Suicide rates are on the rise, especially in rural America, according to a study published Friday.

From 1999 to 2016, the rate of suicide among Americans ages 25 to 64 rose by 41 percent, researchers reported in JAMA Network Open. Rates among people living in rural counties were 25 percent higher than those in major metropolitan areas.

A number of factors appear to be driving suicide rates up in rural America, including poverty, low income and underemployment, said lead study author Danielle Steelesmith, a postdoctoral fellow at Ohio State University’s Wexner Medical Center.

“Those factors are really bad in rural areas,” said Steelesmith.

The study also found that counties with high levels of social fragmentation — based on the levels of single-person households, unmarried residents and transient residents — and a high percentage of veterans had higher rates of suicide. All of those factors were more pronounced in rural counties.

The presence of more gun shops was also associated with an increase in suicide rates in all counties, except for the most rural ones, the researchers reported.

To take a closer look at suicide rates in America, Steelesmith and her colleagues turned to data from the National Vital Statistics System, a database that includes information on suicide deaths, including year of death, gender, age and county of residence.

The researchers also used information from several other databases, including the U.S. Census, the American Community Survey, County Business Patterns, Area Health Resource Files, and the North American Industry Classification System.

They found that, from 1999 to 2016, there were 453,577 suicides among Americans ages 25 to 64, with the largest proportion occurring during the final three years studied. The majority of those who killed themselves were male (349,082), and suicides were more common among middle-aged adults than younger and older adults.

Counties with the highest risk of suicide were in the West, including in Colorado, New Mexico, Utah and Wyoming; Appalachia, including counties in Kentucky, Virginia, West Virginia; and the Ozarks, including counties in Arkansas and Missouri.

A “growing American tragedy”

The rise in suicide rates in rural counties is “alarming,” said Oren Miron, a researcher at the Clalit Research Institute in Israel, who also studies suicide rates in collaboration with the Harvard Medical School.

Miron, who wasn’t involved with the new research, said two of the factors identified in the study — high veteran rates and unemployment — “may interact in a dangerous way.”

“If a veteran returns from deployment to a county without jobs, he might lose hope in rejoining civilian life,” Miron said. “The re-entry to civilian life is a period with high suicide risk, which raises the need to help veterans from rural counties in getting their first job.”

Special programs, such as job training, might help improve the situation, Steelesmith said.

Suicide “is a growing American tragedy,” said Dr. Albert Wu, an internist and a professor of health policy and management at the Johns Hopkins Bloomberg School of Public Health. “It has become a leading cause of death in the U.S., and is a major public health problem.”

In rural areas, “many of the most pernicious health and social problems intersect,” Wu said.

Lack of access to health care in rural areas further compounds the problem. “Insurance can be a proxy for people’s access to mental health care,” Steelesmith said.

Wu agreed. “Lack of health insurance kills people,” he said. “More insurance, including the expansion of Medicaid, could help.”

Still, “the social determinants of health are really important,” said Dr. David Brent, the endowed chair in suicide studies and a professor of psychiatry at the University of Pittsburgh. “You can’t make a dent in these kinds of public health problems without doing something to deal with [those social determinants]. Yes, you can provide more services to impoverished people, but there’s nothing like helping people get out of poverty.”

If you or someone you know is in crisis, call the National Suicide Prevention Lifeline at 800-273-8255, text HOME to 741741 or visit SpeakingOfSuicide.com/resources for additional resources.

Follow NBC HEALTH on Twitter & Facebook.