Sleep disturbances in schizophrenia: what we know, what still needs to be done

doi:10.1016/j.copsyc.2019.09.011

Current Opinion in Psychology

Volume 34, August 2020, Pages 68-71

https://doi.org/10.1016/j.copsyc.2019.09.011 Get rights and content

Sleep disturbances are commonly observed in schizophrenia (SCZ) and are associated with worse psychotic symptoms and poorer clinical outcomes. Early polysomnography studies have focused on characterizing differences in sleep architecture between patients with SCZ and healthy controls. More recently, research has focused on sleep-specific EEG oscillations, such as sleep spindles and slow waves, which reflect the integrity of underlying thalamo-cortical networks. Furthermore, high-density (hd)-EEG (≥64 channels), which affords enhanced spatial resolution, has been employed to better localize abnormalities in sleep characteristics and related thalamo-cortical circuits in patients with SCZ and related disorders. In this article, we will review the most relevant sleep abnormalities reported in SCZ, with an emphasis on recent findings, and propose directions for future research.

Introduction

It has long been known that sleep disturbances occur frequently in patients with SCZ and are associated with more severe psychotic symptoms and worse clinical outcomes [1^•]. Early polysomnography studies have focused on characterizing differences in sleep architecture between SCZ patients and healthy controls, and it has been shown that SCZ patients often experience delayed sleep onset, difficulty maintaining sleep, reduced total sleep time, and decreased sleep efficiency [2]. More recently, research has focused on sleep-specific EEG oscillations, such as sleep spindles and slow waves, which reflect the integrity of underlying thalamo-cortical networks [3]. Slow waves are 1 Hz, large amplitude oscillations that are primarily generated and coordinated within the cortex, whereas sleep spindles are 12–16 Hz, waxing and waning oscillations that are initiated by the thalamic reticular nucleus and regulated by thalamo-reticular and thalamo-cortical circuits. Abnormalities in sleep spindles, and to a lesser extent, slow waves have been reported by several recent studies [4^•]. Furthermore, high-density (hd)-EEG (≥64 channels), which offers enhanced spatial resolution, has been employed to better localize abnormalities in sleep characteristics and related thalamo-cortical circuits in patients with SCZ and related disorders [5,6]. Dysfunctions within the thalamo-cortical system are thought to play a critical role in the pathophysiology of SCZ [7], and sleep hd-EEG recordings can uniquely characterize the spatiotemporal dynamics of such dysfunctions. During sleep, possible confounds like presence of symptoms or cognitive effort are also minimized, thus better allowing for the assessment of intrinsic oscillatory properties and related molecular mechanisms of dysfunctional neural circuits in SCZ patients [8^•]. Here, we will review the most relevant sleep abnormalities reported in SCZ, with an emphasis on recent findings, and propose directions for future research.

Section snippets

Sleep EEG abnormalities

Studies of SCZ have detected several abnormalities in sleep architecture, with earlier studies focusing on common features of sleep and how they relate to symptomatology. Initial studies found a reduction in slow wave sleep (SWS), which represents the deepest stage of non-rapid eye movement (NREM) sleep, in patients with SCZ relative to HC. Furthermore, SWS is the only significant predictor among other sleep variables (amount of stage 1 (N1), stage 2 (N2), and REM sleep) of future social

Medication effects on sleep EEG

The effects of medication on sleep are also relevant, as many medications used to treat SCZ either directly affect sleep (by their sedating effect, like quetiapine and risperidone) or indirectly affect sleep (by leading to other changes, such as weight gain, like olanzapine and clozapine, that can contribute to the development of sleep disorders). For example, olanzapine has been found to significantly increase the amount of SWS and decrease sleep spindle density [26], and eszopiclone has been

Sleep and cognitive function

Sleep and cognitive functioning are strongly linked, though how this link is affected in SCZ by disturbed sleep is not yet known. Diminished cognitive ability is a core feature of SCZ, as are circadian and sleep disturbances. Circadian disturbances include a delayed phase type, in which the timing of the desired sleep period is significantly delayed, an advanced phase type, in which one is unable to remain awake until the desired or socially accepted time, and an irregular sleep–wake type, in

Conclusions

A primary goal of future research will be to characterize in greater details slow wave and sleep spindle deficits in SCZ at illness onset. In recent studies, we found that both slow wave and sleep spindle deficits were present in FEP patients. However, it will be important to replicate these findings in larger group of patients, including SCZ and other psychotic disorders. This will help establish whether these sleep disturbances are consistently present in SCZ at the beginning of the illness.

Conflict of interest statement

Nothing declared.

References and recommended reading

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

• of special interest
•• of outstanding interest

References (41)

I. Robertson et al.
Insomnia in patients with schizophrenia: current understanding and treatment options
Prog Neuropsychopharmacol Biol Psychiatry
(2019)
A. Castelnovo
Sleep spindles and slow waves in schizophrenia and related disorders: main findings, challenges and future perspectives
Eur J Neurosci
(2018)
F. Ferrarelli et al.
Reduced sleep spindle activity point to a TRN-MD thalamus-PFC circuit dysfunction in schizophrenia
Schizophr Res
(2017)
J.E. Overall et al.
The brief psychiatric rating scale for children
Psychopharmacol Bull
(1982)
F. Ferrarelli et al.
The thalamic reticular nucleus and schizophrenia
Schizophr Bull
(2011)
J.A. Pratt et al.
The thalamic reticular nucleus: a functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery
J Psychopharmacol
(2015)
A. Buchmann
Reduced mediodorsal thalamic volume and prefrontal cortical spindle activity in schizophrenia
Neuroimage
(2014)
R.E. Kaskie et al.
Reduced frontal slow wave density during sleep in first-episode psychosis
Schizophr Res
(2019)
I. Merikanto
Genetic risk factors for schizophrenia associate with sleep spindle activity in healthy adolescents
J Sleep Res
(2019)
A. D’Agostino
Sleep endophenotypes of schizophrenia: slow waves and sleep spindles in unaffected first-degree relatives
NPJ Schizophr
(2018)

E.J. Wamsley

The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: a randomized placebo-controlled trial

Sleep

(2013)

E.J. Wamsley

Reduced sleep spindles and spindle coherence in schizophrenia: mechanisms of impaired memory consolidation?

Biol Psychiatry

(2012)

T. Takahashi

Quality of life in individuals with attenuated psychotic symptoms: possible role of anxiety, depressive symptoms, and socio-cognitive impairments

Psychiatry Res

(2017)

D.S. Manoach et al.

Abnormal sleep spindles, memory consolidation, and schizophrenia

Annu Rev Clin Psychol

(2019)

J.M. Monti et al.

Sleep disturbance in schizophrenia

Int Rev Psychiatry

(2005)

J.M. Saletin et al.

Structural brain correlates of human sleep oscillations

Neuroimage

(2013)

F. Ferrarelli

Sleep in patients with schizophrenia

Curr Sleep Med Rep

(2015)

I. Pisarenco

High-density electroencephalography as an innovative tool to explore sleep physiology and sleep related disorders

Int J Psychophysiol

(2014)

N.D. Woodward et al.

Mapping thalamocortical functional connectivity in chronic and early stages of psychotic disorders

Biol Psychiatry

(2015)

H.J. Drews

Slow-wave sleep predicts long-term social functioning in severe mental illness

PLoS One

(2018)

Cited by (17)

Multivariate patterns of disrupted sleep longitudinally predict affective vulnerability to psychosis in 22q11.2 Deletion Syndrome
2023, Psychiatry Research
22q11.2 deletion syndrome (22q11DS) contributes dramatically to increased genetic risk for psychopathology, and in particular schizophrenia. Sleep disorders, including obstructive sleep apnea (OSA), are also highly prevalent, making 22q11DS a unique model to explore their impact on psychosis vulnerability. Still, the contribution of sleep disturbances to psychosis vulnerability remains unclear. We characterized the sleep phenotype of 69 individuals with 22q11DS and 38 healthy controls with actigraphy and sleep questionnaires. Psychiatric symptoms were measured concomitantly with the baseline sleep assessment and at longitudinal follow-up, 3.58±0.85 years later. We used a novel multivariate partial-least-square-correlation (PLSC) approach to identify sleep patterns combining objective and subjective variables, which correlated with psychiatric symptoms. We dissected longitudinal pathways linking sleep disturbances to psychosis, using multi-layer-network-analysis. 22q11DS was characterized by a non-restorative sleep pattern, combining increased daytime fatigue despite longer sleep duration. Non-restorative sleep combined with OSA symptoms correlated with both emotional and psychotic symptoms. Moreover, a sleep pattern evocative of OSA predicted longitudinal worsening of positive and negative symptoms, by accentuating the effects of emotional dysregulation. These results suggest that sleep disturbances could significantly increase psychosis risk, along an affective pathway. If confirmed, this suggests that systematic screening of sleep quality could mitigate psychosis vulnerability in 22q11DS.
The Feature of Sleep Spindle Deficits in Patients With Schizophrenia With and Without Auditory Verbal Hallucinations
2023, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Previous sleep electroencephalography studies have detected abnormalities in sleep architecture and sleep spindle deficits in schizophrenia (SCZ), but the consistency of these results was not robust, which might be due to the small sample size and the influence of clinical factors such as the various medication therapies and symptom heterogeneity. This study aimed to regard auditory verbal hallucinations (AVHs) as a pointcut to downscale the heterogeneity of SCZ and explore whether some sleep architecture and spindle parameters were more severely impaired in SCZ patients with AVHs compared with those without AVHs.
A total of 90 SCZ patients with AVHs, 92 SCZ patients without AVHs, and 91 healthy control subjects were recruited, and parameters of sleep architecture and spindle activities were compared between groups. The correlation between significant sleep parameters and clinical indicators was analyzed.
Deficits of sleep spindle activities at prefrontal electrodes and intrahemispheric spindle coherence were observed in both AVH and non-AVH groups, several of which were more serious in the AVH group. In addition, deficits of spindle activities at central and occipital electrodes and interhemispheric spindle coherence mainly manifested accompanying AVH symptoms, most of which were retained in the medication-naive first-episode patients, and were associated with Auditory Hallucination Rating Scale scores.
Our results suggest that the underlying mechanism of spindle deficits might be different between SCZ patients with and without AVHs. In the future, the sleep feature of SCZ patients with different symptoms and the influence of clinical factors, such as medication therapy, should be further illustrated.
Association of neurocognitive functioning with sleep stage dissociation and REM sleep instability in medicated patients with schizophrenia
2021, Journal of Psychiatric Research
Citation Excerpt :
In recent years, studies of microstructural sleep abnormalities representing dysfunctional brain circuits have gained increasing interest in schizophrenia research. Sleep spindles have been investigated in schizophrenia with consistent findings of a correlation with symptom severity (Kaskie and Ferrarelli, 2019). Reduced spindle frequency has been suggested as an endophenotype for schizophrenia (Manoach et al., 2016) and has been found closely related to impaired sleep-dependent procedural learning as assessed using a simple motor task (Manoach et al., 2004).
Many patients with schizophrenia present with impaired cognitive functioning and sleep disturbances. Dissociated stages of sleep represent instability within distinct sleep regulatory cerebral networks. Previous studies found increased rates of rapid eye movement (REM) sleep abnormalities in patients with schizophrenia and a positive association with psychopathology. In this study, we examined if sleep stage dissociation and REM sleep instability was associated with neurocognitive functioning in a sample of medicated patients with schizophrenia. The analyses were performed on 31 baseline polysomnographic recordings as well as baseline data on neurocognitive performance. Regression models were built with the cognitive composite score as primary dependent variable and measures of sleep stage dissociation, including REM sleep without atonia (RSWA), REM sleep without eye movements, non-REM sleep with eye movements, REM sleep percentage in REM periods and REM sleep stability as independent variables. Analyses were adjusted for age, gender, total antipsychotic dose, total benzodiazepine dose, and symptom severity. After correction for multiple testing, we found that the neurocognitive composite score was inversely associated with the degree of RSWA. Exploratory analyses with the cognitive sub scores as dependent variables showed that RSWA was associated with cognitive performance across several sub domains. Dissociated sleep stages, specifically the RSWA feature, might represent a new treatment target for improving cognitive impairment in patients with schizophrenia.
Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis
2021, Cell
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Furthermore, CH has been associated with addiction and psychiatric disease even after correction for smoking (Zink et al., 2017). These conditions are linked with severe chronic stress and sleep disturbance (Kaskie and Ferrarelli, 2020). It is important to note that chronic psychosocial stress also causes increased HSC proliferation (Heidt et al., 2014).
Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2^−/− cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.
Neuromodulation of sleep rhythms in schizophrenia: Towards the rational design of non-invasive brain stimulation
2020, Schizophrenia Research
Citation Excerpt :
Patients with schizophrenia are commonly experiencing sleep disturbances, which is reflected in longer time needed to fall asleep, problems staying asleep and overall reduced sleep efficiency (Chan et al., 2017;Kaskie and Ferrarelli, 2020;Robertson et al., 2019).
Brain function critically depends on oscillatory synchronization of neuronal populations both during wake and sleep. Originally, neural oscillations have been discounted as an epiphenomenon. More recently, specific deficits in the structure of brain oscillations have been linked to psychiatric diseases. For example, schizophrenia is hallmarked by abnormalities in different brain oscillations. Key sleep rhythms during NEM sleep such as sleep spindles, which are implicated in memory consolidation and are related to cognitive functions, are strongly diminished in these patients compared to healthy controls. To date, it remains unclear whether these reductions in sleep oscillations are causal for the functional impairments observed in schizophrenia. The application of non-invasive brain stimulation permits the causal examination of brain network dynamics and will help to establish the causal association of sleep oscillations and symptoms of schizophrenia. To accomplish this, stimulation paradigms that selectively engage specific network targets such as sleep spindles or slow waves are needed. We propose that the successful development and application of these non-invasive brain stimulation approaches will require rational design that takes network dynamics and neuroanatomical information into account. The purpose of this article is to prepare the grounds for the next steps towards such rational design of non-invasive stimulation, with a special focus on electrical and auditory stimulation. First, we briefly summarize the deficits in network dynamics during sleep in schizophrenia. Then, we discuss today's and tomorrow's non-invasive brain stimulation modalities to engage these network targets.
Slow wave oscillations in Schizophrenia First-Degree Relatives: A confirmatory analysis and feasibility study on slow wave traveling
2020, Schizophrenia Research
Citation Excerpt :
These oscillations and their traveling have been linked to the integrity of white matter tracts (Buchmann et al., 2011; Piantoni et al., 2013; Kurth et al., 2017; Schoch et al., 2018) and increasing evidence suggests they might be a fingerprint of brain connectivity (Kurth et al., 2017). Sleep oscillations have been extensively explored in SCZ, and impaired spindle density has been the most consistent finding (Castelnovo et al., 2016, 2018; Zhang et al., 2019; Kaskie and Ferrarelli, 2019). However, results are not unanimous, especially among the few papers addressing early-course psychosis.
Abnormal sleep oscillations have recently been proposed as endophenotypes of schizophrenia. However, optimization of methodological approaches is still necessary to standardize analyses of their microstructural characteristics. Additionally, some relevant features of these oscillations remain unexplored in pathological conditions. Among others, slow wave traveling is a promising proxy for diurnal processes of brain connectivity and excitability. The study of slow oscillations propagation appears particularly relevant when schizophrenia is conceptualized as a dys-connectivity syndrome. Given the rising knowledge on the neurobiological mechanisms underlying slow wave traveling, this measure might offer substantial advantages over other approaches in investigating brain connectivity.
Herein we: 1) confirm the stability of our previous findings on slow waves and sleep spindles in FDRs using different automated algorithms, and 2) report the dynamics of slow wave traveling in FDRs of Schizophrenia patients. A 256-channel, high-density EEG system was employed to record a whole night of sleep of 16 FDRs and 16 age- and gender-matched control subjects. A recently developed, open source toolbox was used for slow wave visualization and detection. Slow waves were confirmed to be significantly smaller in FDRs compared to the control group. Additionally, several traveling parameters were analyzed. Traveled distances were found to be significantly reduced in FDRs, whereas origins showed a different topographical pattern of distribution from control subjects. In contrast, local speed did not differ between groups.
Overall, these results suggest that slow wave traveling might be a viable method to study pathological conditions interfering with brain connectivity.

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View full text

Sleep disturbances in schizophrenia: what we know, what still needs to be done

Introduction

Section snippets

Sleep EEG abnormalities

Medication effects on sleep EEG

Sleep and cognitive function

Conclusions

Conflict of interest statement

References and recommended reading

Prog Neuropsychopharmacol Biol Psychiatry

Eur J Neurosci

Schizophr Res

Psychopharmacol Bull

Schizophr Bull

J Psychopharmacol

Neuroimage

Schizophr Res

J Sleep Res

NPJ Schizophr

Sleep

Biol Psychiatry

Psychiatry Res

Annu Rev Clin Psychol

Sleep disturbance in schizophrenia

Int Rev Psychiatry

Structural brain correlates of human sleep oscillations

Neuroimage

Sleep in patients with schizophrenia

Curr Sleep Med Rep

High-density electroencephalography as an innovative tool to explore sleep physiology and sleep related disorders

Int J Psychophysiol

Mapping thalamocortical functional connectivity in chronic and early stages of psychotic disorders

Biol Psychiatry

Slow-wave sleep predicts long-term social functioning in severe mental illness

PLoS One