Individuals who meet at least one of the criteria for physical frailty are at higher risk of also developing depression, a new Yale study finds.

The findings—which also include insights into the specific inflammatory molecules and changes in brain structure that could underlie this association between frailty and depression—point to a need for routine assessment of physical frailty in clinical practice, researchers said.

The study was published May 23 in Nature Communications.

In clinical settings, physical frailty is marked by five indicators: weight loss, exhaustion, feelings of weakness, physical inactivity, and slow walking speed. The condition also puts people at greater risk for health challenges such as bone fractures, hospitalization, lower quality of life, and premature death.

Previous research has also found a link between physical frailty and a decline in mental health.

To better understand this relationship, Yale researchers used data from the UK Biobank, a long-term, large-scale study that has collected extensive health information from more than 500,000 adults in the United Kingdom. From that dataset, information about more than 350,000 individuals between the ages of 37 and 73 were included in the new analysis. Those participants had undergone an initial UK Biobank assessment between 2006 and 2010 and a second assessment approximately 12 years later.

The researchers grouped participants into three categories based on their initial assessment: non-frail (reporting none of the five frailty indicators), pre-frail (reporting one or two indicators), or frail (reporting three or more indicators). They then evaluated how many of the participants had later been diagnosed with depression as reported in their 12-year follow-up.

They found that, compared with non-frail individuals, those individuals classified as "pre-frail"or "frail" were 1.6- and 3.2-times more likely, respectively, to be diagnosed with depression after their first assessment. That relationship became more acute as frailty became increasingly severe, the researchers say, with those meeting more criteria for frailty more likely to report depression during follow-up assessments.

"We also found this association was stronger in males and in middle-aged individuals—people younger than 65—than it was for females or older individuals," said Rongtao Jiang, lead author of the study and a postdoctoral associate in the lab of Dustin Scheinost in Yale School of Medicine's Department of Radiology and Biomedical Imaging.

As part of the same study, researchers also explored factors that might underlie this link between frailty and depression, uncovering contributions from inflammatory molecules and brain structure.

Specifically, they performed a series of "mediation analyses," a statistical approach that examines whether the relationship between two factors (frailty and depression, in this case) might be influenced, or mediated, by a third factor.

They found that certain markers of inflammation—including neutrophils and leukocytes, both of which are white blood cells, and C-reactive protein, made by the liver—mediated the relationship between frailty and depression. Reduced volume in five brain regions mediated the relationship as well.

"This tells us that maybe the association between frailty and depression can occur through the regulation of inflammatory markers or brain volume," said Jiang.

It is possible, for instance, that frailty leads to inflammation in the brain and changes in brain structure, which in turn lead to depression. While more research is needed to clarify that progression, the findings do provide strong evidence that frailty and depression are connected.

"Frailty may be a very important risk factor for the development of depression," said Jiang. "Depression affects millions of people around the world, but we don't have very effective treatments or prevention strategies. This significant association between frailty and depression tells us that if we can modify someone's frailty status, maybe it will have important implications for prevention of depression."

Incorporating frailty assessments into routine health care visits may be one way to reduce depression incidence, by preventing or delaying its onset, said the researchers.

"Assessing frailty is a relatively inexpensive and easy procedure," said Scheinost, associate professor of radiology and biomedical imaging and senior author of the study. "More research is needed, but it's possible frailty might be a target for intervention."