Credit: Illustration by Carl De Torres

A few months after the world went grey, Sue Wright checked into a hospital. A social slight had flipped a switch in her mind, draining life of colour and joy. Blue skies became dull; laughter was unthinkable. Often, the depression left her bedridden. “I had prided myself on being able to get through anything,” says Wright, now a social worker in Germantown, Maryland. “Suddenly, I couldn't.”

Wright's story is familiar to too many people. Depression is not just the most common mental-health disorder: it is responsible for a greater burden of disability than any other cause. In this special issue, Nature asks why that burden is so great, how science is helping and where research is running aground.

Nature special: Depression

A graphic tour on page 180 shows that depression is far from a Western blight, and that many of the countries most afflicted by it are those with the least resources to help. Some mental-health experts say that the high levels of undiagnosed or untreated depression would not be tolerated for a disease such as cancer, and a News Feature (page 182) examines this claim. It finds that the absence of a crisp diagnosis and a lack of tools to understand the brain's complexities have held back therapy and research.

The urgent question is how to overcome those barriers, and scientists are exploring several routes. Some argue that there is much to be learned from studying the mechanisms of existing antidepressants; others that there is most promise in teasing apart the affected brain circuits (see page 200) or gleaning information on common medicines that might have unexpected benefits for brain disorders (see page 165). Identifying the genes associated with depression has been a thankless task, but ambitious studies involving many thousands of patients are now called for (see page 189). There is also plenty to be done to refine existing treatments, such as cognitive behavioural therapy, and to tailor them to groups who might benefit most (page 185).

Medication, counselling and electroshock therapy did not work for Wright. After trawling through medical journals, she found a psychiatrist prescribing drug combinations that may boost the effect of antidepressants. After weeks of one such combination plus therapy, Wright realized that the sky was blue again. It took months for her to find a way out; the hope is that research will find a faster route to relief.