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Antidepressant treatment: specific variations in two genes linked to suicidal thinking

Specific variations in two genes are linked to suicidal thinking that sometimes occurs in people taking the most commonly prescribed class of antidepressants, according to a large study led by scientists at the National Institute of Mental Health ( NIMH ).

Depending on the particular mix inherited, these versions increased the likelihood of such thoughts from 2- to15-fold, the study found.
About 1 percent of adult patients were deemed to be at high genetic risk, 41 percent at elevated risk and 58 percent at lower risk.

If confirmed, the findings may hold promise for genetic testing, as more such markers are identified.

Risk increased proportionately if a participant had two, as opposed to just one of the suspect versions. Both genes code for components of the brain’s glutamate chemical messenger system, which recent studies suggest is involved in the antidepressant response.

Overall, about 6 percent of 1,915 patients with depression reported that they started to have suicidal thoughts while taking an antidepressant. This rate soared to 36 percent among the few patients with both of the suspect gene versions; 59 percent of the patients who had suicidal thoughts had at least one of the versions.

In the most comprehensive study of its kind to date, researchers screened genetic material from 1,915 adult participants with major depression in level one of the NIMH-funded STAR*D ( Sequenced Treatment Alternatives for Depression ) trial.
Study participants were treated with the selective serotonin reuptake inhibitor ( SSRI ) Citalopram ( Celexa ).
The researchers looked for associations between self-reports of suicidal thinking and more than 700 sites in 68 suspect genes where letters in the genetic code vary across individuals, creating different versions of the same gene.

The researchers found that certain versions of two genes that code for glutamate receptors – the receiving stations for the neurotransmitter’s chemical messages – were more prevalent in patients with suicidal thinking. How the newly identified versions affect the workings of glutamate receptors to confer increased risk remains to be discovered. It’s also not yet known whether the findings generalize to other antidepressants.

One percent of the study participants had a version of the kainate receptor gene, GRIK2, that increased the odds for suicidal thinking more than 8-fold. Forty-one percent of participants had a version of the AMPA receptor gene, GRIA3, that raised the odds nearly 2-fold. About one-half of 1 percent of participants had both high risk gene versions, boosting the odds 15 fold – but this was the case for only 11 participants, of whom four developed suicidal thinking.

Neither version was related to self-reported history of suicide attempts. This suggests that the versions are specific to suicidal thoughts that occur during antidepressant treatment, rather than the much more common suicidal thoughts and behavior that occur outside of the treatment setting.

More than 40 percent of those who developed suicidal thoughts lacked either of the two versions, indicating that other genes and environmental factors were also likely involved. But the potential value of predictive testing is increasing as more genes are analyzed.
Researchers at Massachusetts General Hospital reported an association between variations in the CREB1 gene and treatment-emergent suicidal thinking among men in the STAR*D sample.

Earlier studies had shown that about 4 percent of youth treated with antidepressants experience suicidal thinking compared with about 2 percent of those taking placebo.

The resultant climate of concern culminated in the 2004 Food and Drug Administration ( FDA ) decision requiring that antidepressants carry a black box warning about risk of suicidal thinking for children and adolescents – and later proposing that it be extended to young adults up to age 24.

In 2004, the Centers for Disease Control ( CDC ) recorded the largest spike in youth suicide rates in 15 years.
Researchers suggested that this may have been related to a drop in antidepressant prescriptions for youth. By contrast, they note that suicide rates reached a record low in 2004 for adults over 60, for whom antidepressant prescription rates continued to rise; this inverse relationship held with increasing age. A more definitive analysis must await release of 2005 U.S. suicide rate data later this year, researchers say.

However, evidence suggests that neither suicidal thoughts, nor the high-risk gene versions, are necessarily related to actual suicide attempts.
Other studies have shown that the rate of such attempts is higher before antidepressant treatment begins – and suicide attempts are not always preceded by suicidal thoughts. For example, in the current study, one of the two participants who actually attempted suicide carried high-risk versions, but denied experiencing suicidal thoughts.

Even if suicidal thinking does not predict suicidal behavior, it is associated with a poorer response to antidepressant medication.
Only 25 percent of patients with suicidal thinking fully recovered from their depression during the initial phase of the STAR*D trial, compared with 42 percent of patients not affected by such thoughts.

Source: National Institutes of Health, 2007