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Genes Tied to Bad Reactions to Antidepressant Drug

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Variations in two genes may increase the likelihood that a person will report suicidal thoughts after taking an antidepressant, researchers reported yesterday. The finding could help doctors develop tests to predict which patients will do well on such medications and which will react badly.

The authors of the study, which was released to reporters yesterday and will appear in The American Journal of Psychiatry on Monday, said that the findings were preliminary and would need to be verified by further testing.

The study focused on reactions to only one drug, Celexa from Forest Laboratories, and found no link between the gene variations and dangerous behavior like suicide attempts.

This distinction is critical, because doctors do not know whether people who report thoughts of ending their lives are at increased risk to act on them. The one patient in the study who attempted suicide consistently denied having any suicidal thoughts.

The findings come at a time when psychiatrists, regulators and some former patients are locked in a furious debate about the risks of antidepressant drugs, which include products like Prozac from Eli Lilly and Zoloft from Pfizer. In recent years, health regulators have required that drug makers post strong warnings on antidepressant labels, saying that some young patients may be at increased risk of suicidal thoughts and behavior.

Some psychiatrists say the warnings have scared off patients who would benefit from the drugs — based largely on reports of suicidal thinking, which may not increase the risk of suicide itself.

"What I would say is that this study is a wake-up call, that we may have the opportunity to use genomic tests to guide personalized care for depression," said Dr. Thomas Insel, director of the National Institute of Mental Health, which helped finance the study.

But Dr. Insel added that the genetic test "is not yet ready for prime time."

The researchers used data from a large government-financed depression study that included more than 4,000 adult patients. They found that about 6 percent of these patients reported having thoughts of suicide after taking the drug, usually within the first few weeks of starting treatment.

They then analyzed blood samples from 120 of those who reported the suicidal thoughts, looking to see whether variations in certain genes were especially common in them.

The scientists found that 36 percent of the patients who had markers for two gene variations reported suicidal thoughts — a more than 10-fold risk compared with those with neither of the gene markers.

These patients were also far less likely to recover taking the drug. Both markers were in genes that affect how the brain processes a chemical messenger called glutamate, which works to activate neurons.

If genetic tests are developed, "they could add to the whole clinical picture," said Dr. Francis McMahon, chief of the genetics and mood disorders unit of the National Institute of Mental Health and the senior author of the study.

"If a patient tells me he thinks his life is not worth living, or I know he's at risk of having that reaction, I'm going to monitor him more closely or treat him differently," Dr. McMahon said.

The researchers searched for links to 68 genes in the patients' blood samples that might influence mood states, but these are clearly not the only genes that could be involved in the emergence of suicidal thoughts.

Many of the patients who reported a sudden urge to end their lives did not have either of the gene variations found to put people at high risk.



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