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Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time
Keith A. Wafford* and Bjarke Ebert‡ Abstract | Sleep is essential for our physical and mental well being. However, when novel hypnotic drugs are developed, the focus tends to be on the marginal and statistically significant increase in minutes slept during the night instead of the effects on the quality of wakefulness. Recent research on the mechanisms underlying sleep and the control of the sleep–wake cycle has the potential to aid the development of novel hypnotic drugs; however, this potential has not yet been realized. Here, we review the current understanding of how hypnotic drugs act, and discuss how new, more effective drugs and treatment strategies for insomnia might be achieved by taking into consideration the daytime consequences of disrupted sleep.
Primary insomnia Humans spend approximately one-third of their lifetime Insomnia is defined as difficulty in initiating and/or Patients who suffer from sleeping, but we still know relatively little about why this maintaining sleep. The incidence of insomnia in the gen- sleeplessness for at least process is so critical for every living animal. Current eral population is between 10–30%, and approximately 1 month that cannot be thinking suggests that waking activity is relatively 50% of the cases complain of serious daytime conse- attributed to a medical, dynamic in terms of using the body’s resources: breaking quences, such as inability to concentrate, reduced energy psychiatric or an environmental cause (such as drug abuse or down proteins, gathering information and expending and memory problems. When this persists for more medications). energy. Sleep is the period of consolidation: processing than 1 month, without an associated mental disorder the information gathered during the day, synthesizing or physical problem, it is classified as primary insomnia. Sedative new proteins from nutrients ingested, and healing wear Transient insomnia is usually associated with specific A substance that depresses and tear of the body’s muscles and tissues. events such as periods of stress or anxiety, and insom- the central nervous system, resulting in calmness, Although the body is relatively inactive during sleep, nia is often linked to other psychological or physical relaxation, reduction of the brain is still very active, and cycles through a number problems such as depression or chronic pain. anxiety and sleepiness. of stages that can be monitored using electroencephalo- Insomnia treatment continues to be dominated by gram electrodes. These changes can be broken down into benzodiazepines and related compounds, which are Tolerance sedatives Reduced drug responsiveness rapid eye movement (REM) and non-REM activity. In powerful that enhance the inhibitory action of with repeated exposure to a primates and felines, non-REM sleep is characterized by GABA (γ-aminobutyric acid) in the brain. But they are constant drug dose. low frequency and gradually higher amplitude electrical also associated with the development of tolerance and activity; it includes light sleep (also referred to as Stage dependence, amnesia and withdrawal problems, particu- 1 or 2) and deep sleep (also referred to as Stage 3 or 4) larly after prolonged use or in elderly patients4,5. We now (BOX 1) . This deep stage of sleep, often called slow-wave understand in detail how benzodiazepines affect GABAA sleep (SWS), is thought to be important for the consoli- receptor function. However, when it comes to linking dation of memories. REM sleep, characterized by high their action to sleep mechanisms, there is still much *Eli Lilly UK, Erl Wood Manor, Windlesham, frequency, low-amplitude electrical activity, has also been to learn. To improve our knowledge of sleep function 1 Surrey GU20 6PH, UK. implicated in this process . In this mode the brain appears and dysfunction, and develop improved therapeutics, it ‡ H. Lundbeck, Ottiliavej 9, to be as active as during wake periods and dreaming will be crucial to understand how modulators of GABAA 2500 Valby, Denmark. occurs, which might represent the replaying of events receptors affect sleep, the impact that other neurotrans- Correspondence to B.E. to be encoded to memory. Recent studies have demon- mitter systems have on sleep and the deeply ingrained e-mail: [email protected] doi:10.1038/nrd2464 strated the cognitive consequences of REM and SWS circadian control over the sleep–wake cycle. Published online disruption, and have also shown that different stages of The development of truly novel therapies, however, 23 May 2008 sleep affect different types of memory consolidation2,3. does not solely require insight into sleep mechanisms
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Box 1 | Sleep parameters and measures The way in which sleep is quantified and described is critical for determining deficiencies in patients with insomnia and has contributed useful metrics for demonstrating the efficacy of hypnotics. Both objective and subjective measures of total sleep time, latency to sleep onset and number of awakenings during sleep, among others, give a good measure of sleep efficiency. The use of polysomnography or electroencephalography has enabled researchers to measure electrical activity in the brain over the course of the night. This activity can be classified into different stages as shown below. During the night, in primates and felines, activity proceeds from waking, through rapid eye movement (REM) and the four stages of non-REM sleep several times, giving a characteristic pattern known as the sleep cycle. Total REM sleep time, the number of non-REM sleep bouts and the time to reach these states are among the variables that can be measured. When combined, these measures allow a detailed picture of an individual or animals’ sleep cycle. The awake stage is characterized by high frequency activity with variable amplitude, combined with active electromyography (EMG). The REM stage is characterized by high frequency activity with high amplitude and no active EMG. Non-REM sleep consists of four stages: • Stage 1: light or drowsy sleep, dominated by theta frequency (4–7 Hz). • Stage 2: unconsciousness, lower EMG, EEG contains sleep spindles (12–15 Hz events). • Stage 3: deep sleep, slow-wave sleep (0.5-4 Hz) occurs less than 50% of time. • Stage 4: deep sleep, slow-wave sleep occurs more than 50% of the time. In rodents, sleep stages are usually divided into REM and non-REM sleep. Non-REM sleep is often subdivided into SWS‑1 and SWS‑2, mimicking Stages 1–2 and 3–4, respectively. a
Awake
Stage 1 REM
Stage 2
Stage 3 b Awake Stage 1 Stage 4 Stage 2 Stage 3 Stage 4 Time (h)
Image modified with permission from Nature Reviews Neuroscience REF. 80 (2002) Macmillan Publishers Ltd. Nature Reviews | Drug Discovery
and drug action. All currently available hypnotic drugs and strategies for their clinical evaluation. Together have been developed with the focus on one particular these might lead to the development of new drugs that patient population: the primary insomniacs. This address the limitations of existing ones. patient population is characterized by having problems in initiating and/or maintaining sleep and complaints Understanding sleep mechanisms about daytime performance, but also without any co- The discovery of specific pathways involved in governing morbidities and thereby with few, or less severe, daytime sleep has greatly improved our understanding of sleep consequences. As the current regulatory environment function and the differences in brain activity while we for novel hypnotic drugs has focused on technical are asleep or awake. A number of key nuclei in the brain- parameters such as sleep induction and maintenance stem and hypothalamus have been proposed to form of sleep in primary insomniacs, the real challenge, that a ‘sleep circuit’. The arousal centres, such as the locus is, to improve the quality of wake time of people suffering coeruleus, dorsal raphe and tuberomamillary nucleus from insomnia, seems to be neglected. By using primary project to the cortex via the hypothalamus. Others, insomniacs as the patient population for the develop- such as the pedunculopontine nucleus and laterodorsal ment of hypnotics, we have limited ourselves from tegmental nuclei, project through the thalamus (FIG. 1). the opportunities of demonstrating positive effects on In turn, inhibition of these arousal centres comes from daytime performance. There is, therefore, a strong need nuclei in the hypothalamus, such as the ventrolateral for new thinking, both by drug developers and from preoptic nucleus (VLPO) and median preoptic nucleus. Hypnotic drugs regulatory authorities. These nuclei form a mutual inhibitory–excitatory loop, A class of drug that induces sleep; used for the treatment Here, we review the current understanding of sleep with arousal centres active during wake and inhibitory of insomnia and to induce mechanisms, briefly discuss existing therapeutic centres active during sleep. The nature of this circuit anaesthesia. agents, and then highlight emerging therapies, targets predisposes it to a ‘flip–flop’ switch mechanism, being
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in either one state or the other, with a very rapid transi- deprivation and recovery highlighted several immediate tion state6. This rapid transition state is highly conserved early genes and heat-shock proteins that were upregu- across species and is an important survival mechanism. lated during sleep deprivation and recovery in mice and The mechanisms that control this circuit, and the rats20–22 (TABLE 1). Furthermore, a study that compared factors that influence it, have been the topic of consider- the action of two widely used hypnotic benzodiazepines, able research, providing new insights and opportuni- triazolam and zolpidem, with sleep recovery following ties for treating sleep-related disorders. Two different deprivation found that only a subset of the genes asso- factors have a major impact on the sleep–wake cycle. ciated with sleep recovery were elevated with hypnotic First, environmental, or homeostatic influences, such treatment23. This suggests that current therapies do not as the accumulation of sleep debt following prolonged provide the full benefits afforded by natural sleep. These wakefulness and/or anxiety, and second, the endogenous studies are the first to address the mechanisms that might circadian rhythm, which produces the 24-hour cycle and underlie insomnia and suggest possible targets for drug governs many biological processes. therapy. Together with proteomic technology, such studies should help to elucidate the changes brought about by Homeostatic control. Depriving any animal of sleep has sleep and how different hypnotic therapies compare with profound physiological effects and, in addition to reduced normal sleep recovery. cognitive function, the immune system becomes weak- ened and metabolism becomes slower7,8. It was thought The circadian process. Homeostatic sleep drive oper- that the increased propensity to sleep after deprivation ates over a background of circadian rhythmicity, which might be due to the accumulation of extracellular adeno- consists of a number of processes under the overall sine, the end product of ATP degradation, in the basal control of the suprachiasmatic nucleus (SCN). Neurons forebrain. Adenosine is generally a sleep-promoting trans- in the SCN exhibit a pacemaker activity that is sensi- mitter, and the antagonist effects of caffeine can promote tive to environmental inputs and outputs in the form
wakefulness. By acting on A1 receptors, adenosine has of hormonal and electrical signals. The circadian bio- been proposed to inhibit the wake-promoting neurons in chemistry has been widely investigated and is reviewed this area9. Recent data have questioned this hypothesis, elsewhere24. Importantly, several genes that influence
as A1 receptor knockout mice still accumulated sleep and regulate the circadian clock, and consequently debt10. Moreover, lesion of cholinergic neurons in the sleep–wake activity, have been identified. Many of basal forebrain abolished the build up of adenosine in these genes have invertebrate homologues that affect this area but did not affect sleep drive after prolonged sleep–wake activity in insects. Indeed, recent studies have 11 waking . In addition to the A1 receptors, studies with shown that mutations in the Shaker potassium channel 12,13 selective agonists and antagonists indicate that A2A gene (Sh) and associated Hyperkinetic gene (Hk) result receptors are important mediators of the hypnotic activity in reduced sleep and impaired memory function in 25,26 of adenosine. A2A receptor agonists might increase the Drosophila melanogaster . Activation of the epidermal activity of sleep-active VLPO neurons, thereby increas- growth factor receptor (EGFR) and extracellular signal- ing sleep drive13. Other potential mediators of the effects regulated kinase (ERK) by the membrane protease rhom- Sleep debt of sleep deprivation are the cytokine interleukin 1β (IL-1β), boid (rho) have also been shown to increase sleep in The cumulative effect on the prostaglandin 2A and nitric oxide. Interestingly, injec- D. melanogaster27. As the mammalian equivalent of rho is body of not getting sufficient tion of selective inhibitors of the two forms of nitric oxide also important for controlling circadian rhythms, studies sleep. synthase (NOS), inducible and neuronal, into the basal of equivalent genes in vertebrates are likely to open up Sleep drive forebrain during sleep deprivation, showed that inducible novel areas of exploration. The homeostatic mechanism NOS was required for non-REM sleep recovery, whereas Mammalian genes that are known to influence cir- that produces an increased neuronal NOS was required for REM sleep recovery14. cadian activity include PER1–3, CRY1/2, BMAL1 (also tendency to fall asleep. The discovery of orexins (also called hypocretins) known as ARNTL) and CLOCK. These are regulated by narcolepsy δ Narcolepsy and their link with has led to the proposal kinases and phosphatases, including casein kinase 1 A sleep disorder that usually that these peptide transmitters, which originate from a (CK1δ)/CK1ε, CK2, protein phosphatase 1 (PP1) and presents in young adulthood, group of neurons in the lateral hypothalamus, are impor- PP2 (Ref. 24). Functional abnormalities in these genes consisting of recurring tant regulators of the sleep cycle15. Orexinergic neurons result in changes in the circadian rhythm and have been episodes of sleep during the project to many of the ascending excitatory pathways implicated in a number of human sleep disorders. For day and often disrupted nocturnal sleep. Narcolepsy and are active during periods of wake and silent during example, familial advanced sleep phase syndrome has 16 affects more than 100,000 sleep . Orexin infusion enhances neuronal activity and been associated with the S662G mutation in the Per2 people in the United States increases arousal17. Orexin neurons originating in the gene and the T44A mutation in Ck1δ. The Per2 muta- alone and seems to have a hypothalamus have widespread projections, and have tion in mice recapitulates the human condition of early genetic basis. now also been implicated in appetite and reward learn- waking and early sleeping28. 18 Rotation adaptation task ing . Selective orexin receptor antagonists enhance Oscillations in the levels of the hormone prokineticin 2 A task in which subjects reach sleep both in animals and humans19, and further studies (PK2) in the SCN, are also important for non-REM sleep for visual targets using a with such compounds might provide novel therapeutic and for ensuring sleep compensation after deprivation29. hand-held cursor while candidates to modulate the sleep circuit. unconsciously adapting to systematic rotations imposed The recent application of microarray technology to Slow-wave sleep. Several studies have linked SWS, cogni- on the perceived cursor the field of sleep has begun to make an impact in this tion and synaptic plasticity. Learning of a motor coordi- trajectory. area. A study investigating genes associated with sleep nation task, such as the rotation adaptation task, was found
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Figure 1 | Sleep and arousal centres in the human a brain. a | Artistic rendering of the human brain in the awake state illustrating important arousal and sleep centres and pathways of neurotransmission. Cholinergic input (orange) from the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei project through the thalamus and facilitate thalamocortical transmission of arousal signals. A second pathway projects through Thalamus the hypothalamus to cortical centres and facilitates the processing of thalamocortical inputs arising from PeF midbrain centres including the noradrenergic (blue) VLPO DMH locus coeruleus (LC); the serotonergic (purple) dorsal SCN LH VPAG raphe (Raphe); the histaminergic (pink) tubero LDT mammillary nucleus (TMN); and the dopaminergic BF TMN PPT (yellow) ventral periaqueductal grey matter (VPAG). Raphe This pathway also receives input from the cholinergic LC (orange) basal forebrain (BF) and the peptidergic neurons of the lateral hypothalamus (LH) and Pons perifornical neurons (PeF), which contain orexin or melanin-concentrating hormone (light green). Cerebellum The melatonergic (red) neural network affects arousal and sleep through regulation of circadian rhythms. This internal biological clock originates in the suprachiasmatic nucleus (SCN), projects through the b dorsomedial hypothalamus (DMH) sending inhibitory signals to the GABA (γ-aminobutyric acid)ergic (grey) ventrolateral preoptic nucleus of the hypothalamus (VLPO). b | Artistic rendering of the human brain in the sleeping state illustrating important sleep and arousal Thalamus centres and pathways of neurotransmission. The VLPO of the hypothalamus sends descending GABAergic VLPO PeF Pin (grey) inhibitory signals to the midbrain arousal centres including the PeF, TMN, VPAG, Raphe, LDT and PPT, and SCN VPAG DMH LC. During the early hours of dark periods the pineal LDT gland (Pin) releases melatonin (red), which has inhibitory BF TMN PPT effects on the SCN and DMH of the melatonergic Raphe system. Nuclei that control neural activity during rapid eye movement (REM) sleep have been identified in the LC PC/PB pontine midbrain. The pericoeruleus (PC) and Pons SLD parabranchial (PB) nuclei send glutaminergic (green) projections through the BF to affect cortical activity Cerebellum during REM sleep, and projections from the sublaterodorsal nucleus (SLD) send glutamatergic signals through the spinal cord to induce atonia that is characteristic of REM sleep.
to trigger a local increase in slow-wave activity in the period. These studies indicate that sleep has an important Nature Reviews | Drug Discovery cortex, corresponding with an improved performance in role in memory consolidation and learning, and that SWS the associated task the following morning30. Conversely, is important not only for a good night’s sleep, but also if synaptic activity is forcibly depressed, by arm immo- for producing adequate cognitive function the follow- bilization, slow-wave activity was reduced in a region ing day34. The development of therapies that specifically of the somatosensory cortex during subsequent sleep31. increase SWS may have significant benefits over those that These experiments demonstrate a direct link between are being used at present. synaptic activity and localized sleep regulation. Further studies have now shown that the degree of Sleep and other neurotransmitters. The neuropeptide expression of the plasticity-related growth factor brain- galanin (GAL) is co-expressed in the VLPO within derived neurotrophic factor (BDNF), is directly linked to GABAergic neurons and has been demonstrated to the amount of exploratory activity during the previous increase both REM sleep and SWS when injected day and the duration of subsequent SWS activity32.Also, intravenously35. Grehlin (GHRL) and neuropeptide Y the importance of SWS for cognitive function was demon (NPY) have also been shown to promote sleep and strated by presenting odour cues that had previously been show clear links to increases in growth hormone (GH) used in the context of a learning task during either SWS and growth-hormone releasing hormone (GHRH), or REM sleep33. Only presentation during SWS increased which themselves increase non-REM sleep36. Another declarative memory consolidation in the subsequent sleep hormone demonstrated to have a role in sleep–wake
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control is melanin-concentrating hormone (MCH). A mouse models have recently identified the α1-subtype recent study described the wake-promoting effects of an as having an important role in the sedative properties of MCH1 antagonist that decreased the duration of both benzodiazepines; however, it is still unclear whether the SWS and REM sleep37. modest in vitro selectivity of these types of compounds Until recently, it was thought that dopamine had provides any advantage in vivo or whether they cause a minor role in the regulation of sleep–wake activity; fewer side effects48. however, several studies have revealed a critical role for
dopamine D2 receptors in the control of REM sleep. Melatonin. The hormone melatonin, which is released Experiments in hyperdopaminergic mice showed that from the pineal gland during the night, is intrinsic to the they exhibit a haloperidol-sensitive REM-like activity control of circadian rhythm in the brain. Low levels of during wake-time, and dopamine-depleted animals show melatonin have been linked to insomnia, and adminis- complete suppression of REM sleep, which is recoverable tration of melatonin is thought to be sleep-promoting49. with dopamine agonists38. This study also demonstrated The mild hypnotic properties of melatonin, and its a link to the sleep disturbances experienced by patients availability in some countries as a ‘natural supplement’, with Parkinson’s disease, such as excessive daytime have led to its widespread use for insomnia50. However, sleepiness and disturbed sleep architecture. Another evidence of the efficacy of melatonin is based on limited study showed increased burst firing of dopaminergic clinical-trial data. Furthermore, the short half-life and neurons in the ventral tegmental area during REM sleep, high first-pass metabolism of melatonin tend to limit an activity known to release dopamine39. its usefulness as an oral agent. The melatonin receptor Despite some major advances in understanding agonist ramelteon is now approved for insomnia, and sleep mechanisms in the past few years (BOX 2), there although no head-to-head reports with other agents has been little progress in understanding insomnia and have been published, clinical data suggest that its efficacy its aetiology. There are clear links between insomnia might be relatively modest compared with that of other and psychiatric disorders, such as anxiety and depres- insomnia therapeutics51. sion, and gaining further insights into these and other sleep disorders will increase our ability to develop more Antihistamines and antidepressants. Mild insomnia can appropriate treatments. also be treated using antihistamines, which produce some degree of sedation. There are many over-the-counter Currently used medications and their limitations treatments containing diphenhydramine or hydroxyzine Benzodiazepine receptor agonists. Benzodiazepines that can give temporary relief for sleep problems52. These modulate GABA receptors — ligand-gated ion channels agents tend to cause daytime drowsiness and are not that mediate the effects of the inhibitory neurotransmitter recommended for continuous use as they also exhibit GABA. The first benzodiazepine sedative, chlordiaze tolerance53. poxide, was developed and launched on the market in In the past few years, several of the serotonin-modulat- 1960 as Librium. The more potent diazepam Valium fol- ing antidepressants such as trazodone and nefazodone, lowed in 1963, and many other related benzodiazepines which in addition to their mood-stabilizing effects also were subsequently launched. This class of compound have sedative effects, have been prescribed for insom- was more potent than previously used sedatives, such nia, especially in depression-related insomnia54,55. These as barbiturates, and did not have the associated toxicity drugs are relatively safe, with no issues regarding tolerance problems or liabilities on overdose; record numbers of or abuse potential, and probably exert their effects by prescriptions were issued in the 1970s and 1980s4. The inhibiting serotonin and histamine receptors. tolerance and abuse potential seen with barbiturates was still present, although slightly reduced, in benzodi- Cognitive behavioural therapy. An alternative to phar- azepines40. However, while they are effective for treating macotherapy for sleep disorders is cognitive behavioural insomnia, benzodiazepine receptor agonists often pro- therapy (CBT). CBT is usually tailored to the specific duce next-day sedation, ataxia, and memory and cogni- problems of the patient and can be used in combination tive impairment41,42. As a result, the use of these drugs with sleep hygiene training, relaxation exercises and has become limited in recent years, despite them being biofeedback (controlling breathing and heart rate). effective and fast-acting drugs for short-term use. Cognitive control and psychotherapy can often help to
There are various subtypes of GABAA receptors, overcome daily anxieties or worries about getting to sleep. which differ in distribution, pharmacology and biophysical In clinical trials, CBT can be as effective, if not better, properties43. One of the more recently developed benzo than pharmacotherapy, with fewer concerns regarding diazepine receptor agonists, zolpidem, demonstrates relapse and tolerance effects56,57. This form of treatment a degree of selectivity for the α1-subunit-containing is in many respects under-utilized as it involves frequent Sleep hygiene subtype and is relatively more effective as a hypnotic visits to sleep specialists, of which there are currently Sleep habits that promote agent than an anxiolytic44,45. Zolpidem has become one very few. healthy sleep such as fixed of the leading current therapies for insomnia and similar bedtime and awakening time, so-called ‘benzodiazepine receptor agonists’, such as Novel approaches to the treatment of insomnia avoiding naps, blocking out noise and light, and avoiding zaleplon, zopiclone, eszopiclone and indiplon (currently Advances in the understanding of sleep mechanisms caffeine and alcohol before under review by the US Food and Drug Administration), have indicated possible approaches for discovering novel sleep. also have a small degree of α1-selectivity46,47. Genetic hypnotic drugs. Here, we will focus on potential new
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Table 1 | Changes in gene expression following sleep modification another 5‑HT2A/5‑HT2C receptor antagonist, has also been demonstrated to promote SWS, although to a Gene (alias) Species Function Association lesser extent than ritanserin64, and an increase in the Arc Rat/mouse Immediate early gene Increased during SD number of REM-sleep episodes has been observed Fos Rat/mouse Immediate early gene Increased during SD following administration of this agent in rats65. It is Fra2 (Fosl2) Rat Immediate early gene Increased during SD and sleep noteworthy that to date no published data exist demon recovery/correlated with SWS strating improvements associated with these SWS- promoting agents on traditional polysomnographic Egr3 Rat/mouse Immediate early gene Increased during SD and sleep transcription factor recovery variables, such as sleep latency or continuity. Clinical studies with compounds like ritanserin and ketan- Grp78 Rat/mouse ER molecular Increased during SD (Hspa5) chaperone protein serin (and others such as pruvanserin, eplivanserin, volinanserin and pimavanserin) are eagerly awaited. Grp94 Rat ER molecular Increased during SD, sleep These compounds appear to be well tolerated and as (Hsp90b1) chaperone protein recovery and benzodiazepine treatment this class of compounds lack abuse potential in the antipsychotic area, it is unlikely that, if approved, they NGFI-B Rat/mouse Immediate early gene Increased during SD scheduled status (Nr4a1) transcription factor will retain the that is associated with benzodiazepines. Preclinical data suggest that they will Nr4a3 Rat/mouse Nuclear receptor Increased during SD be targeted towards improving sleep maintenance and subfamily 4 quality rather than latency. + Shal1 (Kcnd2) Rat K channel peptide Increased during SD and Another class of compounds that have been found decreased on sleep recovery to increase SWS activity are the calcium channel α2δ- Egr1 Rat/mouse Immediate early gene Increased during SD subunit modulators related to gabapentin. Pregabalin Homer1 Rat Activity and Increased during SD enhanced SWS and significantly improved sleep in a neurotransmitter human trial66. Consequently, several analogues are now induced early gene in development for the treatment of insomnia, including *Data from Refs 17,19,79,85. ER, endoplasmic reticulum; SD, sleep deprivation; PD‑200390, which is in Phase II trials. The question SWS, slow-wave sleep. regarding scheduled status with these compounds is not as clear — pregabalin was classified as Schedule V in the United States. therapies that enhance SWS, such as gaboxadol (which
selectively activates δ-containing GABAA receptors); Modulation of circadian rhythms. As mentioned above,
5-hydroxytryptamine 2A (5-HT2A) receptor antagonists, sleep disturbances may be a consequence of disrupted such as MDL 100907; sedative antidepressants; melatonin circadian rhythmicity. The hormone melatonin serves Polysomnographic variables receptor agonists, such as ramelteon; and orexin receptor as a sleep-anticipating cue in humans, and several stud- Physiological variables that antagonists (TABLE 2). ies have indicated a reduced production of melatonin are captured during electro encephalography sleep in patients who are elderly or depressed. Melatonin analysis, for example, brain Enhancing SWS. Until recently, it seemed that the receptor agonists represent a novel approach in the electrical rhythms, eye GABAA receptor field would offer novel approaches therapeutic management of insomnia. There are two movements, muscle activity for the treatment of insomnia. Gaboxadol, a GABAA melatonin-binding sites: MT1 is a high-affinity site or skeletal muscle activation, receptor agonist with functional selectivity for the and is found in the SCN and cardiac vessels; MT2 is heart rhythm and breathing function or respiratory effort extrasynaptic GABAA receptors, which are untouched a low-affinity site that also appears to have a role in 67,68 during sleep. These also by the benzodiazepines, was in Phase III clinical trials the modulation of circadian rhythms . As melatonin include variables such as sleep before clinical development was discontinued. Unlike exerts its effects by binding to MT1 and MT2, high- latency and maintenance, benzodiazepine receptor agonists, gaboxadol signifi- affinity MT1/MT2 agonists with a longer half-life than duration of rapid eye movement (REM) and non- cantly enhanced SWS activity and the duration of sleep melatonin (half-life of 1–2 hours compared with the REM sleep. and, relative to zolpidem, it had modest but significant <0.5 hour for melatonin) might also show beneficial effects on the induction of sleep. Gaboxadol was found effects on sleep duration. Sleep latency to selectively activate the α4β2δ-containing GABAA Numerous studies with melatonin have not been able The time it takes to go from full receptor subtype located extrasynaptically on neurons in to provide a coherent picture of robust and clinically wakefulness to being asleep. the ventrobasal thalamus58. Treatment with this subtype- significant effects on sleep parameters. However, a modi- 48,59,60 Scheduled status selective compound improved sleep quality and had fied-release formulation of melatonin that mimics the A controlled drug for which positive effects on daytime performance in primary normal circadian variation in plasma levels of melatonin in use and distribution is tightly insomniacs61. However, no studies were conducted in subjects below the age of 55 during the night, led to robust regulated owing to its abuse subjective sleep parameters potential or risk. Classified by patients with severe impairments in either SWS activity or improvements in and daytime 69 the US Food and Drug daytime performance, so it is still questionable whether performance , and had marginal effects on sleep induc- Administration from I to V with GABAergic compounds that enhance SWS activity will tion (as measured by electroencephalography analysis)70. Schedule I drugs exhibiting have superior benefits over classical hypnotics. The effects of the modified melatonin release formulation the highest risk. Most benzo- In this context, compounds acting as 5‑HT /5‑HT were studied in people aged above 55 years — a popula- diazepines are Schedule IV 2A 2C meaning that they can only receptor antagonists are interesting. Ritanserin has tion in which the frequency of low endogenous melatonin be supplied and produced by been found to increase the amount of SWS in healthy levels is most frequent. It might therefore be that this those authorized to do so. volunteers and in young, poor sleepers62,63. Ketanserin, approach is limited to patient populations with low levels
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Box 2 | Techniques in sleep research potential in the treatment of insomnia. Will agomelatine, which has been able to phase-shift humans and increase Different approaches have been taken to non-REM sleep72, have additional effects on improving explore the mechanism and function of sleep parameters? Will the 5-HT effect act synergisti- sleep. Electrophysiological measures 2c such as electroencephalography (EEG) cally with the melatonergic effect? It could be that the are vital for providing insight into the 5-HT2c receptor antagonism of this compound in com- activity of the brain during this process. bination with selective serotonin reuptake inhibitors, More recently, functional imaging has for example, could increase the onset of antidepressant also shed light on this activity, by using action. The melatonergic properties of agomelatine positron-emission tomography (PET) might alleviate the sleep disturbances that are associated scanning and functional magnetic resonance imaging (fMRI) techniques81. Although at with depression and help prevent relapse, which is often an early stage, these studies are providing a way to identify in more detail the regions Nature Reviews | Drug Discovery linked to sleep problems. of the brain that are involved in sleep and the importance of this activity for cognitive The link to antidepressants is further supported by function. For example, sleep deprivation has been associated with declines in cerebral the development of low-dose doxepin for insomnia73. As metabolism, particularly in the frontoparietal cortex and in the thalamus82,83. The fMRI images above show a marginal activation of the auditory cortex (left image) upon well as being a muscarinic antagonist, doxepin is a hista- acoustic stimulation in a healthy sleeping subject during non-rapid eye movement mine H1/H2 receptor antagonist, which might explain (REM) sleep. During REM sleep, however, the brain is hardly stimulated by external its hypnotic profile. This compound is in Phase III clini- stimuli, but shows independently generated activity in many brain areas, which is cal trials and is anticipated to reach the marketplace in
thought to be indicative of dreaming (right image). 2008. A combined histamine H1 and 5-HT2A antagonist Advances in genetics have enabled the identification of genes involved in the sleep (Hyp‑10275) is also in development by Eli Lilly (no pub- process (TABLE 1). Several studies using microarray technology have identified genes lished data are currently available); the combined effects that are associated with sleep deprivation and recovery, as well as the action of of simultaneous activity at these two targets might prove hypnotic drugs. The fruitfly Drosophila melanogaster, which is amenable to rapid to be highly efficacious. genetic manipulation, is also revealing novel genes and pathways involved in sleep. These studies identify new avenues, which can be followed up in mammalian systems. The genetic manipulation of mice also provides a tool for investigating the role of Orexinergics. In light of the wake-promoting effects novel genes and proteins in sleep function. Combining these approaches with direct of the endogenous peptide orexin, the development of measures, such as EEG, creates a powerful means for understanding more about the orexin receptor antagonists acting selectively at OX1 or
function of sleep and identifying new ways to develop sleep therapeutics. OX2, or unselectively, is not unexpected. The effects of one of these compounds (ACT‑078573), which is This image is reproduced with permission from REF. 84 (2007) Blackwell Publishing. in Phase III clinical development, indicate that these types of compounds might promote REM and non- REM sleep19. However, as in the case with melatonin of melatonin or circadian-rhythm disorders. Whether and other sleep-related neurotransmitters, an important the effects on subjective sleep parameters will translate question is whether hyperfunction of the orexinergic into an improvement in the quality of life of patients who system in the general insomniac population actually suffer from depression or other types of disorders is still contributes to their poor sleep, or whether this only unknown. Given the relatively weak effects in acute relates to a specific subpopulation. A recent study has studies, patient populations other than primary insom- demonstrated hyperarousal and elevated orexin A in the niacs (with short-term complaints) might experience hypothalamus of maternally deprived rats, suggesting greater benefits from this type of compound. that elevated orexins could contribute to insomnia in Ramelteon, a MT1/ MT2 agonist, has been on the this model74. market in the United States since 2005. In line with the findings with melatonin, this compound is able Benzodiazepine receptor agonists. Despite the number to induce sleep; however, subjective measures of sleep of benzodiazepine receptor agonists that are currently quality were not improved51. This suggests that either on the market, there are still several in development. all types of melatonin receptors should be targeted or NG‑2‑73 is described as an α3-subtype-selective partial that selection of the relevant patient population is para- agonist and is currently in Phase II trials. Evotec also mount for drugs that interact with the melatonin-receptor has a partial agonist (EVT‑201) in Phase II trials for system. The major challenge for these compounds is that insomnia. It is not currently known what advantages their sleep induction and maintenance properties will these compounds might offer over similar drugs that be compared with benzodiazepine receptor agonists, are already on the market. Subjective sleep parameters which are effective over a broad range of indications. In Using questionnaires, patients our opinion, this class of compounds will find its niche Other emerging targets. The discovery of new genes rate their feelings of time to sleep, time awake and number in patient populations in which circadian rhythmicity and pathways involved in the control of sleep has of awakenings during the night underlies the sleep disturbances and not primary insom- revealed a number of potential new drug targets. in addition to the quality of nia, in which overall melatonin levels are quite similar Those involved in controlling circadian rhythms, such sleep and feeling ‘refreshed’ to non-insomniacs. as PK2 (Ref. 29), have already begun to be studied, and in the morning. the generation of novel ligands will not only contribute Phase-shift Combination therapy. The development of agomelatine, to the understanding of these pathways, but might An induced temporal shift of a combined 5-HT2C receptor antagonist and a melatonin also lead to the discovery of more efficacious clinical the normal circadian rhythm. receptor agonist, for depression71 might hold great therapeutics.
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Table 2 | Novel insomnia therapeutics in at least Phase II development Drug name Pharmacological Company Indication Development target phase
Silenor H1/H2 antagonist, Somaxon Sleep disorders Phase III muscarinic antagonist Pharmaceuticals
Indiplon IR, GABAA BZ-site Neurocrine Sleep disorders Awaiting Indiplon MR modulator Biosciences approval
Eplivanserin, 5-HT2A receptor Sanofi–Aventis Sleep disorders Phase III SR 46349 antagonist
Volinanserin, 5-HT2A antagonist Sanofi–Aventis Sleep disorders Phase III M-100907 VEC-162 Melatonin receptor Vanda Sleep disorders, Phase III agonist Pharmaceuticals depression ORG 50081 Noradrenergic, Organon Sleep disorders, Phase III specific serotonergic International hot flushes antidepressant
Agomelatine 5-HT2B/5-HT2C Novartis Depression, Phase III antagonist, melatonin sleep disorders agonist
Almorexant, OX1 and OX2 receptor Actelion Sleep disorders Phase III ACT-078573 antagonist PD-6735 Melatonin receptor Phase 2 Discovery Sleep disorders Phase II agonist
Pruvanserin, 5-HT2A antagonist Eli Lilly Sleep disorders Phase II EMD 281014
APD125 5-HT2A inverse agonist Arena Sleep disorders Phase II
ACP-103 5-HT2A receptor inverse Acadia Sleep disorders, Phase II agonist, dopamine Pharmaceuticals antipsychotic-
D2/D3 receptor partial induced side effects, agonist, acetylcholine Parkinson’s disease
M1 receptor agonist PD 200-390 α2δ calcium channel Pfizer Sleep disorders Phase II blocker
HY10275 5-HT2A and H1 receptor Eli Lilly Sleep disorders Phase II inverse antagonist GW649868 Orexin receptor GlaxoSmithKline Sleep disorders Phase II antagonist
Adipiplon, NG-2-73 GABAA BZ-site Neurogen Sleep disorders Phase II modulator
EVT-201 GABAA BZ-site Evotec Sleep disorders Phase II modulator
5-HT2A/5-HT2B/5-HT2C, 5-hydroxytryptamine (serotonin) receptor 2A/2B/2C; BZ, benzodiazepine; D2/D3, dopamine receptor 2/3; GABAA, γ-aminobutyric acid receptor A; H1/H2, histamine receptor 1/2; M1, muscarinic receptor 1; OX1/OX2, orexin receptor 1/2.
Challenges for novel insomnia therapies insomnia in the Diagnostic and Statistical Manual of The development of hypnotic drugs has always focused Mental Disorders, 4th edition as: “… causing clinically on the induction and maintenance of sleep. In populations significant distress or impairment in social, occupational with severe sleep-induction problems, the highly used or other important areas of functioning”. benzodiazepine receptor agonists reduce the time it takes Some studies have characterized the daytime conse- to fall asleep by approximately 30 minutes and increase quences of disrupted sleep and established correlations the time spent sleeping through the night by 10–20 min- between disrupted sleep and a number of co-morbidities. utes, thus improving the total sleep in a standard night by Thus, sleep disturbances appear to be inherent to symp- approximately 40 minutes. tom complexes describing depression and anxiety76, However, few studies have looked at the functional Alzheimer’s disease77, and chronic pain78. Despite this, consequences for the daily living of dosing with hypnot- hardly any hypnotic compounds have adequately been ics75. Drug companies and regulatory agencies seem described in these highly relevant populations and, more to have focused heavily on the metrics of sleep and importantly, no insomnia drug has been developed for neglected the quality-of-life aspect in the definition of these indications. Instead, all compounds have been
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developed in primary insomniacs, who suffer from and instead of only collecting sleep data, by statistical disrupted sleep but have no psychiatric co-morbidities analysis it was possible to demonstrate that eszopiclone and, therefore, daytime function is less impaired. In most significantly improved the antidepressant action of sleep studies that are conducted in primary insomniacs, fluoxetine and parameters other than sleep. daytime function is measured. However, seldom do So will it be possible to focus on subjective sleep meas- these daytime function parameters indicate anything ures and daytime performance? The European Medicines but absence of impairment, and this is probably due Agency has recently approved Circadin (prolonged- to the selected patient population studied. In addition, release melatonin; Neurim Pharmaceuticals) on the basis poor daytime function underlies the secondary effects, of subjective sleep measures. However, the indication for including a large proportion of road traffic accidents and this compound was narrowed to primary insomnia in work-related accidents that occur due to insomnia. elderly patients, suggesting that with this compound the It is surprising that compounds are developed in the European authorities only relied on the clinical studies primary insomnia population and then extrapolated into conducted and did not accept the translation into the patient populations who have co-morbidities. Normally, general elderly population. The consequences of the at the time of launch of these compounds, no studies approval should not be underestimated. If approval of have been conducted in the relevant patient populations, novel sleep compounds will be based on the popula- and thus, knowledge outside of primary insomnia is tions included in the clinical development programme, lacking. One might expect that the indication would be this might encourage companies to develop compounds for primary insomniacs only, but the US Food and Drug for the relevant patient populations and thus, select the Administration, and until recently also the European optimal clinical outcome parameters. However, if compa- Medicines Agency, has allowed the much broader indi- nies and regulatory authorities continue to focus on the cation ‘insomnia’, implicitly assuming that if compounds metrics of sleep in easily definable populations, such as are active in primary insomniacs, they will also be active primary insomnia, very little innovation or benefit for the in other types of insomnia, such as those associated with other patient subpopulations will be obtained. other co-morbidities. This might be the case for benzo- diazepines (in which the general suppression of arousal Final comments and future directions systems and cortical structures in the CNS leads to an For the past four decades, benzodiazepines or non- improved induction and possibly maintenance of sleep) benzodiazepines have been the predominant hypnotic but when it comes to the functional consequences for drugs. These compounds are very effective in induc- daytime living, little is known. ing and maintaining sleep. However, the risk that is Guidelines for the development of hypnotic drugs associated with these compounds after long-term use focus on primary insomnia and the simple metrics of (dependence, increased abuse potential and to some sleep, whereas other populations and measurements degree withdrawal symptoms) suggests that novel have been neglected. In order to reflect the clinical approaches for the treatment of insomnia are required. unmet needs, it would be highly relevant and timely Current research seems to be moving away from the
to update these guidelines for hypnotics. At present, major inhibitory GABAA receptor system and towards daytime performance is considered as an absence of modulating more subtle endogenous pathways that impairment — improvement of function with benzo- control the sleep–wake cycle. These approaches might diazepines or benzodiazepine receptor agonists has be more adequate for helping particular subpopulations never been demonstrated. We would argue that more suffering from insomnia, but at the same time a number relevant populations should be chosen to demonstrate of limitations are inherent to this approach. Only specific both improvements and impairments79. Another impor- populations will respond to the treatment, hence the need tant issue in this context is the application of subjective for better diagnostic criteria and a deeper understanding parameters in the evaluation of clinical effects of the of insomnia. Modulation of the sleep–wake cycle is very hypnotics. Perhaps the use of disability scales such as much a question of timing of dosing, so the develop- the Montgomery–Åsberg depression rating scale or the ment of dosage forms, and application systems that can Sheehan disability scale would be more suitable for evalu- ensure dosage at the correct time, will be essential for ating daytime performance instead of the often-used this approach. tests measuring the ability to recollect items or separate The development of compounds that are active in the Montgomery–Åsberg lights (such as critical flicker fusion). CNS is expensive, and if they are only to benefit particular depression rating scale Following approval for primary insomnia, most hypno- patient subpopulations, the risk–benefit ratio of these An 11-item clinician- tics undergo evaluations in small-scale studies using other compounds needs to be established carefully at an early administered questionnaire insomnia populations. In most of these studies, the focus stage of clinical development. This will demand that the that is used to rate the severity of a patient’s depression. is still on the induction and maintenance of sleep, with industry, in collaboration with regulatory authorities most recently developed hypnotics being benzodiazepine and clinical experts, define and agree on both the patient Sheehan disability scale receptor agonists. It is hardly surprising that data from populations and the types of outcomes, other than sleep A patient self-reporting tool primary insomnia easily translates into the same metrics parameters, to be monitored in the relevant populations. developed to assess functional in these populations. Only Sepracor has conducted some The consequences for the development of novel hypnotics impairment in work/school, social and family life. It uses relatively innovative studies. In the post-filing evaluation will hopefully be that sleep problems will eventually be a series of 10-point visual of eszopiclone in the United States, eszopiclone was evalu- considered as an integral part of, instead of secondary to, analogue scales. ated in combination with the antidepressant fluoxetine, diseases such as depression and Alzheimer’s disease.
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