Genetic Markers Linked With Suicidal Ideation During Citalopram Therapy

Marlene Busko

October 04, 2007

October 4, 2007 — Markers in 2 genes in the glutamate signaling pathway were associated with treatment-emergent suicidal ideation during antidepressant therapy with the selective serotonin reuptake inhibitor (SSRI) citalopram ( Celexa, Forest Pharmaceuticals), in a large study of adult outpatients with major depressive disorder.

The study, by Gonzalo Laje, MD, from the National Institutes of Mental Health (NIMH), in Bethesda, Maryland, and colleagues, is published in the October issue of the American Journal of Psychiatry.

Having specific variations in these 2 genes increased the likelihood of suicidal thoughts from 2- to 15-fold, a press release issued by the NIMH states. In addition, about 1% of the patients were deemed to be at high genetic risk, 41% at elevated risk, and 58% at lower risk.

"The highlights of this paper [are] the potential for a genetic test that would tell us who is at risk of experiencing this severe side effect and providing us with more and more evidence to suggest that glutamate would have a potentially significant role in antidepressant treatment and side effects," Dr. Laje told Medscape Psychiatry.

The group writes that earlier studies showed that 4% of youths treated with antidepressants and 2% treated with placebo develop suicidal thoughts and behaviors, but the biologic basis of treatment-emergent suicidal ideation is unknown.

The researchers aimed to look for potential genetic markers to identify patients at increased risk of developing this rare adverse event.

They prospectively examined a cohort of outpatients age 18 to 75 years with major depression who were enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial and who were treated with citalopram for up to 14 weeks.

DNA samples were collected from 1915 trial participants. The researchers chose 68 genes from serotonin, glutamate, dopamine, norepinephrine, neurotrophin, and other signaling pathways and looked at 768 single-nucleotide polymorphisms in these candidate genes.

Potential "Glutamate Approach" for Depression Treatment

Based on the responses to the Quick Inventory of Depressive Symptomatology—Self Report, which the patients answered at specified times during the study, they identified 120 patients with treatment-emergent suicidal ideation.

Patients with suicidal thinking that developed during citalopram therapy were more likely to have certain versions of genes that code for glutamate receptors. 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; 41% had a version of the AMPA receptor gene, GRIA3, that raised the odds nearly 2-fold; and about one-half of 1% had both high-risk gene versions that elevated the risk 15-fold.

If confirmed, these preliminary findings have the potential to identify patients who are at high risk for emergent suicidal ideation during citalopram treatment and who may benefit from closer monitoring, alternative treatment, or specialty care, the group writes.

Even if suicidal thinking does not predict suicidal behavior, it is associated with a poorer response, the group notes, since only 25% of patients with suicidal thinking fully recovered from their depression during the initial phase of the STAR*D trial, compared with 42% of patients not affected by such thoughts.

"I believe that in the very near future we're going to be hearing a lot more about glutamate and glutamatergic drugs — a more glutamate approach to think about and treat depression," said Dr. Laje. He noted that the group has since expanded their study from a candidate-gene approach to a genomewide study and has identified 2 other genes that are associated with suicide ideation. They will be presenting these findingssoon at an upcoming conference.

"Our goal is for people who suffer from depression to feel safe that they can take an antidepressant, and really the only way to prevent suicide is to treat depression," he said. "This is just the beginning, in helping us understand the biological basis for this phenomenon."

The study was funded by the intramural rssearch programs of NIMH, the National Institute on Alcohol Abuse and Alcoholism, the National Human Genome Research Institute, the National Institutes of Health, and the Swedish Research Council.

Am J Psychiatry. 2007;164:1530-1538. Abstract

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