Sleep Disturbance in Bipolar Disorder: Neuroglia and Circadian Rhythms.
Ontology highlight
ABSTRACT:
SUBMITTER: Steardo L
PROVIDER: S-EPMC6656854 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.
| S-EPMC8589670 | biostudies-literature
Project description:Sleep and circadian rhythm disturbances in schizophrenia are common, but incompletely characterized. We aimed to describe and compare the magnitude and heterogeneity of sleep-circadian alterations in remitted schizophrenia and compare them with those in interepisode bipolar disorder. EMBASE, Medline, and PsycINFO were searched for case-control studies reporting actigraphic parameters in remitted schizophrenia or bipolar disorder. Standardized and absolute mean differences between patients and controls were quantified using Hedges' g, and patient-control differences in variability were quantified using the mean-scaled coefficient of variation ratio (CVR). A wald-type test compared effect sizes between disorders. Thirty studies reporting on 967 patients and 803 controls were included. Compared with controls, both schizophrenia and bipolar groups had significantly longer total sleep time (mean difference [minutes] [95% confidence interval {CI}] = 99.9 [66.8, 133.1] and 31.1 [19.3, 42.9], respectively), time in bed (mean difference = 77.8 [13.7, 142.0] and 50.3 [20.3, 80.3]), but also greater sleep latency (16.5 [6.1, 27.0] and 2.6 [0.5, 4.6]) and reduced motor activity (standardized mean difference [95% CI] = -0.86 [-1.22, -0.51] and -0.75 [-1.20, -0.29]). Effect sizes were significantly greater in schizophrenia compared with the bipolar disorder group for total sleep time, sleep latency, and wake after sleep onset. CVR was significantly elevated in both diagnoses for total sleep time, time in bed, and relative amplitude. In both disorders, longer overall sleep duration, but also disturbed initiation, continuity, and reduced motor activity were found. Common, modifiable factors may be associated with these sleep-circadian phenotypes and advocate for further development of transdiagnostic interventions that target them.
| S-EPMC7505194 | biostudies-literature
Project description:UNLABELLED:Bipolar disorder (BD) is associated with mood episodes and low amplitude circadian rhythms. Previously, we demonstrated that fibroblasts grown from BD patients show weaker amplification of circadian rhythms by lithium compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels (LTCC) have emerged as genetic risk factors for BD, we examined whether loss of function in LTCCs accounts for the attenuated response to lithium in BD cells. We used fluorescent dyes to measure Ca(2+) changes in BD and control fibroblasts after lithium treatment, and bioluminescent reporters to measure Per2::luc rhythms in fibroblasts from BD patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. Longitudinal expression of LTCC genes (CACNA1C, CACNA1D and CACNB3) was then measured over 12-24 h in BD and control cells. Our results indicate that independently of LTCCs, lithium stimulated intracellular Ca(2+) less effectively in BD vs. control fibroblasts. In longitudinal studies, pharmacological inhibition of LTCCs or knockdown of CACNA1A, CACNA1C, CACNA1D and CACNB3 altered circadian rhythm amplitude. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium's ability to amplify rhythms. Knockdown of CACNA1A or CACNB3 altered baseline rhythms, but did not affect rhythm amplification by lithium. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium, and the expression profiles of CACNA1C, CACNA1D and CACNB3 were altered in BD vs. CONTROLS:We conclude that in cells from BD patients, calcium signaling is abnormal, and that LTCCs underlie the failure of lithium to amplify circadian rhythms.
| S-EPMC4681663 | biostudies-literature
Project description:Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.
| S-EPMC8418615 | biostudies-literature
Project description:We previously found normal polysomnographic (PSG) sleep efficiency, increased slow-wave sleep (SWS), and a blunted melatonin secretion in women with premenstrual dysphoric disorder (PMDD) compared to controls. Here, we investigated the effects of exogenous melatonin in five patients previously studied. They took 2 mg of slow-release melatonin 1 h before bedtime during their luteal phase (LP) for three menstrual cycles. At baseline, patients spent every third night throughout one menstrual cycle sleeping in the laboratory. Measures included morning urinary 6-sulfatoxymelatonin (aMt6), PSG sleep, nocturnal core body temperature (CBT), visual analog scale for mood (VAS-Mood), Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM), and ovarian plasma hormones. Participants also underwent two 24-hour intensive physiological monitoring (during the follicular phase and LP) in time-isolation/constant conditions to determine 24-hour plasma melatonin and CBT rhythms. The same measures were repeated during their third menstrual cycle of melatonin administration. In the intervention condition compared to baseline, we found increased urinary aMt6 (p < 0.001), reduced objective sleep onset latency (p = 0.01), reduced SWS (p < 0.001), and increased Stage 2 sleep (p < 0.001). Increased urinary aMt6 was correlated with reduced SWS (r = -0.51, p < 0.001). Circadian parameters derived from 24-hour plasma melatonin and CBT did not differ between conditions, except for an increased melatonin mesor in the intervention condition (p = 0.01). Ovarian hormones were comparable between the conditions (p ≥ 0.28). Symptoms improved in the intervention condition, as measured by the VAS-Mood (p = 0.02) and the PRISM (p < 0.001). These findings support a role for disturbed melatonergic system in PMDD that can be partially corrected by exogenous melatonin.
| S-EPMC8664575 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by a complex and multifaceted neurobehavioral syndrome. In the last decades, several studies highlighted an increased prevalence of sleep problems in ASD, which would be associated with autonomic system and circadian rhythm disruption. The present review aimed to summarize the available literature about sleep problems in ASD subjects and about the possible biological factors implicated in circadian rhythm and autonomic system deregulation in this population, as well as possible therapeutic approaches. Shared biological underpinnings between ASD symptoms and altered circadian rhythms/autonomic functions are also discussed. Studies on sleep showed how ASD subjects typically report more problems regarding insufficient sleep time, bedtime resistance and reduced sleep pressure. A link between sleep difficulties and irritability, deficits in social skills and behavioral problems was also highlighted. Among the mechanisms implicated, alteration in genes related to circadian rhythms, such as CLOCK genes, and in melatonin levels were reported. ASD subjects also showed altered hypothalamic pituitary adrenal (HPA) axis and autonomic functions, generally with a tendency towards hyperarousal and hyper sympathetic state. Intriguingly, some of these biological alterations in ASD individuals were not associated only with sleep problems but also with more autism-specific clusters of symptoms, such as communication impairment or repetitive behaviors Although among the available treatments melatonin showed promising results, pharmacological studies for sleep problems in ASD need to follow more standardized protocols to reach more repeatable and reliable results. Further research should investigate the issue of sleep problems in ASD in a broader perspective, taking into account shared pathophysiological mechanisms for core and associated symptoms of ASD.
| S-EPMC9082467 | biostudies-literature
Project description:See "Akula et al., Molecular Psychiatry in Press". RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality post-mortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false-discovery rate of <5%, we detected 5 differentially-expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, PROM1/CD133 and ABCG2 play important roles in neuroplasticity. We also show for the first time differential expression of long non-coding RNAs (lncRNAs) in BD. DE transcripts include those of SRSF5 and RFX4, which along with lncRNAs play a role in mammalian circadian rhythms. The DE genes were significantly enriched for several Gene Ontology (GO) categories. Of these, genes involved with GTPase binding were also enriched for BD-associated SNPs from previous genome-wide association studies, suggesting that differential expression of these genes is not simply a consequence of BD or its treatment. Many of these findings were replicated by microarray in an independent sample of 60 cases and controls. These results highlight common pathways for inherited and non-inherited influences on disease risk that may constitute good targets for novel therapies. Brain transcriptome in bipolar disorder
2014-01-08 | E-GEOD-53239 | biostudies-arrayexpress
Project description:Circadian rhythms are 24-h rhythms in physiology and behaviour generated by molecular clocks, which serve to coordinate internal time with the external world. The circadian system is a master regulator of nearly all physiology and its disruption has major consequences on health. Sleep and circadian rhythm disruption (SCRD) is a ubiquitous feature in today's 24/7 society, and studies on shift-workers have shown that SCRD can lead not only to cognitive impairment, but also metabolic syndrome and psychiatric illness including depression (1,2). Mouse models of clock mutants recapitulate these deficits, implicating mechanistic and causal links between SCRD and disease pathophysiology (3-5). Importantly, treating clock disruption reverses and attenuates these adverse health states in animal models (6,7), thus establishing the circadian system as a novel therapeutic target. Significantly, circadian and clock-controlled gene mutations have recently been identified by Genome-Wide Association Studies (GWAS) in the aetiology of sleep, mental health and metabolic disorders. This review will focus upon the genetics of circadian rhythms in sleep and health.
| S-EPMC5886477 | biostudies-literature
Project description:ObjectivesTo study the longitudinal course of sleep timing and circadian preferences in individuals with bipolar disorder (BP) compared to individuals with non-BP psychopathology and healthy controls.MethodsIndividuals with bipolar I and bipolar II disorder (n = 257), non-BP psychopathology (n = 105), and healthy controls (n = 55) (mean age 40.2 years, 21.3% male, 85.1% Caucasian) were followed on average every 27 months for a mean of four years. Sleep timing parameters and circadian preference were reported using the Sleep Timing Questionnaire and The Composite Scale for Morningness. Group comparisons were adjusted for multiple comparisons and between-group differences in demographic variables and psychopharmacological treatment.ResultsRegardless of their current mood state, individuals with BP showed more sleep onset latency (SOL), wakening after sleep onset (WASO), and evening preference in comparison to both individuals with non-BP psychopathology and healthy controls. Individuals with BP also showed less stability of bed and awakening times in comparison to the other two groups, though these results were dependent on mood state. Non-BP individuals only showed more WASO and less stability in bed and awakening times before work/school days than healthy controls. Adjusting for comorbid disorders yielded similar results. Within-group analyses found little to no effect of time and BP subtype on sleep timing and circadian preference.ConclusionsDisturbances of sleep timing are prominent in individuals with BP. These disturbances are worse during mood episodes, but still apparent during euthymic periods. Evening preference was not associated with polarity type, or mood state in BP, suggesting that this characteristic may be a trait marker.
| S-EPMC4458164 | biostudies-literature
Project description:RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality postmortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false discovery rate of <5%, we detected five differentially expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, Prominin 1/CD133 and ATP-binding cassette-sub-family G-member2 (ABCG2) have important roles in neuroplasticity. We also show for the first time differential expression of long noncoding RNAs (lncRNAs) in BD. DE transcripts include those of serine/arginine-rich splicing factor 5 (SRSF5) and regulatory factor X4 (RFX4), which along with lncRNAs have a role in mammalian circadian rhythms. The DE genes were significantly enriched for several Gene Ontology categories. Of these, genes involved with GTPase binding were also enriched for BD-associated SNPs from previous genome-wide association studies, suggesting that differential expression of these genes is not simply a consequence of BD or its treatment. Many of these findings were replicated by microarray in an independent sample of 60 cases and controls. These results highlight common pathways for inherited and non-inherited influences on disease risk that may constitute good targets for novel therapies.
| S-EPMC5560442 | biostudies-literature