Chronobiology, excessive daytime sleepiness and depression: Is there a link?

Abstract

The complaint of excessive daytime sleepiness (EDS), commonly encountered in clinical practice, may arise from a variety of psychiatric disorders, most importantly depression. Even though EDS frequently leads depressed patients to seek medical assistance, it is commonly under-evaluated and under-diagnosed. Therefore, a comprehensive understanding and management of EDS is essential in the clinical assessment of depression. Within a theoretical framework, a chronobiological approach may shed new light on the complex interaction of EDS and depression. In this review, studies on EDS and depression are summarized and discussed within the context of circadian and sleep regulatory mechanisms. Furthermore, potential chronobiological therapeutic strategies are proposed to address some of the unmet needs in the treatment of EDS and depression.

Introduction

Excessive daytime sleepiness (EDS) is a tendency to fall asleep despite volitional attempts to remain alert. Chronic sleep loss and/or poor sleep quality are the major underlying reasons for EDS. They occur in numerous sleep disorders, such as obstructive sleep apnea and narcolepsy, as well as in psychiatric disorders, particularly depression. Approximately 80% of depressive states are associated with comorbid insomnia, related or not to EDS [1]. Depressed patients exhibit a plethora of complaints related to daytime energy levels. However, even though sleep quality and quantity are very often substantially decreased in depression, patients do not necessarily have a higher propensity to fall asleep during the day, but rather experience a subjective state of sleepiness [1], [2]. This state of sleepiness in depression differs from EDS as typically encountered in narcolepsy and obstructive sleep apnea (OSA). In the former, subjects experience EDS as “sleep attacks,” namely short and recurrent periods of sleep in the daytime, regardless of the prior amount or quality of night sleep. In OSA, there is a higher propensity to fall asleep during the daytime, possibly due to sleep fragmentation and/or hypoxemia related to chronic intermittent respiratory events [3].

There is ample evidence for an association between daytime sleepiness and moderate to severe depression [4], [5]. Given that insomnia, particularly when associated with impaired daytime function, plays a key role in the onset of depression [6], it is of significant clinical importance to unravel the link between EDS and depression. Furthermore, knowledge on the inter-relation between EDS and mood disorders may have ramifications for the treatment of depression [7], [8].

Apart from the sleep perspective, circadian rhythms play a key role in the association between depression and EDS. Depression is strongly intertwined with biological rhythms on a wide range of dimensions, which includes neurobiological systems that underlie both the pathophysiology of depression, such as the serotonergic system, as well as the clinical aspects of depression [9]. This rhythmicity can manifest itself as an intra-episodic symptomatic expression – such as diurnal variation of mood and early morning awakening – or as an inter-episodic expression – such as seasonal recurrence of clinical depression or reappearance after therapeutic management. Disorders of the human circadian system per se can result in circadian misalignment, leading to sleep disturbances (namely, insomnia and/or EDS), reduced attention and impaired daytime alertness, lack of energy, lower performance, negative mood and gastrointestinal disorders. Interestingly, these symptoms also occur in depression, which further extends the idea that depression and circadian rhythms are intimately connected. Among depressive disorders, major depression, bipolar depression and seasonal affective disorder are defined as being both episodic and recurrent, thus possibly reflecting a chronobiological disorder [10]. Together with the rhythmicity of clinical symptoms, the aforementioned disorders have been associated with alterations of the rhythm of several physiological variables. These include sleep–wake cycle disruption and pathophysiological changes in the secretion of an array of hormones, including cortisol, TSH, GH and melatonin, among others [11], [12], [13], [14].

The application of chronobiological and sleep regulatory concepts in the treatment of depressive disorders has led to effective therapeutic strategies, among which bright light therapy and sleep deprivation can be highlighted [9], [11]. Furthermore, there is evidence that the circadian system is implicated in pharmacological treatment mechanisms, such as lithium therapy for bipolar depression [15]. Lithium can modify the phase-angle between circadian temperature rhythm and rest–activity cycle and lengthens the period of circadian rhythms by increasing the circadian period of firing rate rhythms of SCN neurons in a concentration-dependent manner [16], [17]. Therefore, the stabilization of circadian rhythms may be a key action of clinically effective mood-stabilizing treatments.

In this review, studies on EDS and depression will be summarized and discussed within the framework of current sleep and chronobiology perspectives. A brief outlook of the probable chronobiological underpinnings will be given in order to provide insights on this inter-relationship and possibilities of chronobiological therapies.