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Gene clue in treatment of depression

17 December 2004
By BioNews
Appeared in BioNews 289

US researchers have identified a genetic variation that affects levels of the 'feel-good' brain chemical serotonin (5-hydroxytryptamine or 5-HT). The study, published in the journal Neuron, could shed light on why some people are prone to depression and other mood disorders. The findings could also explain why some patients respond well to anti-depressants such as Prozac, which aim to boost brain serotonin levels, while others do not.

The researchers, based at Duke University Medical School in North Carolina, previously showed that in mice, different versions of a gene called Tph2 are linked to different levels of serotonin in the brain. Serotonin is a neurotransmitter, a chemical that enables brain cells to communicate with each other. Scientists have long suspected that levels of serotonin are linked to feelings of emotional well-being - a study published last year showed that a gene involved in serotonin production appears to affect a person's ability to cope with stressful life events.

In the latest study, the scientists looked at the TPH2 gene, the human equivalent of mouse Tph2. Both genes make a protein called tryptophan hydroxylase-2, which controls production of brain serotonin. The researchers identified a mutated version of TPH2 which, in cells grown in the laboratory, produces 80 per cent less serotonin than the normal protein.

The team then looked for the mutated TPH2 gene in 87 people with major depression, 60 with bipolar disorder (previously called manic depression) and 219 control patients. They found that nine of the people with major depression (10 per cent) had the faulty TPH2, compared to just three of the controls (one per cent). None of the people diagnosed with bipolar disorder had the faulty gene. Also, although the three control patients had not been diagnosed with major depression, all had some clinical signs of the condition, including generalised anxiety and mild depression.

Patients with depression are often prescribed drugs that boost brain serotonin levels, called selective serotonin reuptake inhibitors (SSRIs), of which Prozac is one. In the Duke study, all of the patients who had the faulty TPH2 either did not respond to treatment with SSRIs, or only responded to very high doses of the drugs. It seems that such patients are making so little serotonin that SSRIs - which make the chemical 'hang around' for longer in the brain - have no effect. Team leader Marc Caron thinks that the mutation may also help explain some of the serious side effects linked to SSRI use in some patients, including psychosis and suicidal behaviour, the journal Science reports.

Gene Discovery May Offer Clues on Depression and Treatment
Los Angeles Times |  10 December 2004
Mutant Gene Tied to Poor Serotonin Production and Depression
Science |  17 December 2004
Newly discovered genetic defect might represent an important risk factor for major depression |  13 December 2004
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