Such recommendations are increasingly prevalent and are evolving into standards of practice. The recently updated Texas Children's Medication Algorithm Project (CMAP) on medication treatment of childhood major depression, for example, recommends assessing suicidal ideation and behavior at every visit, including frequency, places, intentions, and potential dangerousness. The CMAP consensus panel states that "careful monitoring and systematic assessment of suicidal thoughts and behavior during medication initiation and dose changes are essential."3Seeking susceptibility
In addition to the determination that those in younger age groups are at higher risk and the recommendation that drug initiation and dosage change warrant close monitoring, efforts are being made to identify individuals who may be particularly susceptible to treatment-emergent suicidality. Several new NIMH-sponsored research projects were reviewed in these pages earlier this year ("FDA, NIMH Scrutinize Antidepressant-Linked Suicidality" by Kenneth J. Bender, March 2007, page 1).
The possibility of a genetic vulnerability to this adverse reaction to antidepressants was recently investigated in a cohort of the large, multicenter STAR*D study. In the June issue of Archives of General Psychiatry, Roy Perlis, MD, of the Depression Clinical and Research Program, Massachusetts General Hospital, Boston, and colleagues reported finding that particular genetic polymorphisms in men, but not women, were associated with emergence of suicidal ideation with antidepressant treatment.4
The researchers had previously reported finding that single nucleotide polymorphisms (SNPs) near the CREB1 (cyclic adenosine(Drug information on adenosine) monophosphate response element binding) gene are associated with anger expression, with its possible direction toward self as well as others.5 Perlis and colleagues note that the transcription factor CREB protein, coded by the CREB1 gene, has been implicated by other researchers in mediating antidepressant response, suicide, and mood disorders in general.
In the present study, Perlis and coauthors analyzed the occurrence of 5 SNPs near CREB1 in more than 1800 STAR*D study patients with depression. Of 539 men without suicidal ideation at baseline, suicidal ideation developed in 54 (10%) during the 12-week course of antidepressant treat- ment. Two of the 5 SNPs were significantly more common in the men with treatment-emergent suicidality. The 2 SNPs occurred in a pattern independent of the patients' history of suicide attempts or severity of depression, which was consistent with a vulnerability to treatment-emergent effect rather than general proneness to suicide.
Perlis and associates suggest that their gender-specific finding could reflect the lower levels of anger or irritability in women in general, and as components of their suicidality. They hypothesize that antidepressant treatment might present an additional stressor in a subset of male patients with depression and a genetic predisposition for hostility and anger expression.
Although the researchers acknowledge that their findings are preliminary and that the functions of the variants are unknown and so cannot be considered causal, they anticipate that this line of investigation will have clinical implications for identifying higher-risk subgroups among depressed patients.
"The ability to identify this group could allow both patients and clinicians to proceed with greater confidence or focus more attention on the high-risk group," Perlis and colleagues wrote.