Sleep and depression are intimately
linked. People with depression can sleep too little or too much; both symptoms are
characteristic of the disease. Disturbances to the sleep-wake cycle are a risk factor for depression, appearing before, during
and after depressive episodes, and predicting the outcome of therapy.
Sleep disturbances are also
associated with stress and anxiety disorders, and may affect mood, but the
relationship between them is not yet clear. Researchers discussed the molecular
mechanisms linking sleep to depression and stress at the 9th FENS Forum of
Neuroscience in Milan last month.
Véronique Fabre of the French
Institute of Health and Medical Research (INSERM) discussed the roles of the
neurotransmitters serotonin and hypocretin in sleep and emotional behavior.
Serotonin is produced mostly in a
part of the brain stem called the raphe nucleus, and is strongly associated with mood, whereas hypocretin (also
known as orexin) is synthesized by the hypothalamus, and is known to be
involved in regulating arousal, wakefulness and appetite.
The human brain contains just 10–20,000
hypocretin-producing neurons, and we now know that degeneration of
hypocretin-producing cells causes narcolepsy, a sleep disorder characterised by
daytime sleepiness and fragmented sleep at night. People with narcolepsy often
develop depression, too.
To test the link between these two
conditions, Fabre and her colleagues have been examining genetically engineered
mice lacking the serotonin
transporter gene, which encodes a membrane protein that removes serotonin from synapses
after it has been released. In humans, variations in this gene are associated
with individual differences in stress
Mice lacking the same gene display
an exaggerated stress response and increased anxiety- and depression-like behaviors,
and thus serve as a useful model of human mood disorders. These animals also
display disturbances in their sleep cycle, spending significantly more time in
the rapid eye movement (REM) stage of sleep than their normal counterparts.
In 2006, Fabre and her colleagues showed
that these animals also have an abnormal response to experimentally-induced
mice respond to this treatment with a delayed increase in the amount of REM
sleep, but the mutant mice do not. Stress also reduces hypocretin activity in healthy
mice, but does the opposite in mice lacking the serotonin transporter gene.
More recently, they reported that blocking a certain type of
serotonin receptor in early life normalizes sleep and depression-like behaviors in the
“Our findings suggest that enhanced
hypocretin transmission is responsible for the abnormal sleep response to
stress,” said Fabre, “and our working hypothesis is that hypocretin- and
serotonin-producing neurons may be responsible for joint regulation of mood and
Peter Meerlo of the University of
Groningen noted that prolonged periods of wakefulness are becoming increasingly
common in our society. He emphasised that losing sleep has immediate effects on
alertness and cognitive performance, and went on to describe his
own research into the neurobiological consequences of chronic sleep
In many cases, insomnia precedes and predicts the
onset of depression, but the research suggests that this is a causal factor rather than a
symptom of the disease.
and his colleagues have been investigating how chronic sleep loss affects the
brains of rats. They have found that sleep loss for periods of a week or more
alters the serotonin
neurotransmitter system and the hypothalamic-pituitary axis, a system of brain structures that regulate the hormonal
response to stress, and that these changes resemble those reported in major
recently, they reported that chronic sleep deprivation in rats causes a reduction
in the volume in the hippocampus,
a brain structure that is critical for learning and memory, and which is known
in patients with depression.
“Most people know from personal
experience what the immediate effects of sleep loss are, but what happens to us
when it becomes chronic?” says Meerlo. “Could it be that it leads to gradually
developing maladaptive changes in the brain and body that increases
susceptibility to diseases?”
Kimura of the Max Planck Institute for Psychiatry in Munich described her
group’s work examining the links between depression, anxiety, and stress hormones,
and the role of corticotropin-releasing hormone (CRH) in particular.
is a stress hormone that is also involved in sleep and wakefulness, and is
known to be over-produced
in depression and anxiety disorders. Kimura and her colleagues generated mutant
mice carrying a version of the gene that over-produces
the hormone to see if it is involved in the sleep disturbances seen in mood
They found that overproduction of CRH led to increased REM sleep, as
seen in patients with depression, and earlier studies have shown that mice lacking one of the CRH
receptors display anxiety-like behaviour and are over-sensitive to stress.
CRH and anxiety, both separately linked to depression, thus also seem to play a
direct role in sleep patterns.
indicates that anxiety might be keeping [depressed patients] awake,” says
Kimura. “Since they can't stay asleep for long periods, their sleep debt
accumulates, so they must sleep during normal waking hours."
Sleep disturbances are not only
associated with psychiatric conditions such as depression, but also with neurodegenerative
diseases such as Alzheimer’s and Parkinson’s, as well as metabolic diseases such as
diabetes and cardiovascular conditions like stroke. It
is becoming increasingly clear that good sleep hygiene throughout life is very
important not just for physical health, but also for mental health.
understanding of the relationship between sleep and disease could eventually
lead to more accurate ways of diagnosing and treating all of these diseases.
“Sleep changes might be a predictor or biomarker for mood disorders," said
Kimura, “and if patients can be helped to sleep better, perhaps might it
improve their mood.”