Sleep/Wake Disorders

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Disorders of sleep and wakefulnessand their treatment

This chapter will provide a brief overview of the psychopharmacology of disorders of sleep and wakefulness. Included here are short discussions of the symptoms, diagnostic criteria, and treatments for disorders that cause insomnia, excessive daytime sleepiness, or both. Clinical descriptions and formal criteria for how to diagnose sleep disorders are mentioned here only in passing. The reader should consult standard reference sources for this material. The discussion here will emphasize the links between various brain circuits and their neurotransmitters and disorders that cause insomnia or sleepiness. The goal of this chapter is to acquaint the reader with ideas about the clinical and biological aspects of sleep and wakefulness, how various disorders can alter sleep and wakefulness, and how many new and evolving treatments can resolve the symptoms of insomnia and sleepiness.

The detection, assessment, and treatment of sleep/wake disorders are rapidly becoming standardized parts of a psychiatric evaluation. Modern psychopharmacologists increasingly consider sleep to be a psychiatric "vital sign," requiring routine evaluation and symptomatic treatment whenever sleep disorders are encountered. This is similar to the situation of pain ( ), whichChapter 10 is also increasingly being considered as another psychiatric "vital sign." That is, disorders of sleep (and pain) are so important, so pervasive, and cut across so many psychiatric conditions that the elimination of these symptoms - no matter what psychiatric disorder may be present - is increasingly recognized as necessary in order to achieve full symptomatic remission for the patient.

Many of the treatments discussed in this chapter are covered in previous chapters. For details of mechanisms of insomnia treatments that are also used for the treatment of depression, the reader is referred to . For those insomnia treatments that are benzodiazepines and share the sameChapter 7 mechanism of action with various benzodiazepine anxiolytics, the reader is referred to Chapter 9. For various hypersomnia treatments, especially stimulants, the reader is referred to on ADHDChapter 12 and to on drug abuse, which also discuss the use and abuse of stimulants. TheChapter 14 discussion in this chapter is at the conceptual level, and not at the pragmatic level. The reader should consult standard drug handbooks (such as Stahl’s Essential Psychopharmacology: the

) for details of doses, side effects, drug interactions, and other issues relevant toPrescriber’s Guide the prescribing of these drugs in clinical practice.

Neurobiology of sleep and wakefulness

The arousal spectrum

Although many experts approach insomnia and sleepiness by emphasizing the separate and distinct that cause them, many pragmatic psychopharmacologists approach insomnia or excessivedisorders

daytime sleepiness as important that cut across many conditions and that occur along asymptoms spectrum from deficient arousal to excessive arousal ( ). In this conceptualization, anFigure 11-1 awake, alert, creative and problem-solving person has the right balance between too much and too little arousal (baseline brain functioning in gray at the middle of the spectrum in ). AsFigure 11-1 arousal increases beyond normal, during the day there is hypervigilance ( ); if thisFigure 11-1 increased, arousal occurs at night and there is insomnia ( , and overactivation of the brainFigure 11-1 in red at the right-hand side of the spectrum in ). From a treatment perspective, insomniaFigure 11-2 can be conceptualized as a disorder of excessive nighttime arousal, with hypnotics moving the patient from too much arousal to sleep ( ).Figure 11-2

On the other hand, as arousal diminishes, symptoms crescendo from mere inattentiveness to more severe forms of cognitive disturbances until the patient has excessive daytime sleepiness with sleep attacks ( , and hypoactivation of the brain in blue at the left-hand side of the spectrum in Figure 11-1

). From a treatment perspective, sleepiness can be conceptualized as a disorder ofFigure 11-3 deficient daytime arousal, with wake-promoting agents moving the patient from too little arousal to awake with normal alertness ( ).Figure 11-3

Note in that cognitive disturbance is the product of both too little and too much arousal,Figure 11-1 consistent with the need of cortical pyramidal neurons to be optimally "tuned," with too much activity making them just as out of tune as too little. Note also in through that the arousalFigures 11-1 11-3 spectrum is linked to the actions of five neurotransmitters shown in the brains represented in these figures (i.e., histamine, dopamine, norepinephrine, serotonin, and acetylcholine). Sometimes these neurotransmitter circuits as a group are called the ascending reticular activating system, because they are known to work together to regulate arousal. This same ascending neurotransmitter system is blocked at several sites by many agents that cause sedation. Actions of sedating drugs on these

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neurotransmitters are discussed in on antipsychotics and illustrated in . Chapter 5 Figure 5-38 Figure also shows that excessive arousal can extend past insomnia to panic, hallucinations, and all the11-1

way to frank psychosis (far right-hand side of the spectrum).

The sleep/wake switch

We have discussed how the ascending neurotransmitter systems from the brainstem regulate a cortical arousal system on a smooth continuum like a rheostat on a lighting system or a volume button on a radio. There is another set of circuits in the hypothalamus that regulate sleep and wake discontinuously, like an on/off switch. Not surprisingly, this circuitry is called the (sleep/wake switch

). The "on" switch is known as the and is localized within theFigure 11-4 wake promoter tuberomammillary nucleus (TMN) of the hypothalamus ( ). The "off" switch is known asFigure 11-4A the and is localized within the ventrolateral preoptic (VLPO) nucleus of thesleep promoter hypothalamus ( ).Figure 11-4B

Two other sets of neurons are shown in as regulators of the sleep/wake switch:Figure 11-4 orexin-containing neurons of the lateral hypothalamus (LAT) and melatonin-sensitive neurons of the suprachiasmatic nucleus (SCN). The lateral hypothalamus serves to stabilize and promote wakefulness via a peptide neurotransmitter known by two different names: orexin and hypocretin. These lateral hypothalamic neurons and their orexin are lost in narcolepsy, especially narcolepsy with cataplexy. New hypnotics on the horizon (orexin antagonists) block the receptors for these neurotransmitters and are discussed later in this chapter. The SCN is the brain’s internal clock, or pacemaker, and regulates circadian input to the sleep/wake switch in response to how it is programmed by hormones such as melatonin and by the light/dark cycle. Circadian rhythms and the SCN are discussed in on antidepressants and illustrated in to .Chapter 7 Figures 7-39 7-42

Figure 11-1. . One’s state of arousal is more complicated thanArousal spectrum of sleep and wakefulness simply being "awake" or "asleep." Rather, arousal exists as if on a dimmer switch, with many phases along the spectrum. Where on the spectrum one lies is influenced in large part by five key neurotransmitters: histamine (HA), dopamine (DA), norepinephrine (NE), serotonin (5HT), and acetylcholine (ACh). When there is good

balance between too much and too little arousal (depicted by the gray [baseline] color of the brain), one is awake, alert, and able to function well. As the dial shifts to the right there is too much arousal, which may cause hypervigilance and consequently insomnia at night. As arousal further increases this can cause cognitive dysfunction, panic, and in extreme cases perhaps even hallucinations. On the other hand, as arousal diminishes, individuals may experience inattentiveness, cognitive dysfunction, sleepiness, and ultimately sleep.

The circadian wake drive is shown in over two full 24-hour cycles. Also shown in Figure 11-5 Figure is the ultradian sleep cycle (a cycle faster than a day, showing cycling in and out of REM and11-5

slow-wave sleep several times during the night). Homeostatic sleep drive, illustrated as well in Figure , increases the drive for sleep as the day goes on, presumably due to fatigue, and diminishes at11-5

night with rest. The novel neurotransmitter adenosine is linked to homeostatic drive, and appears to accumulate as this drive increases during the day, and to diminish at night. Caffeine is now known to be an antagonist of

Figure 11-2. Insomnia is conceptualized as being related toInsomnia: excessive nighttime arousal? hyperarousal at night, depicted here as the brain being red (overactive). Agents that reduce brain activation, such as positive allosteric modulators of GABA receptors (e.g., benzodiazepines, "Z drugs"), histamine 1A antagonists, and serotonin 2A/2C antagonists, can shift one’s arousal state from hyperactive to sleep.

Figure 11-3. . Excessive sleepiness isExcessive daytime sleepiness: deficient daytime arousal conceptualized as being related to hypoarousal during the day, depicted here as the brain being blue (hypoactive). Agents that increase brain activation, such as the stimulants, modafinil, and caffeine, can shift one’s arousal state from hypoactive to awake with normal alertness.

Figure 11-4. . The hypothalamus is a key control center for sleep and wake, and the specificSleep/wake switch circuitry that regulates sleep/wake (i.e., whether the dimmer switch is set all the way to the left for sleep or is somewhere else along the continuum for wake) is called the sleep/wake switch. The "off" setting, or sleep promoter, is localized within the ventrolateral preoptic nucleus (VLPO) of the hypothalamus, while "on" - the wake promoter - is localized within the tuberomammillary nucleus (TMN) of the hypothalamus. Two key neurotransmitters regulate the sleep/wake switch: histamine from the TMN and GABA from the VLPO. (A) When the TMN is active and histamine is released to the cortex and the VLPO, the wake promoter is on and the sleep promoter inhibited. (B) When the VLPO is active and GABA is released to the TMN, the sleep promoter is on and the wake promoter inhibited. The sleep/wake switch is also regulated by orexin/hypocretin neurons in the lateral hypothalamus (LAT), which stabilize wakefulness, and by the suprachiasmatic nucleus (SCN) of the hypothalamus, which is the body’s internal clock and is activated by melatonin, light, and activity to promote either sleep or wake.

Figure 11-5. . Several processes that regulate sleep/wake are shown here. TheProcesses regulating sleep circadian wake drive is a result of input (light, melatonin, activity) to the suprachiasmatic nucleus. Homeostatic sleep drive increases the longer one is awake and decreases with sleep. As the day progresses, circadian wake drive diminishes and homeostatic sleep drive increases until a tipping point is reached and the ventrolateral preoptic sleep promoter (VLPO) is triggered to release GABA in the tuberomammillary nucleus (TMN) and inhibit wakefulness. Sleep itself consists of multiple phases that recur in a cyclical manner; this process is known as the ultradian cycle, and is depicted at the top of this figure.

adenosine, and this may explain in part its ability to promote wakefulness and diminish fatigue, namely by opposing endogenous adenosine’s regulation of the homeostatic sleep drive.

Two key neurotransmitters regulate the sleep/wake switch: histamine from the TMN and GABA (-aminobutyric acid) from the VLPO. Thus, when the sleep/wake switch is on, the wake promoter TMS is active and histamine is released ( ). This occurs both in the cortex to facilitateFigure 11-4 arousal, and in the VLPO to inhibit the sleep promoter. As the day progresses, circadian wake drive diminishes and homeostatic sleep drive increases ( ); eventually a tipping point isFigure 11-5 reached, and the VLPO sleep promoter is triggered, the sleep/wake switch is turned off, and GABA is released in the TMN to inhibit wakefulness ( ).Figure 11-4

Disorders characterized by excessive daytime sleepiness can be conceptualized as the sleep/wake switch being off during the daytime. Wake-promoting treatments such as modafinil given during the day tip the balance back to wakefulness by promoting the release of histamine from TMN neurons. The exact mechanism of this enhancement of histamine release by modafinil or stimulants is not known, but is currently hypothesized to be related in part to a downstream consequence of the actions of wake-promoting drugs on dopamine neurons, especially by blocking the dopamine transporter DAT.

On the other hand, disorders characterized by insomnia can be conceptualized as the sleep/wake switch being on at night. Insomnia can be treated either by agents that enhance GABA actions, and thus inhibit the wake promoter, or by agents that block the action of histamine released from the wake promoter and act at postsynaptic H receptors.1

Disorders characterized by a disturbance in circadian rhythm can be conceptualized as either "phase delayed," with the wake promoter and sleep/wake switch being turned on too late in a normal 24-hour cycle, or "phase advanced," with the wake promoter and sleep/wake switch being turned on

too early in a normal 24-hour cycle. That is, individuals who are phase delayed, including many depressed patients and many normal adolescents, still have their sleep/wake switch off when it is time to get up (see discussion in and ). Giving such individuals morning lightChapter 7 Figure 7-39 and evening melatonin can reset the circadian clock in the SCN so that it wakes the person up earlier. Other individuals may be phase advanced, including many normal elderly people. Giving these individuals evening light and morning melatonin can reset their SCNs so that the sleep/wake switch stays off a bit longer, returning the patient to a normal rhythm.

Figure 11-6. . Histidine (HIS), a precursor to histamine, is taken up into histamine nerveHistamine is produced terminals via a histidine transporter and converted into histamine by the enzyme histidine decarboxylase (HDC). After synthesis, histamine is packaged into synaptic vesicles and stored until its release into the synapse during neurotransmission.

Figure 11-7. . Histamine can be broken down intracellularly by two enzymes.Histamine’s action is terminated Histamine -methyl-transferase (histamine NMT) converts histamine into -methyl-histamine, which is thenN N converted by monoamine oxidase B (MAO-B) into the inactive substance -methyl-indole-acetic acid (N-MIAA).N

Histamine

Histamine is one of the key neurotransmitters regulating wakefulness, and is the ultimate target of many wake-promoting drugs (via downstream histamine release) and sleep-promoting drugs (antihistamines). Histamine is produced from the amino acid histidine, which is taken up into histamine neurons and converted to histamine by the enzyme histidine decarboxylase ( ).Figure 11-6 Histamine’s action is terminated by two enzymes working in sequence: histamine N -methyl-transferase, which converts histamine to -methyl-histamine, and MAO-B, which converts N N -methyl-histamine into N-MIAA ( -methyl-indole-acetic acid), an inactive substance ( ).N Figure 11-7 Additional enzymes such as diamine oxidase can also terminate histamine action outside of the brain. Note that there is no apparent reuptake pump for histamine. Thus, histamine is likely to diffuse widely away from its synapse, just like dopamine does in prefrontal cortex.

There are a number of histamine receptors ( through ). The postsynaptic histamineFigures 11-8 11-11 1 (H ) receptor is best known ( ) because it is the target of "antihistamines" (i.e., H1 Figure 11-9A 1 antagonists) ( ). When histamine itself acts at H receptors, it activates aFigure 11-9B 1 G-protein-linked second-messenger system that activates phosphatidyl inositol, and the transcription factor cFOS, and results in wakefulness, normal alertness, and pro-cognitive actions ( ).Figure 11-9A When these H receptors are blocked in the brain, they interfere with the wake-promoting actions of1 histamine, and thus can cause sedation, drowsiness, or sleep ( ).Figure 11-9B

Histamine 2 (H ) receptors, best known for their actions in gastric acid secretion and the target of a2

number of anti-ulcer drugs, also exist in the brain ( ). These postsynaptic receptors alsoFigure 11-10 activate a G-protein second-messenger system with cAMP, phosphokinase A, and the gene product CREB. The function of H receptors in brain is still being clarified, but apparently is not linked directly2 to wakefulness.

A third histamine receptor is present in brain, namely the H receptor ( and ).3 Figures 11-8 11-11

Synaptic H receptors are presynaptic ( ) and function as autoreceptors (3 Figure 11-11A Figure 11-11B

). That is, when histamine binds to these receptors, it turns

Figure 11-8. . Shown here are receptors for histamine that regulate its neurotransmission.Histamine receptors Histamine 1 and histamine 2 receptors are postsynaptic, while histamine 3 receptors are presynaptic autoreceptors. There is also a binding site for histamine on NMDA receptors - it can act at the polyamine site, which is an allosteric modulatory site.

Figure 11-9. . (A) When histamine binds to postsynaptic histamine 1 receptors, itHistamine 1 receptors activates a G-protein-linked second-messenger system that activates phosphatidyl inositol and the transcription factor cFOS. This results in wakefulness and normal alertness. (B) Histamine 1 antagonists prevent activation of this second messenger and thus can cause sleepiness.

Figure 11-10. . Histamine 2 receptors are present both in the body and in the brain.Histamine 2 receptors When histamine binds to postsynaptic histamine 2 receptors it activates a G-protein-linked second-messenger system with cAMP, phosphokinase A, and the gene product CREB. The function of histamine 2 receptors in the brain is not yet elucidated but does not appear to be directly linked to wakefulness.

off further release of histamine ( ). One novel approach to new wake-promoting andFigure 11-11B pro-cognitive drugs is to block these receptors, thus facilitating the release of histamine, allowing histamine to act at H receptors to produce the desired effects ( ). Several H1 Figure 11-11C 3 antagonists are in clinical development.

There is a fourth type of histamine receptor, H , but these are not known to occur in the brain.4 Finally, histamine acts also at NMDA ( -methyl- -aspartate) receptors ( ). Interestingly,N D Figure 11-8 when histamine diffuses away from its synapse to a glutamate synapse containing NMDA receptors, it can act at an allosteric modulatory site called the polyamine site, to alter the actions of glutamate at NMDA receptors ( ). The role of histamine and function of this action are not well clarified.Figure 11-8

Histamine neurons all arise from a single small area of the hypothalamus known as the tuberomammillary nucleus (TMN), which is part of the sleep/wake switch illustrated in .Figure 11-4 Thus, histamine plays an important role in arousal, wakefulness, and sleep. The TMN is a small bilateral nucleus that provides histaminergic input to most brain regions and to the spinal cord (Figure

).11-12