Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

In Search of a Good Night's Sleep

Laura G. Leahy, DrNP, APRN, FAANP

Abstract

A good night's sleep is essential to overall physical, cognitive, and emotional well-being. Sleep deprivation, whether general or related to time changes (e.g., daylight saving time), contributes to decreased cognition, impaired memory, poor coordination, mood fluctuations, increased risk of heart disease and diabetes, and weight gain, among others. The sleep cycle is defined by five stages and two distinct parts—rapid eye movement (REM) and non-REM sleep—that work to promote not only the quantity of sleep but also the quality of sleep, which impacts overall health. Each stage of sleep is influenced by various neurochemical actions among the brain regions. The neurochemistry and neuropath-ways related to the sleep/wake cycle as well as the mechanisms of action of sleep-inducing and wake-promoting medications are explored. [Journal of Psychosocial Nursing and Mental Health Services, 55(10), 19–26.]

Abstract

A good night's sleep is essential to overall physical, cognitive, and emotional well-being. Sleep deprivation, whether general or related to time changes (e.g., daylight saving time), contributes to decreased cognition, impaired memory, poor coordination, mood fluctuations, increased risk of heart disease and diabetes, and weight gain, among others. The sleep cycle is defined by five stages and two distinct parts—rapid eye movement (REM) and non-REM sleep—that work to promote not only the quantity of sleep but also the quality of sleep, which impacts overall health. Each stage of sleep is influenced by various neurochemical actions among the brain regions. The neurochemistry and neuropath-ways related to the sleep/wake cycle as well as the mechanisms of action of sleep-inducing and wake-promoting medications are explored. [Journal of Psychosocial Nursing and Mental Health Services, 55(10), 19–26.]

“Sleep is an ancestral and primitive behavior that is shared across the planet by over a billion people on a daily basis.” (Cappuccio, D’Elia, Strazzullo, & Miller, 2010, p. 585)

A good night's sleep is essential to overall physical, cognitive, and emotional well-being. Psychiatric nurses frequently observe the impact of sleep deprivation on their patients. Lack of sleep contributes to decreased cognition; impaired memory; poor coordination; increased risk of accidents; mood fluctuations and irritability; elevated blood pressure; increased risk of heart disease, weight gain, and diabetes; weakened immunity; diminished libido; manic episodes; seizures; and even increased risk of early mortality (Pietrangelo & Watson, 2017). In fact, a systematic review and meta-analysis by Cappuccio et al. (2010) found that sleeping less than 6 to 8 hours per night could increase the risk of early death by approximately 12%.

The current article explores the adverse health outcomes related to sleep deprivation, the five stages of sleep, the neurobiology of sleep and wakefulness, and the various medications and supplements that may improve the ability to “catch some Zs.”

Daylight Saving and Adverse Health Outcomes

As much of the United States gears up to “fall back” with daylight saving time (DLS) set to occur on November 5, 2017, nurses need to be aware of this annual change on the sleep patterns and mental health of their patients. On an annual basis, sleep is disrupted in at least a portion of 70 of the world's 195 countries, affecting more than 25% of the world's population, through the observance of DLS by “springing forward” and “falling back” (TimeandDate.com, 2017). In Northern hemispheres, “springing forward” typically occurs between the months of March and April and “falling back” occurs between late September and early November; in the Southern hemispheres, the time periods are reversed (TimeandDate.com, 2017).

Not only has general sleep deprivation been associated with adverse health outcomes, DLS transitions have also been implicated in changes to physical and emotional health. An analysis of approximately 200,000 hospital contacts for unipolar depression showed an 11% increase in depressive episodes during the transition from DLS to standard time (Hansen, Sønderskov, Hageman, Dinesen, & Østergaard, 2017). Similarly, increased rates of acute myocardial infarction were found following the spring change to DLS and decreased incidences of acute myocardial infarction were found following the DLS transition in the fall (Sandhu, Seth, & Gurm, 2014). In a retrospective study exploring the impact of DLS on spontaneous pregnancy loss in patients undergoing in vitro fertilization, the rate of loss after embryo transfer was significantly higher during spring DLS transitions (Liu et al., 2017). In studies conducted by the American Academy of Neurology (AAN; 2016), researchers found that the incidence of ischemic stroke was 8% higher in the 2 days following DLS transitions in the spring and fall. The AAN (2016) also found that individuals with cancer were 25% more likely to experience a stroke after the DLS transition, with a 20% even greater incidence in those older than 65. In addition to the adverse health effects related to the annual DLS transitions, studies have also shown increases in traffic accidents and work-related injuries and decreased work productivity (Deans, 2016). Thus, the need to monitor and maintain adequate sleep is essential, and nurses must be cognizant of the potential health risks associated not only with general sleep deprivation but also the risks posed by the 1-hour change that occurs with DLS transitions in the spring and fall of each year.

Stages of Sleep

Sleep is not simply a one-step process. There are a series of five stages to the sleep cycle, each offering a different role in promoting an individual's quality of sleep and overall health. On an average night in which an individual obtains 8 hours of sleep, he/she will undergo approximately five sleep cycles (National Sleep Foundation, 2017). Each cycle has two distinct parts: non-rapid eye movement (REM) sleep and REM sleep. Non-REM sleep comprises Stages 1 through 4 of the sleep cycle and REM sleep comprises Stage 5 (Figure).

The sleep cycle.Adapted from the National Sleep Foundation (2017).

Figure.

The sleep cycle.

Adapted from the National Sleep Foundation (2017).

According to the National Sleep Foundation (2017), Stage 1 comprises approximately 5% or 5 to 15 minutes of the entire cycle. In Stage 1 of the sleep cycle, individuals vacillate between consciousness and sleep (i.e., still somewhat alert and can be easily awakened). This stage is also when individuals experience muscle twitching or jerking, “the nods,” and/or hypnagogic hallucinations. It is estimated that approximately 40% of the population experience hypnagogic hallucinations, which may take the form of auditory, tactile, visual, or other sensory experiences (Ohayon, Priest, Caulet, & Guilleminault, 1996). It is also important to note that individuals diagnosed with anxiety, depression, and/or bipolar disorder were found to have a two-fold increase in the incidence of hypnagogic or hypnopompic hallucinations on a weekly basis (Ballas, 2006). Clinicians must screen for sleep-onset–related sensory experiences as they are different than hallucinations related to psychosis.

Stage 2 of the sleep cycle occurs over a period of approximately 45 minutes. During this stage, the brain “powers down,” sleep is light, heart rate slows, body temperature drops, and the body prepares for deep restorative sleep, which occurs in Stages 3 and 4 (National Sleep Foundation, 2017). In Stages 3 and 4 of the sleep cycle, sleep is deeper and it is more difficult to arouse the individual. The body begins to repair and restore tissues, strengthen the immune system, build muscle and bone, stimulate growth and development, and build energy stores for the coming day (National Sleep Foundation, 2017). This phase of non-REM sleep occurs over a period of approximately 20 minutes in each 90-minute sleep cycle.

Stage 5, or the REM stage of the sleep cycle, occurs approximately 90 minutes after initially falling asleep. During this phase, the brain becomes more active, dreaming occurs, eyes move and jerk in different directions, and heart rate, blood pressure, and breathing increase. With each sleep cycle, the REM stage gets longer, with the final period of REM sleep lasting up to 1 hour prior to waking (Blahd, 2016). Adults spend approximately 20% of total sleep in REM, whereas infants spend up to 50% in the REM stage (Blahd, 2016). REM sleep is important to cognitive and emotional health, as this is when the brain consolidates and processes the prior day's information for storage in the long-term memory (National Sleep Foundation, 2017).

The Neuroscience of Sleep and Wakefulness

To better understand the impact of the one third of life dedicated to sleep, the neurobiology and neurochemistry of sleep and wakefulness must be reviewed. There is no one portion of the brain that is solely responsible for regulating sleep and wakefulness; the sleep cycle involves a complex series of brain structures and neurotransmitters. Wakefulness is thought to be regulated by structures in the brainstem, cerebellum, hypothalamus, and basal forebrain, whereas sleep is induced by inhibition of the brain's arousal center via the ventrolateral preoptic nucleus (VLPN) (HowSleepWorks.com, 2017). REM sleep is regulated by the pons region of the brainstem, which also regulates the basic functions of breathing, heart rate regulation, and sensory perception, whereas deep, restorative sleep, also known as non-REM sleep, involves a circuit extending from the thalamus to the cortex (HowSleepWorks.com, 2017) allowing the body to rejuvenate and heal.

As with a majority of disorders affecting the emotional health of patients, the neurotransmitters serotonin, norepinephrine, and dopamine as well as GABA, glutamate, histamine, orexin, and acetylcholine play a large role in the regulation of the sleep/wake cycle. Imbalances in these and other neurotransmitters may significantly influence not only the amount of sleep an individual is able to achieve but also the quality of sleep. Table 1 provides an overview of the various neurochemicals and associated brain regions as well as their effect and impact on waking and REM and non-REM sleep.

The Neuroscience of Sleep and Wakefulness

Table 1:

The Neuroscience of Sleep and Wakefulness

Of the tri-monoamines, serotonin, in the raphe nucleus, plays a role in sleep and wakefulness. Serotonin is involved in arousal and directly promotes wakefulness and the stimulation of executive brain functions during periods of waking (Cushner, 2017). Similar to norepinephrine, in the locus coeruleus, serotonin also inhibits REM sleep and contributes to arousal at the end of the sleep cycle (Gerber, 2016). Dopamine, in particular the D4 receptors along the pineal gland and in the ventral tegmental area of the brain, regulates the sleep/wake cycle and contributes to arousal by down-regulating melatonin, the hormone responsible for sedation (Gerber, 2016; Welsh, 2012). Interestingly, REM sleep is the only time of day in which the tri-monoamines (serotonin, norepinephrine, and dopamine) are not actively firing (Klemm, 2011).

The orexins, a group of excitatory neurochemicals commonly associated with appetite regulation, promote arousal and wakefulness when stimulated in the hypothalamus (Schwartz & Kilduff, 2015). Orexin is increased in waking through the increase of serotonin and decreased in REM sleep through the increase of GABA (Morrell, Palange, Levy, & De Backer, 2012). In addition to their role in the sleep/wake cycle, the orexins are involved in the regulation of blood pressure, body temperature, and neuroendocrine functions and are implicated in the sleep disorder narcolepsy when stores of orexin are depleted (Schwartz & Kilduff, 2012). The orexins also regulate dopamine, norepinephrine, histamine, and acetylcholine (Lu et al., 2002). Acetylcholine, a neurochemical associated with voluntary muscle movement, when activated in the dorsolateral pons and basal forebrain, is important for the initiation of Stage 5 REM sleep increasing levels to promote wakefulness (Gerber, 2016; Hall, 1998). Similarly, although antihistamine pharmaceutical agents are commonly used to treat insomnia, the neurotransmitter histamine promotes arousal and wakefulness through its activation in the tuberomammillary nucleus and hypothalamus (Morrell et al., 2012). Histamine is also important to the regulation of appetite and mental alertness/cognition (Morrell et al., 2012).

Glutamate is one of the most abundant and common excitatory neurotransmitters in the brain; however, it is the concentrations of glutamate in the hypothalamus and cerebellum that are found to regulate the length of sleep, promote arousal, and enhance cognition (Gerber, 2016). Glutamate is also the precursor to the main inhibitory neurotransmitter of the central nervous system, GABA, which induces deep sleep (Stages 3 and 4) when activated in the VLPN of the posterior hypothalamus (Schwartz & Kilduff, 2015). GABA has no effect on waking or the state of wakefulness as its main purpose is to down-regulate or inhibit neurons, producing a calming/sedating effect (Gerber, 2015).

Although not technically a neurotransmitter, melatonin, which is converted from serotonin in the pineal gland, is the hormone most commonly associated with the regulation of circadian rhythm (Hardeland, Pandi-Perumal, & Cardinali, 2006). Melatonin levels are higher at night when the environment is darker, contributing to sleep, and levels are lower when there is greater light in the surroundings, contributing to wakefulness (Brown, 1994).

The process of obtaining a good night's sleep is complex from a neurochemical and neuroanatomical perspective. There are multiple complex interactions between neurotransmitters, which influence the various phases of the sleep cycle to produce the most effective sleep and allow the body to heal, rejuvenate, process information from the day, and store memories. When any of these circuits is disrupted or a neurotransmitter fails to activate, sleep can be interrupted, contributing to all of the physical, cognitive, and emotional health adverse events previously mentioned.

Medications Associated with Sleep and Wakefulness

The quest to obtain a restful night's sleep to energize for the next day's activities has led many individuals to try various over-the-counter medications and supplements as well as prescription medications. Although the current article focuses on the neuro-science of sleep and the medications associated with sleep and wakefulness, it is essential that individuals experiencing disruption to their sleep cycle be educated about and engage in the practice of healthy sleep hygiene techniques. The next section explores the various agents used in the treatment of sleep/wake disorders. Table 2 offers an overview of these medications and their associated mechanisms of action; however, it is meant solely as a guide to identify agents by the neurochemical actions that may impact the states of sleep and/or wakefulness.

Medications Associated with Sleep and Wakefulness

Table 2:

Medications Associated with Sleep and Wakefulness

Although ethanol is likely the most widely used agent to induce sleep, with more than 22% of individuals who experience chronic insomnia reporting the use of alcohol as a hypnotic, it can contribute to multiple health concerns, including dependence, hepatotoxicity, and reduced sleep quality and efficiency (Pagel & Parnes, 2001; Sateia, Doghramji, Hauri, & Morin, 2000). Other sleep-promoting agents, available without a prescription, include diphenhydramine medications and melatonin supplements. Histamine (H1) receptor antagonists, such as diphenhydramine, have been used for decades in an off-label capacity to treat insomnia (Nicholson, Pascoe, & Stone, 1985). These products typically act as histamine blockers, resulting in decreased sleep latency. Melatonin supplements, on the other hand, act with the body's hormonal system, regulating the circadian rhythm as it relates to daylight and darkness, inducing sleep or maintaining wakefulness (National Sleep Foundation, 2017). Diphenhydramine agents and melatonin supplements are widely available without a prescription in local retail locations. Two melatonin receptor agonists (i.e., ramelteon [Rozerem®] and tasimelteon [Hetlioz®]) are approved by the U.S. Food and Drug Administration (FDA) as prescription medications for the treatment of sleep onset insomnia and non-24-hour sleep-wake disorder, respectively (Chawla, 2016; Drugs.com, 2017).

Prescription medications, acting as H1 antagonists, which have been used to induce sleep and relieve insomnia, include various antidepressant agents and first- and second-generation antipsychotic agents. One of the most common antidepressant agents used to treat sleep disturbances is trazodone. Trazodone not only blocks H1 receptors but is also characterized by serotonin-2 receptor antagonism resulting in enhanced sleep and minimal suppression of REM sleep (Winokur & Demartinis, 2012). Similarly, mirtazapine and certain tricyclic antidepressant agents may improve sleep quality and efficiency by the same mechanisms of action; however, the majority of tricyclic antidepressant agents are known to markedly suppress REM sleep, the aforementioned being the exceptions (Winokur & Demartinis, 2012).

Orexin receptor antagonists, such as suvorexant (Belsomra®), have recently been approved for the treatment of insomnia and the associated difficulties with sleep onset and sleep maintenance (Chawla, 2016). Through the blockage of the orexin receptors, suvorexant is thought to suppress the wake drive, thus maintaining sleep (Chawla, 2016). Quality, restful sleep for patients with post-traumatic stress disorder (PTSD) can be elusive. Over the past decade, an older antihypertensive agent, prazosin (Minipress®), has shown efficacy in treating sleep-related nightmares associated with PTSD (Keller, 2012). Prazosin is an alpha-adrenergic antagonist that crosses the blood–brain barrier and is believed to diminish the effects of norepinephrine thought to contribute to nightmares (Keller, 2012). This off-label treatment option may be beneficial for this specific population of individuals with PTSD.

A majority of prescription medications indicated and used for the treatment of sleep-related disorders stimulate the inhibitory neurochemical GABA. The GABA agonists include benzodiazepine agents, “Z-drugs” (also known as non-benzodiazepine sleep agents), and other drugs such as the anticonvulsant gabapentin. Benzodiazepine agents suppress REM sleep, which is important for learning and memory consolidation; withdrawal from these medications often results in an increase in REM sleep or rebound REM sleep (Pagel & Parnes, 2001). Non-benzodiazepine sleep agents (Z-drugs), such as zolpidem (Ambien®), eszopiclone (Lunesta®), and zaleplon (Sonata®), also potentiate the inhibitory and calming effects of GABA by increasing the frequency in which the chloride channel opens, thus inducing sleep and improving sleep onset (Chawla, 2016). These agents are less likely to cause a rebound or increase in REM sleep if abruptly withdrawn. Benzodiazepine agents and Z-drugs are on the Beer's Criteria of medications that may not be appropriate for use in older adults; therefore, caution is advised due to the risk of falls and potential for prolonged half-life extending the adverse effects of the medication in the individual's waking hours (Chawla, 2016).

As not everyone who experiences sleep disturbances responds to the sedating effects of the previously reviewed medications, there are drugs that promote wakefulness. Atomoxetine (Strattera®) is approved by the FDA for the treatment of attention-deficit/hyperactivity disorder (ADHD). This non-stimulant agent is a selective norepinephrine reuptake inhibitor, which can increase dopamine in the prefrontal cortex and improve alertness and wakefulness in those struggling with daytime sleepiness (Chang & Shen, 2013). Psychostimulant agents, such as methylphenidate (Ritalin®) and amphetamine (Adderall®), are dopamine/norepinephrine reuptake inhibitors whose purpose is to increase motivation and alertness, improve attention and concentration, enhance mood and cognition, increase energy, and improve wakefulness (Sadock, Sadock, & Sussman, 2014). Although the primary indication for psychostimulant agents remains ADHD, there is efficacy for their clinical use in treating narcolepsy, depression, and other disorders in which diminished alertness or daytime sedation occurs (Chang & Shen, 2014).

The antidepressant agent bupropion (Wellbutrin®) also acts as a dopamine/norepinephrine reuptake inhibitor; however, unlike most antidepressant medications, it does not suppress REM sleep but rather increases the amount of time spent in REM sleep (Nofzinger et al., 1995), allowing for enhanced learning and consolidation of memories as well as improved daytime wakefulness. Similarly, the serotonin reuptake inhibitor antidepressant agents fluoxetine (Prozac®) and citalopram (Celexa®) have shown efficacy in promoting wakefulness by modulating non-REM sleep in the raphe nucleus (Guzman, 2017; Morrell et al., 2012).

The orexin agonists modafinil (Provigil®) and its racemic enantiomer armodafinil (Nuvigil®) have a mechanism of action distinctly different from psychostimulant agents (Chang & Shen, 2013). These agents are FDA approved as wakefulness-promoting medications. Modafinil activates orexin, an excitatory neurochemical, producing arousal and wakefulness in the tubero-mammillary nucleus (Scammel et al., 2000). In addition, studies by Ferraro et al. (1999, 1996) have shown that racemic mixtures of modafinil increase levels of glutamate and decrease GABA levels, contributing to the drug's wake-promoting properties. The complexities of the mechanism of actions of these medications are not yet fully understood.

Conclusion

As DLS ends on November 5, 2017, nurses must be attuned to the potential for sleep disruptions in their patients regardless of clinical setting. The single “fall back” hour can be enough to contribute to dysregulation of the exquisitely balanced sleep/wake cycle. Although there are many neurochemicals and neuropathways governing the sleep/wake cycle, many agents can treat insomnia and/or excessive daytime sleepiness. As holistic providers of care, nurses can also offer their patients techniques to improve their sleep hygiene and ways to avoid disruption to the sleep/wake cycle. Sleep is a necessary function of life to promote and restore physical and mental health and maintain alertness and sound cognition.

References

  • American Academy of Neurology. (2016, February9). Does daylight saving time increase risk of stroke? Retrieved from https://www.sciencedaily.com/releases/2016/02/160229220653.htm
  • Ballas, P. (2006). First-known hypnopompic hallucination occurring in-hospital: Case report. Jefferson Journal of Psychiatry, 20, 38–42.
  • Blahd, W. (2016). What are REM and non-REM sleep? Retrieved from http://www.webmd.com/sleep-disorders/guide/sleep-101
  • Brown, G.M. (1994). Light, melatonin and the sleep-wake cycle. Journal of Psychiatry & Neuroscience, 19, 345–353.
  • Cappuccio, F.P., D'Elia, L., Strazzullo, P. & Miller, M.A. (2010). Sleep duration and all-cause mortality: A systematic review and meta-analysis of prospective studies. Sleep, 33, 585–592. doi:10.1093/sleep/33.5.585 [CrossRef]
  • Chang, S.-C. & Shen, W.W. (2013). Stimulants, wakefulness-promoting agents, and nonstimulant attention deficit hyperactivity disorder medications. Journal of Experimental and Clinical Medicine, 5, 210–216. doi:10.1016/j.jecm.2013.10.010 [CrossRef]
  • Chawla, J. (2016). Insomnia medication. Retrieved from http://emedicine.medscape.com/article/1187829-medication#2
  • Cushner, K. (2017, February20). Explanation of neurotransmitters. Retrieved from https://www.tuck.com/neurotransmitters
  • Deans, E. (2016, November5). Your brain on daylight savings. Retrieved from https://www.psychologytoday.com/blog/evolutionary-psychiatry/201611/your-brain-daylight-savings
  • Drugs.com. (2017). Hetlioz. Retrieved from https://www.drugs.com/pro/hetlioz.html
  • Ferraro, L., Antonelli, T., Tanganelli, S., O'Connor, W.T., Perez de la Mora, M., Mendez-Franco, J. & Fuxe, K. (1999). The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: Prevention by local GABA-A receptor blockade. Neuropsychopharmacology, 20, 346–356. doi:10.1016/S0893-133X(98)00085-2 [CrossRef]
  • Ferraro, L., Tanganelli, S., O'Connor, W.T., Antonelli, T., Rambert, F. & Fuxe, K. (1996). The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: Possible involvement of the serotonergic 5-HT3 receptor. Neuroscience Letter, 220, 5–8. doi:10.1016/S0304-3940(96)13212-2 [CrossRef]
  • Gerber, C. (2016, October5). These neurotransmitters are probably keeping you up at night. Retrieved from https://www.forbes.com/sites/quora/2016/10/05/these-neurotransmittersare-probably-keeping-you-up-at-night/#
  • Guzman, F. (2017, February11). Psychopharmacology of sleep and wakefulness: Understanding neurotransmitters and pathways in clinical practice. Retrieved from http://psychopharmacologyinstitute.com/sleep-insomnia/psychopharmacology-sleep-wakefulness-understanding-neurotransmitters-pathways-clinical-practice
  • Hall, R.H. (1998). Neurotransmitters and sleep. Retrieved from http://web.mst.edu/~rhall/neuroscience/03_sleep/sleepneuro.pdf
  • Hansen, B.T., Sønderskov, K.M., Hageman, I., Dinesen, P.T. & Østergaard, S.D. (2017). Daylight savings time transitions and the incidence rate of unipolar depressive episodes. Epidemiology, 28, 346–353. doi:10.1097/EDE.0000000000000580 [CrossRef]
  • Hardeland, R., Pandi-Perumal, S.R. & Cardinali, D.P. (2006). Melatonin. International Journal of Biochemistry & Cell Biology, 38, 313–316. doi:10.1016/j.biocel.2005.08.020 [CrossRef]
  • HowSleepWorks.com. (2017). Neurological mechanisms of sleep. Retrieved from https://www.howsleepworks.com/how_neurological.html#
  • Keller, D.M. (2012, March12). Prazosin relieves nightmares and sleep disturbance in PTSD. Retrieved from http://www.medscape.com/viewarticle/760070
  • Klemm, W.R. (2011). Why does REM sleep occur? A wake-up hypothesis. Frontiers in Systems Neuroscience, 5, 73. doi:10.3389/fnsys.2011.00073 [CrossRef]
  • Liu, C., Politch, J.A., Cullerton, E., Go, K., Pang, S. & Kuohung, W. (2017). Impact of daylight savings time on spontaneous pregnancy loss in in vitro fertilization patients. Journal of Biological and Medical Rhythm Research, 24, 571–577. doi:10.1080/07420528.2017.1279173 [CrossRef]
  • Lu, J., Bjorkum, A.A., Xu, M., Gaus, S.E., Shiromani, P.J. & Saper, C.B. (2002). Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep. Journal of Neuroscience, 22, 4568–4576.
  • Morrell, M.J., Palange, P., Levy, P. & De Backer, W. (2012). Neuroanatomy and neurobiology of sleep. In Simonds, A. & De Backer, W. (Eds.), ERS handbook of respiratory sleep medicine (2nd ed.). Sheffield, UK: European Respiratory Society.
  • National Sleep Foundation. (2017). The sleep disorders. Retrieved from http://sleepdisorders.sleepfoundation.org
  • Nicholson, A.N., Pascoe, P.A. & Stone, B.M. (1985). Histaminergic systems and sleep: Studies in man with H1 and H2 antagonists. Neuropharmacology, 24, 245–250. doi:10.1016/0028-3908(85)90081-4 [CrossRef]
  • Nofzinger, E.A., Reynolds, C.F. III. , Thase, M.E., Frank, E., Jennings, J.R., Fasiczka, A.L. & Kupfer, D.J.(1995). REM sleep enhancement by bupropion in depressed men. American Journal of Psychiatry, 152, 274–276. doi:10.1176/ajp.152.2.274 [CrossRef]
  • Ohayon, M.M., Priest, R.G., Caulet, M. & Guilleminault, C. (1996). Hypnagogic and hypnopompic hallucinations: Pathological phenomena?British Journal of Psychiatry, 169, 459–467. doi:10.1192/bjp.169.4.459 [CrossRef]
  • Pagel, J.F. & Parnes, B.L. (2001). Medications for the treatment of sleep disorders: An overview. Primary Care Companion Journal of Clinical Psychiatry, 3, 118–125. doi:10.4088/PCC.v03n0303 [CrossRef]
  • Pietrangelo, A. & Watson, S. (2017). The effects of sleep deprivation on your body. Retrieved from http://www.healthline.com/health/sleep-deprivation/effects-on-body
  • Sadock, B.J., Sadock, V.A. & Sussman, N. (2014). Kaplan and Sadock's pocket handbook of psychiatric drug treatment. Philadelphia, PA: Lippincott Williams & Wilkins.
  • Sandhu, A., Seth, M. & Gurm, H.S. (2014). Daylight savings time and myocardial infarction. Open Heart, 1, e000019. doi:10.1136/openhrt-2013-000019 [CrossRef]
  • Sateia, M.J., Doghramji, K., Hauri, P.J. & Morin, C.M. (2000). Evaluation of chronic insomnia. Sleep, 23, 243–308. doi:10.1093/sleep/23.2.1l [CrossRef]
  • Scammel, T.E., Estabrooke, I.V., McCarthy, M.T., Chemelli, R.M., Yanagisawa, M., Miller, M.S. & Saper, C.B. (2000). Hypothalamic arousal regions are activated during modafinil-induced wakefulness. Journal of Neuroscience, 20, 8620–8628.
  • Schwartz, M.D. & Kilduff, T.S. (2015). The neurobiology of sleep and wakefulness. Psychiatric Clinics of North America, 38, 615–644. doi:10.1016/j.psc.2015.07.002 [CrossRef]
  • Smale, S. (2015). The neuromatrix of pain overlaps with the functional neuroanatomy of sleep. Retrieved from http://www.raynersmale.com/blog/2015/9/11/the-neuromatrix-of-pain-overlaps-with-functional-neuroanatomy-of-sleep
  • TimeAndDate.com. (2017). Daylight saving time around the world 2017. Retrieved from https://www.timeanddate.com/time/dst/2017.html
  • Welsh, J. (2012, June19). Feel-good brain chemical's role in sleep. Retrieved from https://www.livescience.com/21050-feel-good-brain-chemical-s-role-in-sleep.html
  • Winokur, A. & Demartinis, N. (2012, June13). The effects of antidepressants on sleep. Retrieved from http://www.psychiatrictimes.com/sleep-disorders/effects-antidepressants-sleep

The Neuroscience of Sleep and Wakefulness

Neurotransmitters and Associated Brain Regions Effects Impact on Waking, REM Sleep, and Non-REM Sleep

GABA Enhances sedation calming effect Increased in non-REM and REM sleep
Ventrolateral preoptic nucleus No effect on waking

Glutamic acid/Glutamate Promotes arousal Increased in waking and REM
Hypothalamus and cerebellum Enhances cognition No effect on non-REM

Dopamine Promotes wakefulness Increased in waking
Ventral tegmental area Increases motivation and pleasure Decreased in non-REM
Enhances cognition and dreaming Markedly decreased in REM

Norepinephrine Promotes wakefulness and attention Increased in waking
Locus coeruleus Formulates memory Decreased in non-REM
Increases heart rate and blood pressure Markedly decreased in REM

Serotonin (5HT) Promotes wakefulness Increased in waking
Raphe nucleus Regulates emotions, appetite, and temperature Modulates non-REM
Decreases time in REM
Formulates memory Increased in shift work sleep disorder

Histamine (H1) Promotes arousal and wakefulness Increased in waking
Tubero-mammillary nucleus Regulates appetite Decreased in non-REM
Hypothalamus Enhances cognition Markedly decreased in REM

Acetylcholine Schedules REM sleep Increased in waking and REM
Dorsolateral pons Regulates temperature Decreased in non-REM

Orexins (hypocretins) Promotes arousal and wakefulness Increased in waking (by increasing 5HT)
Hypothalamus Regulates appetite Decreased in REM (by increasing GABA)

Melatonin (N-Acetyl-5-Methoxy-Tryptamine) Modulates circadian rhythm and seasonal cycles Decreased in REM
Pineal gland in the epithalamus Induces sleep Increased in non-REM

Medications Associated with Sleep and Wakefulness

Sleep Wakefulness
Mechanism of Action Medication Mechanism of Action Medication
GABA agonists Benzodiazepines: <list-item>

clonazepam (Klonopin®)

</list-item><list-item>

lorazepama (Ativan®a)

</list-item><list-item>

temazepama (Restorila)

</list-item><list-item>

flurazepama (Dalmane®a)

</list-item><list-item>

estazolama,c

</list-item><list-item>

triazolama (Halcion®a)

</list-item>
Z-drugs: <list-item>

zolpidema (Ambien®a, Ambien CR®a, Edluar®a, Intermezzo®a, Zolpimist®a)

</list-item><list-item>

eszopiclonea (Lunesta®a)

</list-item><list-item>

zaleplona (Sonata®a)

</list-item>
Other: <list-item>

gabapentin (Neurontin®)

</list-item>
Orexin agonists <list-item>

modafinilb (Provigil®b)

</list-item><list-item>

armodafinilb (Nuvigil®b)

</list-item>
Alpha 1 antagonists <list-item>

prazosin (Minipress®)

</list-item>
Dopamine/norepinephrine agonists Psychostimulants: <list-item>

methylphenidateb (Ritalin®b)

</list-item><list-item>

amphetamineb (Adderall®b)

</list-item>
Other: <list-item>

bupropion (Wellbutrin®)

</list-item>
Orexin antagonists <list-item>

suvorexant (Belsomra®a)

</list-item>
Norepinephrine reuptake inhibitors <list-item>

atomoxetine (Strattera®)

</list-item>
Serotonin (5HT) antagonists <list-item>

doxepin (Silenor®a)

</list-item><list-item>

trazodone (Oleptra®a, Desyrel®)

</list-item><list-item>

mirtazapine (Remeron®)

</list-item><list-item>

amitriptyline (Elavil®)

</list-item><list-item>

nortriptyline (Pamelor®)

</list-item>
Serotonin (5HT) reuptake inhibitors <list-item>

fluoxetine (Prozac®)

</list-item><list-item>

citalopram (Celexa®)

</list-item>
Histamine (H1) antagonists <list-item>

doxepin (Silenor®a)

</list-item><list-item>

trazodone (Oleptra®a, Desyrel®)

</list-item><list-item>

olanzepine (Zyprexa®)

</list-item><list-item>

quetiapine (Seroquel®)

</list-item><list-item>

risperidone (Risperdal®)

</list-item><list-item>

chlorpromazine (Thorazine®)

</list-item><list-item>

diphenhydramine (Benadryl® and “PM” OTC agents)

</list-item>
Melatonin supplements <list-item>

melatonin (various OTC supplements)

</list-item><list-item>

tasimelteon (Hetlioz®a)

</list-item><list-item>

ramelteon (Rozerem®a)

</list-item>
Authors

Dr. Leahy is Family Psychiatric Advanced Practice Nurse and Master Clinician in Psychopharmacology, APNSolutions, LLC, Sewell, New Jersey.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Laura G. Leahy, DrNP, APRN, FAANP, Family Psychiatric Advanced Practice Nurse and Master Clinician in Psychopharmacology, APNSolutions, LLC, 123 Egg Harbor Road, Suite 703, Sewell, NJ 08080; e-mail: lgleahy@apnsolutions.com.

10.3928/02793695-20170919-02

Sign up to receive

Journal E-contents