Like a watch with a rundown battery, the internal biological clock governing our cellular selves — mood, appetite, sleep, and more — may be severely disrupted in individuals with depression, a new study shows.

In the brains of severely depressed people, the circadian rhythm of behavior of many genes spanning multiple regions appeared so disrupted that the internal clock read "a.m." instead of "p.m.," and vice versa, researchers reported Monday in the Proceedings of the National Academy of Sciences.

Investigators from the University of Michigan Medical School and other institutions examined material from brains donated shortly after death, in addition to reams of clinical data about the donors. By hand and with lasers, they dissected each brain to measure gene activity before employing advanced data-mining tools to produce a gush of new information.

Previous research established the pattern of gene activity as distinct at any one time of day, meaning researchers could accurately predict time of death by looking at each donated brain, essentially glancing at a "stopped clock." In depressed patients, however, the gene activity of the brain failed to correctly match the time of death recorded in the clinical data, according to Jun Li, lead author and assistant professor at the Michigan's department of human genetics.

"There really was a moment of discovery," Li said. "It was when we realized that many of the genes that show 24-hour cycles in the normal individuals were well-known circadian rhythm genes - and when we saw that the people with depression were not synchronized to the usual solar day in terms of this gene activity. It's as if they were living in a different time zone than the one they died in."

Within the brains of 55 donors who were not depressed, researchers examined 12,000 gene transcripts isolated from six regions, noting which genes were active at the time of death. In comparison, similar gene activity within the brains of 34 depressed donors failed to match expectations for the particular time of day when they died.

Huda Akil, the co-director of the Michigan's Molecular & Behavioral Neuroscience Institute and co-director of the university's site of the Pritzker Neuropsychiatric Disorders Research Consortium, said the findings surpass previous research on circadian rhythms, which used animals or human skin cells.

"Hundreds of new genes that are very sensitive to circadian rhythms emerged from this research — not just the primary clock genes that have been studied in animals or cell cultures, but other genes whose activity rises and falls throughout the day," she said. "We were truly able to watch the daily rhythm play out in a symphony of biological activity, by studying where the clock had stopped at the time of death. And then, in depressed people, we could see how this was disrupted."

The new research may allow scientists to use biomarkers to develop depression treatments tailored to the individual, with implications for the 350 million people who suffer from the condition worldwide. But researchers have no idea why the circadian clock of depressed people would be disrupted. "We can only glimpse the possibility that the disruption seen in depression may have more than one cause. We need to learn more about whether something in the nature of the clock itself is affected, because if you could fix the clock you might be able to help people get better," Akil said.

The study received funding from the Pritzker Neuropsychiatric Disorders Research Fund, with researchers from the University of Michigan, the University of California at Irvine and Davis, Weill Cornell Medical College, the Hudson Alpha Institute for Biotechnology, and Stanford University.

Below is a video on circadian rhythm:

Source: PNAS Early Edition.