Published: 22-08-2025 11:13 | Updated: 22-08-2025 11:13

Depression shown to be both cause and consequence of poor health

A large international study led by researchers at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, shows that major depressive disorder (MDD) not only increases risk for a wide range of diseases and social problems, but is also partly driven by factors such as loneliness, obesity, smoking, and chronic pain.

Joëlle Pasman

The study, published in Nature Mental Health, applied genetic methods to systematically test which traits are causes, and which are consequences, of depression. The findings highlight the double burden of MDD: it both arises from and contributes to poor health, making prevention and treatment particularly urgent.

“We show that depression sits at the center of a web of health problems,” says Joëlle Pasman, research associate at Amsterdam UMC and Karolinska Institutet, who led the study. “It is not only a debilitating condition in itself but also increases the risk of many diseases, while at the same time being triggered by social, behavioral, and medical factors.”

Genetic tools to test causality

A key challenge in mental health research is separating cause from correlation. Traditional observational studies cannot always distinguish if depression causes poor health, or if poor health causes depression. To overcome this, the researchers used Mendelian Randomization (MR), a method that exploits genetic variants fixed at conception as natural “instrumental variables.” Because genetic variants are randomly assigned at conception, they act like nature’s randomizer, so that they can be used to test whether one factor truly causes another.

The team reviewed over 200 traits previously linked to depression, including lifestyle, medical, and social variables, and tested causal relationships for 135 of them.

Causes and consequences of depression

The research team saw that many factors appear to contribute to the development of depression. These include loneliness, low income, smoking initiation, obesity, chronic pain, and certain endocrine traits such as younger age at menarche. Lifestyle factors such as lower physical activity and risky behaviors also increased depression risk.

At the same time, the study found that genetic liability to depression increases risk for a wide spectrum of outcomes, including cardiovascular disease, type 2-diabetes, hypothyroidism, chronic pain, inflammation, and reduced physical activity. Depression also contributed to lower educational attainment, reduced income, relationship difficulties, and increased suicidal thoughts and behaviors.

Many of these relationships were bidirectional, meaning that depression and its risk factors can reinforce each other in self-perpetuating cycles – for instance, depression can increase loneliness, while loneliness in turn raises the risk of depression. Overall, however, the study found stronger evidence for depression leading to other health problems than the other way around, showing that depression has far-reaching effects across medical and social aspects of life.

Lu Yi, principal researcher at the Department of Medical Epidemiology and Biostatistics. Photo: Ulf Sirborn

Implications for prevention and treatment

The findings suggest that breaking the cycle of depression requires a dual approach: reducing risk factors that predispose people to depression, and providing effective treatment to prevent downstream health consequences. Because many associations were bidirectional, targeting both sides of the relationship will be essential – for example, addressing obesity, smoking, or loneliness may lower depression risk, while treating depression itself can reduce the risk of these problems arising or worsening.

“Depression should be seen as both an outcome of adverse social and medical conditions, and a key driver of poor health in its own right,” says Lu Yi, the leading senior author of the study. “This dual role underlines the importance of prevention strategies targeting modifiable causes, while also ensuring timely treatment to reduce the cascade of negative consequences.”