Gene plus stress equals depression debate

The last thing depression investigators need is another dead-end research downer. Efforts to find genes that directly contribute to depression have come up empty. And a research team now concludes, after a closer inspection of accumulated research, that a gene variant initially tagged as a depression promoter when accompanied by stressful experiences actually has no such effect.

By showing that follow-up studies collectively don’t support the study that launched this line of research, two new analyses debunk the proposed pathway to depression. The chances of becoming depressed rise as stressful events mount, regardless of genetic makeup, report statistical geneticist Neil Risch of the University of California, San Francisco, and his colleagues.

The new studies, published together in the June 17 Journal of the American Medical Association, also demonstrate the difficulty of replicating reports of any gene variants that appear to work with environmental triggers to foster psychiatric disorders. Individual studies typically lack the statistical power to detect gene-by-environment interactions correctly because most candidate genes and stressful events exert modest effects on mental ailments at best, the scientists say.

“I’m supportive of looking for gene-by-environment risk factors, but we’ll need much larger samples to find interactions that can be independently replicated,” Risch says. In his view, statistically rigorous studies will need tens of thousands of participants.

In 2003, scientists led by Avshalom Caspi and Terrie Moffitt, both psychologists at Duke University in Durham, N.C., studied 847 New Zealand volunteers who had been followed since age 3. Between ages 21 and 26, those who encountered several stressful events — such as health crises, money woes and relationship breakups — and who had inherited either one or two copies of a short version of the serotonin transporter gene exhibited high depression rates.

The serotonin transporter gene makes a protein that reduces transmission of serotonin, a mood-related chemical messenger in the brain. Many depression medications block the serotonin transporter gene’s protein.

Caspi and Moffitt’s report elicited much excitement among researchers who had been unable to link any genes directly to depression or other psychiatric conditions.

But two new meta-analyses directed by Risch challenge the Caspi-Moffitt findings. In the first, Risch’s team combined and reanalyzed data on 14,250 participants in 14 studies published through March 2009. A second meta-analysis included unpublished information on 10,943 of the volunteers from 10 of the 14 studies. With that unpublished data, the researchers could identify any interactions between the key gene and stressful events for men and women separately.

Both meta-analyses transformed data on participants’ depression levels and exposure to stressful events into a format that could be compared with the 2003 study.

Meta-analyses have their own problems, though. Chief among them is the difficulty of mixing studies with different sample sizes, participant characteristics and measurements of varying quality into a mathematically meaningful concoction.

Although the new meta-analysis could not totally avoid such problems, it raises a valid concern that Caspi and Moffitt’s original results have yet to be replicated, says psychiatrist Kenneth Kendler of Virginia Commonwealth University School of Medicine in Richmond.

Alleged replications have measured stressful events in a variety of ways and have usually included only male or only female volunteers, he says. Some reports have defined genetic risk as the presence of two copies of the critical gene variant, whereas others have required only one copy.

Kendler directed a 2005 study that uncovered an enhanced depression risk for carriers of the short serotonin transporter gene who had been exposed to mild stress levels. Since Caspi and Moffitt reported that high, not mild, stress levels raised the depression risk for people with the gene variant, “we don’t really have a replication,” Kendler says.

In a joint comment, Caspi and Moffitt say the new meta-analyses underscore the need not for larger samples but for “more research of better quality” into gene-by-environment interactions.

The team’s meta-analyses, like meta-analyses in general, give more mathematical weight to studies with larger samples, Caspi and Moffitt note. But in this case, larger studies — which contained as many as 2,179 participants — assessed stressful life events and depression symptoms via phone or questionnaires, rather than in comprehensive interviews. “Not surprisingly, these big studies with weak measures did not find positive results, and this tilted the meta-analysis toward a null finding,” the scientists say.

In the past six years, they add, several studies have found that people who possess the short serotonin transporter gene display especially pronounced brain, hormone and mental responses to stressful laboratory situations. None of these studies was included in the new meta-analyses.

Epidemiologist Myrna Weissman, a depression researcher at Columbia University, notes that Caspi and Moffitt’s study set the methodological bar high by interviewing a large group of young people over an extended period. Thus, the researchers could determine that stressful life events occurred before rather than after first episodes of depression. Studies that have failed to replicate those findings fall short of that methodological rigor, Weissman asserts.