To treat depression, some people choose not to sleep

Leviathan Press:

On the one hand, modern medicine has long confirmed the existence of biological clocks in the human body. As the sun rises and sets every day, the hormone secretion in our body will also undergo periodic rhythmic changes. On the other hand, we also have a certain understanding of the physiological basis of depression (this is also the principle basis of all psychiatric drugs), and artificial intervention in the body of patients with depression through medical means complements psychological treatment. The "awake/awakening therapy" proposed in this article hopes to adjust the patient's biological clock rhythm through sleep deprivation, thereby affecting the hormone secretion in the brain. Although it is still in the research stage, it may be a way.

There are many people with depression around me (two of whom have passed away unexpectedly). I sincerely hope that they can read this article and it will help them. I also wish them a speedy recovery.

There was something strange about Angelina. The first sign was her hands. As she chatted with the nurse in Italian, she would make motions in the air with her hands. As time went on, Angelina became more animated, and I noticed that there seemed to be a music in her voice. I was sure she hadn't been like this before. The wrinkles on her forehead seemed to soften, and the movement and stretching of her lips, and the wrinkles at the corners of her eyes, all told me her mental state, just like a reliable translator.

Angelina was getting more active, but I was getting more tired. It was 2 a.m., and we were sitting in the brightly lit kitchen of the Milan Psychiatric Hospital, eating pasta. My head was aching and my mind was wandering, but Angelina wouldn't go to bed for at least 17 hours, so I had a long night ahead of me.

I gave myself a pep talk. In case I doubted her resolve, Angelina took off her glasses, looked me straight in the eye, and used her thumb and index finger to pull apart the wrinkled, gray skin around her eyes. She said, eyes wide open: "Open your eyes."

Angelina had to stay awake for three nights in a row, and this was the second night.

Angelina, who suffers from bipolar disorder and has been suffering from severe depression for the past two years, may have thought staying up late was the last thing she needed. But Angelina and her doctors hoped it was the medicine that would save her.

For 20 years, Francesco Benedetti, head of the psychiatry and clinical psychobiology department at Milan’s San Raffaele Hospital, has been studying so-called wakefulness therapy, a combination of bright light exposure and lithium salts. It can be used as an alternative when antidepressants no longer work. Then psychiatrists in the United States, Britain and other European countries began to take notice and developed variations of it in their own clinics. These “chronotherapies” seem to work by restarting the body’s clock. In doing so, doctors are also gaining new insights into the underlying pathology of depression and the role of sleep.

"Sleep deprivation has opposite effects on healthy people and those with depression," Benedetti said. "If you're healthy and you don't sleep, you're going to feel bad. But if you're depressed, sleep deprivation can promote immediate improvements in mood and cognition." However, Benedetti also added that this treatment comes at a cost - once you go to bed and make up for lost sleep, the chance of a relapse of depression will reach 95%.

The idea that sleep deprivation could treat depression was first reported in a German report in 1959. This attracted the attention of Burkhard Pflug, a young researcher in Tübingen, Germany. He continued to study this effect in his doctoral thesis and subsequent studies in the 1970s, and conducted experiments in which he systematically deprived patients of sleep. He eventually proved that just one night of sleep deprivation could help patients get rid of their depression.

Benedetti became interested in this discovery as a young psychiatrist in the early 1990s. Prozac had revolutionized depression treatment a few years earlier, but few such drugs had been tested on patients with bipolar disorder. Benedetti had learned from painful experience that no matter what antidepressant, it had little effect on patients with bipolar depression.

Patients were desperate for alternative treatments, and Enrico Smeraldi, Benedetti's mentor, had an idea. After reading some of the early papers on lucidity, he tested the theories on his own patients with positive results. "We knew it was working," Benedetti said. "Some patients with terrible histories recovered very quickly. My job was to find a way to keep their prognosis that good."

So he and his colleagues continued to look for inspiration in the literature. A handful of studies from the United States suggested that lithium might prolong the therapeutic effects of sleep deprivation. They investigated this and found that when patients taking lithium salts were re-evaluated three months later, about 65% of the patients showed continued feedback from sleep deprivation, compared with only 10% of patients who did not take lithium salts.

But even a brief nap could undermine the effects of the treatment. So they began looking for new ways to keep patients awake at night, and took inspiration from aviation medicine, where bright lights were used to keep pilots alert. This also prolonged the effects of sleep deprivation, to a similar degree of effectiveness as lithium.

"We decided to give the whole package to our patients, and it worked really well." By the late 1990s, they had begun routinely giving their patients a triple chronotherapy: sleep deprivation, lithium, and light. The sleep deprivation was followed by 30 minutes of bright light exposure every morning for two weeks. They still use this regimen today.

"We can think of this not as depriving people of sleep, but as modifying or expanding the sleep cycle from 24 hours to 48 hours," Benedetti said. "People go to bed every other night, but when they go to bed, they can sleep as long as they want."

San Raffaele Hospital first introduced Triple Chronotherapy in 1996. Since then, the hospital has treated nearly a thousand patients with bipolar disorder, many of whom did not respond to antidepressants. The results are clear: according to the latest data, 70% of patients with treatment-resistant bipolar disorder responded to Triple Chronotherapy within the first week, and 55% of patients experienced sustained relief of depression symptoms after one month.

Antidepressants, if they work at all, take at least a month to work and can increase the risk of suicide. Meanwhile, chronotherapy often reduces suicidal thoughts immediately and lastingly, at the cost of just one sleepless night.

Angelina was first diagnosed with bipolar disorder 30 years ago. She was almost 40 at the time. Before the diagnosis, she was going through a very stressful period: her husband was taken to court because of his work. They worried about not having enough money to support themselves and their children. Angelina fell into depression for nearly three years. Since then, her mood swings have been intermittent, but mostly low. She took a lot of medication, including antidepressants, mood stabilizers, anti-anxiety drugs, and sleeping pills. She didn't like these drugs because they made her feel like a patient, even though she had to admit that she was a patient.

She said that if I had met her three days ago, I might not have recognized her. At that time, she didn't want to do anything, didn't wash her hair, didn't put on makeup, and smelled bad. She also felt very pessimistic about the future. After staying up all night, she felt more energetic, but this disappeared after she recovered her sleep. Even so, today she at least had enough motivation to greet me. She even went to the barber shop to get a new hairstyle for it. In response to my compliment on her appearance, she patted her newly dyed blonde hair and smiled.

At 3am we arrived at the light therapy room. Entering here was like stepping onto the street at noon, with bright sunlight pouring in from the skylight overhead and falling on the five armchairs lined up against the wall. It was an illusion, of course. The blue sky and bright sun were nothing but colored plastic and very bright lights. But the effect was exciting and sobering nonetheless. The only thing I couldn't feel while sitting on a sun lounger at "noon" was the heat of the "sun".

Seven hours earlier, when I interviewed her with the help of a translator, Angelina had answered questions with a blank expression. Now, at 3:20 a.m., she was smiling and even began to speak to me in English, which she had claimed she did not speak. At dawn, Angelina told me about the family history she was writing, something she had interrupted but was eager to resume, and she invited me to her home in Sicily.

How could something as simple as staying up late bring about such a change?

Uncovering the mechanism isn’t easy: We still don’t fully understand the nature of depression or the function of sleep, both of which involve multiple areas of the brain. But recent research is beginning to shed some light.

People with depression have different brain activity during sleep and wakefulness than healthy people. During the day, arousal signals from the circadian system help us wake up from sleep, and at night these signals are replaced by sleep-promoting signals. Our brain cells also work at their own rhythms, becoming increasingly excited in response to stimuli during wakefulness and fading when we sleep. But in people with depression and bipolar disorder, these fluctuations seem to be dampened or nonexistent.

(www.ncbi.nlm.nih.gov/pmc/articles/PMC3181883/)

(www.ncbi.nlm.nih.gov/pmc/articles/PMC3181772/)

Depression is also associated with changes in the daily rhythms of hormone secretion and body temperature. The more severe the condition, the greater the disruption. Like sleep signals, these rhythms are driven by the body's circadian system, which itself is driven by a series of interacting proteins.

These proteins, encoded by "clock genes," are expressed in a rhythmic pattern throughout the day. They drive hundreds of different cellular processes, allowing them to switch on and off in unison in unison. The circadian clock ticks in every cell in your body, including your brain cells. They are coordinated by a region of the brain called the suprarenal nucleus, which is very sensitive to light.

(www.ncbi.nlm.nih.gov/pmc/articles/PMC2612129/)

“When people are severely depressed, their circadian rhythms tend to be very disrupted, so they don’t have the normal increase in melatonin at night, and their cortisol levels stay high instead of going down at night,” says Steinn Steingrimsson, a psychiatrist at Sahlgrenska University Hospital in Gothenburg, Sweden, who is currently conducting a trial of wake-up therapy.

Recovery from depression is associated with the normalization of these cycles. "I think depression may be one of the results of a disruption of circadian rhythms and homeostasis in the brain," Benedetti said. "When we deprive people of sleep, we restore this cycle."

But how is this recovery achieved? One possibility is that people with depression simply need an increase in sleep pressure to kick-start this sluggish system. Sleep pressure, our urge to sleep, is thought to be caused by the gradual release of adenosine in the brain. It builds up throughout the day and attaches to adenosine receptors on neurons, making us feel sleepy. Drugs that activate these receptors have the same effect, while drugs that block them, such as caffeine, make us feel more alert.

(www.ncbi.nlm.nih.gov/pmc/articles/PMC5992708/)

To investigate whether this process might be the root cause of the antidepressant effects of long-term wakefulness, researchers at Tufts University in Massachusetts conducted experiments with mice with depressive-like symptoms, injecting them with high doses of a compound that activates adenosine receptors, mimicking what happens when sleep is deprived. After 12 hours, they measured how long the mice spent trying to escape when forced to swim or suspended by their tails, and found that the mice's condition improved.

We also know that sleep deprivation has other effects on the depressed brain. It helps improve the homeostatic balance of neurotransmitters in the mood-regulating brain regions and restores normal activity in the emotion-processing areas of the brain while strengthening the connections between them.

If wake-up therapy resets a slowed circadian rhythm, as Benedetti and his team found, lithium and light therapy appear to help maintain it, too. Lithium has been used as a mood stabilizer for years, but no one really understood how it worked, except that it boosted the expression of a protein called Per2, which is a well-known circadian protein.

At the same time, bright light can alter the rhythm of the brain's suprachiasmatic nucleus, as well as directly boost activity in the brain's emotion-processing areas. In fact, the American Psychiatric Association notes that light therapy is as effective as most antidepressants in treating nonseasonal depression.

Despite its promising results in treating bipolar disorder, arousal therapy has been slow to spread to other countries. “You could be cynical and say it’s because you can’t patent it,” says David Veale, a consultant psychiatrist at the South London and Maudsley NHS Foundation Trust.

Of course, Benedetti has never received funding from a pharmaceutical company to conduct his chronotherapy trials. Even until recently, he has relied on government funding, which is often in short supply. His current research is funded by the European Union. If he had followed the traditional route and accepted industry funding to conduct drug trials on patients, he quips, he might not be living in a two-bedroom apartment and driving a 1998 Honda Civic.

Many psychiatrists have long favored medication, which has kept chronotherapy off the radar. “A lot of people haven’t even heard of it,” Weir says.

And it's hard for researchers to find a placebo to replace sleep deprivation or bright light exposure. That means there haven't been large randomized placebo-controlled trials of chronotherapy. Because of this, people remain skeptical about its true effectiveness. "Although there's growing interest in this approach, I don't think many treatments based on this approach can be used routinely," said John Geddes, professor of epidemiology and psychiatry at the University of Oxford. "We need better evidence, and there are still some practical difficulties in implementing sleep deprivation and other aspects."

Even so, interest in chronotherapy is growing. "What we now know about the biology of sleep and the circadian system offers hope for developing new treatments," says Golds. "This goes beyond drugs. Psychological treatments for sleep may also help or even prevent psychiatric disorders."

In the UK, US, Denmark and Sweden, psychiatrists are investigating chronotherapy as a treatment for depression. "Many of the studies that have been done so far have been small," says Weir, who is currently planning a feasibility study at the Maudsley Hospital in London. "We need to show that this is a definitive and universal approach."

So far, the results of existing studies have been mixed. Klaus Martiny, an expert in non-drug treatments for depression at the University of Copenhagen in Denmark, has published two clinical trials to investigate the effects of sleep deprivation, morning brightness, and regular sleep on common depression. In the first study, 75 patients were given the antidepressant duloxetine in combination with either chronotherapy or daily exercise. After the first week, 41% of the patients in the chronotherapy group had their symptoms reduced by half, compared with only 13% in the exercise group. After 29 weeks, 62% of the chronotherapy patients had completely resolved their symptoms, while only 38% of the exercise group had a significant effect.

In Martini’s second study, hospitalized patients with severe depression who had not responded to antidepressants received chronotherapy as a supplement to the medication and psychotherapy they were receiving. After one week, the chronotherapy group had improved significantly more than the group receiving standard care, though the control group caught up in the following weeks.

(pubmed.ncbi.nlm.nih.gov/23059149/)

No one has yet compared chronotherapy with antidepressants or lithium alone to determine its effectiveness. But even if this emerging treatment works for only a few people, many depression patients and psychiatrists find the idea of ​​a non-drug approach appealing.

“I make my living pushing drugs into the clinic, but I’m still quite attracted to something that has nothing to do with drugs,” says Jonathan Stewart, a professor of clinical psychiatry at Columbia University in New York who is currently conducting a trial of arousal therapy at the New York State Psychiatric Institute.

Unlike Benedetti, Stewart keeps his patients through just one night. “I don’t think many people would agree to stay in the hospital for three nights, and it would require a lot of care and resources,” he says. Instead, he uses a method called sleep phase advancement, in which the time a patient falls asleep and wakes up is systematically advanced over the days following a night of sleep deprivation. So far, Stewart has treated about 20 patients with the protocol, 12 of whom have shown positive responses, mostly in the first week.

It could also serve as a preventive measure: Recent research suggests that teens who go to bed early when their parents enforce it are at less risk for depression and suicidal thoughts. Like light therapy and sleep deprivation, the exact mechanism is unclear, but researchers suspect that a closer alignment between sleep timing and the natural light-dark cycle is important.

(www.ncbi.nlm.nih.gov/pmc/articles/PMC2802254/)

But the practice of advancing sleep stages has yet to go mainstream. And, Stewart admits, it's not for everyone. "For those for whom it's appropriate, it's a miracle cure. But just as Prozac doesn't make everyone who takes it better, neither does this. My problem is that I don't know in advance what kind of patients will benefit from this therapy."

Depression can happen to anyone, but there is growing evidence that genetic variations can disrupt the circadian system, making some people more susceptible. Some clock gene variants have been linked to an increased risk of developing mood disorders.

(www.ncbi.nlm.nih.gov/pmc/articles/PMC2574897/)

Stress can further complicate the problem. Our response to stress is primarily mediated through the hormone cortisol, which is greatly affected by the day-night shift. At the same time, cortisol itself directly affects the timing of our circadian clock. So if your body clock is already susceptible to environmental disruptions, the added burden of stress may be enough to completely paralyze your system.

In fact, when you repeatedly subject mice to noxious stimuli, such as electric shocks, that prevent them from escaping, the mice develop symptoms of depression. This phenomenon is called learned helplessness. Faced with this continued stress, the animals eventually give up and exhibit depression-like behaviors. When David Welsh, a psychiatrist at the University of California, San Diego, analyzed the brains of mice with symptoms of depression, he found that the circadian rhythms of two key areas of the brain's reward circuitry were disrupted. The reward circuit system is strongly associated with depression.

But Welsh also points out that disruptions to the circadian system can lead to similar depressive symptoms. When he knocked out a key gene in the master clock in the brains of healthy mice, the mice looked just like the depressed mice he had previously studied. “They don’t need to learn helplessness; they’re already helpless,” Welsh says.

So, if circadian disruptions are a cause of depression, what can we do to prevent them, not just treat them? Rather than remedying depressive symptoms by forgoing sleep, could we improve psychological resilience by strengthening our circadian rhythms?

Martini agrees. He is currently running a trial to test whether a regular sleep schedule can prevent depression relapses in hospitalized patients after they are discharged. "Trouble usually comes unexpectedly," he says. "Once they are discharged, their depression gets worse again."

Peter is a 45-year-old nursing assistant from Copenhagen who has struggled with depression since his teenage years. Like Angelina and many others with depression, his first bout came after a period of high stress. When he was 13, his older sister, who had raised him, ran away from home. He was left with a mother who showed little interest in him and a father who also suffered from severe depression. Not long after, his father died of cancer. This was another blow, and his father kept his illness a secret until a week before his death.

Peter was hospitalized six times for depression, including a whole month in April 2017. “In a way, being in hospital was a relief,” he says, yet he feels guilty about the impact on his two sons, aged seven and nine: “My youngest son said he cried every night when I was in hospital because I wasn’t there to hug him.”

So when Martini told Peter that he was recruiting volunteers for an experiment, Peter readily agreed to participate. This treatment is called "circadian-reinforcement therapy." The therapy strengthens people's circadian rhythms by encouraging them to maintain regularity in their sleep, wake-up, eating and exercise times, and by encouraging them to spend more time outdoors and exposed to sunlight.

Peter was discharged from hospital in May 2018. For four weeks after his discharge, he wore a device that tracked his activity and sleep and filled out regular mood questionnaires. If there were any deviations from his daily routine, he would receive a call to find out what was going on.

When I met Peter, we joked about his tan. Clearly, he had been taking the advice seriously. “Yes, I go outside to the park,” he said with a smile. “If the weather is nice, I take the kids for a walk on the beach or to the playground because then I get some sun and it improves my mood.”

These aren’t the only changes he’s made. He now wakes up at 6 a.m. to help his wife with the kids. He eats breakfast even if he’s not hungry. He usually has yogurt with muesli to balance out his diet. He never takes a nap and tries to be in bed by 10 p.m. If Peter wakes up during the night, he practices mindfulness, a technique he learned in the hospital. Martini pulls up Peter’s data on his computer. It confirms his earlier and earlier bedtimes and shows an improvement in his sleep quality, which is reflected in his mood scores. After he was discharged, his average score was just 6 out of 10. But two weeks later, he was consistently at 8 or 9, and one day he scored 10. In early June, he returned to work at the nursing home, putting in 35 hours a week. “Having a routine has really helped me,” he says.

So far, Martini has enrolled 20 patients in his trial, and his goal is 120. So it’s too early to tell how many people will turn out to be like Peter, or whether their mental health will be maintained. Even so, there is growing evidence that good sleep habits can help our mental health.

According to a study published in Lancet Psychiatry in September 2017, which is also the largest randomized trial of psychological intervention to date, insomnia patients underwent 10 weeks of cognitive behavioral therapy to address their sleep problems. As a result, the patients' symptoms of paranoia and hallucinations continued to decrease. During the trial, their depression and anxiety symptoms also improved, nightmares decreased, mental health and daily functioning improved, and the likelihood of depressive episodes or anxiety disorders was reduced.

(www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(17)30328-0/fulltext)

Sleep, a regular schedule and sunbathing. It's a simple formula that's easy to take for granted. But imagine if it could actually reduce rates of depression and help people recover from depression more quickly, it would not only improve the quality of life for countless people, but also save money for the health system.

As for wake therapy, Benedetti cautions that people shouldn’t try it on their own at home. Especially for anyone with bipolar disorder, there’s a risk of triggering a switch to mania. Although in his experience, that risk is smaller than that posed by taking antidepressants. And staying awake overnight can be difficult, with some patients temporarily slipping back into depression or into mixed mood states, which can be dangerous. “I want to be there for them when that happens,” Benedetti says. And suicide often follows such mixed mood states.

A week after my interview with Angelina, I called Benedetti to check on her progress. He told me that after her third all-nighter, her symptoms had completely resolved and she had returned to Sicily with her husband, who was celebrating their 50th wedding anniversary that week. When I asked her if her husband had noticed a change in her symptoms, Angelina said she hoped he would notice the change in her appearance.

Hope. For Angelina, who has lived without it for most of her life, I think the return of hope is the most precious golden wedding gift.

By Linda Geddes
Translated by Sue

Proofreader/Pharmacist

Original article/mosaicscience.com/story/staying-awake-surprisingly-effective-way-treat-depression/

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