Advances in the management of insomnia

Insomnia is a prevalent disorder, altering night time sleep, daytime mood and performance. Current treatment strategies, used separately or in combination, include pharmacological, circadian, behavioural and cognitive therapy. An increased diversity of available hypnotics with different potency, pharmacodynamic and pharmacokinetic profiles and improved side effect profiles provides more flexibility in designing individual treatment strategies. Melatonin, a pineal hormone with acute sleep-promoting and chronobiotic properties, allows additional possibilities in treating insomnia and circadian sleep disorders. Current studies of processes involved in normal sleep regulation and pathophysiology of insomnia should result in the development of new medications based on physiological mechanisms of sleep.     

Neurochemical and neuropharmacological aspects of circadian disruptions: an introduction to asynchronization

Circadian disruptions are common in modern society, and there is an urgent need for effective treatment strategies. According to standard diagnostic criteria, most adolescents showing both insomnia and daytime sleepiness are diagnosed as having behavioral-induced sleep efficiency syndrome resulting from insomnia due to inadequate sleep hygiene. However, a simple intervention of adequate sleep hygiene often fails to treat them. As a solution to this clinical problem, the present review first overviews the basic neurochemical and neuropharmachological aspects of sleep and circadian rhythm regulation, then explains several circadian disruptions from similar viewpoints, and finally introduces the clinical notion of asynchronization. Asynchronization is designated to explain the pathophysiology/pathogenesis of exhibition of both insomnia and hypersomnia in adolescents, which comprises disturbances in various aspects of biological rhythms. The major triggers for asynchronization are considered to be a combination of light exposure during the night, which disturbs the biological clock and decreases melatonin secretion, as well as a lack of light exposure in the morning, which prohibits normal synchronization of the biological clock to the 24-hour cycle of the earth and decreases the activity of serotonin. In the chronic phase of asynchronization, involvement of both wake- and sleep-promoting systems is suggested. Both conventional and alternative therapeutic approaches for potential treatment of asynchronization are suggested.     

Cognitive and behavioral treatment options for insomnia

Insomnia is a costly disorder that affects a significant number of people. In many cases, insomnia is comorbid with other illnesses, which complicates its diagnosis and treatment. Most often it is treated with medication; however, patients are not always safe using hypnotics, and medication does not attack the source of the disorder. Cognitive behavioral therapies are better for long-term treatment because they address factors causing or perpetuating insomnia, as opposed to treatments that focus on symptoms. This article examines various nonpharmacological treatments for insomnia. In addition, because circadian rhythm disorders may exhibit symptoms similar to insomnia, there is also a brief overview of 2 common circadian rhythm disorders, delayed sleep phase syndrome and advanced sleep phase syndrome.     

Sleep disturbances in patients with post-traumatic stress disorder: epidemiology, impact and approaches to management

Subjective reports of sleep disturbance indicate that 70-91% of patients with post-traumatic stress disorder (PTSD) have difficulty falling or staying asleep. Nightmares are reported by 19-71% of patients, depending on the severity of their PTSD and their exposure to physical aggression. Objective measures of sleep disturbance are inconsistent, with some studies that used these measures indicating poor sleep and others finding no differences compared with non-PTSD controls. Future research in this area may benefit from examining measures of instability in the microstructure of sleep. Additionally, recent findings suggest that sleep disordered breathing (SDB) and sleep movement disorders are more common in patients with PTSD than in the general population and that these disorders may contribute to the brief awakenings, insomnia and daytime fatigue in patients with PTSD. Overall, sleep problems have an impact on the development and symptom severity of PTSD and on the quality of life and functioning of patients. In terms of treatments, SSRIs are commonly used to treat PTSD, and evidence suggests that they have a small but significant positive effect on sleep disruption. Studies of serotonin-potentiating non-SSRIs suggest that nefazodone and trazodone lead to significant reductions in insomnia and nightmares, whereas cyproheptadine may exacerbate sleep problems in patients with PTSD. Prazosin, a centrally acting alpha1-adrenoceptor antagonist, has led to large reductions in nightmares and insomnia in small studies of patients with PTSD. Augmentation of SSRIs with olanzapine, an atypical antipsychotic, may be effective for treatment-resistant nightmares and insomnia, although adverse effects can be significant. Additional medications, including zolpidem, buspirone, gabapentin and mirtazapine, have been found to improve sleep in patients with PTSD. Large randomised, placebo-controlled trials are needed to confirm the above findings. In contrast, evidence suggests that benzodiazepines, TCAs and MAOIs are not useful for the treatment of PTSD-related sleep disorders, and their adverse effect profiles make further studies unlikely. Cognitive behavioural interventions for sleep disruption in patients with PTSD include strategies targeting insomnia and imagery rehearsal therapy (IRT) for nightmares. One large randomised controlled trial of group IRT demonstrated significant reductions in nightmares and insomnia. Similarly, uncontrolled studies combining IRT and insomnia strategies have demonstrated good outcomes. Uncontrolled studies of continuous positive airway pressure for SDB in patients with PTSD show that this treatment led to significant decreases in nightmares, insomnia and PTSD symptoms. Controlled studies are needed to confirm these promising findings.     

Role of the melatonin system in the control of sleep: therapeutic implications

The circadian rhythm of pineal melatonin secretion, which is controlled by the suprachiasmatic nucleus (SCN), is reflective of mechanisms that are involved in the control of the sleep/wake cycle. Melatonin can influence sleep-promoting and sleep/wake rhythm-regulating actions through the specific activation of MT(1) (melatonin 1a) and MT(2) (melatonin 1b) receptors, the two major melatonin receptor subtypes found in mammals. Both receptors are highly concentrated in the SCN. In diurnal animals, exogenous melatonin induces sleep over a wide range of doses. In healthy humans, melatonin also induces sleep, although its maximum hypnotic effectiveness, as shown by studies of the timing of dose administration, is influenced by the circadian phase. In both young and elderly individuals with primary insomnia, nocturnal plasma melatonin levels tend to be lower than those in healthy controls. There are data indicating that, in affected individuals, melatonin therapy may be beneficial for ameliorating insomnia symptoms. Melatonin has been successfully used to treat insomnia in children with attention-deficit hyperactivity disorder or autism, as well as in other neurodevelopmental disorders in which sleep disturbance is commonly reported. In circadian rhythm sleep disorders, such as delayed sleep-phase syndrome, melatonin can significantly advance the phase of the sleep/wake rhythm. Similarly, among shift workers or individuals experiencing jet lag, melatonin is beneficial for promoting adjustment to work schedules and improving sleep quality. The hypnotic and rhythm-regulating properties of melatonin and its agonists (ramelteon, agomelatine) make them an important addition to the armamentarium of drugs for treating primary and secondary insomnia and circadian rhythm sleep disorders.     

Drugs for insomnia

Introduction: Sleep is a vital neurochemical process involving sleep-promoting and arousal centers in the brain. Insomnia is a pervasive disorder characterized by difficulties in initiating or maintaining or non-refreshing (poor quality) sleep and clinically significant daytime distress. Insomnia is more prevalent in women and old age and puts sufferers at significant physical and mental health risks. This review summarizes published data on the current and emerging insomnia drug classes, rationale for development and associated risks/benefits. (Summary of Product Characteristics and Medline search on "hypnotic" or specific drug names and "Insomnia"). Areas covered: GABA(A) receptor modulators facilitate sleep onset and some improve maintenance but increase risk of dependence, memory, cognitive and psychomotor impairments, falls, accidents and mortality. Melatonin receptor agonists improve quality of sleep and/or sleep onset but response may develop over several days. They have more benign safety profiles and are indicated for milder insomnia, longer usage and (prolonged release melatonin) older patients. Histamine H-1 receptor antagonists improve sleep maintenance but their effects on cognition, memory and falls remain to be demonstrated. Late-stage pipeline orexin OX1/OX2 and serotonin 5HT2A receptor antagonists may hold the potential to address several unmet needs in insomnia pharmacotherapy but safety issues cast some doubts over their future. Expert opinion: Current and new insomnia drugs in the pipeline target different sleep regulating mechanisms and symptoms and have different tolerability profiles. Drug selection would ideally be based on improvement in the quality of patients' sleep, overall quality of life and functional status weighed against risk to the individual and public health.     

用于治疗失眠的褪黑激素受体激动剂研究进展

褪黑激素为一种内源性生理物质,可通过激动褪黑激素受体MT1和MT2来调节昼夜节律及睡眠质量。MT1和MT2由此成为失眠治疗药物的潜在靶点。介绍褪黑激素的作用机制,以及可用于治疗失眠的褪黑激素受体激动剂的研究进展,并初步探讨其构效关系。     

Ramelteon: TAK 375

Ramelteon [TAK 375] is a melatonin (MT1/MT2) receptor agonist that is being developed by Takeda as a treatment for sleep disorders. It is undergoing regulatory review in the US, phase III trials in Europe, and phase II trials in Japan for the treatment of insomnia. Phase II trials are also being conducted in the US for the treatment of circadian rhythm sleep disordersIn September 2004, Takeda submitted an NDA to the US FDA for ramelteon for the treatment of insomnia. In May 2003, data presented at the 156th Annual Meeting of the American Psychiatric Association report that ramelteon is highly selective for the MT1 receptor, and has greater affinity, selectivity and potency than melatonin.     

Sleep disorders in patients with traumatic brain injury: a review

Traumatic brain injury (TBI) is a global problem and causes long-term disability in millions of individuals. This is a major problem for both military- and civilian-related populations. The prevalence of sleep disorders in individuals with TBI is very high, yet mostly unrecognized. Approximately 46% of all chronic TBI patients have sleep disorders, which require nocturnal polysomnography and the Multiple Sleep Latency Test for diagnosis. These disorders include sleep apnoea (23% of all TBI patients), post-traumatic hypersomnia (11%), narcolepsy (6%) and periodic limb movements (7%). Over half of all TBI patients will have insomnia complaints, most often with less severe injury and after personal assault, and half of these may be related to a circadian rhythm disorder. Hypothalamic injury with decreased levels of wake-promoting neurotransmitters such as hypocretin (orexin) and histamine may be involved in the pathophysiology of excessive sleepiness associated with TBI. These sleep disorders result in additional neurocognitive deficits and functional impairment, which might be attributed to the original brain injury itself and thus be left without specific treatment. Most standard treatment regimens of sleep disorders appear to be effective in these patients, including continuous positive airway pressure for sleep apnoea, pramipexole for periodic limb movements and cognitive behavioural therapy for insomnia. The role of wake-promoting agents and CNS stimulants for TBI-associated narcolepsy, post-traumatic hypersomnia and excessive daytime sleepiness requires further study with larger numbers of patients to determine effectiveness and benefit in this population. Future research with multiple collaborating centres should attempt to delineate the pathophysiology of TBI-associated sleep disorders, including CNS-derived hypersomnia and circadian rhythm disturbances, and determine definitive, effective treatment for associated sleep disorders.     

Drugs for insomnia

Introduction: Sleep is a vital neurochemical process involving sleep-promoting and arousal centers in the brain. Insomnia is a pervasive disorder characterized by difficulties in initiating or maintaining or non-refreshing (poor quality) sleep and clinically significant daytime distress. Insomnia is more prevalent in women and old age and puts sufferers at significant physical and mental health risks. This review summarizes published data on the current and emerging insomnia drug classes, rationale for development and associated risks/benefits. (Summary of Product Characteristics and Medline search on "hypnotic" or specific drug names and "Insomnia").

Areas covered: GABA_A receptor modulators facilitate sleep onset and some improve maintenance but increase risk of dependence, memory, cognitive and psychomotor impairments, falls, accidents and mortality. Melatonin receptor agonists improve quality of sleep and/or sleep onset but response may develop over several days. They have more benign safety profiles and are indicated for milder insomnia, longer usage and (prolonged release melatonin) older patients. Histamine H-1 receptor antagonists improve sleep maintenance but their effects on cognition, memory and falls remain to be demonstrated. Late-stage pipeline orexin OX1/OX2 and serotonin 5HT2A receptor antagonists may hold the potential to address several unmet needs in insomnia pharmacotherapy but safety issues cast some doubts over their future.

Expert opinion: Current and new insomnia drugs in the pipeline target different sleep regulating mechanisms and symptoms and have different tolerability profiles. Drug selection would ideally be based on improvement in the quality of patients' sleep, overall quality of life and functional status weighed against risk to the individual and public health.     

New perspectives for the treatment of disorders of sleep and arousal

A variety of molecules with novel mechanisms of action are currently being evaluated for their potential as treatments for sleep disorders. The GABA-A receptor complex remains an important target for hypnotic drugs (eg gaboxadol, indiplon). However, drugs acting through histamine, calcium channels and serotonin receptors may also be of interest for the treatment of insomnia. In the case of the 5HT2A subtype of serotonin receptors, several molecules which improve sleep maintenance and modify sleep architecture by increasing slow wave sleep are currently being tested (eg eplivanserin). Two new drugs with efficacy in excessive sleepiness (modafinil, sodium oxybate) have improved the treatment of this condition. However, the mechanisms of action of these agents are poorly understood. The recent discovery of the hypocretin arousal system in the hypothalamus may aid the identification of additional new drugs. An agonist at receptors for the pineal hormone melatonin is available in some countries (ramelteon) but is currently used only for the treatment of insomnia associated with difficulties of sleep onset. Additional melatonin receptor agonists are being developed and may have potential for treating several conditions including circadian rhythm disorders and depression.     

Lormetazepam in depressive insomnia: new evidence of phase-response effects of benzodiazepines

Benzodiazepines can shift the phase of circadian rhythms in mammalian species, but few data are available on their phase-response effects in humans, and on possible links between timing of administration and hypnotic efficacy. Using a placebo-controlled, cross-over design, we evaluated the hypnotic effect of lormetazepam 0.03 mg/kg and placebo in 38 inpatients who were affected by a major depressive episode. Patients were divided into three groups, receiving treatment at 18.00 h, 20.00 h or 22.00 h, respectively. Sleep and psychiatric symptoms were evaluated with self-administered scales and a sleep diary. The results demonstrate that active treatment significantly improved insomnia independent of the severity of depression, which remained unchanged. Timing of treatment influenced changes in timing of sleep observed with active treatment. Although sleep duration was equally improved in all treatment groups, patients who received treatment at 20.00 h showed an acute advance of sleep onset, with no changes in morning awakening. Patients who received treatment at 22.00 h showed an acute delay in morning awakening, with no changes of sleep onset. Finally, patients who received treatment at 18.00 h showed a non-significant trend in the same direction. These effects reverted with cross-over return to placebo. The perceived degree of improvement of insomnia was proportional to the advance in timing of sleep onset obtained with treatment. Our results suggest that the effects of lormetazepam on the subjective sleep of patients affected by a major depressive episode depend upon the timing of administration, and that improvement in subjective sleep is related to advance of sleep onset, and not to delay of morning awakening.     

Ramelteon

Ramelteon, approved in the US for the treatment of insomnia characterised by difficulty with sleep onset, is a highly selective agonist for the melatonin MT1/MT2 receptors, which are believed to mediate the circadian rhythm in mammals. Ramelteon has negligible affinity for the MT3 binding sites and other receptors in the brain, including the opiate, dopamine, benzodiazepine and serotonin receptors, which may explain the lack of significant adverse events and lack of abuse or dependence potential observed with ramelteon. In three clinical trials in patients with chronic insomnia, ramelteon 8mg was effective in reducing sleep latency, without being associated with any significant or clinically relevant residual effects. It also generally increased total sleep time and, where assessed, sleep efficiency. In a first-night-effect model of transient insomnia, ramelteon 8mg was significantly more effective than placebo at reducing sleep latency and increasing total sleep time. Ramelteon was generally well tolerated; the most commonly reported adverse events occurring in more ramelteon than placebo recipients were somnolence (5% vs 3%), fatigue (4% vs 2%) and dizziness (5% vs 3%). Adverse events were mostly mild or moderate in nature. Ramelteon has been shown to have no potential for abuse or dependence.     

Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep‐Wake Disorders

Circadian rhythm sleep‐wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non–24‐hour sleep‐wake disorder (or non‐24). However, three additional commercially available melatonin receptor agonists—agomelatine, prolonged‐release melatonin, and ramelteon—have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.     

Patent Update: Central & Peripheral Nervous System: Agents for the treatment of sleep disorders: patent activity July 1992 to June 1994

This update includes basic patents and patent applications published between July 1992 and June 1994 which may have utility for the treatment of three major groups of sleep disorders, namely, simple insomnia, sleep disorders secondary to anxiety or mood disorders, and sleep disorders stemming from circadian rhythm disruptions. Accordingly, the patents are grouped by their presumed mode of action as non-psychotropic agents, psychotropic agents, and chronobtotic agents. For the purposes of this review, only those patents and applications which specifically describe or claim sleep enhancing or sedative-hypnotic properties are included. Coverage is limited to novel small-molecule, non-peptidergic agents.     

Methylphenidate Modifies the Motion of the Circadian Clock

People with attention-deficit/hyperactivity disorder (ADHD) often experience sleep problems, and these are frequently exacerbated by the methylphenidate they take to manage their ADHD symptoms. Many of the changes to sleep are consistent with a change in the underlying circadian clock. The present study was designed to determine if methylphenidate alone could alter properties of the circadian clock. Young male mice were examined in light–dark cycles and in constant darkness and recordings were performed on behavioral activity, sleep, and electrical activity in the suprachiasmatic nucleus (SCN) of freely moving mice. Methylphenidate in the drinking water (0.08%) significantly increased activity in the mid-to-late night, and led to a delay in the onset of activity and sleep relative to the light–dark cycle. While locomotor levels returned to baseline after treatment ended, the phase angle of entrainment required at least a week to return to baseline levels. In constant darkness, the free-running period of both wheel-running and general locomotor rhythms was lengthened by methylphenidate. When the treatment ended, the free-running period either remained stable or only partially reverted to baseline levels. Methylphenidate also altered the electrical firing rate rhythms in the SCN. It induced a delay in the trough of the rhythm, an increment in rhythm amplitude, and a reduction in rhythm variability. These observations suggest that methylphenidate alters the underlying circadian clock. The observed changes are consistent with clock alterations that would promote sleep-onset insomnia.     

Orexin receptor antagonists – a patent review (2010 to August 2014)

Introduction: The orexin (hypocretin) system is an evolutionarily conserved neuropeptide-G-protein-coupled receptor system, consisting of two neuropeptides the orexin-A and the orexin-B peptides as well as two receptors the orexin-1 and the orexin-2 receptors. The orexin system is crucially involved in the regulation of the circadian rhythm, states of wakefulness and arousal and the modulation of emotions and has attracted the interest of many researchers which resulted in an enormous amount of insight, mainly in the field of antagonists. Clinical proof of concept was obtained with dual orexin receptor antagonists in primary insomnia. Merck’s suvorexant got FDA approval on 13 August 2014 for the treatment of insomnia.

Areas covered: The patent applications from Thomson Reuters Integrity Database (covering 2010 – August 2014) are summarized, analyzed and discussed in the review.

Expert opinion: Intense patenting activities have been observed over the past 3 years in the field of orexin antagonists. Several compounds have been investigated in clinical trials mainly for the treatment of primary insomnia. The advantage of orexin antagonists, based on animal pharmacology results, is the promotion and maintenance of physiological sleep which should avoid hangover phenomena reported as side effects of approved treatments. Many other potential treatment options are mentioned for orexin antagonists of different selectivity profiles.     

Rapid-acting antidepressant strategies: mechanisms of action

Current antidepressants are ineffective in many depressed patients. Thus there is an urgent need to develop treatment strategies which have significantly faster response, can be sustained and have minimal side-effects. This paper reviews clinical data, potential biomarkers, mechanisms of action and future research directions for two proven strategies that produce marked improvement in severe depressive symptoms within 48 h, ketamine and sleep deprivation therapy (SDT). These treatments provide unequivocal evidence that the depressive process can be rapidly reversed in a subgroup of patients. Seventeen ketamine studies in over 150 patients showed a rapid response. Low-dose intravenous ketamine produced mild psychotomimetic effects but response has not been effectively sustained. SDT has been investigated in over 60 studies with a 40-60% response rate within 48 h. Although SDT is often used in Europe to initiate a rapid response, it is less utilized within the USA, in part, because it has a short duration when administered alone. We review data concerning chronotherapeutic strategies of bright-light therapy (BLT) and sleep-phase advance (SPA) which successfully sustain the antidepressant efficacy of SDT. Evidence is further discussed that a significant group of mood disorders have abnormal circadian rhythms which are known to be controlled by clock genes. It is hypothesized that chronotherapeutic manipulations can reset clock genes and thus, abnormalities in circadian rhythms. Further findings are reviewed that ketamine, in addition to its role as an NMDA antagonist, can also alter circadian rhythms. Thus, ketamine may share a critical mechanism with SDT.     

Current treatment options for insomnia

Patient complaints of insomnia continue to perplex many physicians because of the vast array of potential causes and multiple strategies to treat this symptom complex. The present review summarizes available pharmacological and nonpharmacological interventions for insomnia. A specialized assessment and treatment plan is required for all patients, taking into account all aspects of their life and the characteristics of their sleep disturbance.     

Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Zaleplon Clinical Study Group

The efficacy and safety of three doses of zaleplon, a novel non-benzodiazepine hypnotic, were compared with those of placebo in outpatients with insomnia in this 4-week study, using zolpidem 10 mg as active comparator. Postsleep questionnaires were used to determine treatment effects on the patient's perception of sleep, as well as any development of pharmacological tolerance during therapy or rebound insomnia or withdrawal symptoms upon discontinuation of therapy. During week 1, sleep latency was significantly shorter with zaleplon 5, 10, and 20 mg compared to placebo. The significant decrease in sleep latency persisted through week 4 with zaleplon 20 mg, and was again evident with zaleplon 10 mg at week 3. Zaleplon 20 mg also had significant effects on sleep duration, number of awakenings, and sleep quality compared to placebo. No pharmacological tolerance developed during treatment with zaleplon and there were no indications of rebound insomnia or withdrawal symptoms after treatment discontinuation. Zolpidem 10 mg had significant effects on sleep latency, sleep duration, and sleep quality compared to placebo. However, a significantly greater incidence of withdrawal symptoms and a suggestion of sleep difficulty after treatment discontinuation (rebound insomnia) for all sleep measures was seen with zolpidem compared to placebo. There was no significant difference in the frequency of adverse events with active treatment compared to placebo. These results show that zaleplon provides effective treatment of insomnia with a favourable safety profile.