Depression vulnerability gene confirmed

An Australian replication study has strengthened evidence that individuals who inherit a common variant of the serotonin transporter gene 5-HTT are more vulnerable to major depression after adverse events in their lives.

Results from the collaborative study, conducted by members of Sydney's Brain Sciences network, based at the University of NSW, were publlished today in the British Journal of Psychiatry.

A research team led by A/Prof Kay Wilhelm, of the UNSW genotyped 127 teachers involved in a long-running study of the association between life history and major depression.

The teachers, who are now in their late 40s, were recruited in their early 20s, and researchers have now followed their life histories for 25 years, recording their response to major adverse events such as a marital breakup, the death of a family member, or a severe health problem.

The study reinforces the findings of a US study published in Science in 2003, which reported a link between major depression, adverse life events, and a variant of the serotonin transporter gene with a shortened promoter region.

UNSW's Prof Phillip Mitchell, who was involved in the latest study, said the serotonin transporter gene is the target for the family of anti-depressant drugs known as selective serotonin reuptake inhibitors (SSRIs). The SSRIs, which include drugs like Prozac, Luvox and Zoloft, have revolutionized the treatment for major depression.

Mitchell said the serotonin transporter protein determines the efficiency with which serotonergic neurons in the brain take up and store serotonin from the synaptic cleft in special vesicles in uptake efficiency of serotonin from the synaptic cleft.

SSRIs alleviate depression by prolonging the time during which the neurotransmitter - the brain's natural calmative - persists in the synaptic cleft, the tiny gap between the originating serotonergic neuron and the dendrites of target neurons in its vicinity.

After a serotonergic neuron 'fires', transmitting the signal its neighbours via dopamine receptors on their dendrites, serotonin is taken up via the serotonin transporter protein and sequestered in specialised vesicles adjacent to the synaptic cleft.

"This is a very strong replicatory study," Mitchell said. "There are now half a dozen reports of this interaction in the research literature, and it looks very robust. For instance, one report showed an association between myocardial infarction [heart attack] and major depression.

"What makes our study unique is that it involves Kay Wilhelm's cohort of teachers, which gave us very strong longitudinal data extending over 25 years."

Mitchell said other studies had looked a narrow cross-sectional windows - 'snapshots' that weakened the statistical association between the timing of adverse life events and the onset of an individual's first episode of major depression.

There are a number of polymorphisms in the 5-HTT gene, but Mitchell there the particular polymorphism associated with vulnerability to depression has a short (s) promoter region. Studies have found no increased risk associated with the long-promoter (l) allele.

Mitchell said the study found that individuals who inherit two copies of the short-promoter variant have a 'dramatically increased' risk of developing major depression after three or more adverse life events, relative to those who inherit two copies of the long-promoter variant.

"The more adverse life events that occur, the more the effect of the 5-HTTLPR allele and the more the two curves diverge," he said.

The short-promoter variant results in reduced expression of the serotonin transporter protein. Mitchell said it was not clear whether the reduction involved reduced transcription, or a post-transcriptional mechanism.

He said the association with adverse life events opened up the possibility of genotyping to identify at-risk individuals, and psychological intervention to improve their ability to handle stressful life events without developing full-blown clinical depression.

"There's an opportunity for preventative therapy," he said. "This gene also offers opportunities for biological intervention - it's already the target for the SSRIs.

He said that about 20 per cent of Australia's population has the 5-HTTLPR s/s genotype, about 25 per cent of people have the l/l genotype, and 55 per cent are heterozygous (l/s).

"That's about what you'd expect, given that major depression is reasonably common in the broad population," he said.