REM sleep dysregulation in depression: State of the art

Summary

Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Since the 1960s polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity, depression is associated with altered sleep architecture, i.e., a decrease in slow wave sleep (SWS) production and disturbed rapid eye movement (REM) sleep regulation. Shortened REM latency (i.e., the interval between sleep onset and the occurrence of the first REM period), increased REM sleep duration and increased REM density (i.e., the frequency of rapid eye movements per REM period) have been considered as biological markers of depression which might predict relapse and recurrence. High risk studies including healthy relatives of patients with depression demonstrate that REM sleep alterations may precede the clinical expression of depression and may thus be useful in identifying subjects at high risk for the illness. Several models have been developed to explain REM sleep abnormalities in depression, like the cholinergic–aminergic imbalance model or chronobiologically inspired theories, which are reviewed in this overview. Moreover, REM sleep alterations have been recently considered not only as biological “scars” but as true endophenotypes of depression. This review discusses the genetic, neurochemical and neurobiological factors that have been implicated to play a role in the complex relationships between REM sleep and depression. We hypothesize on the one hand that REM sleep dysregulation in depression may be linked to a genetic predisposition/vulnerability to develop the illness; on the other hand it is conceivable that REM sleep disinhibition in itself is a part of a maladaptive stress reaction with increased allostatic load. We also discuss whether the REM sleep changes in depression may contribute themselves to the development of central symptoms of depression such as cognitive distortions including negative self-esteem and the overnight consolidation of negatively toned emotional memories.

Introduction

Depression as a clinical disorder is a common condition1, 2, 3 and has become increasingly prevalent in Western industrialized countries,⁴ with a point-prevalence of ca. 5% and estimates of lifetime-prevalence ranging up to 20% of the general population. Depression has severe consequences and is associated with increased rates of disability, morbidity and mortality.⁴ Symptoms of depression include depressed mood, loss of interest and fatigue/tiredness, cognitive dysfunction, i.e., negative view of the self, negative ruminations, loss of appetite and libido, suicidality and sleep problems. Disturbed sleep is reported by up to 90% of depressed subjects⁵ and might be involved, at least partially, in the onset and course of depression⁴ and in the response to treatment.4, 6 Patients suffering from depression complain of sleep disruptions mainly consistent with symptoms of insomnia (i.e., prolonged sleep latency, frequent nocturnal awakenings and early morning awakening), which are part of the core complaints of depression.4, 7, 8, 9, 10, 11, 12 Sleep disturbances in depression have interested many researchers and for many decades sleep research has been a major pillar of neurobiological investigations into its cause, onset and course. Since the 1960s polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity7, 8, 9, 10, 11 a typical constellation of sleep-electroencephalography (EEG) architecture changes is present in depression.12, 13, 14, 15, 16 The most reliable EEG sleep changes include a decrease in rapid eye movement (REM) latency (REM latency = interval between sleep onset and the occurrence of the first REM sleep period), an increase in total REM sleep time and REM density (i.e., the frequency of rapid eye movements per REM period), and diminished slow wave sleep (SWS) production.12, 13, 14, 15, 16 REM sleep alterations, especially shortened REM sleep latency, might have prodromal4, 13, 17, 18 and residual properties4, 13, 18 with respect to depressive episodes. REM sleep alterations in fact often persist beyond the clinical episode and thus are supposed to increase the vulnerability to relapse or recurrence and in general may have a negative effect on treatment response.4, 6 High risk studies investigating hitherto unafflicted relatives of patients with depression demonstrated that particularly REM density changes are already present before the onset of the disorder and may predict its development.19, 20, 21, 22

The phenomenology of sleep alterations in depression will be reviewed in more detail in the next chapter, followed by an overview concerning the impact of antidepressant medication on sleep (see below). REM sleep alterations, especially shortened REM sleep latency, have been interpreted as biological markers for depression and even been assumed to be of differential diagnostic value for the classification of depressive disorders.23, 24, 25, 26, 27 Some theoretical models to explain REM sleep abnormalities in depression hypothesize a key role of these sleep phenomena for the etiology/pathophysiology of depression, while others interpret REM sleep changes as mere consequences of the neurobiological processes underlying depressive disorders. Doubtlessly, genetic factors might be involved in the development of REM sleep changes in depression, which are mediated by complex neurobiological processes involving among others noradrenergic, serotoninergic, cholinergic and orexinergic neurotransmitter systems. Presently, REM sleep alterations are not only seen as state markers or biological “scars”, but even as vulnerability markers or “true” endophenotypes of depression.16, 28, *29, 30 A review of presently discussed models will be given below followed by a critical discussion of these concepts. At present, none of the established models sufficiently explain the whole range of sleep abnormalities in depression.4, 16, 31 A novel pathophysiological concept of depression, to be outlined in this review, therefore proposes that a dysfunction of neural plasticity might represent a final common pathway underlying the biological and clinical characteristics of the disorder. Interestingly, changes in neurogenesis have been implicated in the pathophysiology of depression, but also in stress-related REM sleep hyperactivation or disinhibition.32, 33, *34 New concepts in depression are reviewed and then we propose a model of the role of REM sleep dysregulation in depression based on the literature taken into consideration.

This paper aims at reviewing data and hypotheses about the complex relationship between REM sleep dysregulation and depression, starting with a brief historical perspective from the first polysomnographic studies in the 1960s to the present situation. This approach will encompass data from different strands of research including psychopathology, experimental and clinical psychology, genetics, electro-, neuro- and psychophysiology, molecular biology and neuroimaging.