Psychiatrists have long known that the children of severely depressed parents are at high risk of developing chronic despair themselves, in part because they inherit a physical susceptibility to the condition. Now researchers have identified more than a dozen specific portions of DNA that probably account for that susceptibility. The findings, based on the first comprehensive genetic analysis of families with depression, are expected to pave the way for isolating specific genes responsible for the illness. The results also could give doctors and patients desperately needed guidance in how best to treat it. Investigators at the University of Pittsburgh studied 81 families prone to the most severe form of depression, which often strikes during adolescence and recurs through much of adult life.

By cataloging each family member's DNA, researchers tracked which segments of genetic material were common to family members who developed depression. They found 19 portions of DNA containing genes likely to put people at risk of the disease. Parents pass on various combinations of these genes, producing different depressive symptoms, the study suggests. "This study is a very big deal," said Dr. Louis Marino, a specialist in depression and chief of geriatric services at Butler Hospital in Providence, R.I. Its findings provide an overall picture of the genetics of the disease, he said, "and helps explain why it has so many faces and can look so different from person to person." The new analysis showed a striking gender difference in inherited susceptibility to the disease.

Four of the DNA regions the researchers identified were linked to depression in women only; just one was male-only. This could explain why women are about twice as likely as men to develop depression, psychiatrists say. The study demonstrated that one DNA region in particular — one containing a gene called CREB1 — is very strongly linked to depression in women. And CREB1 is known to interact with female hormones. "This is a neat explanation for why the risk of depression is greater during puberty, pregnancy, menstrual cycles," times when hormone levels are changing, said Dr. George Zubenko, a research psychiatrist at the University of Pittsburgh and lead author of the study. The research supports a shift in thinking about the biology of such mood disorders as depression. Once thought by some doctors to be triggered by a chemical imbalance in the brain — too much of one brain messenger, say, or too little — mood problems might in fact stem from genetic difficulties in regulating sudden changes in brain chemistry, said Dr. Bruce Cohen, chief of psychiatry at McLean Hospital in Belmont, Mass.

When hit with a flash flood of stress hormones, for example, normal brain cells respond, in part, by blunting their sensitivity to the hormones, buffering themselves against the onslaught. Cohen compares these regulating systems to shock absorbers that, in chronically depressed people, don't work as well as they should. "It's like if the shocks go out on your car," he said, "you not only feel every bump, your head hits the roof."  The findings should help vanquish much of the self-blame depressed people so often heap on themselves, as if their moodiness were a character flaw or somehow resulted from a failure of will, said Zubenko. Many overcome serious depression on their own; but some need more help than others because of the genetic cards they were dealt, the research suggests.

In coming years, psychiatrists expect research into the genetics of depression to give rise to new drugs that shut down the disease closer to its source, rather than simply treat its symptoms. In the meantime, Zubenko said, drug researchers can use the newly identified segments of DNA to individualize treatment with antidepressants. The drugs act differently in people with different genetic make-ups; using the panel of newly identified genetic segments, doctors can study which antidepressant drugs work best in whom, with fewest side effects. "Right now, it's really hit or miss" when doctors choose an antidepressant, he said. "It can be weeks before patients get the best treatment."