Long established as the preeminent source in its field, the eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! With its use of icons and figures that form Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. Every aspect of the book has been updated, with the clarity of explanation that only Dr Stahl can bring.
Disorders of Sleep and Wakefulness and Their Treatment: Neurotransmitter Networks for Histamine and Orexin
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 with 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,” thus requiring routine evaluation and symptomatic treatment whenever encountered. This is similar to the earlier discussion in Chapter 9, where pain 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 and functional 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 Chapter 7; for those insomnia treatments that are benzodiazepines, the reader is also referred to Chapter 7. For various hypersomnia treatments, especially stimulants, the reader is referred to Chapter 11 on attention deficit hyperactivity disorder (ADHD) and to Chapter 13 on impulsivity, compulsivity, and addiction for additional information. The 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 Prescriber’s Guide) for details of doses, side effects, drug interactions, and other issues relevant to the prescribing of these drugs in clinical practice.
Although many experts approach insomnia and sleepiness by emphasizing the separate and distinct disorders that cause them, many pragmatic psychopharmacologists approach insomnia or excessive daytime sleepiness as important symptoms that cut across many conditions and that occur along a spectrum from deficient arousal to excessive arousal (Figure 10-1). In this conceptualization, an awake, alert, creative, and problem-solving person has the right balance between too much and too little arousal (baseline brain functioning in the middle of the spectrum in Figure 10-1). As arousal increases beyond normal, during the day there is hypervigilance (Figure 10-1); if this increased arousal occurs at night, there is insomnia (Figure 10-1, overactivation of the brain). From a treatment perspective, insomnia can be conceptualized as a disorder of excessive arousal, with drugs having hypnotic actions moving the patient from too much arousal to sleep (specific drugs with hypnotic actions discussed below).
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 (Figure 10-1, hypoactivation of the brain). From a treatment perspective, sleepiness can be conceptualized as a disorder of deficient arousal, with wake-promoting agents moving the patient from too little arousal to awake with normal alertness (specific wake-promoting agents are discussed below).
Note in Figure 10-1 that cognitive disturbance is the product of both too little as well as too much arousal, consistent with the need for cortical pyramidal neurons to be optimally “tuned,” with too much activity making them just as out of tune as too little. Note also in Figure 10-1 that the arousal spectrum is linked to the actions of several neurotransmitters that will be explained in detail in the following paragraphs (i.e., histamine, orexin, dopamine, norepinephrine, serotonin, acetylcholine, and γ-aminobutyric acid [GABA]). Several of these neurotransmitter circuits as a group are called the ascending reticular activating system, because they are known to work together to regulate arousal. This was discussed in Chapter 5 and illustrated for histamine, dopamine, and norepinephrine in Figure 5-14. This same ascending neurotransmitter system is blocked at several sites by many agents that cause sedation (see Chapter 5 and Figures 5-8 and 5-13). Figure 10-1 also shows that excessive arousal can extend past insomnia to panic, hallucinations, and all the way to frank psychosis (far right-hand side of the spectrum).
Histamine is one of the key neurotransmitters regulating wakefulness, and is the ultimate target of many wake-promoting drugs (via enhancement of histamine release) and sleep-promoting drugs (antihistamines that block histamine at H1 receptors). Histamine is produced from the amino acid histidine, which is taken up into histamine neurons and converted into histamine by the enzyme histidine decarboxylase (Figure 10-2). Histamine’s action is terminated by two enzymes working in sequence: histamine N-methyltransferase, which converts histamine to N-methylhistamine, and monoamine oxidase B (MAO-B), which converts N-methylhistamine into N-MIAA (N-methylindoleacetic acid), an inactive substance (Figure 10-3). Additional enzymes such as diamine oxidase can also terminate histamine action outside 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 the prefrontal cortex.
There are a number of histamine receptors (Figures 10-4 through 10-7). The postsynaptic histamine 1 (H1) receptor is best known (Figure 10-5) because it is the target of “antihistamines” (i.e., H1 antagonists) (see below). When histamine itself acts at H1 receptors, it activates a G-protein-linked second-messenger system that activates phosphatidylinositol, and the transcription factor cFOS, and results in wakefulness, normal alertness, and pro-cognitive actions (Figure 10-5). When these H1 receptors are blocked in the brain, this interferes with the wake-promoting actions of histamine, and thus can cause sedation, drowsiness, or sleep (see below).
Histamine 2 (H2) receptors, best known for their actions in gastric acid secretion and the target of a number of anti-ulcer drugs, also exist in the brain (Figure 10-6). These postsynaptic receptors also activate a G-protein second-messenger system with cyclic adenosine monophosphate (cAMP), phosphokinase A (PKA), and the gene product CREB. The function of H2 receptors in brain is still being clarified, but apparently is not linked directly to wakefulness.
A third histamine receptor is present in brain, namely the H3 receptor (Figure 10-7). Histamine H3 receptors are presynaptic (Figure 10-7A) and function as autoreceptors (Figure 10-7B). That is, when histamine binds to these receptors, it turns off further release of histamine (Figure 10-7B). One novel approach to new wake-promoting and pro-cognitive drugs is to block these receptors, thus facilitating the release of histamine, allowing histamine to act at H1 receptors to produce the desired effects (see below).
There is a fourth type of histamine receptor, H4, but these are not known to occur in the brain. Finally, histamine acts also at NMDA (N-methyl-D-aspartate) receptors (Figure 10-4). Interestingly, 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 (Figure 10-4). The role of histamine and function of this action are not well clarified.
Histamine neurons all arise from a single small area of the hypothalamus known as the tuberomammillary nucleus (TMN) (Figure 10-8), which regulates arousal. 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 10-8).
These are peptide neurotransmitters with two names because two different groups of scientists simultaneously discovered them, and named them differently. One group reported the discovery of neurotransmitters in the lateral hypothalamus that were oddly similar to the gut hormone secretin, a member of the incretin family, so they named it “hypocretin” to stand for a hypothalamic member of the incretin family. At the same time, another group reported the discovery of the “orexins” to reflect the orexigenic (appetite-simulating) activity of these neurotransmitter peptides. Soon it was realized that these were the same neurotransmitters: excitatory neuropeptides with approximately 50% sequence identity produced by cleavage of a single precursor protein to form orexin A with 33 amino acids and orexin B with 28 amino acids. This nomenclature can certainly be confusing but many now recognize the history of the discovery of hypocretin by using “hypocretin” to refer to the gene or genetic products and “orexins” to refer to the peptide neurotransmitters themselves. The use of both terms remains a practical necessity because “HCRT” is the standard gene symbol in databases and “OX” is used to refer to the pharmacology of the peptide system by international societies.
Orexin/hypocretin neurons are localized exclusively in certain hypothalamic areas (lateral hypothalamic area, perifornical area, and posterior hypothalamus) (Figure 10-9). These hypothalamic neurons degenerate in a condition called narcolepsy, characterized by the inability to stabilize wakefulness and thus sleep attacks in the daytime. Loss of these neurons causes the inability of orexin to be produced and released downstream on wake-promoting neurotransmitter centers and thus lack of stabilizing wakefulness. Treatment of narcolepsy is discussed below.
Orexin/hypocretin neurons in the hypothalamus make two neurotransmitters: orexin A and orexin B, which are released from their neuronal projections all over the brain (Figures 10-9 and 10-10), but especially in the monoamine neurotransmitter centers in the brainstem (Figure 10-9). The postsynaptic actions of the orexins are mediated by two receptors called orexin 1 and orexin 2 (Figure 10-11). Orexin A is capable of interacting with both receptors, whereas the neurotransmitter orexin B binds selectively to the orexin 2 receptor (Figure 10-11). The binding of orexin A to the orexin 1 receptor leads to increased intracellular calcium as well as activation of the sodium/calcium exchanger (Figure 10-11). The binding of orexin A or B to orexin 2 receptors leads to increased expression of N-methyl-D-aspartate (NMDA) glutamate receptors as well as inactivation of G-protein-regulated inwardly rectifying potassium (GIRK) channels (Figure 10-11).
In addition to their role in stabilizing wakefulness, orexins also are thought to regulate feeding behavior, reward, and other behaviors (Figure 10-12). During periods of wakefulness, orexin/hypocretin neurons are active and fire with tonic frequency to maintain arousal, but when presented with a stimulus – either external, such as an escapable stressor, or internal, such as elevated blood CO2 levels – orexin neurons exhibit a more rapid phasic burst firing pattern (Figure 10-12). This excitement of hypocretin/orexin neurons leads to increased activation not only of orexin but of all the other brain areas that orexin stimulates, hypothetically leading in turn to execution of appropriate behavioral responses such as attainment of reward or the avoidance of potential danger. In this way, the hypocretin/orexin system not only mediates wakefulness, but also allows for the facilitation of goal-directed, motivated behaviors, including increased food intake in response to hunger (Figure 10-12).
Orexin 1 receptors are highly expressed in the noradrenergic locus coeruleus, whereas orexin 2 receptors are highly expressed in the histaminergic tuberomammillary nucleus (TMN). It is believed that the effect of orexin/hypocretins on wakefulness is largely mediated by activation of the TMN histaminergic neurons that express orexin 2 receptors. However, orexin receptors and orexin projections to all the arousal neurotransmitter centers make orexins ideally situated to regulate wakefulness indirectly by effects on the multitude of arousal neurotransmitters (see Figures 10-13 through 10-16). Thus, orexins may be not so much arousal neurotransmitters themselves to cause wakefulness, but rather serve to stabilize wakefulness by interacting with all the arousal neurotransmitters (Figures 10-10 and 10-13 through 10-16). For example, orexin’s actions to maintain wakefulness and attention may be mediated by stimulation of acetylcholine from the basal forebrain and the pedunculopontine and laterodorsal tegmental (PPT/LDT) nuclei (Figure 10-13); dopamine release from the ventral tegmental area (VTA) (Figure 10-14); norepinephrine release from the locus coeruleus (LC) (Figure 10-15); serotonin release from the raphe nuclei (RN) (Figure 10-16) and histamine release from the tuberomammillary nucleus (TMN) (Figure 10-8). Wow!
When circadian drives, homeostatic drives, and darkness all act together at the end of the day and in the dark, orexin levels are low, wakefulness is no longer stabilized, and sleep is promoted from the ventrolateral preoptic area (VLPO) with GABA (γ-aminobutryric acid) neurotransmission enhanced (Figure 10-17), thus inhibiting all the wake-promoting neurotransmitter centers (Figures 10-8, 10-13 through 10-16).
We have indicated that a multitude of neurotransmitters are involved in the regulation of arousal and have illustrated their pathways in Figures 10-8, 10-9, and 10-13 through 10-17. This regulation results in a daily cycle of sleep and wakefulness mediated by two opposing drives: the homeostatic sleep drive and the circadian wake drive (Figure 10-18). The homeostatic sleep drive accumulates throughout periods of wakefulness and light and is opposed by the circadian wake drive.
The longer an individual is awake, the greater the homeostatic drive to sleep. The homeostatic sleep drive is dependent upon the accumulation of adenosine, which increases as the person tires with fatigue throughout the day, and ultimately leads to the disinhibition of the ventrolateral preoptic (VLPO) nucleus and the release of GABA in the sleep circuit (Figure 10-17), facilitating onset of sleep.
The circadian wake drive, mediated by light acting upon the suprachiasmatic nucleus, stimulates the release of orexin as part of the wake circuit to stabilize wakefulness by enhancing the release of several other wake-promoting neurotransmitters. During periods of light, histamine is released from the tuberomammillary nucleus onto neurons throughout the cortex and in the ventrolateral preoptic area, inhibiting the release of GABA (Figure 10-8). Histamine from the tuberomammillary nucleus also stimulates the release of orexin from the lateral hypothalamus as well as the perifornical area and the posterior hypothalamus. Then, orexin has a number of knock-on effects:
Orexin induces the release of acetylcholine from the basal forebrain in cortical areas and from the pedunculopontine and laterodorsal tegmental nuclei onto the thalamus (Figure 10-13)
Orexin also causes the release of dopamine from the ventral tegmental area onto cortical areas (Figure 10-14)
Orexin stimulates the release of norepinephrine from the locus coeruleus onto cortical areas (Figure 10-15)
Finally, orexin also instigates the release of serotonin from the raphe nuclei onto both the basal forebrain and the thalamus (Figure 10-16)
Then, as light fades, norepinephrine from the locus coeruleus and serotonin from the raphe nuclei build up and are released onto neurons in the lateral hypothalamus, causing negative feedback inhibiting the release of orexin. Without orexin, wakefulness is no longer stabilized, and the VLPO and GABA take charge and suppress all the arousal neurotransmitters (Figure 10-17). Thus, sleep is facilitated and melatonin is secreted at night in the dark. Then the cycle repeats itself as rest restores homeostatic sleep drive and light initiates wakefulness neurotransmitters.
In addition to the daily sleep/wake cycle (Figure 10-18), there is also an ultradian sleep cycle (see inset of Figure 10-18; this cycle occurs faster [ultra] than a day [dian] and is thus called ultradian). A complete ultradian sleep cycle (non-REM [rapid eye movement] and REM) lasts approximately 90 minutes and occurs four to five times a night (Figure 10-18, inset). Stages 1 and 2 of sleep make up non-REM sleep, whereas stages 3 and 4 of the sleep cycle are part of deeper, slow-wave sleep. During the normal sleep period, the duration of non-REM sleep is gradually reduced during the night while the duration of REM sleep is increased. REM sleep is characterized by faster activity on an electroencephalogram (EEG) – similar to that seen during periods of wakefulness – as well as distinct eye movements, and peripheral muscle paralysis and loss of muscle tone called atonia. It is during REM sleep that dreaming occurs, and positron emission tomography (PET) studies have shown activation of the thalamus, the visual cortex, and limbic regions accompanied by reduced metabolism in other regions, such as the dorsolateral prefrontal cortex and the parietal cortex during REM sleep. In contrast, there is overall reduced brain activity during non-REM sleep.
Neurotransmitters (Figures 10-8, 10-9, and 10-13 through 10-17) not only have a role in regulating the daily sleep/wake cycle (Figure 10-18), but also in regulating the various phases of sleep with the ultradian sleep cycle (see inset of Figure 10-18). Thus, neurotransmitters fluctuate not only on a circadian (24-hour) basis, but also throughout the various phases of the sleep cycle every night (Figures 10-19 through 10-22). Not surprisingly, GABA is “on” all night, rising steadily during the first few hours of sleep, plateaus, and then steadily declines before one wakens (Figure 10-19). Also, not surprisingly, the pattern for orexin is exactly the opposite: namely, orexin levels steadily decrease during the first few hours of sleep, plateau, and then steadily increase before one wakens (Figure 10-20). The pattern of the other neurotransmitters is sleep-phase dependent (Figures 10-21 and 10-22). That is, acetylcholine levels fluctuate throughout the sleep cycle, reaching their lowest levels during stage 4 sleep and peaking during REM sleep, tracing the ups and downs between stage 4 and REM every cycle (Figure 10-21). On the other hand, dopamine, norepinephrine, serotonin, and histamine levels demonstrate a different trend. They all act together to peak during stage 2 sleep and are at their lowest during REM sleep (Figure 10-22).
There is still much debate over the purpose of sleep. Some propose that sleep is essential for synaptic growth, while others argue that sleep is necessary for synaptic pruning (Figure 10-23). Regardless of which hypothesis – or some combination of both – is more accurate, it has become increasingly evident that disturbances of the sleep/wake cycle have a detrimental effect on a myriad of physiological and psychiatric functions. Aside from the economic costs of sleep/wake disorders, the risk of cardiometabolic disease, cancer, mental illness, and overall poorer quality of life are all increased when the sleep/wake cycle is disturbed (Figure 10-23). Disturbances in the sleep/wake cycle can have profound effects on cognitive functioning, including impairments in attention, memory deficits, and an inability to process new information (Figure 10-24). In fact, 24 hours of sleep deprivation or chronic short sleep duration (i.e., 4–5 hours per night) results in cognitive impairments equivalent to those seen when legally intoxicated with alcohol. Both REM and non-REM sleep appear to be essential for optimal cognitive functioning, with REM sleep modulating affective memory consolidation and non-REM sleep being critical for declarative and procedural memory. At the neurobiological level, there is evidence that disruption of the sleep/wake cycle impairs hippocampal neurogenesis, which may partly explain the behavioral effects of sleep/wake cycle disturbances on cognition.
In recent years, much interest in the relationship between sleep and cardiometabolic issues such as type 2 diabetes and obesity has been expressed (Figure 10-25). Although much remains unknown, an impaired sleep/wake cycle has been shown to disrupt the circulating levels of both the anorectic (appetite-inhibiting) hormone leptin and the orexigenic (appetite-stimulating) hormone ghrelin (Figure 10-25). These changes lead to dysfunctional insulin, glucose, and lipid metabolism; in turn, this may increase the risk of obesity, type 2 diabetes, and cardiovascular disease. Additionally, an altered sleep/wake cycle has been shown to disturb the natural fluctuations in gut microbiota, perhaps further promoting glucose intolerance and obesity.