The first sign that something is happening is Angelina’s hands. As she chats to the nurse in Italian, she begins to gesticulate, jabbing, moulding and circling the air with her fingers. As the minutes pass and Angelina becomes increasingly animated, I notice a musicality to her voice that I’m sure wasn’t there earlier. The lines in her forehead seem to be softening, and the pursing and stretching of her lips and the crinkling of her eyes tell me as much about her mental state as any interpreter could.

Angelina is coming to life, precisely as my body is beginning to shut down. It’s 2am, and we’re sat in the brightly lit kitchen of a Milanese psychiatric ward, eating spaghetti. There’s a dull ache behind my eyes, and I keep on zoning out, but Angelina won’t be going to bed for at least another 17 hours, so I’m steeling myself for a long night. In case I doubted her resolve, Angelina removes her glasses, looks directly at me, and uses her thumbs and forefingers to pull open the wrinkled, grey-tinged skin around her eyes. “Occhi aperti,” she says. Eyes open.

This is the second night in three that Angelina has been deliberately deprived of sleep. For a person with bipolar disorder who has spent the past two years in a deep and crippling depression, it may sound like the last thing she needs, but Angelina – and the doctors treating her – hope it will be her salvation. For two decades, Francesco Benedetti, who heads the psychiatry and clinical psychobiology unit at San Raffaele Hospital in Milan, has been investigating so-called wake therapy, in combination with bright light exposure and lithium, as a means of treating depression where drugs have often failed. As a result, psychiatrists in the USA, the UK and other European countries are starting to take notice, launching variations of it in their own clinics. These ‘chronotherapies’ seem to work by kick-starting a sluggish biological clock; in doing so, they’re also shedding new light on the underlying pathology of depression, and on the function of sleep more generally.

“Sleep deprivation really has opposite effects in healthy people and those with depression,” says Benedetti. If you’re healthy and you don’t sleep, you’ll feel in a bad mood. But if you’re depressed, it can prompt an immediate improvement in mood, and in cognitive abilities. But, Benedetti adds, there’s a catch: once you go to sleep and catch up on those missed hours of sleep, you’ll have a 95 per cent chance of relapse.

The antidepressant effect of sleep deprivation was first published in a report in Germany in 1959. This captured the imagination of a young researcher from Tübingen in Germany, Burkhard Pflug, who investigated the effect in his doctoral thesis and in subsequent studies during the 1970s. By systematically depriving depressed people of sleep, he confirmed that spending a single night awake could jolt them out of depression.

Benedetti became interested in this idea as a young psychiatrist in the early 1990s. Prozac had been launched just a few years earlier, hailing a revolution in the treatment of depression. But such drugs were rarely tested on people with bipolar disorder. Bitter experience has since taught Benedetti that antidepressants are largely ineffective for people with bipolar depression anyway.

His patients were in desperate need of an alternative, and his supervisor, Enrico Smeraldi, had an idea up his sleeve. Having read some of the early papers on wake therapy, he tested their theories on his own patients, with positive results. “We knew it worked,” says Benedetti. “Patients with these terrible histories were getting well immediately. My task was finding a way of making them stay well.”

So he and his colleagues turned to the scientific literature for ideas. A handful of American studies had suggested that lithium might prolong the effect of sleep deprivation, so they investigated that. They found that 65 per cent of patients taking lithium showed a sustained response to sleep deprivation when assessed after three months, compared to just 10 per cent of those not taking the drug.

Since even a short nap could undermine the efficacy of the treatment, they also started searching for new ways of keeping patients awake at night, and drew inspiration from aviation medicine, where bright light was being used to keep pilots alert. This too extended the effects of sleep deprivation, to a similar extent as lithium.

“We decided to give them the whole package, and the effect was brilliant,” says Benedetti. By the late 1990s, they were routinely treating patients with triple chronotherapy: sleep deprivation, lithium and light. The sleep deprivations would occur every other night for a week, and bright light exposure for 30 minutes each morning would be continued for a further two weeks – a protocol they continue to use to this day. “We can think of it not as sleep-depriving people, but as modifying or enlarging the period of the sleep–wake cycle from 24 to 48 hours,” says Benedetti. “People go to bed every two nights, but when they go to bed, they can sleep for as long as they want.”

San Raffaele Hospital first introduced triple chronotherapy in 1996. Since then, it has treated close to a thousand patients with bipolar depression – many of whom had failed to respond to antidepressant drugs. The results speak for themselves: according to the most recent data, 70 per cent of people with drug-resistant bipolar depression responded to triple chronotherapy within the first week, and 55 per cent had a sustained improvement in their depression one month later.

And whereas antidepressants – if they work – can take over a month to have an effect, and can increase the risk of suicide in the meantime, chronotherapy usually produces an immediate and persistent decrease in suicidal thoughts, even after just one night of sleep deprivation.