SSRI-Suicide Link in Men May Have Genetic Basis

BOSTON, June 4 -- Suicidal tendencies that arise in some men who start on the antidepressant citalopram (Celexa) may be linked to genetic mutations, suggested investigators here.

Among 1,447 patients enrolled in a multicenter open-label study of citalopram, men with two single nucleotide polymorphisms spanning a gene linked to both suicide and to antidepressant action were significantly more likely to have new-onset suicidality when they started on the drug, found Roy H. Perlis, M.D., of Massachusetts General Hospital, and colleagues.

"Regardless of specificity, the associations noted between symptoms and suicidal thinking have potential clinical implications in identifying a higher-risk subgroup among depressed patients; interventions that benefit most patients may still be associated with worsening in a small subset," the authors wrote in the June issue of the Archives of General Psychiatry.

Testing for the presence of the polymorphisms could give clinicians and patients more confidence in the use of antidepressants in short-term therapy, the investigators said. It may also allow closer monitoring of those who might be at risk for developing suicidal ideation.

"Converging lines of evidence implicate the transcription factor cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein, coded by the CREB1 gene, in antidepressant response and suicide, as well as mood disorders in general," the authors wrote.

They had previously found an association between single nucleotide polymorphisms (SNPs), in the region of the gene and variations in anger expression among men with major depressive disorder. Anger variation in men with depression is also associated with suicidality, they noted.

To see whether point mutations in the CREB1 gene might be linked to suicidality in patients taking selective serotonin reuptake inhibitors for depression, they conducted a nested case-control study derived from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

The STAR*D study was a multicenter, prospective, open-label trial of citalopram, conducted in outpatient primary care and psychiatric clinics.

In the current study, the authors looked at men and women who took part in STAR*D for whom DNA samples were available. The patients had non-psychotic major depressive disorder, did not report suicidal ideation at study entry, and were subsequently treated with citalopram hydrobromide for up to 12 weeks.

The main study outcome was emergent suicidal ideation, defined as a score of 2 or higher on any post-baseline visit for participants with a baseline score of 0 or 1 on the 16-item Quick Inventory of Depressive Symptomatology- Clinician Rated suicide item.

They identified 1,447 patients, 124 (8.6%) reporting suicidality on at least one visit, and these patients were the chosen as the cases for comparison with the remaining 1,324 participants.

The authors found that in the overall group there were no significant associations between any of five SNPs and treatment-emergent suicidality. However, when they conducted a gene-by-sex analysis, they found that among the 539 men in the study, 54 (10%) developed suicidal ideation after starting on the drug, and among these men, two polymorphisms were significantly linked to the increased risk.

"Among the men, the rs7569963 and rs4675690 SNPs showed a significant association with suicidality with permuted P=0.005," the authors wrote.

When they adjusted for a history of suicide attempt or overall depression, they found that the results were essentially unchanged, and when they looked at SNP haplotypes, they found that two of the eight allele groupings were significantly associated with suicidality.

The most common haplotype was underrepresented among the patients who developed suicidal ideation, and thus may be protective, the investigators suggested.

"The sex-specific nature of the association is intriguing and merits further study," they wrote. "We hypothesized a gene-by-sex interaction based on evidence from a prior study of CREB1 and anger expression in major depressive disorder.

"Interestingly, Zubenko et al [Am J Med Genet 2002; 114:980-987] reported linkage between the CREB1 region and recurrent, early-onset major depressive disorder in women but not men. Female patients with depression may express lower levels of anger or irritability in general; in the same way, their antidepressant response phenotype may differ from that of men."

The authors acknowledged that the study was limited by their reliance on a single rating scale item to detect suicidal ideation. They also pointed out that neither of the two SNPs they found in association with suicidal ideation was located in coding region for CREB1.