Insomnia is the most common sleep disorder and is one of the
most common medical complaints. Someone with insomnia may
have trouble falling asleep (increased sleep latency) or
may wake frequently during the night and have difficulty getting
back to sleep (decreased sleep efficiency). The lack
of sleep or poor quality of sleep may cause problems with daytime
function, such as drowsiness, lack of energy, or an inability to
Various factors can cause insomnia. Insomnia frequently
arises as a consequence of behavioral stress, or some other factor
which is thought to create a situation of hyperarousal.
In hyperarousal, there is increased activation of the
arousal-promoting nuclei, which can overcome the inhibition from
the sleep-promoting nucleus, the VLPO.
Insomnia can be successfully treated with behavioral therapy,
which involves techniques designed to overcome poor sleep habits
and to address issues that may be contributing to stress and
hyperarousal. Behavioral treatments for insomnia may be more
effective over the long-term than drug treatments.
Drug therapy for insomnia usually involves the use of
benzodiazepines or Z-drugs, which work as GABA potentiators.
The GABA potentiators vary mainly in terms of their half-life,
which reflects how long the drug will be effective. For
instance, Zaleplon (Sonata®) has a very short half-life, and is
used to treat insomnia in which the main problem is with increased
sleep latency. Drugs with a longer half-life are used to
increase sleep efficiency, although these drugs may cause daytime
sleepiness and incoordination. Benzodiazepines and Z-drugs are
also generally not intended for long-term use.
Suvorexant (Belsomra®) is an orexin antagonist that was
approved by the FDA in August 2014. Orexin is a peptide
neurotransmitter that is released by a relatively restricted set
of neurons located in the LHA nucleus of the hypothalamus (see
below under "Narcolepsy"). Orexin-releasing neurons are
active during waking and thought to help maintain the awake
state. It remains to be seen whether these drugs will be
safe and effective treatments for insomnia.
The melatonin agonist ramelteon (Rozerem®) is a drug that
has been approved for long-term use in the
treatment of insomnia. Ramelteon may also be better for
treating insomnia in the elderly, because it is less likely to
cause next-day drowsiness and incoordination. Insomnia tends
to be more common in the elderly population, and may be related to
decreased melatonin secretion. Another melatonin agonist,
tasimelteon, has been approved to treat sleep disorders that occur
due to problems with circadian rhythms.
Sleep apnea is another common disorder that may lead to excessive daytime sleepiness. Sleep apnea is really a respiratory disorder: “apnea” means lack of breathing. The most common form of sleep apnea is obstructive sleep apnea, which results because physical factors lead to obstruction of the airways during sleeping. The lack of ventilation triggers an increase in respiratory effort that causes the person to wake. These constant disruptions cause inadequate sleep and lead to daytime sleepiness. Obstructive sleep apnea is treated with a device attached to a mask that provides higher pressure to keep the airways open (continuous positive airway pressure or CPAP).
Narcolepsy is a sleep disorder in which there is a loss of
stability in the maintenance of the awake and sleep states, so
that aspects of sleep intrude into wakefulness and vice versa.
Narcolepsy is characterized by excessive daytime sleepiness.
This excessive sleepiness may cause a narcoleptic individual to
fall asleep at inappropriate times ("sleep attacks"). Note
that although there is daytime sleepiness, someone with narcolepsy
does not sleep more than normal. Narcolepsy also often
causes disturbed sleep at night, with frequent wakings. As
well, about half of the people with narcolepsy experience the
following symptoms, in which aspects of REM sleep are seen
the late 1990's researchers in several labs determined that
narcolepsy is caused by a deficiency of orexin signaling.
Orexin (also called hypocretin) is a peptide neurotransmitter
released by neurons found in the LHA. The activity of the
LHA is thought to stabilize the awake state through excitation of
the arousal-promoting nuclei (see figure). In the absence of
activity from the orexin-releasing neurons of the LHA, unwanted
transitions are made between sleeping and waking. The
frequent transitions result in a lack of consolidation of both the
arousal and sleep states.
Cataplexy is thought to occur through dysregulation of the system
responsible for REM atonia (the lack of skeletal muscle
activity during REM sleep). During REM sleep, a nucleus in
the pons (the REM atonia controller) activates inhibitory neurons
that turn off activity of somatic efferent neurons in the spinal
cord. In the absence of orexin release from the LHA, the REM
atonia controller nucleus is turned on inappropriately, causing
Narcolepsy is treated using a variety of drugs. Daytime
sleepiness is treated with stimulants such as modafinil.
Cataplexy is treated with antidepressants, drugs that
increase norepinephrine and serotonin. These
neurotransmitters are thought to prevent activation of the nucleus
that turns on REM atonia. GHB (Xyrem®) is a hypnotic
that is taken at night to promote sleep consolidation.
Treatment with GHB also reduces cataplexy, although the mechanism
REM sleep behavior disorder (RBD) is a disorder in which there is
strong and disturbing motor behavior during REM sleep. Individuals
with this disorder often have violent and disturbing dreams in
which they scream or swear, and which are accompanied by movements
that are related to dream content. This disorder
predominantly affects men, usually in late middle age.
RBD is diagnosed using polysomnography, where EEG
recording is combined with EMG recording to look at skeletal
muscle activity during sleep. Polysomnography reveals that
REM atonia fails to occur. A hypothesis is that RBD is
caused by dysregulation of the pathway controlling REM atonia.
One intriguing aspect of RBD is that a large proportion of
individuals diagnosed with the disorder subsequently go on to
develop neurodegenerative diseases in which there is an abnormal
accumulation of the protein alpha-synuclein.
Parkinson's disease is the most well-known example.
RBD can be effectively treated with the benzodiazepine drug
clonazepam. The mechanism of action in reducing muscle movements
during REM sleep is not known.