Disorders of sleep and their treatments Flashcards
Denise is a 32-year-old patient with shift work disorder who reports that she is having difficulty in her
job as a pastry chef due to excessive sleepiness during her shift. Which of the following is a potential
therapeutic mechanism to promote wakefulness?
A. Inhibit GABA activity
B. Inhibit histamine activity
C. Inhibit orexin activity
D. All of the above
E. None of the above
The hypothalamus is a key control center for sleep and wake, and the specific circuitry that regulates
sleep/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 Correct. When the VLPO is active and GABA is released to the TMN, the sleep promoter is on
and the wake promoter is inhibited. Thus, inhibiting GABA activity can promote wakefulness.
B Incorrect. When the TMN is active and histamine is released to the cortex and the VLPO, the
wake promoter is on and the sleep promoter is inhibited. Thus, inhibiting histamine activity can
promote sleep, not wakefulness.
C Incorrect. The sleep/wake switch is also regulated by orexin neurons in the lateral
hypothalamus, which stabilize wakefulness. Inhibition of orexin would therefore promote sleep,
not wakefulness. In fact, a deficiency of orexin is an underlying cause of the extreme and sudden
sleepiness seen in narcolepsy.
D and E Incorrect
A 42-year-old police officer presents with sleep cycle disturbances. After sufficient consultation you
prescribe her eszopiclone. Which receptors are primarily being targeted by this treatment?
A. Histamine 1
B. Histamine 2
C. Serotonin 2C
D. GABAA alpha 1 isoform
E. GABAA alpha 2 and 3 isoforms
A and B Incorrect. Histamine 1, histamine 2, and histamine 3 are targets of both sleep- and wakepromoting
agents including histamine releasers, antihistamines, and selective histamine
antagonists.
C Incorrect. Serotonin 2C antagonism can be sedating and is one of the targets of some sleep
agents, including trazodone and agomelatine.
D Correct. Eszopiclone is a positive allosteric modulator at GABAA receptors. Eszopiclone
primarily targets receptors containing the alpha 1 isoform and this is responsible for its effects
on sleep.
E Incorrect. Although eszopiclone may target GABA A receptors that contain the alpha 2 and 3
isoforms, this is not its primary action nor is it related to the sleep effects. Instead, alpha 2 and 3
receptor subtypes are related to anxiolytic, muscle relaxant, and alcohol-potentiating factors
A 72-year-old woman has been having difficulty sleeping for several weeks, including both difficulty
falling asleep and frequent nighttime awakenings. Medical examination rules out an underlying condition
contributing to insomnia, and she is not taking any medications that are associated with disrupted sleep.
The patient is retired and spends the day caring for her grandchildren, including driving the older ones to
school in the morning. Which of the following would be the most appropriate treatment option for this
patient?
A. Flurazepam
B. Temazepam
C. Zaleplon
D. Zolpidem CR
The half-lives of hypnotics can have an important impact on their tolerability and efficacy profiles.
A Incorrect. Hypnotics with ultra-long half-lives (greater than 24 hours: for example, flurazepam
and quazepam) can cause drug accumulation with chronic use. This can cause impairment that
has been associated with increased risk of falls, particularly in the elderly.
B Incorrect. Hypnotics with moderate half-lives (15–30 hours: estazolam, temazepam, most
tricyclic antidepressants, mirtazapine, olanzapine) may not wear off until after the individual
needs to awaken and thus may have “hangover” effects (sedation, memory problems). Given that
the patient needs to drive early in the morning, this may not be the best option for her.
C Incorrect. Hypnotics with ultra-short half-lives (1–3 hours: zaleplon, triazolam, zolpidem,
melatonin, ramelteon) can wear off before the individual needs to awaken and thus cause loss of
sleep maintenance, which is already a problem for this patient.
D Correct. Hypnotics with half-lives that are short but not ultra-short (approximately 6 hours:
zolpidem CR, eszopiclone, and perhaps low doses of trazodone or doxepin) may provide rapid
onset of action and plasma levels above the minimally effective concentration only for the
duration of a normal night’s sleep. Thus, of the answer choices, zolpidem CR may best treat the
patient’s difficulties with sleep onset and maintenance while avoiding risks associated with
agents with longer half-lives. The dose of zolpidem CR in eldery patients is 6.25 mg/night.
A 33-year-old man taking estazolam to help him sleep through the night complains that his symptoms have
returned despite his adherence to the medication regimen for the past 6 months. You suspect he has
developed a tolerance to this drug and elect to switch him to:
A. Temazepam
B. Ramelteon
C. Trazodone
D. Chlordiazepoxide
With long-term use, benzodiazepine hypnotics can cause tolerance and, if discontinued, withdrawal
effects.
A and D Incorrect. Because this patient has developed tolerance to his current benzodiazepine,
another benzodiazepine such as temazepam and chlordiazepoxide may not be the best choices.
B Incorrect. Ramelteon has not been reported to cause tolerance and can be used for sleep
initiation; however, it is not necessarily used for sleep maintenance.
C Correct. Trazodone works by a serotonergic and histaminergic mechanism unique from
estazolam and may be able both to induce sleep and suppress any mild withdrawal insomnia when
estazolam is stopped. However, if severe insomnia results from estazolam discontinuation, a
tapering of this may be necessary until rebound insomnia resolves, while adding trazodone.
A 75-year-old man in good physical shape is having sleep problems. He wakes up at 4 am and although
he tries to stay awake in the evening to prevent this early rising, he usually falls asleep right after dinner,
often before 7 pm. Which of the following treatment options may be most beneficial for this patient?
A. Early morning melatonin
B. Evening melatonin
C. Late afternoon/evening light
D. A and C
E. A and B
F. B and C
A and C Partially correct.
B, E, and F Incorrect. Evening melatonin would not be appropriate for this patient who is phaseadvanced.
Rather, evening melatonin (and morning light) may benefit patients with phase-delayed
circadian rhythms, potentially resetting the suprachiasmatic nucleus (SCN) so that the sleep/wake
switch turns on earlier.
D Correct. This patient is phase-advanced. Phase-advanced circadian rhythms may benefit from
early morning melatonin and evening light, which could help reset the SCN so that the sleep/wake
switch stays off longer
A 45-year-old woman was prescribed doxepin 10 mg/night for insomnia. She reports that it helped only a
little, so she has been increasing the dose, up to 100 mg/night, as an attempt to increase the hypnotic
effects (with some success). She also reports dizzy spells and constipation. Which property does doxepin
exhibit in higher doses that could be the cause of these side effects?
A. Inhibiting reuptake of serotonin and norepinephrine
B. 5HT2A and 5HT2C antagonism
C. Alpha 1 adrenergic and muscarinic 1 antagonism
D. 5HT2A and 5HT2B antagonism
A, B and D Incorrect. Higher doses of doxepin inhibit reuptake of serotonin and norepinephrine,
but such effects are not likely to explain these side effects.
C Correct. Low-dose doxepin is selective for histamine 1 receptors, which is why it can act as a
hypnotic. It is likely that alpha 1 adrenergic and muscarinic 1 receptor antagonism seen with
higher doses of doxepin would explain these side effects.
Although he sleeps soundly through the night, a 54-year-old man, whom you have previously treated for
depression, describes feeling physically exhausted, sometimes with sore muscles, when he wakes up in
the morning. His wife reports that she frequently wakes in the middle of the night from his movements.
Which of the following tests would you refer him to take?
A. Polysomnograph
B. Multiple sleep latency test
C. Maintenance of wakefulness test
D. A and B
E. B and C
F. A and C
G. A, B, and C
A Correct. It is likely that this patient is suffering from periodic limb movements of sleep (PLMS)
or periodic limb movement disorder (PLMD), for which a polysomnograph test is recommended.
B Incorrect. Multiple sleep latency tests are recommended for narcolepsy without cataplexy and
idiopathic hypersomnia
C Incorrect. Maintenance of wakefulness tests are recommended for treatment assessment for
narcolepsy, with or without cataplexy and idiopathic hypersomnia.
D–G Incorrect
A patient recently diagnosed with narcolepsy and treated with a stimulant comes to your office with
concerns about attention problems associated with narcolepsy, which he read about on the Internet and
which have not been responsive to his treatment so far. Which of the following is true?
A. As a sleep disorder, narcolepsy is usually not associated with cognitive disturbances
B. The cognitive disturbances associated with narcolepsy can be worsened by stimulants
C. Stimulants used to treat narcolepsy can restore cognitive performance
D. Narcolepsy can sometimes lead to cognitive disturbances, but little is known about treating these
A and D Incorrect. Individuals with untreated narcolepsy have difficulty sustaining attention,
which is associated with inefficient activation in the dorsolateral prefrontal cortex and is
indicated by poor performance on an n-back test.
B Incorrect. Stimulants can improve, not worsen, cognitive disturbances associated with
narcolepsy.
C Correct. Dopaminergic wake-promoting agents may enable individuals with narcolepsy to
sustain activation of the dorsolateral prefrontal cortex, thus improving cognitive performance.
For this patient, modafinil, a higher dose of his stimulant, or a different stimulant may
successfully treat these symptoms.
A patient started working a night shift as a security guard 1 week ago. At this time, he is most likely to have a disrupted \_\_\_\_\_\_\_\_\_\_ drive while his \_\_\_\_\_\_\_\_\_\_\_ drive is unaffected. A. Ultradian… circadian B. Circadian…homeostatic C. Homeostatic…ultradian D. Ultradian…homeostatic E. Circadian…ultradian F. Homeostatic…circadian
B Correct. Circadian (wake) drive is the result of input such as light, melatonin, and physical
activity to the suprachiasmatic nucleus. Homeostatic (sleep) drive increases the longer one is
awake without sleep and is associated with an accumulation of the neurotransmitter adenosine.
An individual working a night shift is not likely to receive normal light input although (s)he may
sleep a normal amount and therefore is likely to have a disrupted circadian drive with an
unaffected homeostatic drive.
Over time, however, individuals who do shift work often sleep fewer hours than they would on a
normal schedule – but not because they actually need less sleep – and thus their homeostatic
drive can build up.
A, C, D, and E Incorrect. Ultradian cycle refers to the cyclical recurrence of the multiple phases
of sleep and is most likely unaffected in this normal individual.
F Incorrect.
A 24-year-old paramedic frequently works night shifts and is having difficulty staying alert throughout his
shift. As part of your recommendations for addressing sleep hygiene, you should advise that he:
A. Avoid caffeine
B. Use caffeine only in the early part of his shift
C. Use caffeine throughout his shifT
B
A 28-year-old woman with chronic insomnia is hoping to find an effective treatment but is reluctant to try
anything that might cause dependence. Her clinician is considering prescribing suvorexant, which acts as
an antagonist at orexin receptors. Specifically, what type of orexin antagonists may be effective for
treating patients with sleep–wake disorders?
A. Single orexin receptor antagonists selective for orexin 1 receptors
B. Single orexin receptor antagonists selective for orexin 2 receptors
C. Dual orexin receptor antagonists that block both orexin 1 and 2 receptors
D. A and B
E. B and C
F. A and C
G. A, B, and C
A Incorrect. Orexin serves to stabilize and promote wakefulness. Its postsynaptic actions are
mediated by two receptors: orexin 1 and orexin 2. Orexin 1 receptors are highly expressed in the
locus coeruleus, where noradrenergic neurons originate, and are thought to play only a
supplementary role in sleep/wake regulation. Consistent with this, preclinical trials with single
orexin receptor antagonists for orexin 1 receptors have not demonstrated an effect on sleep.
B Partially correct. Orexin 2 receptors are highly expressed in the tuberomammillary nucleus,
where histaminergic neurons originate. It is believed that the effect of orexin on wakefulness is
largely mediated by activation of the TMN histaminergic neurons that express orexin 2 receptors.
Presumably, orexin 2 receptors therefore play a pivotal role in sleep/wake regulation. Consistent
with this, there are promising preclinical results of single orexin receptor antagonists for orexin 2
receptors.
C Partially correct. Dual orexin receptor antagonists, such as suvorexant, have evidence of
efficacy in the treatment of insomnia.
D Incorrect (A and B).
E Correct (B and C).
F Incorrect (A and C).
G Incorrect (A, B, and C).
The suprachiasmatic nucleus, or “circadian pacemaker,” is influenced by activity, light, and which one of the following neurotransmitters? A. Acetylcholine B. Melatonin C. Norepinephrine D. Serotonin
A Incorrect. Acetylcholine is formed in cholinergic neurons and is primarily involved in cognitive
functioning. It does not have a prominent role in regulation of circadian rhythms.
B Correct. Melatonin is secreted by the pineal gland and mainly acts in the suprachiasmatic
nucleus to regulate circadian rhythms.
C Incorrect. Norepinephrine is involved in many functions, including sleep. However, it does not
have a primary role in regulating the suprachiasmatic nucleus.
D Incorrect. Serotonin, like norepinephrine, is involved in many functions, including sleep. It
does not, however, play a prominent role in regulating the suprachiasmatic nucleus.
