How do scientists measure serotonin levels
Depressed people sleep differently
Sleep profiles provide indications of mental illness
The world often looks rather dreary when you are not well rested. If the tiredness lasts for weeks or even months, the gloomy mood can become pathological and lead to depression. But vice versa, depression is often associated with severe sleep disorders. Axel Steiger and his team at the Max Planck Institute for Psychiatry in Munich are investigating the connection between sleep disorders and depression. To do this, he measures human brain activity in the sleep laboratory.
Text: Catarina Pietschmann
Stress at work, relationship problems or moving to another city can literally keep people awake. According to the Robert Koch Institute, every third German citizen has suffered from insomnia at one point or another. Sleep disorders usually go away on their own once the trigger is over. However, if they persist for weeks and months, those affected should seek advice from a doctor.
Bad sleep can have physical or psychological causes. “Sleep disorders can be the cause and consequence of depression, or to put it another way: They are a symptom and at the same time a risk factor. For example, they massively increase the risk of depression, ”says Axel Steiger, senior physician and head of the outpatient clinic for sleep medicine at the Max Planck Institute for Psychiatry in Munich-Schwabing. The traditional clinic, which focuses on the secondary diseases of stress such as depression, sleep disorders and anxiety disorders, was founded by Emil Kraepelin in 1917 as the German Research Institute for Psychiatry and incorporated into the Kaiser Wilhelm Society in 1924. It combines five wards with a total of 120 beds, a day clinic, various special outpatient clinics and research facilities under one roof.
Patients can voluntarily take part in scientific studies - for Steiger, who has headed the sleep endocrinology research group since 1991, an ideal environment for his research. The doctor and his team are examining, among other things, the connection between sleep patterns and nocturnal hormone release in depression. While the test subjects spend a night in the sleep laboratory, the scientists measure brain and muscle currents, record eye movements and regularly take a little blood to analyze the amount of certain hormones in them.
From the wave patterns of the electroencephalogram (EEG), the researchers, together with the other measurements, deduce the sequence of the individual sleep stages, the so-called sleep profile or hypnogram. It has the shape of a staircase and consists of several steps: At the beginning of the night, the sleeping person descends to deeper and deeper sleep. The amplitude of the EEG waves increases with the depth of sleep. In the waking state and in REM sleep it is low, in deep sleep, the bottom step of the stairs, it is high.
The latest variant, the high-density EEG (HD-EEG), is also used at the institute to examine brain activity. The test person is given a “sleeping cap” with 118 fine electrodes - usually ten are usually placed - on their head. While he is slumbering peacefully in the soundproofed room, his brain, facial muscles and heart are constantly sending data to a computer via fine cables. This gives the researchers insights into the cerebral cortex and deeper parts such as the limbic system, the emotional part of the brain.
In the schematic representations of the hypnograms, REM sleep, which is characterized by rapid eye movements, and which is often dreamy, differs significantly from non- (non) -REM sleep. It is shown as a level below the waking state, but clearly above deep sleep. Blood pressure and pulse then increase, but the skeletal muscle culture is completely relaxed. Four, five, sometimes six or more cycles of deep sleep and REM sleep per night are the norm. In turn, deep sleep is a component of non-REM sleep. It is most pronounced in healthy young people at the beginning of the night, but does not occur or hardly occurs in the early morning.
Most people sleep extra deeply for about 90 minutes right after falling asleep. Then comes the first REM phase. “Depressed people, on the other hand, fall into REM sleep more quickly, sometimes after ten minutes,” says Steiger. In addition, the first REM phase of the night is usually longer in patients with depression.
If you place the hormone curves over the sleep profiles, it is noticeable that less growth hormone is released in depressed patients than in healthy people. The cortisol values also differ: in many patients they rise much more, especially in the second half of the night. Cortisol is an important stress hormone. Its production is regulated by the brain through the corticotropin-releasing hormone (CRH). In the case of an infection, for example, CRH indirectly stimulates the secretion of cortisol in the adrenal glands. The cortisol then activates the immune system. The same thing happens with exam stress or a heated argument. Once the situation has calmed down, the stress hormones also come back into balance. The released cortisol now slows down the release of CRH and thus slows down its own production.
“We suspect that this feedback mechanism does not work properly in patients with depression, probably because the cortisol receptors in the brain, which are used to reduce the release of the hormone in healthy people, are disrupted,” explains Steiger. When the depression subsides again, the cortisol level first drops, while the sleep pattern remains disturbed for a while.
This interplay between CRH and cortisol also takes place in the body of mice. The head of the “Core Unit” sleep and telemetry at the institute, Mayumi Kimura, uses the small rodents, in which certain genes have been specifically switched off or activated, in order to study their precise function. Mice that have been stressed for a long time as well as genetically modified mice that produce more CRH in the brain than usual fall into REM mode more quickly and more often when they sleep. That makes them the ideal animal model for depression.
But are there really depressed mice? “Of course we don't know whether they really feel like human patients. But they definitely behave in a similar way to depressed patients, ”says Kimura. For example in the so-called “Forced Swimm” test: while healthy mice start swimming and try to persevere longer, “depressed” mice give up more quickly. And although mice generally wake up more often and hardly sleep longer than ten minutes at a time, the REM sleep profile of mice with increased CRH secretion bears a striking resemblance to the depressed patient.
Back to people: It is noticeable that the sleep pattern of depressed patients is similar to that of healthy older people. “Some depression is actually like aging early,” confirms Steiger. Deep sleep phases are rarer in old age, older people also wake up more often at night and sleep less overall.
The fact that the majority of women become depressed does not seem to be a coincidence: Hormone fluctuations during the cycle, pregnancy and as a result of menopause are partly responsible for the fact that women are two to three times more likely to develop depression than men during their fertile phase. There is also an increased risk of depression during menopause. Conversely, the female sex hormones protect against psychosis: This is probably why men develop schizophrenia earlier in life than women.
The fact that, in addition to stress, age and gender, certain genes also make people susceptible to depression is shown in healthy people with an increased risk of depression. In an earlier study, researchers at the Max Planck Institute observed that the children and siblings of depressed patients showed increased rapid eye movements during the first REM period, even though they were healthy. “We also found out that healthy test subjects can exhibit abnormal sleep patterns if they have certain risk genes for depression,” explains Steiger. For one of these genes, the P2RX7, a connection with unipolar depression was found in previous studies at the Munich Institute.
The researchers were also able to observe that risk genes for depression influence sleep behavior in mice: Mayumi Kimura and her colleagues recorded the sleep of animals equipped with the human version of the P2RX7 variant. They found that the mice show clear changes in their EEG patterns that are similar to those of depressed patients. With the help of the genetically modified mice, Kimura now wants to research the effects of new antidepressants.
The genes also affect how well an antidepressant works in a patient. The ABCB1 gene researched at the institute is available in two versions that determine how efficiently certain active ingredients cross the blood-brain barrier. There is now a DNA test with which the doctor can test which class of active ingredient is suitable for his patient before starting therapy.
So there are different genes that increase the risk of developing depression. The researchers therefore suspect that different forms of depression also exist, depending on the gene. The psychiatric classification of depression has so far been based on the symptoms that occur in each case. However, different diseases can trigger the same symptoms. “Sleep profiles could help classify the types of depression. However, we do not yet know the exact relationship between sleep patterns and genes in patients, ”says Steiger.
Sleep can play a role not only in diagnosis, but also in therapy. Short-term sleep deprivation has proven to be a blessing in psychiatry, especially in the second half of the night, because it has an antidepressant effect very quickly. “We practice this at the clinic with patient groups twice a week. The participants get up at half past two in the morning and go for a walk accompanied by students. They chat or spend the time until morning playing board games, ”explains Steiger. The following evening you can go back to bed as usual.
During a sleepless night, the body produces more mood-enhancing substances such as serotonin and tryptophan than during sleep. Sleep disorders are a double-edged sword: on the one hand, they are a risk factor for depression, on the other hand, sleep deprivation has an antidepressant effect. "But it is a ray of hope for the patients because we can show them that their condition is not as hopeless as they think," explains Steiger. "You feel: my brain is not irrevocably defective."
Sleep profiles therefore provide indications of depression and other mental illnesses. Steiger hopes that this will enable doctors to recognize early on whether a patient will respond to an antidepressant. “Up to now, it took four to five weeks before we knew whether the patient was responding to a drug or not. Now, after just one week of therapy, we can get an indication of whether it is working from a parameter for local brain activity (“cordance”) obtained during REM sleep, ”says Steiger.
There has not been a new breakthrough drug treatment for depression in 30 years. However, a precise classification of the various forms of depression may one day enable a therapist to find the right medication for his patient more quickly. One of the keys to this lies in sleep.
P2RX7 gene: The gene contains the information for a calcium channel in the membrane of nerve and glial cells in different brain regions. It influences the transmission of signals between cells and thus in the brain. There is evidence that both unipolar and bipolar depression are due to changes in this gene, among other things.
ABCB1 gene: The gene is active in cells on the inside of small blood vessels in the brain. It actively transports certain substances back into the blood, preventing them from reaching the brain. These include various antidepressants. The two existing variants of the ABCB1 gene fulfill this task with different degrees of effectiveness. A test can be used to determine which variant a patient has and how he would consequently respond to an antidepressant.
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