“When people are seriously depressed, their circadian rhythms tend to be very flat; they don’t get the usual response of melatonin rising in the evening, and the cortisol levels are consistently high rather than falling in the evening and the night,” says Steinn Steingrimsson, a psychiatrist at Sahlgrenska University Hospital in Gothenburg, Sweden, who is currently running a trial of wake therapy.

Recovery from depression is associated with a normalization of these cycles. “I think depression may be one of the consequences of this basic flattening of circadian rhythms and homeostasis in the brain,” says Benedetti. “When we sleep-deprive depressed people, we restore this cyclical process.”

But how does this restoration come about? One possibility is that depressed people simply need added sleep pressure to jump-start a sluggish system. Sleep pressure–our urge to sleep–is thought to arise because of the gradual release of adenosine in the brain. It builds up throughout the day and attaches to adenosine receptors on neurons, making us feel drowsy. Drugs that trigger these receptors have the same effect, whereas drugs that block them–such as caffeine–make us feel more awake.

To investigate whether this process might underpin the antidepressant effects of prolonged wakefulness, researchers at Tufts University in Massachusetts took mice with depression-like symptoms and administered high doses of a compound that triggers adenosine receptors, mimicking what happens during sleep deprivation. After 12 hours, the mice had improved, measured by how long they spent trying to escape when forced to swim or when suspended by their tails.

We also know sleep deprivation does other things to the depressed brain. It prompts changes in the balance of neurotransmitters in areas that help to regulate mood, and it restores normal activity in emotion-processing areas of the brain, strengthening connections between them.

And as Benedetti and his team discovered, if wake therapy kick-starts a sluggish circadian rhythm, lithium and light therapy seem to help maintain it. Lithium has been used as a mood stabilizer for years without anyone really understanding how it works, but we know it boosts the expression of a protein, called Per2, that drives the molecular clock in cells.

Bright light, meanwhile, is known to alter the rhythms of the suprachiasmatic nucleus, as well as boosting activity in emotion-processing areas of the brain more directly. Indeed, the American Psychiatric Association states that light therapy is as effective as most antidepressants in treating non-seasonal depression.