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The Neuroscience Institute by 9M0qQk


									Sleep Disturbance and Depression 9Part I)

The Neuroscience Institute

Elizabeth P. Goodale, PharmD, GlaxoSmithKline, Research Triangle Park, North
Carolina, USA and J. Andrew Johnston, PharmD, Innovaa Research, LLC, Chapel
Hill, North Carolina, USA


Sleep disturbances such as insomnia, hypersomnia and excessive sleepiness are
among the most common symptoms of depression. These changes in sleep and
wakefulness are associated with diminished quality of life and impaired
occupational functioning and are among the most important predictors of relapse
and recurrence of depression. Recognition and treatment of sleep disturbances
are important aspects of managing depression.


Sleep disturbances are a central feature of depression and are included among
the diagnostic criteria for major depressive disorder (MDD).[1] Most patients
with depression experience subjective sleep changes such as insomnia,
hypersomnia, and excessive sleepiness, as well as subjective changes in sleep
architecture.[2-8] All depressed patients should be assessed for sleep
disturbances, and when needed, clinical intervention should be undertaken.The
purpose of this review is to provide a general review of the relationship
between sleep and depression. A summary of the characteristics of normal sleep
physiology is included to provide context for discussion.

Normal Sleep

Behaviorally, sleep is defined as a reversible behavioral state of perceptual
disengagement from and unresponsiveness to the environment.[9] Sleep is a brain
process, but is not a unitary process, and some sleep processes are active,
involving significant cortical activation.[10] Sleep is primarily studied
through the use of overnight continuous electroencephalogram (EEG) sleep
recordings which is referred to as polysomnography (PSG). In addition,
electrooculograms (EOG) are included to measure eye movements and
electromylograms (EMG) are used to record muscle activity. Two separate sleep
states have been identified, non-rapid eye movement (NREM) and rapid eye
movement (REM). NREM sleep has been divided into Stages 1-4. Thus during sleep
individual 30 second recording periods (one epoch) are categorized as
wakefulness (W or Stage 0) or Stage 1, 2, 3, or 4, or REM.[9,10] It is also been
found that W, NREM and REM sleep are not mutually exclusive with elements of one
or more of these states appearing simultaneously.[11]

During NREM sleep the brain is relatively inactive. The 4 NREM stages roughly
parallel a depth of sleep continuum, with arousal thresholds generally lowest in
Stage 1 and highest in Stage 4 sleep.[9] Stages 3 and 4 (referred to as slow
wave sleep [SWS]) occur when there is 20-50% and greater than 50% delta wave
activity, respectively.[9,10] In contrast to NREM sleep, REM sleep is defined by
EEG activation, muscle atonia, and episodic bursts of rapid eye movements. The
mental activity of REM sleep is associated with dreaming.[9]

Other physiologic activities may accompany REM sleep including middle ear muscle
activity, periorbital integrated potentials, and in males, sleep-related
erections. There are two phases of REM sleep referred to as "phasic REM sleep"
and "tonic REM sleep". Phasic REM sleep occurs when REM and other phasic
activity are high, and tonic REM sleep occurs when REM background activity is
present but there is very little phasic activity.[10]

Onset of sleep is not easily defined but is considered to occur with EEG changes
from W to Stage 1 with the presence of slow eye movements.[9] With a normal
pattern of sleep, humans progress through NREM sleep (stages 1-4) with some
fluctuation before entering REM sleep. NREM and REM sleep alternate in a
cyclical fashion. The normal pattern is 90 - 120 minute long cycles of NREM and
REM sleep. Sleep patterns for young adults are similar for men and women. A
young adult who is a good sleeper has 95% sleep efficiency which means that 5%
or less of the total time in bed is spent awake. Sleep onset typically occurs in
less than 15 minutes and nocturnal awakening are few and brief.[10] Stage 1
represents a very small portion of the total sleep time, 1-5%, with Stage 2
accounting for the largest portion, approximately half the nights sleep. REM
sleep is greatest in the latter third of the night usually making up 20% to 25%
of total sleep. Generally, there are 4-6 episodes of REM sleep with the latter
episodes becoming progressively longer.[9,10] The remaining sleep time is made
up of SWS, i.e. Stages 3 and 4. SWS predominates in the first third of the

Sleep patterns are driven by circadian rhythm. Anything that disrupts this
rhythm can affect sleep. For example, REM sleep can occur earlier, essentially
reversing the sleep pattern. This can be seen in shift workers or frequent
flyers.[9] Human sleep should be viewed as a component of the 24-hour sleep-wake
cycle rather than a discrete entity.

The precise neurophysiologic basis for the sleep-wake cycle is not known. Brain
function is supported by activating and inhibitory processes. Brain activation
is high during waking, decreases during NREM sleep, and increases again during
REM sleep. This involves nearly all structures of the brain. Neurotransmitters
involved include γ-aminobutyric acid (GABA), glutamate, acetylcholine,
norepinephrine, serotonin, dopamine, histamine, hypocretin and others.[9,12-13]
Sleep patterns can be different based on a number of factors. With increasing
age, there is a gradual decline in total sleep associated with fragmentation or
greater wakefulness intermixed with sleep.[10] SWS is maximal in young children
and decreases with age.[9] SWS may not be present after age 60, particularly in
men.[10] Elderly people typically spend more time in bed but less time sleeping.
Sleep patterns will also be different depending on prior sleep history.[9]
Following sleep loss on previous nights, recovery sleep occurs which is usually
prolonged and deeper.

Pharmacotherapy commonly affects the sleep state distribution. Taking advantage
of this, pharmacologic treatments have been developed for the treatment of sleep
disorders, e.g. benzodiazepines. Most pertinent to this review, many
antidepressants are known to cause disruption of sleep and the sleep

Lastly, sleep is affected by pathology. There are a number of disorders which
are specifically related to sleep such as narcolepsy, sleep apnea, restless leg
syndrome and parasomnias (undesirable behavioral or experiential phenomena
occurring during sleep).[11] Many medical conditions can affect sleep and most
psychiatric conditions affect sleep.

Sleep Disturbances in Depression
Between 50 and 90% of patients with depression complain of sleep changes.[15]
Sleep disturbances in depression can be divided into subjective symptoms,
typically patient reports of insomnia, hypersomnia, and excessive sleepiness,
and objective findings, PSG recordings. While insomnia is commonly thought of as
the classical sleep disturbance in depression, approximately 16-20% of depressed
patients report hypersomnia. Hypersomnia is more typically reported in the
significant subset of depressed patients with atypical features.[1,2] Insomnia
may consist of difficulty falling asleep, frequent awakenings, or, most commonly
in depression, early morning awakening. In addition, patients may complain of
non-restorative sleep, decreased total sleep and disturbing dreams.[16] Insomnia
in depressed patients often results in daytime sleepiness.[17]

In reference to other psychiatric disorders, patients with affective disorders
differ more frequently and significantly on PSG findings from normal
controls.[18] However, not all patients with depression have abnormal PSGs. In
one study 45% of outpatients and 83% of inpatients had abnormal sleep studies
compared to 10% of healthy controls.[19] Abnormal PSG findings can be divided
into three categories: sleep continuity disturbances, NREM sleep deficits and
REM sleep abnormalities.[16] Total sleep time and sleep efficiency are decreased
and sleep latency (time to sleep onset) is increased.[18] NREM sleep deficits
include decreased amount of NREM sleep and decreased NREM percentage of total
sleep. With regard to REM sleep, decreased REM latency is the most consistently
reported finding. Other REM sleep disturbances reported in depressed patients
include prolongation of first REM period, increased REM activity, increased REM
density and increased REM percentage of total sleep.[15,16,18]

It is not clear if sleep abnormalities in depression are "state dependent" or
"trait" markers. It has been reported that REM sleep abnormalities are state
dependent and normalize in remission following treatment. However, treatment
usually includes antidepressants, many of which affect sleep architecture.[15]
Studies using non-pharmacologic treatments also show improvement in sleep
parameters, but suggest that continuing sleep abnormalities can predict
relapse.[20] Other studies have shown that PSG changes in depressed patients are
not state dependent and persist during remission.[15] Further research is needed
in this area.


Normal human sleep and sleep changes associated with depression have been well
characterized. Depressed patients exhibit characteristic changes in sleep
architecture including impaired sleep continuity and disturbed REM sleep.
Understanding normal sleep architecture and the changes associated with
depression will allow for better patient assessment and treatment.


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