Association between treatment-emergent suicidal ideation with citalopram and polymorphisms near cyclic adenosine monophosphate response element binding protein in the STAR*D study

Context: A small subset of patients with depression exhibit new or worsening suicidal thoughts or behavior during short-term treatment with antidepressants. Because cyclic adenosine monophosphate response element binding (CREB) protein has been implicated in both antidepressant mechanisms and suicide, the CREB1 gene represents a gene that possibly influences the risk for treatment-emergent suicidality. Objective: To examine polymorphisms that span CREB1, which was previously associated with anger expression in men with major depressive disorder, for association with new or worsening suicidality. Design: Nested case-control study derived from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D)study, a multicenter, prospective, open,12-week effectiveness trial from July 1, 2001, to September 30, 2006. Setting: Outpatient primary care and psychiatric clinics. Patients: Individuals with nonpsychotic major depressive disorder for whom DNA was available and who did not report suicidal ideation at study entry were subsequently treated with citalopram hydrobromide for up to 12 weeks. Main Outcome Measure: Emergent suicidal ideation, defined as a score of 2 or higher on any postbaseline visit for participants whose baseline score was 0 or 1 on the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated suicide item. Results: Of 1447 participants, 124 (8.6%) subsequently reported suicidality on at least 1 visit; these individuals were compared with the remaining 1324 participants. Of 5 single nucleotide polymorphisms (SNPs) examined, none were significantly associated with treatment-emergent suicidality overall. However, 2 SNPs revealed a gene-by-sex interaction with suicidality. Among the 539 men, these 2 SNPs and 2 of the 5 SNP haplotypes were significantly associated with new-onset suicidality. Conclusions: Polymorphisms that span CREB1 were associated with treatment-emergent suicidality among men with depression, extending an observation of association with male anger expression in a prior independent cohort. If replicated, this finding would suggest that pharmacogenetic testing could facilitate the identification of the small subset of individuals at greater risk during short-term antidepressant treatment.