Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 6 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Clinical Drug Research - CNS and Neurological Disorders
- Sprache: Englisch
Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system CNS and other ner
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Veröffentlichungsjahr: 2018
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PREFACE
Frontiers in Clinical Drug Research - CNS and Neurological Disorders presents recent important developments in the treatment of central nervous system (CNS) and nerve disorders. The book is a valuable resource for pharmaceutical scientists, postgraduate students and researchers seeking recent information for developing clinical trials and devising research plans in the field of neurology. The chapters are written by eminent authorities in the field. The contents of this volume cover recent researches on depression and insomnia, combination therapy of hypothermia, tinnitus, and protein misfolding.
I hope that the readers will find these reviews valuable and thought provoking so that they may trigger further research in the quest for new and novel therapies against neurological disorders.
I am grateful for the timely efforts made by the editorial personnel, especially Mr. Mahmood Alam (Director Publications), and Mr. Shehzad Iqbal Naqvi (Senior Manager Publications) at Bentham Science Publishers.
List of Contributors
Depression, Insomnia and Atypical Antidepressants
Laura Betti1,*,Lionella Palego2,Gino Giannaccini1Abstract
A high incidence of people suffering from depression displays a disrupted sleep and, in particular, insomnia. Persistent sleep loss can significantly worsen the quality of life and prognosis of patients, by increasing the risk of relapse during remission and even suicidality. Moreover, an ever emerging issue in the management of depressed patients is the possible arise of poor sleep during an antidepressant treatment. This presumably results from the complex interweave between mood and sleep physiology, which can make it considerably difficult to apply suitable diagnoses and interventions for psychiatrists and physicians. Beside behavioral/psychotherapy approaches, pro-hypnotic drugs are considered preferential overall for treating geriatric depressive patients with insomnia or cases showing refractory poor-quality sleep. Among elective pro-hypnotic compounds, some antidepressants acting on multiple pharmacological targets, also called atypical, have been found particularly effective and well tolerated for these patients.
In this book chapter, we will thus present some aspects of the neurobiology of sleep, current focuses concerning the interlaces between sleep and mood, as well as sleep physiology alterations present in depression subtypes, also in respect to their onset as an antidepressant side-effect.
Afterwards, we will discuss the effectiveness and advantages of atypical antidepressants on hypnotic and antidepressant responses, overall on those acting on the serotonin and melatonin systems, together with our specific aims in this search field. A deeper knowledge of the mechanisms of action of these drugs could indeed help to elucidate, on the one hand, the physiopathology of sleep, while, on the other, would better define their usefulness in the clinical practice and stimulate the discovery of new drugs.
INTRODUCTION
Sleep disorders, in particular sleep loss and chronic insomnia, are very common in the world general population. In European countries, many epidemiological surveys report an average incidence of insomnia as high as 16-19% [1]. Beside insomnia, sleep disorders, which have been grouped as Sleep-wake Disorders in the recent DSM-V psychiatric diagnostic tool [2], include several other conditions as hypersomnolence disorder, narcolepsy, the parasomnias, as well as central and obstructive sleep apneas [2, 3]. Even if the use of this classification is being discontinued [2], sleep disturbances are also sub-divided into the primary ones, which are not derived from other clinical/psychiatric illnesses, and those secondary to other pathological conditions. Sleep disruption is often identified with a neuropsychiatry illness, with insomnia being the common core symptom [4,5], or considered in co-morbidity with depressed mood [5]. Without any doubt, more than 80% of depressed patients complain of poor sleep, a value which is thought to be even underestimated [6]. Indeed, despite much effort has been done in this area of the clinical research, the identification of a “full” Insomnia Disorder in respect to a poor sleep symptom in the context of a psychiatry disease is not easy to perform: if sleep loss can be identified within a mood-anxiety disorder, it can also be the almost unique prodromal symptom in an emerging psychiatric disturbance [7], making the diagnosis confusing. At the same time, poor sleep can be residual after remission from depression, exposing patients to an increased risk of relapse if untreated [8]. Furthermore, sleep symptoms secondary to affective disorders may be sub-threshold, often undiagnosed and invalidating in the long-term. The alterations of the duration, rhythm, and quality of sleep have diagnostic and prognostic significance with respect to the basic psychiatric disorder, while being a source of elevated distress and increased suicidality [6]. Accordingly, it is clear that the concept of secondary sleep dysfunctions as more easily treatable than primary ones is not all the time true by virtue of the multiplicity of implicated variables, especially for the management of psychiatric patients. In fact, the high variability and degree of severity of psychopathological frameworks, the presence of co-morbidity with somatic conditions, previous or current treatments for the underlying disorder, the possibility of persistence or arise of a disruption of sleep physiology during treatment, are supposed to require ‘ad hoc’ clinical evaluations and interventions at various levels. Thus, it can be hypothesized that a pathoplastic effect of psychiatric disorders on formal and structural aspects of altered sleep exist, leading to distinct manifestations in distinct neuropsychiatric conditions [9].
This is the reason why sleep disorders and insomnia are the object of intense investigation in clinical psychiatry, especially in the attempt to define their specific relevance and polysomnographic alterations [10]. To help physicians and psychiatrists, the DSM-V revision has focalized the problem concerning the treatment of altered sleep, both as a symptom or in co-morbidity with a psychiatric disorder, by adopting the strategy to separately treat the occurring sleep disturbance [2]. However, the degree of superposition of mood and sleep symptoms remains an open question.
To introduce this book chapter, we will first describe some basic aspects of the neurobiology of sleep, presenting then current knowledge on the neurochemical interlocks between sleep and mood, as well as on some specific aspects of insomnia in different types of depression, also in respect to poor sleep onset as a possible side-effect during a treatment with antidepressants [10-12]. After that, we will discuss the use in the clinical practice of second generation and atypical antidepressants, in particular those acting on the serotonin and melatonin systems, and their advantages to treat insomnia, together our specific aims in this search field.
Neurobiology of Sleep
Mammalian Sleep: Evolution and Architecture
Life functions are punctuated by relevant biorhythms. In particular, the balanced alternation of rest-activity phases permits to maintain energy homeostasis and long-term survival in all living organisms [13]. High vertebrates and mammals have built-up a fine-tuned behavior, sleep, which is the object of query and interest since the time of ancient Greek and Roman philosophers [14]. A variety of hypotheses have been formulated trying to explain why and how evolution has favored a long-lasting behavior which is antagonist to alertness [15]. After years of research, there is still uncertainty on the topic, but a more widely accepted theory suggests that high vertebrate sleep derives from a weighted equilibrium between the necessity of restoring brain activities, enhancing processes of memory consolidation, reparative anti-oxidant and anti-infectious activities while sleeping [14-16], and that of feeding, reproducing or reducing the risk of predation while being vigilant [17]. Mammalian sleep is a behavior principally defined by closed eyes, recumbent or lying posture, a slow breath, the decrease or lack of active movements, the reduced threshold to sensorial stimuli, and the presence of brain activities with specific electrographic EEG profiles, which display a high variance among the different species. The sleep architecture in most mammals, including humans, is in fact heterogeneous and polyphasic, being defined by the alternation of two main states: 1) a quite sleep, also named non-rapid eye movement (NREM) sleep, characterized by the absence of eye movements, the appearance of EEG spindles and the progressive passage from synchronized high wave activity to low wave one, and 2) a paradoxical sleep (PS) or rapid eye movement (REM) sleep, characterized by desynchronized, mixed EEG activity waves, and the specific presence of saccadic eye movements, in the context of muscle atonia [18]. The REM phase has been related to the active dreaming phase of sleep. Normal human sleep, which lasts 7-9 h, is composed, on average, by about the 70% and 30% of NREM and REM phases, respectively, each shifting to the other through continuous cycles, about 1 cycle each 90-100 min, with inter-individual variance. NREM sleep is further divided into 3 main stages (N1-N3, Table 1), the third one also named “slow wave sleep” (SWS), where a “slow wave activity” (SWA) is preponderant [19]. Polysomnography is considered a valuable tool to evaluate sleep architecture, since it permits to record individual NREM and REM phases and reciprocal patterns; in particular, it permits the concomitant measure of EEG brain waves, skeletal muscle activity, blood oxygen levels, heart and breathing rates and eye movements [18]. During wakefulness, the prevalent EEG waves are the gamma (γ) and beta (β) ones, at low amplitude and high frequency, desynchronized and comprised between 12 and 100 Hz, with γ bands being the most powerful (40-110 Hz). While falling asleep, EEG waves increase their amplitude decreasing their frequency and the alpha (α) waves, at 8-12 Hz, are dominant. During the sleep phases, theta (θ, 4-8 Hz) and delta (δ, 0.5-4 Hz) waves are instead prevalent. The δ waves, at very high amplitude, are typical of SWS. In REM sleep, mixed EEG wave patterns are present, responsible of the relative brain activity and dreaming, both distinctive of this phase [18].
In Table 1 the NREM-REM phases of a healthy individual are reported, also showing typical polysomnography results. Moreover, the Table presents the chief neurochemical patterns involved in the nighttime promotion and maintaining of sleep, also showing melatonin profiles.
Both animal and human studies have permitted to elucidate the neuroanatomy, neurobiology and neurophysiology of sleep. The pioneers of these studies are Moruzzi and Magoun (1949) [20], who demonstrated that the main centers of sleep-arousal control engage subcortical neurons and the synthesis of excitatory and inhibitory neurotransmitters, neuropeptides and neuromodulators.
The wake-promoting nuclei have been first localized in the midbrain ascendant reticular formation, but, subsequently, cell populations residing in pons, basal forebrain (BF) or hypothalamus were also found responsible of the wakefulness state: these neurons and nuclei have been localized as depicted in Fig. (1). The wake-promoting regions shown in this figure projects to the thalamus and all other brain regions, as the basal ganglia, limbic structures and neo-cortex, being prevalently active in the synthesis and release of specific neurotransmitters/ neuromodulators [21].
Wakefulness activities and relays enable voluntary movements, memory skills, attention, conscious thinking, decisiveness, self-defense, social behaviors, and any other function typical of the vigilant life. Beside neurotransmitters, the peptidergic hypocretin/orexin system produce two main actors of vigilance, hypocretin1/orexin-A and hypocretin2/orexin-B [22], which activate locus coeruleus and noradrenergic system. Wakefulness EEG profile is formed by low amplitude, high frequency waves, as above reported. Sleep-promoting neurons are instead localized in the basal forebrain and mainly in hypothalamus at the level of the ventrolateral preoptic nucleus (VLPO, cluster and extended), which release two inhibitory effectors, the neurotransmitter GABA and the neuropeptide galanin.
Accordingly to currently accepted hypotheses, arousal- and sleep-promoting populations of neurons communicate through regulatory networks [23-25].Sleep time occurs when arousal population of neurons switch-off or slow down their firing rate in favor of other neurons, following a flip-flop switch model: at sleep time (“open sleep gate”), serotonin, noradrenalin, histamine, glutamate and acetylcholine releasing neurons decrease their activity, while the GABAergic ones increase this last [25, 26] (Fig. 2A).
Fig. (2)) (A) The “flip-flop” model of sleep-arousal switch; (B) the circadian and homeostatic sleep-wake drives with some hypothalamic nuclei and effectors. DMH: Dorsomedial Hypothalamus; VMH: Ventromedial Hypothalamus; ARCN: Nucleus Arcuatus; LH: Lateral Hypothalamus; SCN: Suprachiasmatic Nucleus; VLPO/MnPO: Ventrolateral and median preoptic nuclei; VH: ventral Hypothalamus; SLD: Sublaterodorsal PontineNnucleusAs a result, also the superior brain areas or cortical regions diminish their activity, leading to fall first in rest and then in the asleep period, defined by NREM-REM stages. This mechanism is complex and takes place in a differential manner for the various neurotransmitters, also depending upon the different sleep stage and involving a variety of neuromodulators and peptides. However, if the comprehension of the neuroanatomy, neurochemistry and architecture of sleep is in progress for understanding sleep disturbances and their treatments, many aspects of the sleeping brain remains still unclear. At this level, about 30 years ago, Borbély [27], has proposed a model for the regulation of sleep-wake brain activities which involves two main sleep driving mechanisms in mammals: a circadian C process and a homeostatic S one, working in parallel and interacting to generate the diverse sleep phases. Circadian processes engage the activity of hypothalamic biological clocks located in the suprachiasmatic nuclei (SCN) and anterior hypothalamus, generating spontaneous pacemakers which adapt metabolism and brain functions to circadian 24-h environmental variations, as temperature and light. One of the circadian mechanisms of SCN consists on the integration, through the superior cervical ganglion, of afferent retinal photic inputs to the pineal gland or epiphysis, provoking the synthesis and secretion of the hormone melatonin, a tryptophan derivative, by pinealocytes at nighttime [28]. The circadian rhythm of melatonin consists in the induction of the biosynthesis of this hormone at evening time to a maximal peak in the night followed by a progressive decrease, drastic at sunrise [29]. Thus, at daytime and sunlight exposition, brain and blood melatonin levels are physiologically minimal (Fig. 2B). Melatonin is thus considered a molecular signal of circadian sleep since it is a highly somnogenic compound, whose release is directed by a light-dependent SCN clock activity. The hypnotic effect of melatonin has been related to the activation of specific G-protein coupled receptors and signal transduction pathways [30]. Besides, the molecular machinery located in the SCN and anterior hypothalamus is formed by a variety of genetic biological clocks, whose expression is self-regulated through negative feed-back mechanisms. These are the period Per and Cryptochrome (Cry) family genes, the CLOCK: BMAL1 system, and the Ror, NPAS2 and CK1 genes [31] which adapt a variety of cell and tissue functions, as glucose metabolism, cell division, apoptosis, fertility and sleep. If circadian processes define sleeping time, the homeostatic ones represent instead the ability of sleep-wake brain nuclei to compensate/re-equilibrate variations of circadian mechanisms and timing [32]. Circadian events are the sleep or wakefulness thresholds, homeostatic events are the regulatory processes of sleep-arousal. It has been hypothesized that, during wake time, synaptic strengthening and long-term potentiation (LTP), mediated by noradrenaline-dependent arousal signals, occur at daytime in response to environmental stimuli and stressful events, whereas during the sleep period, a synaptic downscaling operates to allow all synapses to reduce potentiation and firing, like a kind of total resetting [33]. At the molecular level, sleep homeostasis has been related to the fact that a variety of sleep promoting molecules progressively cumulate during wakefulness till a saturating point; during sleep these molecules decrease. This process is linked to refreshing and invigorating sleep and essentially to SWS, since it enables neurons and synapses to recharge themselves from the energy expenditure which takes place during the wake period. The existence of robust homeostatic mechanisms during SWS has been demonstrated through animal and human studies showing that manipulations of the duration of wakefulness proportionally affect SWS [34]. Moreover, the study of sleep architecture has revealed the progressive decrease of SWS duration after two or three NREM-REM cycles [34]. At the molecular level, several compounds of different chemical nature have been linked to sleep homeostasis, for instance cytokines, antioxidant systems, metabolism products as adenosine or reduced glycogen during wakefulness which also define the cooperative activity between neuron and astrocytes [35,36]. Other newer and relevant theories on homeostatic sleep drive implicate brain mechanisms of clearance of metabolic products, supposed to prevent neurodegeneration and β-amyloid accumulation [37]. Fig. (2B) is a schematic view of the two processes working to generate sleep or to provoke awakening.
For a good quality sleep both processes are needed, ensuring not only total time duration but also its quality, in terms of efficiency and duration of each NREM phase or REM stage, even conditioning its continuity during the night.
The precise orchestration and interaction mechanisms between circadian and homeostatic drives is not known. Some investigations are trying to elucidate the molecular cross talks between homeostatic and circadian drives [38].
A signal possibly acting at the interface between circadian and homeostatic processes could be melatonin itself, which, beside its light-dependent circadian peak and somnogenic effect, acts also as a scavenger, anti-oxidant molecule [39]. A high inter-individual variation of circadian rhythms has been reported in healthy adults, a finding which allowed to identify diverse chronotypes, as morning– or evening-types, showing preferential working or resting phases [40]. These variations have been linked at least in part to genetic variations of bio-clocks or polymorphisms of circadian drives, for instance concerning melatonin secretion and body temperature regulation. Inter-individual variation of chronotypes also involve homeostatic S processes, which concomitantly regulate sleep [40].
Sleep and Mood
Mood is under the control of several neurotransmitters and CNS modulators, in particular monoamines, which have attracted the attention of the scientific community since more than 50 years, allowing the development of past and current antidepressant drugs. Indeed, antidepressants prevalently act on the noradrenergic and serotonergic systems, thus sustaining theories of unbalanced serotonin or both serotonin and catecholamine neurotransmission in depression [41]. Impaired neuroendocrine responses to stressors and stressful events have been also involved, as a blunted functioning of the hypothalamus, pituitary, adrenal axis [42, 43]. New theories are developing which include brain metabolism, glial cells, cytokine release, and even oxidative stress [44-46], nutrient bioavailability and metabolism. The molecular effectors of mood and sleep have been found to match in many aspects: if a bright mood resides upon a good brain arousal and circadian regulation, a good sleep also depends on the metabolic continuum with biomarkers of arousal when considering the homeostatic S processes. Therefore, a disrupted brain metabolism or homeostasis in response to stress as reported in depression can also affect sleep metabolism and neurotransmission. In substance, exposition to stressors during the vigilance state in healthy subjects is compensated by adapted sleep driving forces, implying the strong power of sleep at reinforcing coping abilities to stressful events for the maintain of resilient behaviors [47]. However, despite such theories and acquisition of new evidences, the molecular relationships between mood and sleep have been partially elucidated so far. The high prevalence of disturbed sleep in mood disorders represents the most important substantiation [47]. This relationship is theoretically bi-directional: a disrupted response to stressors, as reported in depressed patients, can affect the sleep molecular machinery, and a chronic malfunctioning of circadian rhythms and/or sleep-wake homeostasis prevents the successful strengthening of neuronal plasticity, thus impinging on mood [47,48]. This suggests that depression would reveal impaired energy homeostasis and production of regulatory pro-hypnotic molecules during wakefulness, leading to disrupted, non-restorative homeostatic sleep. A demonstration of the interactions between sleep and mood is also given by short-term (24 h) sleep deprivation which exerts an antidepressant effect on about 50% of treated patients [49], at least for a period next to the treatment and, overall, in severe, endogenous depression. This phenomenon has been observed also in rodent models, where “acute” sleep deprivation was found to stimulate serotonin release from SCN [50]. However, although sleep deprivation reveals interlaced sleep and mood, the model presents limitations, especially at the therapeutic level, since not all patients constantly respond or only for a short period, probably due to the heterogeneity of clinical depression.
Some scientists consider however that the application of a sleep deprivation therapy, conducted by a skilled medical staff under controlled standard conditions, can represent a valuable and safe alternative or integrated therapeutic approach in the care of severe depression [51], at least in adults < 65 years. Moreover, the sleep deprivation model could help to elucidate those paths and crossroads entailing sleep and mood: recently, the neurotrophin brain-derived neurotrophic factor (BDNF) has been found to increase after acute sleep deprivation [52]. A deeper investigation should be thus conducted in this field.
Sleep and Ageing
An interesting aspect of sleep neurobiology is given by its significant changes during the lifespan, in particular during development, adult life and in the elderly [53,54]. It is also well known that sleep architecture varies in different period of life. In particular, in the healthy elderly population which is also defined by a higher risk for developing depressive episodes, significant changes at the level of EEG sleep patterns have been reported, especially a reduction of SWS [55], further supporting the interweave between sleep behavior and mood [56]. Besides, gender differences in terms of different sleep patterns in men vs. women have been identified [57]. Hormonal, social and cultural differences are supposed to subtly shape sleep in women and men, as demonstrated by gender differences in sleep disorders [57]. With aging, circadian processes are less robust and melatonin levels are decreased [58].
Subjective Evaluations of Sleep
Beside objective EEG or polysomnographic measures, which provide information upon sleep physiology, other important instruments of sleep evaluation are subjective parental, familial or self-reports. A variety of questionnaires have been statistically validated and introduced into the clinical practice containing specific items in respect to sleep duration, quality, restoring properties and insomnia evaluation. These are valuable instruments of sleep monitoring much contributing to the improvement of diagnosis and treatment of sleep disorders or symptoms. Questionnaires and rating scales are easy to perform, provide direct information about the patient quality of life to physicians, they are not invasive tools and are usually administered with a high compliance of patients or volunteers. Among these insomnia or sleep quality rating scales, we mention here the Insomnia Severity Index (ISI) [59], the Pittsburgh Sleep Quality Index (PSQI) [60], the Medical Outcomes Study (MOS) Sleep Scale, the Pittsburgh Sleep Diary (PSD) [61], but many others are also valuable and available to physicians [62, 63]. The primary advantage of these questionnaires is that they can be varied in respect to specific aspects of sleep, including also emotional and behavioral components, or in respect to different ages, gender [63, 64] and pathological conditions [65]; moreover, they can help to establish personalized interventions, being complementary to objective evaluations. All these instruments of investigation report a score or sub-scores as a final result which can be interpreted by physicians in the context of the clinical case as well as for clinical research. Each scale provides also a cut-off value allowing clinicians to discard or to accept the clinical relevance of a sleep disturbance.
INSOMNIA IN DEPRESSION
Despite the diffusion of new technologies applied to neurosciences and clinical psychology, together the great number of investigations carried out in this field, the current management of altered sleep in depression can result problematic. As discussed before, this can be due to the incomplete knowledge of the molecular networks relying mood and sleep. Therefore, to introduce the topic of this chapter, we will present in this paragraph some aspects of sleep disruption and insomnia, contextually to different subtypes of depression.
Major Depression
Disturbed sleep is often reported in patients with depression and can contribute to the onset, progression of the disease as well as to the lack of response to treatments. Patients suffering from depression mainly complain insomnia, frequent nocturnal awakenings, early morning awakening, and consequent hypersomnia. The relationship between major depression and sleep disorders has been thus the object of great scientific interest and extensive literature. Almost 50% of polysomnographic studies in psychiatry has been performed in depressed patients [66]: this has been mainly favored by the high prevalence of depression in the general population and by the patients’ motivation to undergo nocturnal recordings in specialized centers. Sleep disorders are reported among the most characteristic symptoms proposed by DSM-IV-TR for a diagnosis of depressive episode, based on epidemiological analyses estimating that sleep disturbances are present in almost the 50- 90% of patients with depression [66]. The DSM also specifies, in agreement with the clinical experience, that the sleep disorder in the course of a depressive episode can also be characterized by increased sleep time and daytime hypersomnia. Hypersomnia is less common than insomnia in major depression, but it can arise at daytime as a consequence of a disrupted sleep at nighttime. In the literature, hypersomnia is present in about the 16-20% of cases with a diagnosis of depressive disorder [6, 66]. These sleep disturbances are also listed in the diagnostic criteria for dysthymic disorder, a form of chronic depressive state. More specifically, the characteristic symptoms of the melancholic forms are early awakening in the morning (at least 2 hours before the usual time). The early awakening in the morning characterizes specifically those depressive forms with a stronger 'organic' connotation, melancholic forms, which also show symptoms of impaired circadian rhythms, involving appetite, body weight and feeding behavior, or net changes in motor activity. Sleep disorders in these forms show the greatest therapeutic difficulties. As aforementioned, a sleep disorder concomitant to depression can be also one of the most common prodromal symptoms that appears before the more specific symptoms of mood, in particular as concerns early morning awakening. Data in the literature have shown that the risk of developing a depressive episode is high in the case of persistent insomnia in the twelve months prior to the episode [67] (39.8% of cases vs 1.9% of controls). Insomnia can therefore be an important predictor for the onset of a depressive disorder even in the absence of significant changes in mood [5]. These clinical data have received a polysomnographic confirmation in a study that showed an increased REM density in healthy relatives of patients with depression and how it was predictive of the onset of a depressive episode [68]. These data are particularly important for an early diagnosis of depression and for the beginning of therapy. After the resolution of the depressive episode and the normalization of mood, in a number of cases some polysomnographic abnormalities can persist, being predictive of a high risk of relapse and assuming “stretch-dependent” characteristics [66]. These changes may be related to residual somatic symptoms after improvement or resolution of depression. The apparent dissociation between a sleep disorder and depressive episodes acquires particular significance in the context of a clinical entity defined “masked” depression. The masked depression is defined as a clinical picture where symptoms of depressed mood are less obvious than dominant somatic ones [69]. This consists in an apparently monosymptomatic depression, defined for instance by a sleep disorder, but, in reality, through a deeper psychopathological investigation, by a depressive 'latent' framework or at least a mitigated depressed mood. In these patients, the differential diagnosis with a “primary” sleep disorder is particularly relevant, requiring different kind of therapeutic approaches. The proposition of the DSM-V to separately treat disturbed sleep, reflects the attempt, in these difficult cases, to identify prodromic sleep disruptions and the development of clinically significant depressive symptoms. Anyway, it emerges that, despite the important and recent advances in the diagnosis and treatment of depression with sleep symptoms, several problems remain still unsolved. Indeed, many clinical cases show co-morbidity pictures or prodromic features, reflecting the existing complex links between sleep and mood. It was found that sleep disorders in youth are related to a cumulative incidence of depressive disorders later in life (31.6 vs. 10.4% in controls) [70]. It was also noted that sleep disorders are an important predictor for depressive disorders in the elderly [71]. The suitable treatment of sleep disorders, even when these appear to be not related to a psychiatric disorder, can thus acquire a protective relevance against the subsequent onset of a full-blown depression. As mentioned before, this reflects the possibility that the symptomatic control of insomnia, which accompanies a depressive disorder, may not only prevent but also improve the course of the latter both in the absence and in the presence of a specific antidepressant treatment. The rationale for this hypothesis is in fact given by the relevant changes in daytime operations observed in long-term insomnia. Indeed, under this latter condition, relevant cognitive impairments (attention, memory), decreased motor functions and abilities, increased vulnerability to handle stress, fatigue, irritability, dysphoric mood, have been reported. It is also proven that the arise of these undesired and chronic dysfunctions can remarkably worsen depression. A main issue in this topic, which is also expected to provide new results in the treatment of depression, concerns the architectural sleep alterations in depression. Consistently, a shortened SWS sleep and REM latency, this last representing the interval between sleep onset and occurrence of the first REM period, have been observed in depression [72]. Alpha-wave intrusion into delta sleep has been also reported [73]. In concomitance, an increased duration and density of REM sleep, in terms of frequency of rapid eye movements per period, have been defined as predictors of relapse and recurrence of mood episodes [74]. Another feature of depressed patients is also the presence of a lower sleep continuity and fragmented sleep. An increased stage 1 of NREM sleep has been reported too. This pattern opens towards many reflections: first, it suggests that the different phases of NREM sleep and the REM period can be temporally interdependent and that the disruption of previous SWS stages can influence brain activities of the subsequent REM phase. An interesting hypothesis considers that polysomnographic features in depression are linked to genetic vulnerabilities, encompassing a lower threshold to pain or the inability at stress coping defined by altered HPA axis responses [75]. Accordingly, these features can lead to abnormal, so called, “allostatic load” responses, producing reduced NREM latency together a consistent REM sleep disinhibition and consolidation of negative memories in patients [75]. Under this light, sleep in depression would be sparse, losing its resilient power, thus reinforcing mood impairment. This encourages at investigating the molecular mechanisms of NREM-REM flip-flop switches and circadian-to-homeostatic sleep drives in major depression [75, 76].
To conclude this section, it should be mentioned that, beside loss of sleep and insomnia, several recent papers highlight the presence of other relevant sleep disturbances in depression, as Obstructive Sleep Apnea (OSA) [77].
In summary, a number of polysomnographic changes in sleep have been reported in major depression. While none of these changes are pathognomic for MD, they are suggestive in the appropriate clinical setting. These changes include: alpha intrusion, shortened N3 duration and decreased REM latency.
Seasonal Depression, Atypical Depression
Seasonal depression is defined by a seasonal recurrence of depressive episodes; winter type, also named “winter blues”, is the most frequent form, defined by occurrence at wintertime and remission at spring or summer for at least two subsequent years [78]. A summer depression form also exists, which is however rare in respect to the winter type, showing an opposite pattern of episode presentation [79]. A higher incidence of women than men shows seasonal depression. During the winter season, patients show a depressed mood, become inactive, overeat, and crave carbohydrates. In spring and summer they are instead more active, and feel good. This form of depression is thus characterized by a high seasonal profile, metereopathy or sensitivity to photoperiod and climatic changes. The pattern of occurrence of seasonal affective disorder suggests that both bio-clock genes and environmental variables may be important in the illness pathogenesis. Recently, mutations at the level of the Per3 circadian clock gene have been linked to concomitant seasonal depression and sleep disturbances [80], providing further support to intertwined mood and sleep. As concerns sleep disorders in this form of depression, it is important to mention that a high incidence of hypersomnia occurs, not necessarily linked to fragmentary sleep at nighttime, a symptom which can be also present in atypical depression, suggesting a degree of overlap between these two conditions [81]. Atypical depression does not fully show the seasonal profile of seasonal depression but both forms share: the presence of significant vegetative disturbances, a high mood reactivity (high response to positive events), increased appetite, the presence of sleep impairment or other sleep disturbances, insomnia, chronic fatigue, and, as already mentioned, hypersomnia signs. Atypical depression, as the seasonal form, can be more linked to blunted circadian processes, as impaired melatonin release at midnight and its shifted peak in the last part of the night [82]. Sleep architecture in patients with atypical depression and insomnia show NREM and REM disturbances similar to those reported in major depression but with a less fragmented sleep pattern and persistent hypersomnia, a finding which can be suggestive for considering this form as a subtype of depression [83].
Depression with Anxiety
Anxiety, linked to an hyperarousal state and excessive fear responses, is obviously antithetical to rest and sleep. Anxiety can be a symptom of a disorder or represent an independent categorical mental disease. This signifies that anxiety, as a symptom, is present in all psychiatric disorders to varying degrees, or can be classified as a full disorder among the different syndromic entities that are part of the spectrum of anxiety disorders. The occurrence of anxiety as a symptom or as a co-morbid condition, can induce sleep symptoms/disorders, or worsening them. At the level of different diagnostic categories, these are characterized by a differentiated incidence of sleep disorders. For greater clarity, we report herein the sleep patterns related to some main anxiety disorders, assuming, to simplify, that the same disturbance occurring as a symptom or in co-morbidity in depression can introduce a comparable sleep features in the clinical case. In Generalized Anxiety Disorder (GAD), which is defined by a generalized state of fear and anxiety without any apparent cause, insomnia is an extremely common symptom. Insomnia produces poor sleep in 70% and more of GAD cases: this consists essentially in the difficulty or delay in falling asleep, but loss of central and terminal sleep can be identified [84, 85]. For these reasons, GAD is a pathological condition where a relatively high risk of abuse or misuse of hypnotic compounds can be reported [86]. Also in Panic Disorder (PD) sleep disturbances are very frequent especially when the illness is associated to a generalized anxiety framework. An important study [87], has reported a relatively high incidence of subjective sleep complaints (67% vs. 20% in controls), in part due to a concomitant depressive condition and nocturnal panic attacks. In Post-Traumatic Stress Disorder (PTSD), sleep disorders are present at high frequency, overall when the cluster of symptoms 'C' of the DSM (hyperarousal) has a dominant weight in the clinical picture. These are difficulties in falling asleep, early awakenings, poor quality of sleep often associated with REM parasomnias. Obsessive Compulsive Disorder (OCD) is inserted in the DSM between the Anxiety Disorders although it really should be the subject of a separate classification. Sleep disorders in OCD are generally disregarded because of dominant anancastic symptoms inherent compulsive behaviors. One work, however, reports that about 58.2% of severely obsessive patients can suffer from insomnia. In OCD, insomnia is mainly initial type (often protracted due to the execution of rituals), but co-morbidity with a major depressive disorder show the presence of terminal sleep loss [88].
