Genes Linked to Suicidal Thoughts During Antidepressant Therapy

Variations in two genes may be responsible for suicidal ideation in patients who are being treated with citalopram for major depression, according to a study in the October American Journal of Psychiatry. The findings suggest a genetic basis underlying the rare emergence of suicidal thoughts associated with taking an SSRI.

Using DNA samples from 1,953 adults, researchers from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed that the likelihood of suicidal thoughts in patients treated with citalopram was highest in individuals who had both the rs4825476 and rs2518224 genetic markers. The rs4825476 marker is located on the GRIA3 gene, while the rs2518224 marker is located on the GRIK2 gene. The researchers examined 768 markers within 68 genes of the patients treated with citalopram, then followed the gene testing by asking the patients a question about “thoughts of death or suicide” from the 16-item Quick Inventory of Depressive Symptomatology–Self Report, a well-validated measurement of symptom severity that is strongly correlated with the Hamilton Depression Rating Scale.

A GENETIC CONNECTION

According to the researchers, approximately 6% of patients reported suicidal ideation during antidepressant treatment. Notably, 11 patients (36%) with both of the identified gene markers had new-onset suicidal ideation during antidepressant therapy. Among the patients with suicidal ideation, 59% had at least one of the markers.

However, the analysis also revealed that more than 40% of patients with treatment-emergent suicidal ideation had neither marker. This finding suggests that other genes and environmental factors may have been responsible for the newly emergent suicidal thoughts.

The researchers explained in their report that although the 68 genes investigated in the trial were selected because they were thought to be “likely candidates for outcomes related to antidepressant treatment,” there may be other genes that have a link to treatment-emergent suicidal ideation that were not examined in this analysis.

The investigators noted that citalopram was the only medication used in the trial, which precludes extrapolation to other antidepressant medications. However, the results are still potentially important given how frequently citalopram is prescribed as well as its similarity to other SSRIs.

SSRIs have been mired in controversy over a possible association with suicidal thoughts or behavior since they were introduced nearly 30 years ago, according to the study authors. In 2004, the FDA mandated that a black box warning be added to the labeling of SSRIs regarding the risk of suicidal ideation related to antidepressant use for patients up to age 24.

The STAR*D trial was undertaken to track treatment-emergent suicidal ideation prospectively in a large cohort of patients treated with citalopram and to determine whether specific genetic markers can identify patients who are at increased risk.

“To our knowledge, this is the first study to detect a significant overall association between a genetic marker and treatment-emergent suicidal ideation,” said Gonzalo Laje, MD, Associate Clinical Investigator with the Genetic Basis of Mood and Anxiety Disorders program at the National Institute of Mental Health in Bethesda, Maryland, and colleagues.

The group was quick to emphasize, however, that suicidal ideation during citalopram treatment of major depression is uncommon and that neither suicidal thoughts nor the high-risk gene versions are predictive of actual suicide attempts.

PREVENTIVE MEASURES

Dr. Laje and colleagues said that the findings, if corroborated by additional research, may be used to help identify which patents are at increased risk of new-onset suicidal ideation during treatment with citalopram. “Such patients,” they wrote, “may benefit from closer monitoring, alternative treatments, or specialty care.”

They emphasized that the findings must be considered preliminary until “functional alleles are demonstrated or replication is shown in an independent sample.” However, while “validation of these findings through replication” will be difficult because treatment-emergent suicidal ideation occurs so infrequently and thus thousands of patients may be needed for such a study to take place, the data are strengthened by the demonstration of multiple “hallmarks of causal associations,” they said. These “hallmarks” include, among others, a large sample size that typifies major depression in the outpatient setting as well as a dose-response relationship between the identified markers and treatment-emergent suicidal ideation.

The researchers noted that patients with suicidal thoughts responded less favorably to treatment. While initial symptom scores were similar in patients with suicidal ideation and in those without suicidal ideation, remission rates were 25% and 42.9%, respectively.

—Jill Stein

Suggested Reading
Laje G, Paddock S, Manji H, et al. Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. Am J Psychiatry. 2007;164(10):1530-1538.

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