Japan. Of 863 participants (mean age = 71.5 years) who did not have depressive symptoms at baseline, 73 participants reported development of depressive symptoms during follow-up (median, 24 months). Compared with the "dark" group (average of <5 lux; n = 710), the LAN group (average of ≥5 lux; n = 153) exhibited a significantly higher depression risk (hazard ratio = 1.89; 95% CI: 1.13, 3.14), according to a Cox proportional hazards model adjusting for age, sex, body mass index, and economic status. Further, the significance remained in a multivariable model adjusting for hypertension, diabetes, and sleep parameters (hazard ratio = 1.72; 95% CI: 1.03, 2.89). Sensitivity analyses using bedroom light data with a cutoff value of ≥10 lux suggested consistent results. In conclusion, these results indicated that exposure to LAN in home settings was independently associated with subsequent depression risk in an elderly general population. 10.1093/aje/kwx290
    The phase shift hypothesis for the circadian component of winter depression. Lewy Alfred J,Rough Jennifer N,Songer Jeannine B,Mishra Neelam,Yuhas Krista,Emens Jonathan S Dialogues in clinical neuroscience The finding that bright light can suppress melatonin production led to the study of two situations, indeed, models, of light deprivation: totally blind people and winter depressives. The leading hypothesis for winter depression (seasonal affective disorder, or SAD) is the phase shift hypothesis (PSH). The PSH was recently established in a study in which SAD patients were given low-dose melatonin in the afternoon/evening to cause phase advances, or in the morning to cause phase delays, or placebo. The prototypical phase-delayed patient, as well as the smaller subgroup of phase-advanced patients, optimally responded to melatonin given at the correct time. Symptom severity improved as circadian misalignment was corrected. Circadian misalignment is best measured as the time interval between the dim light melatonin onset (DLMO) and mid-sleep. Using the operational definition of the plasma DLMO as the interpolated time when melatonin levels continuously rise above the threshold of 10 pg/mL, the average interval between DLMO and mid-sleep in healthy controls is 6 hours, which is associated with optimal mood in SAD patients.
    Invited Commentary: "Bedroom Light Exposure at Night and the Incidence of Depressive Symptoms: A Longitudinal Study of the HEIJO-KYO Cohort". American journal of epidemiology In modern society, we are increasingly disconnected from natural light/dark cycles and beset by round-the-clock exposure to artificial light. Light has powerful effects on physical and mental health, in part via the circadian system, and thus the timing of light exposure dictates whether it is helpful or harmful. In their compelling paper, Obayashi et al. (Am J Epidemiol. 2018;187(3):427-434.) offer evidence that light at night can prospectively predict an elevated incidence of depressive symptoms in older adults. Strengths of the study include the longitudinal design and direct, objective assessment of light levels, as well as accounting for multiple plausible confounders during analyses. Follow-up studies should address the study's limitations, including reliance on a global self-report of sleep quality and a 2-night assessment of light exposure that may not reliably represent typical light exposure. In addition, experimental studies including physiological circadian measures will be necessary to determine whether the light effects on depression are mediated through the circadian system or are so-called "direct" effects of light. In any case, these exciting findings could inform novel approaches to preventing depressive disorders in older adults. 10.1093/aje/kwx288
    Biphasic Glucocorticoid Rhythm in One-Month-Old Infants: Reflection of a Developing HPA-Axis? The Journal of clinical endocrinology and metabolism CONTEXT:The hypothalamus-pituitary-adrenal (HPA) axis displays a diurnal rhythm. However, little is known about its development in early life. OBJECTIVE:To describe HPA-axis activity and study possible influencing factors in 1-month-old infants. DESIGN:Observational. SETTING:Amsterdam University Medical Center, location VU University Medical Center (VUMC), and Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam. PARTICIPANTS:Fifty-five mother-infant pairs. INTERVENTIONS:Collection of breast milk and infants' saliva 1 month postpartum for analysis of glucocorticoids (GCs; ie, cortisol and cortisone) using liquid chromatography- tandem mass spectrometry. MAIN OUTCOME MEASURE:GC rhythm in infants' saliva and associations with vulnerability for maternal psychological distress (increased Hospital Anxiety and Depression Scale [HADS] score) or consultation at the Psychiatric Obstetric Pediatric (POP clinic), season at sampling, sex, and breast milk GC rhythmicity analyzed with SigmaPlot 14.0 software (Systat Software, San Jose, CA, USA) and regression analyses. RESULTS:A significant biphasic GC rhythm was detected in infants, with mean peaks [standard error of the mean, SEM] at 6:53 am [1:01] and 18:36 pm [1:49] for cortisol, and at 8:50 am [1:11] and 19:57 pm [1:13] for cortisone. HADS score, POP consultation, season at sampling, and sex were not associated with the infants' GC rhythm. Breast milk cortisol maximum was positively associated with infants' cortisol area-under-the-curve (AUC) increase and maximum. Higher breast milk cortisone AUC increase, AUC ground, and maximum were associated with an earlier maximum in infants. Breast milk and infant GC concentrations were associated between 6:00 am and 9:00 am. CONCLUSIONS:A biphasic GC rhythm, peaking in the morning and evening, was seen in 1-month-old infants at a group level. Breast milk GC parameters might be associated with the infants' GC rhythm, possibly caused by a signaling effect of breast milk GCs, or as an associative effect of increased mother-infant synchrony. These results contribute to an increased understanding of early life HPA-axis development. 10.1210/clinem/dgz089
    Increased melatonin and delayed offset in menopausal depression: role of years past menopause, follicle-stimulating hormone, sleep end time, and body mass index. Parry Barbara L,Meliska Charles J,Sorenson Diane L,López Ana M,Martínez Luis F,Nowakowski Sara,Hauger Richard L,Elliott Jeffrey A The Journal of clinical endocrinology and metabolism CONTEXT:The constellation of endocrine patterns accompanying menopausal depression remains incompletely characterized. OBJECTIVE:Our objective was to test the hypothesis that the amplitude or phase (timing) of melatonin circadian rhythms differs in menopausal depressed patients (DP) vs. normal controls women (NC). DESIGN:We measured plasma melatonin every 30 min from 1800-1000 h in dim light (<30 lux) or dark, serum gonadotropins and steroids (1800 and 0600 h), and mood (Hamilton and Beck depression ratings). SETTING:The study was conducted at a university hospital. PARTICIPANTS AND SETTING:Twenty-nine (18 NC, 11 DP) peri- or postmenopausal women participated. MAIN OUTCOME MEASURES:We measured plasma melatonin (onset, offset, synthesis offset, duration, peak concentration, and area under the curve) and mood. RESULTS:Multi- and univariate analyses of covariance showed that melatonin offset time was delayed (P = 0.045) and plasma melatonin was elevated in DP compared with NC (P = 0.044) across time intervals. Multiple regression analyses showed that years past menopause predicted melatonin duration and that melatonin duration, body mass index, years past menopause, FSH level, and sleep end time were significant predictors of baseline Hamilton (P = 0.0003) and Beck (P = 0.00004) depression scores. CONCLUSIONS:Increased melatonin secretion that is phase delayed into the morning characterized menopausal DP vs. NC. Years past menopause, FSH, sleep end time, and body mass index may modulate effects of altered melatonin secretion in menopausal depression. 10.1210/jc.2006-2853
    Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem? Stevens Richard G,Zhu Yong Philosophical transactions of the Royal Society of London. Series B, Biological sciences Over the past 3 billion years, an endogenous circadian rhythmicity has developed in almost all life forms in which daily oscillations in physiology occur. This allows for anticipation of sunrise and sunset. This physiological rhythmicity is kept at precisely 24 h by the daily cycle of sunlight and dark. However, since the introduction of electric lighting, there has been inadequate light during the day inside buildings for a robust resetting of the human endogenous circadian rhythmicity, and too much light at night for a true dark to be detected; this results in circadian disruption and alters sleep/wake cycle, core body temperature, hormone regulation and release, and patterns of gene expression throughout the body. The question is the extent to which circadian disruption compromises human health, and can account for a portion of the modern pandemics of breast and prostate cancers, obesity, diabetes and depression. As societies modernize (i.e. electrify) these conditions increase in prevalence. There are a number of promising leads on putative mechanisms, and epidemiological findings supporting an aetiologic role for electric lighting in disease causation. These include melatonin suppression, circadian gene expression, and connection of circadian rhythmicity to metabolism in part affected by haem iron intake and distribution. 10.1098/rstb.2014.0120
    Biological rhythms and mood disorders. Salvatore Paola,Indic Premananda,Murray Greg,Baldessarini Ross J Dialogues in clinical neuroscience Integration of several approaches concerning time and temporality can enhance the pathophysiological study of major mood disorders of unknown etiology. We propose that these conditions might be interpreted as disturbances of temporal profile of biological rhythms, as well as alterations of time-consciousness. Useful approaches to study time and temporality include philological suggestions, phenomenological and psychopathological conceptualizatíons, clinical descriptions, and research on circadian and ultradían rhythms, as well as nonlinear dynamics approaches to their analysis.
    Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. Alesci Salvatore,Martinez Pedro E,Kelkar Sujata,Ilias Ioannis,Ronsaville Donna S,Listwak Samuel J,Ayala Alejandro R,Licinio Julio,Gold Herman K,Kling Mitchel A,Chrousos George P,Gold Philip W The Journal of clinical endocrinology and metabolism BACKGROUND:Major depressive disorder (MDD) is associated with increased risk for premature coronary heart disease and bone loss. Single time measurements of plasma IL-6, a good predictor of future risk for both cardiovascular disease and osteoporosis, revealed significant elevations in depressed patients. The objective of this study was to rigorously compare plasma IL-6 levels, measured over 24 h, in MDD patients and healthy controls. Given the activating role of IL-6 on the hypothalamic-pituitary-adrenal (HPA) axis, and the relevance of its dysregulation in MDD, we also analyzed the relations between IL-6 and cortisol levels. METHODS:We studied nine patients and nine controls, individually matched by gender, age (+/-5 yr), body mass index (+/-2 kg/m2), and menstrual cycle phase. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnostic criteria. Self-reported mood ratings were assessed by multiple visual analog scales. The rhythmicity and complexity of IL-6 and cortisol secretion were tested by cosinor analyses, approximate entropy (ApEn) and cross-ApEn algorithms. RESULTS:MDD patients had significant mean IL-6 elevations from 1000-1200 h and at 1500 h (P ranging from <0.05 to <0.01) vs. controls. In addition, in MDD, the circadian rhythm of IL-6 was shifted by 12 h, and its physiological complexity was reduced, with no difference in the cross-ApEn of IL-6 and cortisol between the two groups, and significant time-lagged correlations only in the controls. IL-6 levels correlated significantly with mood ratings. CONCLUSIONS:We report profound morning elevations of plasma IL-6 and a reversal of its circadian rhythm in MDD patients, in the absence of hypercortisolism. These findings may be relevant to the increased risk for coronary heart disease and bone loss in MDD. 10.1210/jc.2004-1667
    Urocortin 2-deficient mice exhibit gender-specific alterations in circadian hypothalamus-pituitary-adrenal axis and depressive-like behavior. Chen Alon,Zorrilla Eric,Smith Sean,Rousso David,Levy Coree,Vaughan Joan,Donaldson Cindy,Roberts Amanda,Lee Kuo-Fen,Vale Wylie The Journal of neuroscience : the official journal of the Society for Neuroscience Gender differences in hypothalamus-pituitary-adrenal (HPA) axis activation and the prevalence of mood disorders are well documented. Urocortin 2, a recently identified member of the corticotropin-releasing factor family, is expressed in discrete neuroendocrine and stress-related nuclei of the rodent CNS. To determine the physiological role of urocortin 2, mice null for urocortin 2 were generated and HPA axis activity, ingestive, and stress-related behaviors and alterations in expression levels of CRF-related ligands and receptors were examined. Here we report that female, but not male, mice lacking urocortin 2 exhibit a significant increase in the basal daily rhythms of ACTH and corticosterone and a significant decrease in fluid intake and depressive-like behavior. The differential phenotype of urocortin 2 deficiency in female and male mice may imply a role for urocortin 2 in these gender differences. 10.1523/JNEUROSCI.3955-05.2006
    The role of circadian clock genes in mental disorders. Lamont Elaine Waddington,Legault-Coutu Daniel,Cermakian Nicolas,Boivin Diane B Dialogues in clinical neuroscience The study of molecular clock mechanisms in psychiatric disorders is gaining significant interest due to data suggesting that a misalignment between the endogenous circadian system and the sleep-wake cycle might contribute to the clinical status of patients suffering from a variety of psychiatric disorders. Sleep disturbances in major depressive disorder (MDD) are characterized by increased sleep latency, poorer sleep efficiency reduced latency to the first rapid eye movement (REM) sleep episode, and early-morning awakening, but there is little data to indicate a role of circadian clock genes in MDD. There is also relatively little information regarding the role of clock genes in anxiety. In contrast, a significant amount of evidence gathered in bipolar disorder (BPD) patients suggests a circadian rhythm disorder, namely an advanced circadian rhythm and state-dependent alterations of REM sleep latency. Most research on the role of clock genes in BPD has focused on polymorphisms of CLOCK, but the lithium target GSK3 may also play a significant role. A circadian phase shift is also theorized to contribute to the pathophysiology of winter seasonal affective disorder (SAD). Certain allelic combinations of NPAS2, PER3, and BMAL1 appear to contribute to the risk of SAD. In chronic schizophrenia, disturbances of sleep including insomnia and reduced sleep efficiency have been observed. Genetic studies have found associations with CLOCK, PER1, PER3, and TIMELESS. Sleep and circadian changes associated with dementia due to Alzheimer's disease suggest a functional change in the circadian master clock, which is supported by postmortem studies of clock gene expression in the brain.
    Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia. Saus Ester,Soria Virginia,Escaramís Geòrgia,Vivarelli Francesca,Crespo José M,Kagerbauer Birgit,Menchón José Manuel,Urretavizcaya Mikel,Gratacòs Mònica,Estivill Xavier Human molecular genetics Previous studies in mice have reported five different microRNAs (miRNAs; miR-219-1/132/183/96/182) to be modulators of the endogenous circadian clock and have presented experimental evidence for some of the genes involved in the molecular clock machinery as target sites. Moreover, disruption of circadian rhythms has long been implicated in the pathophysiology of major depression (MD). We investigated these miRNAs and some of their target sites at the sequence and functional levels as possible predisposing factors for susceptibility to MD and related chronobiological subphenotypes. Mutational screening was performed in a sample of 359 MD patients and 341 control individuals. We found a significant association between the T allele of the rs76481776 polymorphism in the pre-miR-182 and late insomnia in MD patients. Previous studies have reported an association between insomnia and CLOCK gene, a predicted miR-182 target site. A significant overexpression of miR-182 was detected by quantitative real-time polymerase chain reaction in cells transfected with the mutated form of the pre-miR-182 when compared with wild-type form. Moreover, a significant reduction in luciferase activity of plasmids with 3' UTR of ADCY6, CLOCK and DSIP genes was shown when transfecting cells with the mutated form of pre-miR-182 compared with cells that did not express miR-182. These data indicate that abnormal processing of pre-miR-182 in patients carrying the T allele of the rs76481776 polymorphism may contribute to the dysregulation of circadian rhythms in MD patients with insomnia, which could influence expression levels of the mature form of miR-182 and might increase downregulation in some of its target genes. 10.1093/hmg/ddq316
    Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder. Bipolar disorders BACKGROUND:Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS:In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS:Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS:Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY:NCT0127253. 10.1111/bdi.13162
    GIRK Channels Mediate the Nonphotic Effects of Exogenous Melatonin. Hablitz Lauren M,Molzof Hylton E,Abrahamsson Kathryn E,Cooper Joanna M,Prosser Rebecca A,Gamble Karen L The Journal of neuroscience : the official journal of the Society for Neuroscience Melatonin supplementation has been used as a therapeutic agent for several diseases, yet little is known about the underlying mechanisms by which melatonin synchronizes circadian rhythms. G-protein signaling plays a large role in melatonin-induced phase shifts of locomotor behavior and melatonin receptors activate G-protein-coupled inwardly rectifying potassium (GIRK) channels in Xenopus oocytes. The present study tested the hypothesis that melatonin influences circadian phase and electrical activity within the central clock in the suprachiasmatic nucleus (SCN) through GIRK channel activation. Unlike wild-type littermates, GIRK2 knock-out (KO) mice failed to phase advance wheel-running behavior in response to 3 d subcutaneous injections of melatonin in the late day. Moreover, in vitro phase resetting of the SCN circadian clock by melatonin was blocked by coadministration of a GIRK channel antagonist tertiapin-q (TPQ). Loose-patch electrophysiological recordings of SCN neurons revealed a significant reduction in the average action potential rate in response to melatonin. This effect was lost in SCN slices treated with TPQ and SCN slices from GIRK2 KO mice. The melatonin-induced suppression of firing rate corresponded with an increased inward current that was blocked by TPQ. Finally, application of ramelteon, a potent melatonin receptor agonist, significantly decreased firing rate and increased inward current within SCN neurons in a GIRK-dependent manner. These results are the first to show that GIRK channels are necessary for the effects of melatonin and ramelteon within the SCN. This study suggests that GIRK channels may be an alternative therapeutic target for diseases with evidence of circadian disruption, including aberrant melatonin signaling. SIGNIFICANCE STATEMENT:Despite the widespread use of melatonin supplementation for the treatment of sleep disruption and other neurological diseases such as epilepsy and depression, no studies have elucidated the molecular mechanisms linking melatonin-induced changes in neuronal activity to its therapeutic effects. Here, we used behavioral and electrophysiological techniques to address this scientific gap. Our results show that melatonin and ramelteon, a potent and clinically relevant melatonin receptor agonist, significantly affect the neurophysiological function of suprachiasmatic nucleus neurons through activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels. Given the importance of GIRK channels for neuronal excitability (with >600 publications on these channels to date), our study should generate broad interest from neuroscientists in fields such as epilepsy, addiction, and cognition. 10.1523/JNEUROSCI.1597-15.2015
    24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment. Linkowski P,Mendlewicz J,Kerkhofs M,Leclercq R,Golstein J,Brasseur M,Copinschi G,Van Cauter E The Journal of clinical endocrinology and metabolism Plasma ACTH, cortisol, and GH concentrations were measured at 15-min intervals for 24 h in 11 men suffering from major depressive illness during an acute episode of depression and during clinical remission following antidepressant treatment with either electroconvulsive therapy or amitriptyline. Seven age-matched normal men also were studied. During the acute phase of the illness, the patients had abnormally short rapid eye movement sleep latencies, hypercortisolism, early timing of the nadirs of the ACTH-cortisol rhythms, and shorter nocturnal periods of quiescent cortisol secretion. GH was hypersecreted during wakefulness, and a major pulse occurred before, rather than after, sleep onset. After treatment, rapid eye movement sleep latencies were lengthened, and cortisol levels returned to normal due to a decrease in the magnitude of episodic pulses. Moreover, the timing of the circadian rhythms of ACTH and cortisol as well as the duration of the quiescent period of cortisol secretion were normalized. The amount of GH secreted during wakefulness decreased to normal values, with fewer significant GH pulses. The major elevation of GH secretion in the early part of the night occurred later than that during the depressive episode. These results demonstrate that a disorder of circadian rhythmicity characterizes acute episodes of major depressive illness and that this chronobiological abnormality as well as the hypersecretion of ACTH, cortisol, and GH are state rather than trait dependent. 10.1210/jcem-65-1-141
    Diurnal variation of depressive symptoms. Wirz-Justice Anna Dialogues in clinical neuroscience Diurnal variation of depressive symptoms appears to be part of the core of depression. Yet, longitudinal investigation of an individual's pattern, regularity, relation to clinical state, and clinical improvement reveals little homogeneity. Morning lows, afternoon slump, evening worsening-all can occur during a single depressive episode. Mood variability, or the propensity to produce mood swings, appears to be the characteristic that most predicts capacity to respond to treatment. Laboratory studies have revealed that mood, like physiological variables such as core body temperature, is regulated by a circadian clock interacting with the sleep homeostat. Many depressed patients, particularly bipolar patients, show delayed sleep phase (late chronotype). Even small shifts in the timing and duration of sleep affect mood state (sleep deprivation and sleep phase advance have an antidepressant effect). The implications for treatment are to stabilize mood state by enhancing synchronization of the sleep-wake cycle with the biological clock (eg, with light therapy).
    The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology. Gottlieb John F,Benedetti Francesco,Geoffroy Pierre A,Henriksen Tone E G,Lam Raymond W,Murray Greg,Phelps James,Sit Dorothy,Swartz Holly A,Crowe Marie,Etain Bruno,Frank Ellen,Goel Namni,Haarman Bartholomeus C M,Inder Maree,Kallestad Håvard,Jae Kim Seong,Martiny Klaus,Meesters Ybe,Porter Richard,Riemersma-van der Lek Rixt F,Ritter Philipp S,Schulte Peter F J,Scott Jan,Wu Joseph C,Yu Xin,Chen Shenghao Bipolar disorders AIMS:To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. METHODS:PRISMA-based systematic review of the literature. RESULTS:The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. CONCLUSIONS:The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered. 10.1111/bdi.12847
    Effects of night shifts in bipolar disorders and extreme morningness. Meyrer Robert,Demling Joachim,Kornhuber Johannes,Nowak Magdalena Bipolar disorders BACKGROUND:Night work and shift work scenarios are increasing in modern society. Instability in the sleep-wake rhythm is an important risk factor for triggering episodes of bipolar disorder. Extreme chronotype has negative effects on shift work ("shift-worker syndrome"). Effects of night or shift work on patients with bipolar disorder and extreme chronotype are not well understood. CASE REPORT:A patient with bipolar II disorder and extreme morning type followed a stable work schedule for a significant period of time, maintaining a stable mood. After changing to a night-shift schedule, depressive symptoms developed. When the night-shift schedule was stopped, her mental state normalised. CONCLUSIONS:This case highlights the possibility of a sensitizing role of chronotype in triggering episodes of bipolar disorder after the sleep-wake rhythm has been disrupted by night work or shift work. The evaluation of a person's capability to perform night work or shift work should take into account psychiatric disorders and chronotype as well as physical conditions. 10.1111/j.1399-5618.2009.00767.x
    The chronobiology and neurobiology of winter seasonal affective disorder. Levitan Robert D Dialogues in clinical neuroscience This review summarizes research on the chronobiology and neurobiology of winter seasonal affective disorder (SAD), a recurrent subtype of depression characterized by a predictable onset in the fall/winter months and spontaneous remission in the spring/summer period. Chronobiological mechanisms related to circadian rhythms, melatonin, and photoperiodism play a significant role in many cases of SAD, and treatment of SAD can be optimized by considering individual differences in key chronobiological markers. Converging evidence also points to a role for the major monoamine neurotransmitters serotonin, norepinephrine, and dopamine in one or more aspects of SAD. Ultimately, as with other psychiatric illnesses, SAD is best considered as a complex disorder resulting from the interaction of several vulnerability factors acting at different levels, the various genetic mechanisms that underlie them, and the physical environment. Models of SAD that emphasize its potential role in human evolution will also be discussed.
    Treatments in depression. Duval Fabrice,Lebowitz Barry D,Macher Jean-Paul Dialogues in clinical neuroscience Major depression is believed to be a multifactorial disorder involving predisposing temperament and personality traits, exposure to traumatic and stressful life events, and biological susceptibility. Depression, both unipolar and bipolar, is a "phasic" disease. Stressful life events are known to trigger depressive episodes, while their influence seems to decrease over the course of the illness. This suggests that depression is associated with progressive stress response abnormalities, possibly linked to impairments of structural plasticity and cellular resilience. It therefore appears crucial to adequately treat depression in the early stages of the illness, in order to prevent morphological and functional abnormalities. While evidence suggests that a severely depressed patient needs antidepressant drug therapy and that a non-severely depressed patient may benefit from other approaches (ie, "nonbiological"), little research has been done on the effectiveness of different treatments for depression. The assertion that the clinical efficacy of antidepressants is comparable between the classes and within the classes of those medications may be true from a statistical viewpoint, but is of limited value in practice. The antidepressant drugs may produce differences in therapeutic response and tolerability. Among the possible predictors of outcome in depression treatment, those derived from clinical assessment, neuroendocrine investigations, polysomnographic sleep parameters, genetic variables, and brain imaging techniques have been extensively studied. This article also reviews therapeutic strategies used when initial treatment fails, and describes briefly new concepts in antidepressant therapies such as the regulation of disturbances in circadian rhythms. The treatment of depressive illness does not stop with treatment of acute episodes, and has to be envisaged as a continuous therapeutic intervention, of which we are still not able to determine the optimal duration of treatment and the moment that it should be ceased.
    Antidepressant chronotherapeutics for bipolar depression. Benedetti Francesco Dialogues in clinical neuroscience Chronotherapeutics refers to treatments based on the principles of circadian rhythm organization and sleep physiology, which control the exposure to environmental stimuli that act on biological rhythms, in order to achieve therapeutic effects in the treatment of psychiatric conditions. It includes manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance, and controlled exposure to light and dark. The antidepressant effects of chronotherapeutics are evident in difficult-to-treat conditions such as bipolar depression, which has been associated with extremely low success rates of antidepressant drugs in naturalistic settings and with stable antidepressant response to chronotherapeutics in more than half of the patients. Recent advances in the study of the effects of chronotherapeutics on neurotransmitter systems, and on the biological clock machinery, allow us to pinpoint its mechanism of action and to transform it from a neglected or "orphan" treatment to a powerful clinical instrument in everyday psychiatric practice.
    Chronobiology and mood disorders. Wirz-Justice Anna Dialogues in clinical neuroscience The clinical observations of diurnal variation of mood and early morning awakening in depression have been incorporated into established diagnostic systems, as has the seasonal modifier defining winter depression (seasonal affective disorder, SAD). Many circadian rhythms measured in depressive patients are abnormal: earlier in timing, diminished in amplitude, or of greater variability. Whether these disturbances are of etiological significance for the role of circadian rhythms in mood disorders, or a consequence of altered behavior can only be dissected out with stringent protocols (eg, constant routine or forced desynchrony). These protocols quantify contributions of the circadian pacemaker and a homeostatic sleep process impacting on mood, energy, appetite, and sleep. Future studies will elucidate any allelic mutations in "circadian clock" -related or "sleep"-related genes in depression. With respect to treatment, antidepressants and mood stabilizers have no consistent effect on circadian rhythmicity. The most rapid antidepressant modality known so far is nonpharmacological: total or partial sleep deprivation in the second half of the night. The disadvantage of sleep deprivation, that most patients relapse after recovery sleep, can be prevented by coadministration of lithium, pindolol, serotonin (5-HT) reuptake inhibitors, bright light, or a subsequent phase-advance procedure. Phase advance of the sleep-wake cycle alone also has rapid effects on depressed mood, which lasts longer than sleep deprivation. Light is the treatment of choice for SAD and may prove to be useful for nonseasonal depression, alone or as an adjunct to medication. Chronobiological concepts emphasize the important role of zeitgebers to stabilize phase, light being the most important, but dark (and rest) periods, regularity of social schedules and meal times, and use of melatonin or its analogues should also be considered. Advances in chronobiology continue to contribute novel treatments for affective disorders.