Archief Roodbont

January 10, 2011 — New findings point to a robust relationship between depression, stress, and the serotonin transporter promoter polymorphism 5-HTTLPR, according to the authors of a meta-analysis in the January 3 online issue of the Archives of General Psychiatry.

In an analysis of 54 studies of more than 40,000 patients, lead author Katja Karg, BSc, of the University of Wuerzburg, Wuerzburg, Germany, and colleagues found "strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the s allele associated with an increased risk of developing depression under stress (P=.00002)."

The new study contradicts findings of 2 smaller meta-analyses by different authors, both showing no evidence of an interaction. Although 56 studies have examined the interaction among stress, depression, and 5-HTTLPR, the earlier meta-analyses included only 5 and 14 of those studies, respectively, the current authors say. Reasons for the omissions included the inability to obtain primary data for many of the studies, and inclusion only of studies that looked at stressful life events (SLEs), and not other stressors such as childhood maltreatment. Rather than limiting their examination to a specific category of studies, "we sought to perform a meta-analysis on the entire body of work assessing the relationship between 5-HTTLPR, stress, and depression," Ms. Karg and her colleagues write. To overcome the problems in comparing data from different study designs, they used the Liptak-Stouffer z score to combine and compare P values across the studies.

All in all, 54 studies involving 40,749 patients met the inclusion criteria. When the authors stratified the patients into subgroups according to specific types of stressors, they found strong relationships between the s allele of 5-HTTLPR and increased stress sensitivity in the childhood maltreatment group (P = .00007) and the specific medical condition group (P = .0004), and marginal evidence of an association between the allele and the SLE group (P = .03).

The studies looking at depression and childhood maltreatment or specific conditions had similar designs, unlike the studies involving SLEs in general, which varied widely in design, Ms. Karg and her colleagues say. This may account for their finding of a more robust relationship between depression and childhood maltreatment or medical conditions vs SLEs.

The method of stress assessment used in the various studies also emerged as an important variable. "In particular, we found that the evidence of genetic moderation was stronger among studies that used objective measures or in-person interviews to assess stress than among studies that used self-report questionnaires," the study authors write.

One drawback to this study is that, by basing their analysis on P values rather than the primary data, the authors may have incorporated any errors or bias in the original data into their own study. Another drawback to the meta-analytic method, they write, is that they could not estimate the magnitude of the genetic effect "and, in particular, how the interaction effect size compares with any genetic main effect."

Despite these limitations, the study authors conclude that "the present study suggests that there is cumulative and replicable evidence that 5-HTTLPR moderates the relationship between stress and depression. Our evidence, particularly the identification of important study characteristics that influence study outcome (stressor type and stress assessment method), can provide guidance for the design of future gene x environment interaction studies."

The study authors have disclosed no relevant financial relationships.

Arch Gen Psychiatry. Published online January 3, 2011. Abstract