Gene Variants Protect Against Adult Depression Triggered By Childhood Stress

"People's biological variations set the stage for how they respond to different environmental factors, like stress, that can lead to depression," said NIMH Director Thomas R. Insel, M.D. "Knowing what those variations are eventually could help clinicians individualize care for their patients by predicting who may be at risk or suggesting more precise avenues for treatment."

Almost 15 million U.S. adults have major depression. The new report adds to evidence that a combination of gene variations and life experiences promote the disorder or protect people from it. Variations in many genes are thought to be involved, but few of them have been identified.

The study also supports previous evidence that a stress hormone, corticotropin-releasing hormone (CRH), plays a role in depression. The variations are in a gene that makes a receptor for the hormone. Receptors are proteins that act as binding sites, in or on cells, for chemical messengers that affect cell function. The receptor for CRH is called CRHR1.

CRH and its receptor are part of a larger hormone system that regulates the response to stress, in part by helping to regulate neurotransmission -- the chemical messages through which brain cells communicate with each other. Extreme stress in childhood caused by factors such as abuse can hyperactivate the system, increasing risk of depression in adulthood.

Some pharmaceutical firms are testing compounds that block CRHR1 as potential medications for depression.

The receptor for a hormone acts like a receiver or radar dish for messages sent between cells. CRH stimulates the pituitary gland to release another hormone, adrenocorticotropin, which in turn induces the release of cortisol from the adrenal cortex.

Extreme stress in childhood can over-activate this cascade of hormones, increasing the risk of depression in adulthood, Dr. Ressler says.

"Our results suggest that genetic differences in signals mediated by CRH may amplify or soften the developmental effects that childhood abuse can have -- effects that can raise the risk of depression in adults," he says.

To conduct their research, scientists interviewed 422 adults, mostly African American, and tested their DNA. About one-third of them had the variations in the CRHR1 gene that appear to be somewhat protective if early-life stress has occurred. Of the people in the study who had a history of child abuse, those with certain variations had only about half the symptoms of moderate to severe depression as those who had more common variations in the same gene.

The finding was strengthened when the researchers repeated the study in 199 white adults and came up with similar results. In addition to racial differences, the two groups differed socioeconomically. The combined findings suggest that the gene variations are protective across the ethnic groups and socioeconomic levels.

"We know that childhood abuse and early life stress are among the strongest contributors to adult depression, and this study again brings to light the importance of preventing them," Ressler said. "But when these tragic events do occur, studies like this one ultimately can help us learn how we might be able to better intervene against the pathology that often follows."

Results of the study were published in the February 4 issue of the Archives of General Psychiatry by Kerry J. Ressler, M.D., Ph.D., of Emory University, Rebekah G. Bradley, of the Atlanta VA Medical Center, and others.

This research was funded substantially by the National Institute of Mental Health (NIMH), part of the National Institutes of Health. Additional research funding from the National Institutes of Health was provided by the National Center for Research Resources and the National Institute on Drug Abuse. Emory University, the Emory and Grady Memorial Hospital General Clinical Research Center, and the Burroughs Wellcome Fund also contributed.