Current Psychiatry Reviews - Volume 10, Issue 3, 2014

Disturbances of the sleep-wake pattern constitute one of the major complaints of patients with a wide range of psychiatric conditions, including major depression disorder, anxiety disorders, bipolar disorders, schizophrenia, borderline personality disorder, eating disorders, and alcohol abuse. Recent advances have cast light on the mecanisms underlying modifications in sleep in psychiatric disorders, offering new approaches in management and opening new avenues of research. Isnomnia and psychiatric disorders, especially depression, are intimately linked. Insomnia, defined as a difficulty in initiating and/or in maintaining sleep leading to daytime repercussions, is not simply a symptom of depression but an independent diagnostic entity, and is known to be an independent risk factor for both depression itself and the development of a new depression episode or relapse. To date, the psychological and neurobiological mechanisms underlying the relationships between insomnia and affective disorders are not yet fully understood. The review by Chiara Baglioni et al. examines the latest findings from several fields of research, with particular attention to alterations of the arousal system leading to hyperarousal and to the possible biological mechanisms involved in the link between sleep alteration, insomnia, regulation of emotion, and mood symptoms. Links between depression sleep and circadian rhythms have long been suspected due to the existence of seasonal depression, where the onset of low mood correlates with a reduction in day length. Seasonal affective disorder (SA) is primarily a circadian rhythm disorder. Alfred Lewy discusses the theory of misalignement between the circadian rhythm of melatonin secretion and the midpoint of the sleep bout, and emphasise the importance or careful timing of treatment administration (bright light or melatonin). Timing of treatment administration requiring detailed information on patients’ phase state and the role of new accessible tools such as dim light melatonine onset are evaluated as are different treatment modalities. The importance of biological rhythms in SA disorder has led to an interest in the role of circadian rhythms in the development of depression. The successes of chronobiotic treatments for SA disorder have led to the trialling of psychological and pharmacological treatments targeting circadian rhythms in unipolar major depression (MDD). The review by Sarah Hartley et al. focuses on the research linking circadian rhythms and depression, and on the evidence for effectiveness of chronobiotic treatments such as high intensity light, melatonin or melatonin agonist or behavioural therapy in MDD. The evidence base for novel antidepressants combining 5HT2c antagonist and melatonin agonist action in acute treatment of unipolar MDD and in relapse prevention is reviewed as is their use in clinical management of MDD. Managing bipolar disorder is a challenge for psychiatrists and it has been long known that sleep disorders are a sign of relapse. Carole Boudebesse et al. examine the evidence that sleep and circadian rhythms are disturbed in bipolar patients during both mood episodes and periods of remission. Therapeutic applications of chronobiology in bipolar disorder, such as specific psychosocial interventions, light therapy and physical exercise are described. Finally, psychiatrists are faced with frequent reports of sleep disorders in adults and children with attentiondeficit/ hyperactivity disorder (ADHD) and, conversely, sleep specialists report certain symptoms of ADHD (attention deficits, fidgeting) in patients suffering from primary sleep disorders. Are ADHD symptoms secondary to sleep fragmentation due to sleep disorders such as sleep disordered breathing and periodic legs movements, and treatable with treatment of these specific disorders? Could some ADHD subjects share a common deficit in the sleep/wake regulation systems resulting in sleep fragmentation? The pathophysiological relationship between sleep disorders and ADHD is complex and probably multidirectional. The hot topic from the team of Astrid Claret et al. reviews the latest research and aims to help clinicians in developing a framework for understanding and treating patients suffering from ADHD and sleep disorders.

Sleep, depression and insomnia have manifold associations. Psychiatric sleep research in affective disorders has demonstrated that sleep in depression is characterized by an impairment of sleep continuity, deficits in slow wave sleep and a disinhibition of REM sleep (including shortened REM latency and increased REM density). Traditionally, insomnia, i.e. prolonged latency to fall asleep and increased frequency of nocturnal wake periods, was considered as an unspecific symptom of affective disorders. In the meantime, a shift in clinical and scientific focus has taken place viewing insomnia in addition as an independent diagnostic entity and as a clinical predictor of depression. Unfortunately, the neurobiological processes underlying the relationships between sleep, insomnia and depression have not been fully identified yet. It is clear that both insomnia and depression are characterized by alterations in the arousal system in the CNS presenting as hyperarousal. Moreover, insomniac patients display reduced and fragmented REM sleep periods, which might interfere negatively with basal processes of emotion regulation. The alterations in the arousal system and the interaction of it with the affect-regulatory system over the course of time might influence cognitive systems and hence lead to the clinical picture of depression. Given the suggestion of insomnia symptoms as possibly involved in the causation and the maintenance of psychopathology in general, this type of sequence might also be found in relation to other mental disorders.

More than three decades ago, bright light was found to be able to suppress melatonin production in humans, a finding which quickly led to identification of seasonal affective disorder (SAD) and its treatment with light. However, current thinking supports a phase shift hypothesis (PSH), according to which SAD is a disorder primarily of phasedelayed circadian misalignment {best assessed by the time interval [or phase angle difference (PAD)]} between the dim light melatonin onset (DLMO) and the midpoint of the sleep bout. It has been heuristically useful to use PAD 6 (a time interval of six hours) as the “sweet spot” for SAD: most patients with SAD have phase-delayed circadian misalignment (that is, have PADs ≤ 6), which explains why bright light exposure scheduled at waketime is the optimal treatment for most patients with SAD. Low-dose melatonin taken in the afternoon/evening also provides a corrective phase advance and is therefore an alternative or “add-on” treatment for these patients. The other SAD patients appear to be phase advanced (with PADs > 6) and respond to evening light and morning melatonin. Other hypotheses have not stood the test of time, including the two-oscillator dawn/dusk model of the endogenous circadian pacemaker which has been at least heuristically useful in rodents. However, recent research on multiple oscillators in the SCN and brain, as well as in other tissues and organs, may yet yield a more refined understanding of circadian misalignment. The salivary home DLMO may soon be the first laboratory test for a psychiatric disorder.

Major depressive disorder (MDD) is a highly prevalent and disabling disease. Recent studies have highlighted the interactions between the circadian system and depression and indicate a probable bidirectional relationship between MDD and the circadian system. In clinical practice MDD leads to circadian disturbances, and circadian disorders increase the risk of depression. Recent interest has focused on the use of melatonin and melatonin agonists in the treatment and relapse prevention of MDD. This review summarises the mechanisms of the biological clock and its links with MDD. It looks at the effects of melatonin and melatonin agonists on sleep and on symptoms of depression and focuses on agomelatine, a MT1/MT2 agonist and a 5-HT2C antagonist which combines a chronobiotic and antidepressant action with similar efficacy to fluoxetine, venlafaxine and sertraline. Relapse rates are reduced on agomelatine compared to placebo. Agomelatine is well tolerated and rapid improvements in disturbed sleep are reported by patients. In the light of these studies, the potential role of melatonin agonists in treating MDD and subtypes of MDD is discussed.

This review considers evidence that sleep and circadian rhythms are disturbed in bipolar patients during both mood episodes and periods of remission. Indeed, bipolar patients display disturbances of subjective and objective circadian markers, in sleep continuity, and in cortisol and melatonin secretion. Better characterization of sleep and circadian rhythms can improve personalized assessment and help identify treatment focusing on normalizing these disturbances. Therapeutic applications of chronobiology in bipolar disorder, such as specific psychosocial intervention, light therapy and physical exercise are described. The study of sleep and circadian rhythms opens innovative avenues in research concerning the pathophysiology of bipolar disorder, including the possible discovery of biomarkers, and may lead to a better understanding of genes role in bipolar disorder regarding associations of some circadian genes polymorphisms with bipolar disorder.

The links between sleep and attention-deficit hyperactivity disorder (ADHD) have been a topic of ongoing research and clinical interest in children over the last three decades and more recently in adults suffering from ADHD. Clinically, psychiatrists are faced with frequent reports of sleep disorders in adults and children with ADHD and conversely, sleep specialists report certain symptoms of ADHD (attention deficits, urge for fidgeting) in patients suffering from primary sleep disorders. Excessive sleepiness is found in ADHD and sleep disorders such as hypersomnia, sleep breathing disorder (SDB), periodic limb movements in sleep (PLMS) and circadian rhythm disorders. This has encouraged authors to suggest a model of ADHD involving a deficit in alertness. The aim of this article is to clarify the pathophysiological rationale for the relationship between sleep/arousal and attention-deficit/hyperactivity disorder and to explore future perspectives in terms of management, treatment and development of research fields.

Perinatal depression is an emerging field with questions that remain to be answered, including the underlying pathogenesis, treatment and counseling. Pregnant women with depression represent a serious risk to themselves due to negative fetal/obstetrical and neonatal outcomes and to their child with respect to development later in life. The immune system plays a crucial role in major depression disorder (MDD), and studies indicate that both immune mediators (cytokines, chemokines) and neuroendocrine hormones cross-talk in MDD. However, the innate immune system is an unexplored field, and its link with prenatal depression has not been fully explored. The innate immune system is tightly regulated during early implantation and placentation of the conceptus, and such regulation is crucial for a successful pregnancy. T lymphocytes, which comprise helper T lymphocytes (Th), and cytotoxic T lymphocytes (CTLs), have been shown to be abundant at the fetomaternal interface together with the recruitment of different subsets of immune cells [Natural Killer cells (NK), Dendritic cells (DCs), Macrophages (Mφs)] during decidualization of the endometrium. Pregnancy is considered to be an inflammatory process in which a Th2 over a Th1 immune response is critical for allowing the development of the fetal allograft. Stressful stimuli and prenatal infections have been shown to deregulate the Th1/Th2 balance and are associated with increased production of proinflammatory cytokines and modification of neonatal immune responses via toll-like receptor (TLR) signaling. The innate immune system could represent a new frontier in exploring the etiology of several mental disorders, as suggested for schizophrenia. However, it is not clear how the innate immune system cross-talks with the fetal brain during perinatal depression.