Sleep and circadian rhythm disruption in neuropsychiatric illness

doi:10.1016/j.conb.2013.03.008

Current Opinion in Neurobiology

Volume 23, Issue 5, October 2013, Pages 888-894

https://doi.org/10.1016/j.conb.2013.03.008 Get rights and content

Highlights

•
Sleep and circadian rhythm disruption (SCRD) is a common comorbidity in psychiatric disorders.
•
Common mechanisms may underlie SCRD and psychiatric disease development.
•
Clock genes have been implicated in the pathophysiology of several diseases including bipolar disorder, schizophrenia and depression.
•
Stabilization of sleep and circadian behaviours is providing new approaches for the treatment of psychiatric illnesses.

Sleep and circadian rhythm disruption (SCRD) is a common feature in many neuropsychiatric diseases including schizophrenia, bipolar disorder and depression. Although the precise mechanisms remain unclear, recent evidence suggests that this comorbidity is not simply a product of medication or an absence of social routine, but instead reflects commonly affected underlying pathways and mechanisms. For example, several genes intimately involved in the generation and regulation of circadian rhythms and sleep have been linked to psychiatric illness. Further, several genes linked to mental illness have recently been shown to also play a role in normal sleep and circadian behaviour. Here we describe some of the emerging common mechanisms that link circadian rhythms, sleep and SCRD in severe mental illnesses. A deeper understanding of these links will provide not only a greater understanding of disease mechanisms, but also holds the promise of novel avenues for therapeutic intervention.

Introduction

Sleep disruption is a notable and long-recognized feature of mental illness. The majority of patients with schizophrenia, bipolar disorder and major depressive disorder report sleep disturbances, although the mechanistic relationship between these neuropsychiatric illnesses and sleep remains unclear [1^•]. Sleep/wake cycles are partially regulated by the circadian clock and recent studies have implicated circadian disruption, both at the level of clock genes themselves and clock outputs, in the aetiology of these disorders. Here we consider the major developments in the last few years linking the circadian clock and sleep with neuropsychiatric disease.

Section snippets

Circadian rhythms and sleep: from basic mechanisms to health

The Earth's 24 hour cycle of light and darkness results in a predictably changing environment, providing a key selective advantage to organisms that are able to anticipate and exploit these rhythmic changes. Consequently, most aspects of physiology and behaviour display 24 hour variations, driven by an endogenous circadian clock (from the Latin circa — approximately and diem — day). In mammals, the mechanism providing this rhythm is a molecular transcriptional-translational feedback loop (TTFL),

Sleep and circadian rhythm disruption (SCRD)

SCRD is a common feature of neuropsychiatric disease. This observation is not new. Indeed, in 1883 Emil Kraepelin described the association between abnormal sleep patterns and mental health [22], and the clear links between sleep and bipolar disorder were described over 30 years ago [23]. Up to 80% of patients with depression or severe mental illness such as schizophrenia report sleep abnormalities [1]. Although SCRD is amongst the diagnostic criteria for psychiatric disorders, the aetiology of

Bipolar disorder

Bipolar disorder is a mood disorder where patients experience cycles of mood elevation and intense activity (mania) followed by depression. The artist Van Gogh, who has been suggested to have suffered from bipolar disorder [26], worked prolifically during manic episodes, followed by periods of exhaustion and depression. Interestingly, reports indicate he also suffered from insomnia and Van Gogh said he spent as much as three weeks at a time without sleep [27].

The links between disrupted sleep

Schizophrenia

Recent studies have provided strong evidence for SCRD in schizophrenia, where abnormal phasing and instability of circadian rhythms, sleep disturbances and fragmented rest-activity patterns have been clearly described [38••, 39, 40]. For example, Wulff et al. [38^••] compared rest-activity patterns in a cohort of patients with schizophrenia with matched healthy unemployed controls and showed significant sleep/circadian disruption in all 20 patients studied. Of these, half showed severe circadian

Depression

Perhaps the clearest links between SCRD and psychiatric disease are in major depressive disorder, where up to 90% of all patients report sleep disruption [1^•]. Since other reviews have considered this topic in some detail (see [1•, 50]), this review will focus only upon recent developments pertinent to the involvement of the circadian/sleep systems. The link between the circadian system and depression has been evident since the 1960s and 70s, when it was discovered that depressive patients lose

Future perspectives

It is becoming increasingly clear that there are common and overlapping pathways that link SCRD and neuropsychiatric illness (Figure 2). As neuropsychiatric disorders involve defects in neurotransmission, and the regulation of sleep is dependent on a broad range of neurotransmitter systems, the involvement of common neurotransmitters probably accounts for the primary comorbidity of these disorders [1^•]. However, although linked by overlapping neural pathways, the SCRD and psychiatric phenotype

Conclusions

Recent research, from both human subjects and animal models has provided strong links between disrupted clock function, sleep regulation and neuropsychiatric disease. Whilst we clearly need a better understanding of the complex mechanisms underlying these associations, the stabilization of sleep and circadian rhythms may provide a novel future approach for the treatment of these devastating illnesses.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work was funded by a Wellcome Trust Strategic Award to RGF and SNP. AJ is funded by a Roche Postdoctoral Fellowship. The authors would also like to thank our colleagues in the Oxford Sleep and Circadian Neuroscience Institute (SCNi) for many stimulating discussions which have greatly contributed to the ideas contained herein. Finally, we would like to thank the Editors for their valuable feedback.

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Cited by (154)

An association study of clock genes with major depressive disorder
2023, Journal of Affective Disorders
To study the relationship between clock genes and Major Depressive Disorder (MDD).
GEO database was used to obtain the chip data and clinical information of datasets GSE98793, GSE39653 and GSE52790. The differentially expressed clock genes were found through the analysis of the differentially expressed genes between MDD and healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) enrichment analysis were performed on the differential expressed clock genes. Lasso Regression and Support Vector Machine (SVM) method were used for screening the differential expressed clock genes. Logistic regression was used to establish a diagnostic model for depression with the screened genes. Receiver Operating Characteristic (ROC) Curve was used to verify the model. Gene differential expression analysis was performed for MDD with high scores and MDD with low scores in the diagnostic model. Gene Set Enrichment Analysis (GSEA) enrichment analysis was performed for differentially expressed genes. Single-gene GSEA was used to analyze each gene in the model separately. Cibersort method was used to analyze the immune infiltration of MDD and healthy controls, and the correlation between immune cells and clock genes was analyzed. Cytoscape was used to analyze the clock gene interaction network. The DGIdb website was used to predict potentially effective therapeutic drugs for clock genes closely related to MDD.
Six genes were identified by differential expression analysis of clock genes between MDD and healthy controls. GO and KEGG enrichment analysis of 6 genes showed that their pathways were concentrated such as circadian rhythm, rhythmic process, TGF − beta signaling pathway, longevity regulating pathway-multiple species, adipocytokine signaling pathway and so on. Lasso regression and SVM were used to screen out 5 clock genes (HDAC1, ID3, NFIL3, PRKAA1, TNF) for MDD. The diagnostic model of depression was established according to the 5 clock genes. The area under the curve (AUC) of the established depression diagnostic model was 0.686. Gene difference analysis was performed between MDD patients with high score of clock gene diagnostic model and MDD patients with low score. GSEA was performed for the differential genes showed that the most enriched pathways were:adipocytokine signaling pathway, TGF beta signaling pathway, oxidative phosphorylation, primary immunodeficiency, and so on. The single gene GSEA showed that the most enriched pathways were Toll like receptor signaling pathway, glucolipid metabolism, amino acid metabolism, neuroactive ligand receptor interaction, and so on. The results of immune infiltration analysis showed that NK cells resting and Macrophages M2 were different between MDD and control groups. In MDD, the gene closely related to NK cells resting was HDAC1, and the genes closely related to Macrophages M2 were HDAC1 and NFIL3. The RNA interactions network of clock genes shows that the regulation process is complex, which can provide a reference for subsequent related research. Potential therapeutic drugs predict display, among the 5 clock genes, TNF, HDAC1, and PRKAA1 may have potential effective therapeutic drugs.
Among all CLOCK genes, HDAC1, ID3, NFIL3, PRKAA1, TNF are closely related to MDD. Among them, TNF, HDAC1, and PRKAA1 may have potential effective therapeutic drugs.
Chronobiological parameters as predictors of early treatment response in major depression
2023, Journal of Affective Disorders
Alterations in circadian system organization have been related to major depressive disorder manifestations. This study aimed to evaluate chronobiological parameters, such as sleep, levels of 6-sulfatoxymelatonin, and others derived from actimetry as potential predictors of adequate treatment response in MDD.
98 adult women with confirmed diagnosis of MDD were included. Participants completed standard questionnaires (Hamilton Depression Rating Scale – HAM-D; Munich Chronotype Questionnaire - MCTQ) at baseline and after 4 weeks of treatment. Urinary samples for assessing 6-sulfatoxymelatonin were collected on the day before and immediately after pharmacological treatment administration, and 28 continuous days of actigraphy data were collected during the protocol. Participants were classified into Responder (R) or Non-responder (NR) to antidepressant treatment in 4 weeks (early responder), which was characterized by a ≥50 % decrease in the HAM-D score.
The following biological rhythms variables significantly predicted a better treatment response in a model controlling for age, sex, and previous treatments: higher levels of activity (M10 - average activity in the 10 most active hours within the 24 h-day) and an earlier center of the 10 most active hours (M10c), as well as lower intradaily variability (IV) of light exposure. Sleep parameters and 6-sulfatoxymelatonin levels did not associate with treatment response prediction.
Actimetry data were not assessed before changing in the treatment plan.
Different patterns in activity and light exposure might be linked to early antidepressant response.
Aging, circadian disruption and neurodegeneration: Interesting interplay
2023, Experimental Gerontology
Citation Excerpt :
In humans, sedentary lifestyles and chronic diseases are further posing a growing threat to a healthy circadian organization which raises the risk of several age-related chronic diseases via multiple discrete mechanisms (Abbott and Zee, 2019). Additionally, the CD is a common aspect of a wide range of diseases including metabolic disorders (Russart and Nelson, 2018), cardiovascular diseases (Rüger and Scheer, 2009), cancer (Lamia, 2017), and neurodegenerative diseases (NDDs) (Jagannath et al., 2013; Wulff et al., 2010). As people age, their circadian rhythm changes dramatically which might accelerate the aging process (Welz and Benitah, 2020).
The circadian system is an intricate molecular network of coordinating circadian clocks that organize the internal synchrony of the organism in response to the environment. These rhythms are maintained by genetically programmed positive and negative auto-regulated transcriptional and translational feedback loops that sustain 24-hour oscillations in mRNA and protein components of the endogenous circadian clock. Since inter and intracellular activity of the central pacemaker appears to reduce with aging, the interaction between the circadian clock and aging continues to elude our understanding. In this review article, we discuss circadian clock components at the molecular level and how aging adversely affects circadian clock functioning in rodents and humans. The natural decline in melatonin levels with aging strongly contributes to circadian dysregulation resulting in the development of neurological anomalies. Additionally, inappropriate environmental conditions such as Artificial Light at Night (ALAN) can cause circadian disruption or chronodisruption (CD) which can result in a variety of pathological diseases, including premature aging. Furthermore, we summarize recent evidence suggesting that CD may also be a predisposing factor for the development of age-related neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), although more investigation is required to prove this link. Finally, certain chrono-enhancement approaches have been offered as intervention strategies to prevent, alleviate, or mitigate the impacts of CD. This review thus aims to bring together recent advancements in the chronobiology of the aging process, as well as its role in NDDs.
Pathophysiology, associations, and consequences of circadian rhythm sleep wake disorders
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
Circadian rhythm sleep–wake disorders (CRSWD's) are a group of sleep disorders characterized by a misalignment between the body's endogenous clock and the 24 h socially and environmentally imposed sleep–wake cycle. According to the International Classification of Sleep Disorders, third Edition (ICSD-3), there are seven distinct CRSD's: (1) Delayed Sleep Wake Phase Disorder (DSWPD); (2) Advanced sleep–wake phase disorder (ASWPD); (3) Irregular Sleep Wake Rhythm Disorder (ISWRD): (4) non-24 h sleep–wake rhythm disorder (N24SWD); (5) Jet Lag Disorder; (6) Shift Work Disorder and (7) Circadian sleep–wake disorder not otherwise specified. This chapter briefly discusses each of the six primary CRSWD's, highlighting the epidemiology; etiology and pathophysiology; predisposing and precipitating factors; and associated complications and consequences of CRSWD's.
The translational genetics of ADHD and related phenotypes in model organisms
2023, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Also, sleep disturbances have been previously reported in Nrx-1 mutants (Drosophila ortholog of NRXN1) (Larkin et al., 2015; Tong et al., 2016) and upon DISC1 overexpression in a Drosophila model of schizophrenia (Sawamura et al., 2008). Defects in circadian rhythm have been extensively connected to many neurodevelopmental and psychiatric disorders including ASD and schizophrenia, and they are increasingly recognized to contribute to the etiology of the disorders rather than only representing a consequence (Jagannath et al., 2013; Menet and Rosbash, 2011). ADHD-associated genes such as DAT, Mef2, and period have been shown to play a role in Drosophila circadian rhythm (Bargiello and Young, 1984; Blanchard et al., 2010; Kume et al., 2005; Sivachenko et al., 2013; Top and Young, 2018).
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder resulting from the interaction between genetic and environmental risk factors. It is well known that ADHD co-occurs frequently with other psychiatric disorders due, in part, to shared genetics factors. Although many studies have contributed to delineate the genetic landscape of psychiatric disorders, their specific molecular underpinnings are still not fully understood. The use of animal models can help us to understand the role of specific genes and environmental stimuli-induced epigenetic modifications in the pathogenesis of ADHD and its comorbidities. The aim of this review is to provide an overview on the functional work performed in rodents, zebrafish and fruit fly and highlight the generated insights into the biology of ADHD, with a special focus on genetics and epigenetics. We also describe the behavioral tests that are available to study ADHD-relevant phenotypes and comorbid traits in these models. Furthermore, we have searched for new models to study ADHD and its comorbidities, which can be useful to test potential pharmacological treatments.
Lower morning levels of cortisol and neuropeptides in blood samples from patients with bipolar disorder
2022, Journal of Affective Disorders Reports
Citation Excerpt :
Lower morning SST, VIP, NPY and cortisol may reflect overall decreased levels or an altered circadian phase in subjects with BPD. The increasing evidence supporting the role of circadian rhythm abnormalities in mood disorders provides support for the latter (Aydin et al., 2013b; Benedetti et al., 2008b; Bersani et al., 2012a; Etain et al., 2011b; Harvey, 2011b; Jagannath et al., 2013b; Kripke et al., 2009a; McClung, 2011a; Nievergelt et al., 2006b; Plante and Winkelman, 2008b; Severino et al., 2009b; Soria et al., 2010a). Studies have shown that circadian rhythm synchronization is reduced in patients with BPD. (
Several lines of evidence indicate that circadian rhythm disruption is associated with bipolar disorder (BPD). This strong association, along with evidence from genome wide association studies (GWAS) implicating clock and clock controlled genes with BDP and efficacy of lithium treatment, suggests that BPD circadian rhythm disruption may represent a core etiology feature. Lower morning expression of the neuropeptide somatostatin (SST) has been previously reported in the brain and cerebral spinal fluid of subjects with BPD, coinciding with increased morning severity of anxiety and depression. We aimed to test the hypothesis that levels of neuropeptides involved in circadian rhythm regulation, including somatostatin (SST), neuropeptide-Y (NPY), arginine vasopressin (AVP), vasoactive intestinal peptide (VIP) and cortisol levels, are altered in blood samples collected in the morning from patients BPD.
Thirty nine patients diagnosed as BPD according to DSM-5, and 38 healthy controls were enrolled in the study. Blood were collected at 9 AM from all subjects. Serum levels of SST, NPY, AVP, VIP and cortisol were measured.
We observed significantly lower levels of SST (p = 0.001), NPY (p = 0.001), VIP (p = 0.001) and cortisol levels (p = 0.001) in the morning in subjects with BPD compared to control subjects. Significant positive effects of Young Mania Rating Scale and lithium treatment with cortisol, SST, and VIP levels were observed.
Our study suggests that lower morning levels of SST, NPY, VIP and cortisol may represent biomarkers underlying disrupted biological rhythms and behavioral and sleep disturbances observed in patients with BPD.

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Sleep and circadian rhythm disruption in neuropsychiatric illness

Highlights

Introduction

Section snippets

Circadian rhythms and sleep: from basic mechanisms to health

Sleep and circadian rhythm disruption (SCRD)

Bipolar disorder

Schizophrenia

Depression

Future perspectives

Conclusions

References and recommended reading

Acknowledgements

Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease

Nat Rev Neurosci

Coordination of circadian timing in mammals

Nature

Resetting of circadian time in peripheral tissues by glucocorticoid signaling

Science

Suprachiasmatic nucleus: the mind's clock

Circadian vision

Curr Biol

Timing to perfection: the biology of central and peripheral circadian clocks

Neuron

Sleep homeostasis and models of sleep regulation

J Biol Rhythms

Homeostatic, circadian, and emotional regulation of sleep

J Comp Neurol

The genetic and molecular regulation of sleep: from fruit flies to humans

Nat Rev Neurosci

Sleep and circadian rhythm disturbances: multiple genes and multiple phenotypes

Curr Opin Genet Dev

The rhythm of rest and excess

Nat Rev Neurosci

A clockwork web: circadian timing in brain and periphery, in health and disease

Nat Rev Neurosci

Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep–wake cycle and temperature regulation

J Neurosci

Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes

Nature

Obesity and metabolic syndrome in circadian Clock mutant mice

Science

Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta

Nature

Circadian rhythms, sleep, and substance abuse

Sleep Med Rev

Sleep inspires insight

Nature

Dependence on REM sleep of overnight improvement of a perceptual skill

Science

Sick and tired: does sleep have a vital role in the immune system?

Nat Rev Immunol

Partial night sleep deprivation reduces natural killer and cellular immune responses in humans

FASEB J

Does abnormal sleep impair memory consolidation in schizophrenia?

Front Hum Neurosci

Circadian rhythm disturbances in manic-depressive illness

Fed Proc

Sleep and circadian rhythms in mood disorders

Acta Psychiatr Scand Suppl

Disturbed circadian rest–activity cycles in schizophrenia patients: an effect of drugs?

Schizophr Bull

Vincent van Gogh's illness: a case record

Bull Hist Med

Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation

Am J Psychiatry

Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock

Science

A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3beta

Proc Natl Acad Sci U S A

Lithium impacts on the amplitude and period of the molecular circadian clockwork

PLoS ONE

Molecular targets of lithium action

Annu Rev Pharmacol Toxicol

Mania-like behavior induced by disruption of CLOCK

Proc Natl Acad Sci U S A

Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior

Biol Psychiatry

The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period

Science