From Jet Lag Pill to Depression Subtype
The molecule at the center of this story was never designed for psychiatry. Melatonin is a hormone the body releases in darkness to signal night; synthetic versions have long been sold to travelers crossing time zones, shift workers, and people who simply cannot fall asleep. Now researchers at the University of Sydney want to test it against a form of depression — a use nobody had in mind when the first melatonin pills were pressed.
The target is what the team calls “circadian depression.” The label rests on six observable signs of a body clock out of step: being an evening type, falling asleep later than most people, waking exhausted no matter how long one slept, sleeping more during a depressive episode, sleeping in late on days off work, and mood, energy, sleep and appetite shifting hard with the seasons. Meet at least three of the six and you fall into the group. By that yardstick, 23 per cent of a large Australian sample qualified — close enough to one in four that the fraction is not a rounding trick. [1] The scale of the sample matters here. More than 10,000 people in Australia with severe, recurrent depression filled out surveys on their sleep patterns and seasonal swings, and gave saliva samples for DNA analysis. Of those, 23 per cent met the circadian threshold.
What separates the two groups is not subtle. Ian Hickie at the University of Sydney describes the machinery in plain terms: the coordination of the body clocks “underpins your mood, your metabolism, your concentration, your sleep-wake cycle and many other key factors.” [1]
An Earlier, Harder Course With the Wrong Drugs
The circadian group did not merely differ in sleep habits. They got sick younger — average age of onset 18, against 23 for the non-circadian group. They arrived with more severe symptoms, including more suicidal thoughts. [1] Their response to standard medication was measurably worse. Against selective serotonin reuptake inhibitors — the SSRI class, drugs like fluoxetine that raise serotonin levels in the brain — they reported less efficacy and more side effects. [1] That engine shows up in the genes. Participants with circadian depression were more likely to have genetic variants linked to sleep problems, higher body weight, inflammatory markers and ADHD. Emiliana Tonini, also at the University of Sydney, puts it directly: “There is an underlying biology that is quite distinct from other forms of depression.” [1] Hickie adds a second cause that requires no genes at all: the way we now live. Body clocks need morning light to reset and hold a steady 24-hour rhythm. Artificial light at hours our ancestors spent in darkness pulls that rhythm apart. His summary of modern routine is blunt — stay inside, sit at a computer all day, avoid the light, then stay up at night under bright lamps. That is, in his words, “a complete reverse of what we’re built for.”
The Trial Ahead and the Line Not Yet Crossed
The next step is a clinical trial, now launching, that will test synthetic melatonin against circadian depression — the sleep-wake hormone repurposed, this time deliberately, as an antidepressant candidate. The same trial will test behaviour: rising at the same time every morning around sunrise and going outside, another outdoor stint at midday when the sun is brightest, and fixed times for meals and exercise during daylight. After dark, Hickie advises against large meals, hard exercise and bright light. “They are all the wrong signals,” he says.
Not everyone is ready to carve out a new diagnosis. Colleen Loo at the University of New South Wales in Sydney calls the findings “really useful because they advance the field in terms of understanding the whole circadian rhythm aspect of depression and how it might be related to biological measures like genetics and inflammatory markers.” But as a clinical psychiatrist she draws a line: “I don’t think it’s time for us to say, ‘Right, based on this, we’re going to say that, if you have these symptoms, we should treat you with this medication rather than that medication.’” More research is needed before circadian depression is formally recognised as a subtype. In the meantime, she says, people with depression could consider trying melatonin and behavioural strategies alongside their current treatments if they believe their body clocks aren’t working well — melatonin requires a prescription in the UK and Australia but not in the US — and all clinicians should be talking to patients about these things if they have sleep disturbances.