Study finds circadian clock rhythms altered in depression

UC Irvine Health researchers have helped discover that genes controlling circadian clock rhythms are profoundly altered in the brains of people with severe depression. These clock genes regulate 24-hour circadian rhythms affecting hormonal, body temperature, sleep and behavioral patterns.

Depression is a serious disorder with a high risk for suicide affecting approximately one in 10 Americans, according to the Centers for Disease Control, and is ranked as fourth of all diseases by the World Health Organization in terms of lifetime disability. Study findings provide the first evidence of altered circadian gene rhythms in brain tissue of people with depression and suggest a physical basis for many of the symptoms that depressed patients report.

The study – which appears online this week in the Proceedings of the National Academy of Sciences – involved researchers from UC Irvine Health, University of Michigan, UC Davis, Cornell University, the Hudson Alpha Institute for Biotechnology and Stanford University.

“Our findings involved the analysis of a large amount of data involving 12,000 gene transcripts obtained from donated brain tissue from depressed and normal people. We were amazed that our data revealed that clock gene rhythms varied in synchrony across six regions of normal human brain and that these rhythms were significantly disrupted in depressed patients. The findings provide clues for potential new classes of compounds to rapidly treat depression that may reset abnormal clock genes and normalize circadian rhythms,” said Dr. William Bunney, the study's senior author, and Distinguished Professor of Psychiatry & Human Behavior at UC Irvine.

Circadian clock genes play an important role in regulating many body rhythms over a 24-hour cycle. Although animal data provide evidence for the circadian expression of genes in brain, little has been known as to whether there is a similar rhythmicity in the human brain.

In the study, the researchers analyzed genome-wide gene expression patterns in brain samples from 55 individuals with no history of psychiatric or neurological illness and compared them to the expression patterns in samples from 34 severely depressed patients.

Lead author Jun Li, Ph.D., an assistant professor in the U-M Department of Human Genetics, describes how this approach allowed the team to accurately back-predict the hour of the day when each non-depressed individual died - literally plotting them out on a 24-hour clock by noting which genes were active at the time they died. They looked at 12,000 gene transcripts isolated from six regions of 55 brains from people who did not have depression.

This provided a detailed understanding of how gene activity varied throughout the day in the brain regions studied. But when the team tried to do the same in the brains of 34 depressed individuals, the gene activity was off by hours. The cells looked as if it were an entirely different time of day.