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Publication of the Association of Polysomnographic Technologists • Spring 2004 • www.aptweb.org
Can’t I Just Take a Pill For It?
BY REGINA PATRICK, RPSGT, ASSOCIATE EDITOR
pon receiving a diagnosis of sleep apnea and on being told that the
most effective treatment for it is a machine that blows air through
the nose all night, patients often ask with timorous hope: “Can’t I just
take a pill for it?”
U
The answer has been a reluctant “no” despite scientists’ efforts for
many years to find drugs that could act as an “apnea pill.” But latest
efforts are encouraging and this answer may soon be changed to a
“yes.” Drugs that target the neurological aspect of respiration have had
the most success in reducing apnea. Of particular interest are drugs
that affect the transmission of the neurotransmitter serotonin.
Serotonin is stored within the terminal of a neuron’s axon. When an
impulse stimulates the neuron, serotonin is released outside of the axon.
The neurotransmitter travels across a small gap (the synaptic cleft) before
reaching and attaching to receptor sites on the next (i.e., post-synaptic) cell.
A small amount of the serotonin, however, is reabsorbed from the
synaptic cleft back onto receptors of the cell (i.e., presynaptic cell) which
released the serotonin. This process of reabsorption is called reuptake.
If the reuptake process is blocked, increased levels of serotonin
remain in the synaptic cleft and the stimulatory effects of serotonin are
increased. It is the increase in one effect — stimulation of the nerves
that supply the upper airway dilator muscles — that may provide a drug
treatment for sleep apnea.
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The serotonergic pathway to the
upper airway dilator muscles begins in the
caudal raphe nuclei. Fibers from the caudal raphe nuclei relay impulses to the
hypoglossal nuclei (which are the origin
for the hypoglossal nerves) in the medulla. The impulse then travels down the
hypoglossal nerves which exit the medulla
and make a pathway toward the jaw. The
nerves break into several branches in Regina Patrick, RPSGT
order to innervate the tongue and various
upper airway muscles.
The upper airway dilator muscles (such as hypoglossus and the
genioglossus muscles) keep the airway open during inspirations. If the
upper airway muscles are weak or do not accurately work in unison to keep
the airway open, the airway can collapse on inspirations and cause apnea.
In a 1996 study on English bulldogs, Sigrid C. Veasey et al.1 theorized that if the stimulatory effect of serotonin on the upper airway
nerves keeps the upper airway open then administration of drugs that
attach to (i.e., antagonize) receptors activated by serotonin would block
the neurotransmitter from stimulating the nerves and allow the upper
airway to collapse. They used ritanserin and methysergide to test this
theory and also to determine which serotonin receptors are specifically
involved in stimulating upper airway nerves. Currently, scientists know of
Publication of the Association of Polysomnographic Technologists • Spring 2004 • www.aptweb.org
seven basic types of serotonin receptors. Some of the receptors — such
as the serotonin type 1 receptor — have several subtypes (denoted by
letters). Some research suggests that primarily type 1C and type 2
receptors allow for stimulation of the upper airway nerves. Ritanserin
binds selectively to these two receptors while methysergide binds to several receptors including the types 1C and 2 receptors. Veasey et al.
expected one of two things to happen: 1) both ritanserin and methysergide would induce apnea if types 1C and 2 receptors are responsible
for nerve stimulation or 2) only methysergide would induce apnea if
receptors other than 1C and 2 were responsible for apnea.
They found that both ritanserin and methysergide caused significant
narrowing of the upper airway. This narrowing occurred during both
wake and sleep. They concluded that serotonin’s effect on type 1C and
type 2 receptors results in stimulation of the nerves to the upper airway
muscles which in turn keeps the airway open.
In a 1999 study on rats, David W.
Carley and Miodrag Radulovacki2 of
the University of Illinois in Chicago
found that the tetracyclic antidepressant mirtazapine reduced sleep apnea
by 50 percent during nonREM sleep
and by 60 percent during REM sleep.
They believe that mirtazapine reduces
apnea in two ways. First, mirtazapine
blocks alpha-adrenergic receptors on
the presynaptic cell. This stimulates
the presynaptic cell to release serotonin. Second, mirtazapine blocks the
serotonin in the synaptic cleft from
attaching to the serotonin type 3 (5HT3) receptor on the post-synaptic
cell. With 5-HT3 receptor blocked, the
serotonin type 1 (5-HT1) receptors
can more easily respond to increased amounts of synaptic serotonin.
The extra stimulation of the 5-HT1 receptors in turn stimulates upper
airway muscles and reduces apneas.
In June 2003 at the 2003 Associated Professional Sleep Societies
(APSS) Conference in Chicago*, Carley and Radulovacki reported results
of their study on 12 human subjects who had used mirtazapine to
reduce sleep apnea. The subjects were given either a placebo or one of
two dosages of mirtazapine. (One dose was approximately four times
greater than the other dose). They found that mirtazapine reduced
apnea by 50 percent and apnea-related arousals by 28 percent. The
larger dose reduced the amount of apneas significantly more than the
smaller dose (unlike their 1999 rat study in which all three dosages
reduced apnea by virtually the same amount).
Because of the great decrease of apnea in both human and animal
studies, Carley and Radulovacki believe that mirtazapine shows the most
promise as an “apnea pill.” However, this drug is currently approved by
the Food and Drug Administration (FDA) only for the treatment of
depression. Its use as an “apnea pill” is still in the research stage.
H. S. Schmidt in the early 1980s was one of the first scientists to
suspect that serotonin may have a role in obstructive sleep apnea. In
one Schmidt study3, L-tryptophan (a precursor of serotonin) taken at
bedtime significantly reduced apneas in subjects who had obstructive
sleep apnea. Interestingly, L-tryptophan did not reduce central apneas.
Nevertheless, Schmidt concluded that an impairment in tryptophanserotonin metabolism could be responsible for sleep apnea.
Since then, scientists have attempted to reduce sleep apnea with
drugs that alter serotonin transmission such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), benzodiazepines,
and serotonin receptor antagonists. Success with these drugs has been
inconsistent (i.e., different studies give conflicting results about a particular drug) or disappointing (e.g., a drug acts differently in REM sleep
than in nonREM sleep). For example:
Brownell et al.4 tested the ability of the tricyclic antidepressant protriptyline to reduce sleep apnea. (Tricyclic antidepressants block the reuptake of serotonin as well as other neurotransmitters which results in
increased levels of the neurotransmitters in the synaptic cleft).
Brownell found that protriptyline
did not reduce the amount of
apnea or the duration of apnea
except during REM sleep.
Hanzel et al.5 compared protriptyline with the SSRI fluoxetine in
12 subjects. (SSRIs block the
reuptake of serotonin but not
other neurotransmitters). Unlike
Brownell et al. who found that protriptyline reduced apnea in REM
sleep, Hanzel et al. found that
both protriptyline and fluoxetine
significantly reduced apneas and
hypopneas in nonREM sleep.
In a 1998 study on rats,
Carley and Radulovacki6 found that two doses (.05 mg/kg and 5
mg/kg) of the benzodiazepine diazepam reduced sleep apnea by
50percent in nonREM but not REM sleep. They postulate that
two different processes may explain this difference. That is, the
process which results in apneas during REM sleep may differ
from the process which results in apneas during nonREM sleep.
Based on the finding by other scientists that the 5-HT3
receptor antagonist ondansetron can reduce central sleep
apnea, Sigrid C. Veasey et al.7 postulated that it could be useful
for obstructive sleep apnea. In 2001, they compared the effects
of two doses (20 mg and 40 mg) of ondansetron on English bulldogs. The 40 mg dose reduced the respiratory disturbance
index (RBI) by 50 percent during REM sleep.
Despite these results, scientists see the potential in manipulating
the serotonergic pathways of respiration in order to treat apnea and are
beginning to develop specially-designed drugs such as the serotonin type
2 [5-HT2] receptor antagonist mianserin specifically to reduce sleep
apnea. (Mianserin does not yet have FDA approval for this use). Once an
effective “apnea pill” is finally developed, people will have another treatment option available if they are unable to tolerate continuous positive
airway pressure (CPAP) treatment or unwilling to undergo surgery. ★
continued on page 30
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Publication of the Association of Polysomnographic Technologists • Spring 2004 • www.aptweb.org
Can’t I Just Take A Pill For It?
continued from page 11
Notes
1. Veasey SC, Panckeri KA, Hoffman EA, et al., “The effects of serotonin antagonists in an
animal model of sleep disordered breathing,” American Journal of Respiratory and Critical
Care Medicine, 153:776 - 786, 1996.
2. Carley DW, Radulovacki M, “Mirtazapine, a mixed-profile serotonin agonist/antagonist
suppresses sleep apnea in the rat,” American Journal of Respiratory and Critical Care
Medicine, 160(6):1824 - 1829, Dec 1999.
3. Schmidt HS, “L-tryptophan in the treatment of impaired respiration in sleep,” Bulletin
Europeen de Physiopathologie Respiratoire, 19(6):625 - 629, Nov-Dec 1983.
4. Brownell LG, West P, Sweatman P, Acres JC, Kryger MH, “Protriptyline in obstructive
sleep apnea: a double-blind trial,” New England Journal of Medicine, 307(17):1037 1042, Oct 21, 1982.
5. Hanzel DA, Proia NG, Hudgel DW, “Response of obstructive sleep apnea to fluoxetine and
protriptyline,” Chest, 100(2):416 - 421, Aug 1991.
6. Carley DW, Trbovic SM, Radulovacki M, “Diazepam suppresses sleep apneas in rats,”
American Journal of Respiratory and Critical Care Medicine, 157(3):917 - 920, Mar 1998.
7. Veasey SC, Chachkes J, Fenik P, Hendricks JC, “The effects of ondansetron on sleep-disordered breathing in the English bulldog,” Sleep, 24(2):155 - 160, Mar 15, 2001.
*For more information about the Carley-Radulovacki mirtazapine study, see University of Illinois News
Bureau June 2, 2003 Press Release, First Effective Drug for Sleep Disorder Identified,
tigger.uic.edu/htbin/cgiwrap/bin/newsbureau/cgi-bin/index.cgi?from=Release&id=502
Bibliography
Kubin L, Kimura H, Tojima H, Davies RO, Pack AI, “Suppression of hypoglossal motoneurons
during the carbachol-induced atonia of REM sleep is not caused by fast synaptic inhibition,”
Brain Research, 611:300 - 312, 1993.
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About the Author
Regina Patrick is a freelance writer and registered polysomnographic technologist having
worked in the sleep disorders field since 1985. She works for St. Vincent Mercy Medical
Sleep Disorders Center in Toledo, Ohio. She is an invited lecturer for sleep technology presentations, and is an associate editor for The A2Zzz. Patrick was last year’s recipient of the
APT Dr. Allen DeVilbiss Literary Award.
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