REVIEWS 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 530 | JUNE 2008 | VOLUme 7 www.nature.com/reviews/drugdisc © 2008 Nature Publishing Group REVIEWS 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 NatUre reViews | DRUG DISCOVERY VOLUme 7 | JUNE 2008 | 531 © 2008 Nature Publishing Group REVIEWS 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