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If you had headaches that were so bad they made you nauseous, landed you in bed and sometimes lasted for days, you’d have a right to be depressed. Indeed, that has long been the reasoning behind the high depression rate among people with migraines — 46%, about four times higher than the rate in the overall population. The cause and effect — bad headaches lead to bad mood — seems obvious.

Now, however, a study in the journal Neurology suggests a more basic connection: genes. “Most people think that migraine patients are depressed because they have headaches,” says the study’s co-author, Dr. Gisela Terwindt, a neurologist at Leiden University in the Netherlands. “We found that there is a genetic predisposition by people with migraines to be depressed.”

Terwindt’s study was based on phone interviews with 977 men and women from an extended family in the southwest of the Netherlands, and the researchers were smart to focus on just that family and not the wider population. Rooting out genetic links to disease is notoriously difficult and often leads to premature conclusions that later wind up being debunked. One problem is that complex disorders like migraines can be caused by multiple genes as well as by other biochemical and environmental factors.

Focusing on a single, well-defined sample group that, in the case of the migraine study, was descended from 22 related couples, helped clarify what proportion of risk was attributable to heredity rather than environment. “What’s fabulous about this study is that they were able to isolate a population so that you have a more uniform environment,” notes Dr. Andrew Ahn, a neurologist at the University of California, San Francisco (UCSF) who authored an independent editorial on the Dutch study.

Such carefully planned research yielded illuminating results. About 25% of family members with migraines were depressed, vs. just 12% of relatives without migraines. Correcting for the role of chance, researchers found that, overall, relatives with migraines are 1.4 times as likely to have migraine and depression together rather than migraine alone. Those suffering from migraine with aura (the flashing lights and tunnel vision that precedes some migraine headaches) were nearly twice as likely to suffer from depression.

At first blush, those odds might seem to cast doubt on a genetic link. After all, previous studies have shown that among unrelated folks, those with migraines are four times as likely to get depression as those without migraines, while this new Dutch study shows that closely related people aren’t even twice as likely to share both conditions. But Terwindt says that’s the wrong comparison to make. She says her team used a much stricter definition of migraine than usual, and still found a positive association between that condition and depression, which serves to support rather than contradict previous studies.

Not every bad headache qualifies as a migraine. Instead, notes UCSF headache specialist Ahn, migraine headaches must be accompanied by at least one other symptom. “Migraine is not defined by severity but by neurological symptoms like nausea and vomiting. The presence of other neurological symptoms is the hallmark of migraine,” says Ahn. The Dutch study used a battery of standardized questions plus a phone interview to minimize the chance of misdiagnosis.

Identifying the genetic link required even more detailed detective work. Rather than compare the rates of depression and migraine of the relatives to those of the general population, the study compared rates within this isolated population itself. For each of the 977 people studied, they calculated how much DNA that person shared with every other member in the study. A brother and sister, for example, share many more genes than distantly related cousins. Comparing these relationships to the prevalence of both diseases enabled researchers to determine that it was genetics, not chance, that led to the association.

But what can you really understand about the general population by studying a single family in the Netherlands? “When you have an isolated population, your findings may not be true of the population at large,” acknowledges Dr. Ellen Schur, an internist at the University of Washington, who has also studied the link between migraines and depression. But her study of 1,064 pairs of female twins, published in the journal Headache in 2009, supports the idea of a common genetic link. Schur found that among her twin sets, migraine was inherited 44% of the time and depression 58%. When one sibling had both diseases, 30% of the time her twin did too.

Researchers like Terwindt and Schur have already begun hunting for the exact genes that may underlie both migraine and depression — information that could lead to novel treatments for both conditions. But headache sufferers needn’t wait around for such results. “If you have a headache that is disabling and comes and goes, the overwhelming odds are that it is migraine,” says Dr. Stephen Silberstein, director of the Jefferson Headache Center in Philadelphia. Sufferers should consult their primary-care physicians for treatment, since there are already very effective treatments for migraines on the market today, and some medications (like the tricyclic amitriptyline) that work well for both migraine and depression, according to UCSF headache specialist Ahn.

Doctors who see patients complaining of headaches should screen them for depression as well, says Dr. Robert Marlow, a family-medicine physician in Scottsdale, Ariz., who recently published a paper on the issue in the Journal of the American Board of Family Medicine. Of course, “just because somebody has migraines doesn’t mean they are depressed,” Marlow notes. But in either case, you’re better off getting diagnosed and treated rather than just suffering through the pain.
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