The Link Between Depression, Sleep, and Stress

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 9^th 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 sensitivity.

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 stress—healthy 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 mutant mice.

“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 sleep.”

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 disruption.

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.

Meerlo 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 depressive disorder.

More 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 to shrink 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?”

Mayumi 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.

CRH 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 disorders.

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.

“This 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.

An 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.”