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The Genetics of Depression

Ongoing, large-scale genetic studies of mood disorders could help researchers understand and treat these devastating diseases.

In the past few years, complex genetic diseases such as Alzheimer's and diabetes have slowly yielded their genetic secrets. But depression and bipolar disorder, two mood disorders that take a massive toll on public health worldwide, have yet to succumb to genetic analysis.

That could change in the next few months with the release of the results of two large-scale studies, one of depression and one of bipolar disorder. Scientists have scoured the genomes of participants in these trials for genetic clues into why they suffer from these diseases, as well as why people respond so differently to drugs.

"We hope genetics will reveal novel biological mechanisms or hypotheses that could open new windows in how to treat the disorder," says Jordan Smoller, a psychiatrist and geneticist at Harvard Medical School and Massachusetts General Hospital, in Boston, who is involved in the studies.

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"We've seen some evidence that those kinds of things are possible in some other conditions, like Alzheimer's disease or obesity, which were not well understood until genetic findings began to reveal unexpected genetic pathways."

While effective treatments exist for some patients suffering from depression or bipolar disorder, a huge number of people fail to find relief in existing drugs. They may spend weeks, months, or even years trying out different medications, some suffering serious side effects in addition to the symptoms of their disease. One recent trial, for example, found that only a third of the people diagnosed with depression see symptoms subside with the first drug they're given. And the second drug works in less than a third of the remaining group.

Uncovering the genetic variations underlying these disorders could help. But mood disorders are likely caused by many different genetic variations, each contributing a relatively small effect. "To find genes associated with macular degeneration, it took about 500 patients, Crohn's disease, 1,500 patients, type 2 diabetes, about 10,000 patients," says Pamela Sklar, a geneticist at the Broad Institute and Massachusetts General Hospital. "We think we'll need 10,000 people to uncover genes for bipolar disorder and schizophrenia, and about 15,000 to 20,000 patients for depression."

Two large-scale, multicenter trials could bring the first wave of answers. The STAR*D (Sequenced Treatment Alternatives for Depression) trial, a seven-year study that concluded last year, was designed to help doctors figure out how to treat patients who fail to respond to the first drug they are given for depression. With 4,000 patients at 30 clinical sites around the country, the trial is the largest of its kind. Researchers are currently analyzing samples from nearly 2,000 participants to try to find both the genes that contribute to depression and those genes that predict how patients will respond to treatment.

Last year, scientists released the results from the first genetic analysis of the STAR*D trial. They found that people with a specific variation in a receptor for the chemical messenger serotonin were more likely to respond to citalopram, an antidepressant that targets the serotonin system. Scientists are now analyzing the DNA of patients in the study who responded to different classes of antidepressants. "We want to determine ifgenetic makeup can tell us which medications are good or bad for individual patients," says A. John Rush, a psychiatrist at the University of Texas Southwestern Medical Center, in Dallas, who is leading the STAR*D trial.

A similar trial for bipolar disorder, called the STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) trial, wrapped up this month, and scientists are running similar genetic studies in search of the genetic roots of this disease. Both groups are focusing on specific regions of the genome that have previously been linked to the disorders, as well as using newer genomics technology--DNA microarrays that can analyze thousands of genetic variations in a single experiment--to scan the entire genome for clues. Scientists say that they expect to publish results within the next few months.

The findings might ultimately help psychiatrists redefine these complex disorders. For example, patients diagnosed with depression can have very different symptoms, and many symptoms are common to both depression and bipolar disorders. "We have diagnosis of mood disorders and other psychiatric disorders, but it's not entirely clear if genes are influencing these disorders per se, or if they influence specific symptoms that cut across diagnostic categories," says Smoller. "Genetic studies may tell us something about how we understand the relationships between different disorders."