Trastornos del Sueño y su tratamiento Flashcards
QUESTION ONE
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 gamma-aminobutyric acid (GABA) activity
B. Inhibit histamine activity
C. Inhibit orexin activity
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.
QUESTION TWO
A 72-year-old man 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 he is not taking any
medications that are associated with disrupted sleep. The patient is
retired and spends the day caring for his grandchildren, including
occasionally driving the older ones to school in the mid-morning.
Which of the following would be the most appropriate treatment
option for this patient?
A. Flurazepam
B. Temazepam
C. Zaleplon
D. Zolpidem CR
For GABA-A medications, such as the benzodiazepines (e.g., flurazepam,
temazepam) and Z-drugs (e.g., zaleplon, zolpidem CR), the critical
threshold of receptor occupancy for onset of hypnotic effects is
25–30%. Both the onset to achieving the threshold and the duration of
time above the sleep threshold are important for efficacy and for safety.
The ideal hypnotic agent would have a duration above the threshold of
approximately 8 hours.
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. For hypnotics with moderately long half-lives (15–
30 hours: for example, estazolam and temazepam), receptor occupancies
above the sleep threshold may not wear off until after the
individual needs to awaken, potentially leading to “hangover”
effects (sedation, memory problems). Other medications with sedating
properties that have moderate half-lives include most tricyclic
antidepressants, mirtazapine, and olanzapine. Given that this
patient sometimes needs to drive in the morning, an agent with a
moderate half-life may not be the best option for him.
C – Incorrect. For hypnotics with ultra-short half-lives (1–3 hours:
zaleplon, triazolam, zolpidem, melatonin, ramelteon), receptor
occupancies
above the sleep threshold may not last long enough,
causing loss of sleep maintenance, which is already a problem for
this patient.
D – Correct. Hypnotics with half-lives that are short but not ultrashort
(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 elderly patients is 6.25 mg/night.
QUESTION THREE
A 75-year-old man in good physical shape is having sleep problems.
He wakes up at 4am and although he tries to stay awake in
the evening to prevent this early rising, he usually falls asleep right
after dinner, often before 7pm. 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
The sleep/wake cycle is mediated by two opposing drives: homeostatic
sleep drive and circadian wake drive. The circadian wake drive
is a result of input (light, melatonin, activity) to the suprachiasmatic
nucleus (SCN) of the hypothalamus, which stimulates the release of
orexin to stabilize wakefulness. Circadian rhythm disorders occur when
the internal circadian clock is out of sync with external cues that signal
daytime and nighttime.
Patients with advanced sleep phase disorder become sleepy and thus go
to bed earlier than desired and also wake up earlier than desired; this
is a common problem for elderly individuals. These individuals have
adequate total sleep time and quality of sleep. Patients with delayed
sleep phase disorder are unable to fall asleep until the early morning
hours and have difficulty waking until late morning/early afternoon.
This is common during the teenage years; these individuals have
adequate total sleep time and quality of sleep; however, the shifted sleep
schedule can often interfere with activities of daily functioning.
A and C – Partially correct.
B, E, and F – Incorrect. Evening melatonin would not be appropriate
for this elderly patient with advanced sleep phase disorder,
because the patient is not having difficulty falling
asleep in the evening. Rather, evening melatonin (and
morning light) may benefit patients with delayed sleep
phase disorder, potentially resetting the SCN so that the
sleep/wake switch turns on earlier.
stahl’s self-assessment examination in psychiatry
D – Correct. This patient is phase advanced. Advanced sleep phase disorder
may be treated with early morning melatonin and evening
light, which could help reset the SCN so that the sleep/wake
switch stays off longer.
QUESTION FOUR
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
QUESTION FIVE
Mary is a 33-year-old patient who complains of excessive sleepiness.
She recently suffered injuries from a motor vehicle accident
where she fell asleep at the wheel. Administration of the Multiple
Sleep Latency Test (MSLT) revealed sleep latency of 5 minutes.
Clinical evaluation revealed cerebrospinal fluid (CSF) hypocretin/
orexin (Hcrt/Ox) levels in the low range (108 pg/mL), and several
sleep-onset REM periods (SOREMPs) on the polysomnography.
After ruling out medical and psychiatric causes of hypersomnia for
this patient, your most likely diagnosis would be:
A. Narcolepsy with cataplexy
B. Narcolepsy without cataplexy
C. Idiopathic hypersomnia
D. Kleine–Levin syndrome
A – Correct. Narcolepsy is characterized by excessive daytime sleepiness,
intrusion of sleep during wake times, and abnormal rapid
eye movement (REM), including SOREMPs. Narcolepsy can
occur with or without cataplexy (loss of muscle tone triggered
by emotion). A CSF Hcrt/Ox level of < 110 pg/mL is diagnostic
for narcolepsy. Even without cataplexy, patients with narcolepsy
demonstrate more than two SOREMPs on the MSLT, as well as
a short sleep latency (≤ 8 minutes). This patient had a very short
sleep latency (5 minutes), and several SOREMPs, which suggests
that she has narcolepsy.
In addition to its role in wakefulness and motivated behaviors,
orexin is also involved in stabilizing motor movements, allowing
normal movement in the day (when orexin levels are high) and
facilitating inhibition of motor movements at night (when orexin
levels are low). When orexin levels are low due to the degeneration
of orexin neurons, this allows intrusion of motor inhibition
and loss of muscle tone during wakefulness, a condition known as
cataplexy. This patient had a Hcrt/Ox level of 108 pg/mL, which is
considered in the low range, and is indicative of cataplexy.
B – Incorrect. The patient meets the criteria for both narcolepsy and
cataplexy.
C – Incorrect. Patients with idiopathic hypersomnia have Hcrt/Ox
levels in the normal range (200–700 pg/mL). Patients with idiopathic
hypersomnia also have less than two SOREMPs, and this
patient had several.
D – Incorrect. Kleine–Levin syndrome is the most common form of
hypersomnia. This rare disorder mostly affects adolescent boys
and is characterized by bouts of hypersomnolence coupled with
cognitive and mood disturbances, compulsive eating, hypersexuality,
and disinhibited behavior. This patient does not exhibit this
profile or behavior. Additionally, patients with forms of recurrent hypersomnia
demonstrate less than two SOREMPs and have
normal
levels of Hcrt/Ox.
QUESTION SIX
Neurotransmitters fluctuate not only on a circadian (24-hour)
basis, but also throughout the sleep cycle. _________ levels steadily
increase during the first couple of hours of sleep, plateau, and then
steadily decline before waking.
A. GABA/galanin
B. Hypocretin/orexin
C. Acetylcholine
D. Histamine
A – Correct. GABA and galanin levels steadily increase during the first
couple of hours of sleep, plateau, and then steadily decline before
waking.
B – Incorrect. Unlike GABA/galanin levels, hypocretin/orexin levels
steadily decrease during the first couple of hours of sleep, plateau,
and then steadily increase before waking.
C – Incorrect. Acetylcholine levels fluctuate throughout the sleep
cycle, reaching their lowest levels during stage 4 sleep and peaking
during REM sleep.
D – Incorrect. Histamine levels fluctuate throughout the sleep cycle,
peaking during stage 2 sleep, and are at their lowest during REM
sleep.
QUESTION SEVEN
A clinician is planning to prescribe eszopiclone for a 34-year-old
male patient with insomnia. What is the correct starting dose for
this patient?
A. 0.5 mg/night
B. 1 mg/night
C. 2 mg/night
D. 3 mg/night
A – Incorrect (0.5 mg/night).
B – Correct. In 2014, the US Food and Drug Administration (FDA)
reduced the recommended starting dose of eszopiclone from
2 mg/night to 1 mg/night for both men and women. This is
because, in some patients, eszopiclone blood levels may be high
enough the next morning to cause impairment in activities that
require alertness, including driving. In 2013, the FDA issued new
dosing requirements for zolpidem due to the risk of next-morning
impairment. However, the label change applied only to dosing in
women (5 mg IR, 6.25 mg XR).
C – Incorrect (2 mg/night). Prior to the revised dosing requirements in
2014, the recommended dose range for eszopiclone was 2–3 mg/
night; however, that is no longer the case.
D – Incorrect (3 mg/night). Prior to the revised dosing requirements in
2014, the recommended dose range for eszopiclone was 2–3 mg/
night; however, that is no longer the case.
QUESTION EIGHT
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 lemborexant,
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
A – Incorrect. Orexin is released widely in the brain, interacting with
all the arousal neurotransmitters to stabilize wakefulness and regulate
attention. Orexin is also involved in other behaviors, including
feeding, motivation, and reward. Its postsynaptic actions are
mediated by two types of G-protein-coupled 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 (TMN), 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 have evidence
of efficacy in the treatment of insomnia. Three such agents,
lemborexant,
daridorexant, and suvorexant, are approved to treat
insomnia.
Suvorexant has comparable affinity for orexin 1 and
orexin 2 receptors, while lemborexant has higher affinity for
orexin 2 receptors than for orexin 1 receptors.
D – Incorrect.
E – Correct (B and C).
QUESTION NINE
A 22-year-old college student stays up all night completing his
thesis paper and then has to work the following day. While taking
his break in the employee lounge he falls asleep in his chair. His
fatigue and urge to sleep are hypothetically related to accumulation
of which of the following neurotransmitters?
A. Adenosine
B. Histamine
C. Melatonin
D. Orexin
A – Correct. The sleep/wake cycle is mediated by two opposing
drives: homeostatic sleep drive and circadian wake drive. Homeostatic
sleep drive is dependent on the accumulation of adenosine,
which increases the longer one is awake and decreases with sleep.
Accumulated adenosine leads to disinhibition of the ventrolateral
preoptic nucleus and thus the release of GABA in the tuberomammillary
nucleus to inhibit wakefulness. Antagonists at adenosine
receptors, therefore, can promote wakefulness by preventing accumulated
adenosine from binding to its receptors. Caffeine is the
most notable example of an adenosine receptor antagonist.
B – Incorrect. Histamine promotes wakefulness, not sleepiness.
C – Incorrect. Endogenous melatonin is secreted by the pineal gland
and mainly acts in the suprachiasmatic nucleus (SCN) to regulate
circadian rhythms. When light enters through the eye it is
translated via the retinohypothalamic tract to the SCN within the
hypothalamus. The SCN, in turn, signals the pineal gland to turn
off melatonin production. During darkness, with no inhibitory
input from the SCN, the pineal gland turns on melatonin production.
Melatonin, in turn, can act on the SCN to reset circadian
rhythms.
D – Incorrect. Orexin stabilizes wakefulness; it does not promote
sleepiness.
QUESTION TEN
Rachel is an obese 35-year-old woman who works the night shift
as an emergency medical responder. Recent evidence indicates that
a disrupted sleep/wake cycle may increase one’s risk for obesity,
diabetes, and cardiovascular disease by:
A. Increasing levels of leptin
B. Increasing levels of ghrelin
C. Increasing levels of both leptin and ghrelin
D. Decreasing levels of both leptin and ghrelin
A – Incorrect. Leptin is an anorectic (appetite inhibiting) hormone.
Increasing levels of leptin would therefore be expected to cause
weight loss rather than obesity. Indeed, a disrupted sleep/wake
cycle has been shown to decrease levels of leptin.
B – Correct. Ghrelin is an orexigenic (appetite stimulating) hormone.
A disrupted sleep/wake cycle has been shown to increase levels of
ghrelin; this increase in ghrelin is hypothesized to contribute to the
increased risk of obesity, diabetes, and cardiovascular disease.
C and D – Incorrect. A disrupted sleep/wake cycle has been shown to
decrease circulating levels of the anorectic (appetite inhibiting)
hormone leptin and increase circulating levels of the
orexigenic (appetite stimulating) hormone ghrelin.
QUESTION ELEVEN
A 12-year-old male patient has been brought to the clinic by his
parents for evaluation. The patient typically sleeps for 10 or more
hours a day (yet still exhibits excessive daytime sleepiness), eats
excessive amounts of food, and demonstrates disinhibited behaviors
including masturbation in public places. This patient most likely
has:
A. Idiopathic hypersomnia
B. Narcolepsy without cataplexy
C. Kleine–Levin syndrome
A – Incorrect. Idiopathic hypersomnia is characterized by either long
or normal sleep duration accompanied by constant excessive
daytime sleepiness, short sleep-onset latency, and complaints of
non-refreshing sleep. Patients with idiopathic hypersomnia may
also report sleep drunkenness and somnolence following sleep. The
diagnosis of idiopathic hypersomnia includes excessive daytime
sleepiness lasting at least 3 months; a sleep latency of under 8 minutes,
as determined by the Multiple Sleep Latency Test (MSLT);
and fewer than two sleep-onset REM periods (SOREMPs).
Although some of the symptoms that this patient is experiencing,
including excessive daytime sleepiness despite long sleep duration,
are in line with idiopathic hypersomnia, the additional symptoms
being exhibited by this patient (including disinhibited and compulsive
behaviors) are suggestive of Kleine–Levin syndrome.
B – Incorrect. Narcolepsy is characterized by excessive daytime sleepiness,
the intrusion of sleep during periods of wakefulness, and
abnormal REM sleep, including periods of REM occurring at the
onset of sleep (SOREMPs). Although some of the symptoms that
this patient is experiencing, including excessive daytime sleepiness,
are in line with narcolepsy, the additional symptoms being exhibited
by this patient (including disinhibited and compulsive behaviors)
are suggestive of Kleine–Levin syndrome.
C – Correct. Kleine–Levin syndrome is the most common form of
recurrent hypersomnia. This rare disorder mostly affects adolescent
boys and is characterized by bouts of hypersomnolence coupled
with cognitive and mood disturbances, compulsive eating, hypersexuality,
and disinhibited behavior.
QUESTION TWELVE
A 45-year-old patient has been unable to sleep more than 4 hours
every night for the past 3 months. Chronic insomnia is believed to
be due to:
A. Hypoarousal during the day
B. Hyperarousal at night
C. A and B
A – Incorrect. Insomnia is not due to hypoarousal during the day.
B – Correct. Insomnia is conceptualized as being related to hyperarousal
at night. Recent neuroimaging data suggest that insomnia
is the result of an inability to switch off arousal-related circuits,
rather than an inability to switch on sleep-related circuits. Some
patients with insomnia experience hyperarousal during the day
as well. To treat insomnia, one can administer medications that
enhance the sleep drive, such as the GABAergic benzodiazepines
or Z-drugs. Alternatively, one can administer medications that
reduce arousal by inhibiting neurotransmission involved in wakefulness;
notably, with antagonists at orexin, histamine, serotonin, or
norepinephrine receptors.
C – Incorrect.
QUESTION THIRTEEN
A 29-year-old male patient with shift work disorder exhibits excessive
daytime sleepiness that is interfering with his ability to perform
duties as a customer service agent. He is initiated on armodafinil
with good therapeutic response. Modafinil and its R-enantiomer,
armodafinil, are hypothesized to promote wakefulness and increase
alertness by:
A. Decreasing dopamine
B. Decreasing hypocretin/orexin
C. Increasing histamine
D. All of the above
E. None of the above
To promote wakefulness, one can administer medications that promote
arousal by enhancing neurotransmission involved in wakefulness (most
notably, by enhancing dopamine and histamine neurotransmission).
A – Incorrect. Modafinil and armodafinil bind with weak affinity to
the dopamine transporter (DAT); however, their plasma levels are
high and this compensates for the low binding. Increased synaptic
dopamine following blockade of DAT leads to increased tonic
firing and downstream effects on neurotransmitters involved in
wakefulness, including histamine and orexin/hypocretin.
B – Incorrect. Orexin/hypocretin is a key component of the arousal
system; thus, the hypothesized action of modafinil and armodafinil
in increasing hypocretin/orexin may help promote alertness.
C – Correct. Modafinil and its R-enantiomer, armodafinil, are
hypothesized to indirectly increase histamine, either by reducing
GABAergic inhibition of histaminergic neurons or via actions at
orexinergic neurons. The increase in histamine may contribute to
both the wake-promoting effects of modafinil as well as the potential
of modafinil to increase alertness.
D and E – Incorrec
QUESTION FOURTEEN
A 43-year-old man with narcolepsy is experiencing significant difficulties
with daytime sleepiness and asks about potential pharmacological
treatment. Which of the following would be a reasonable
treatment option to address his daytime sleepiness?
A. Histamine 1 antagonist
B. Histamine 3 antagonist
C. Both A and B
D. Neither A nor B
A – Incorrect. When histamine binds to postsynaptic histamine 1
receptors, it activates a G-protein-linked second messenger system
that activates phosphatidyl inositol and the transcription factor
cFOS. This results in wakefulness and normal alertness. Histamine
1 antagonists prevent activation of this second messenger and thus
can cause sleepiness.
B – Correct. Histamine 3 receptors are presynaptic autoreceptors and
function as gatekeepers for histamine. When H3 receptors are
not bound by histamine, the molecular gate is open and allows
histamine release. When histamine binds to the H3 receptor, the
molecular gate closes and prevents histamine from being released.
When an antagonist blocks the H3 receptor (e.g., pitolisant), this
disinhibits, or turns on, the release of histamine, and can promote
wakefulness.
C and D – Incorrect.
