An international study of the genetics of 300,000 people has confirmed that physical activity can help prevent depression, and provided some solid evidence that it works the other way. A lack of exercise can cause depression.

Previous studies have found a link between lack of exercise and depression, but none has shown that a lack of exercise can actually cause depression. It was thought equally possible that being depressed simply led people to exercise less.

However, this new work by a team at Massachusetts General Hospital, US, shows a causal link between exercising and avoiding depression, and also shows that the opposite is not true – being depressed does not cause people to exercise less.

The findings are published in a report in the journal JAMA Psychiatry.

“We know depression is a leading cause of disability around the world but we know much less about how to prevent this difficult condition,” says lead author Karmel Choi, from the MGH Centre for Genomic Medicine.

“We wanted to harness the advances of large-scale genomics studies to validate a promising target for depression.”

The researchers focussed on physical activity because “it is something people can change” and used a Mendelian randomisation design, which can treat genetic variation between people as a kind of natural experiment.

“Although Mendelian randomisation is not without its own limitations, it can be used to answer familiar questions using a very different approach from what has been done before,” Choi says.

“Put simply,” adds Adam Mourad Chekroud in a related editorial, “if exercise causally reduces the incidence of depression, then people who carry gene variants that increase exercise should proportionally be less likely to get depressed.”

The strengths of the design help to rule out confounding factors like weight, education and income. It can also clarify whether physical activity prevents risk of depression, and whether not exercising increases risk, Chekroud explains.

The researchers used genetic physical activity and depression data from the UK Biobank and a global Psychiatric Research Consortium. Physical activity was measured using participants’ self-reported activity levels and accelerometers – motion-detecting sensors worn to track activity levels.

Results suggest that activity measured using the accelerometers did protect against risk of depression, but self-reported activity did not.

The authors propose this could result from bias and inaccuracies in self-reported physical activity. Objective readings from the accelerometers capture activities like climbing stairs, walking to the shops or housework, which people might not think of as physical activity.

With accelerometer data, the researchers found that replacing sedentary behaviour with just 15 minutes of vigorous physical activity, like running, or an hour of moderate activity, like fast walking, reduces depression risk by 26%.

That’s not just mild depression, but the more severe major depressive disorder.

“We see this study as fitting into a larger puzzle that is looking highly promising for the role of physical activity in mental health,” Choi says.

The study doesn’t explain how physical activity might mitigate depression, but Choi highlights several possibilities.

“From a biological perspective,” she says, “physical activity has been linked to the release of ‘feel-good’ hormones in the brain that can lead to a positive mood.”

Physical activity can also reduce inflammation and improve heart health, both of which have been linked to depression, she adds.

From another perspective, “behavioural activation” is a helpful strategy for combating depression, she says. “Keeping active in the world, especially doing enjoyable or meaningful activities, can combat isolation and improve mood.”

Depression is a debilitating condition affecting more than 300 million people around the world, and the primary cause of disability.

But it’s not typically linked to physical health and wellbeing.

“We’ve talked about being fat and diabetes,” says Professor Ian Hickie, a member of the consortium that contributed data to the project, “but the exercise effect is not just about weight loss – it’s about feeling well and well-being”.