Genetic Crystal Ball?

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It has long puzzled even the sharpest minds why some people succumb to depression while others march on no matter what life hurls at them. An example of the latter, Peter Hamer is a retired school principal who, over the years, has endured a divorce, the deaths of both parents and a job that often frayed his nerves; he's now supporting his wife through a battle with breast cancer. To many, those hardships would sound like the normal rough and tumble of life. But they'd be enough to tip others into a state that would pass these days for clinical depression. Hamer says he's never felt down for long. "When trouble happened at work," he says, "I asked myself what part I played in causing it, then looked at how to fix it."

Hamer, in other words, knows how to hold it together. And certain methods of coping may be shown one day to be important in staving off depression. But what is theory and what's fact? On March 1, reporting on a 28-year study in which Hamer is a participant, a team of Sydney researchers announced that depression is most likely to strike a person who is genetically vulnerable to the condition and who experiences three or more unhappy or stressful events within one to five years. In most cases of depression, says team member Gordon Parker, the trigger is neither genes nor environment alone but "an exquisite nuance of their interaction."

The team's findings, just published in a paper in the British Journal of Psychiatry, have far-reaching implications, argues co-author Philip Mitchell, convenor of Brain Sciences UNSW, which encompasses staff from the University of New South Wales and affiliated institutes. By helping to predict the likelihood and timing of depressive episodes, Mitchell says, "this gives us the potential for true prevention of depression." Any move into prevention, however, raises issues that the authors of the paper have only begun to grapple with.

The researchers began their study in 1978, wanting to learn more about why anxiety disorders are more common in women than men. On recruiting 165 student teachers from a Sydney college, they interviewed them about their personal lives and medical histories, and followed them up every five years to record changes in their circumstances. In the meantime, research elsewhere was linking variations in the gene that controls the movement of the neurotransmitter serotonin with susceptibility to depression. The serotonin transporter comes in three distinct genotypes, and depending on which one a person has, he or she is believed to be prone to depression, partially protected from it, or neither.

In 2003, researchers based in Dunedin, New Zealand, reported a relationship between these different genotypes, adverse life events and depression. The Sydney researchers, including lead author Kay Wilhelm, soon realized they were sitting on a goldmine: hundreds of detailed personal histories covering 25 years that were perfectly suited to the testing of a brand new discovery. Some 127 of the original group - now mostly in their early 50s - agreed to give dna samples, which were crosschecked with their life stories. The result is a guide for working out depression risk: for example, a person with the high-risk genotype who experiences three or more adverse life events in a year has an 80% risk of becoming depressed, compared with a 30% risk for someone with the protective genotype. Studies involving genetically at-risk people are the next step, say the researchers, who want to explore what types of intervention - psychological or pharmacological - might help these people cope with crises like break-ups and bereavements.

But any talk of prevention involving drugs alarms psychiatry's skeptics, who would question whether it's feasible to target something as vague as pre-onset depression. That goal would become especially problematic should the research lead to wider use of antidepressants, shown to cause moderate to profound agitation in 7% of users. And will people need a dna test to find out their genetic vulnerability to depression? There is probably some personality marker for the high-risk genotype, says Parker. Despite a trawl of the data, however, "we haven't found it yet. We've looked at all varieties of anxiety and numerous personality styles," but at this stage without any luck.

In any event, it's debatable whether people should be encouraged to determine their genetic susceptibility to depression. "One of the difficulties we face whenever we talk about a gene," says the study's geneticist, Peter Schofield, "is that everybody wants to attribute to that gene absolute causality. In this case it merely sits in the background as a predisposer." For now, the authors suspect, testing is premature.

Study participant Hamer raves about the professionalism of the researchers, but he wonders whether they're missing something. A single genotype and life events couldn't be the only factors in the depression equation, could they? What about parenting styles and coping reserves built up in childhood? Schofield agrees: "We've got it down to two dimensions because of where this study's gone." But research, he says, will reveal "more environmental dimensions, more genes at play, and potentially there'll be interplay between genes." The riddle of depression is looking trickier than ever.