Time moderates the interplay between 5-HTTLPR and stress on depression risk: gene x environment interaction as a dynamic process

Abstract

The serotonin-transporter-linked promoter region (5-HTTLPR) has been widely investigated as contributing to depression vulnerability. Nevertheless, empirical research provides wide contrasting findings regarding its involvement in the etiopathogenesis of the disorder. Our hypothesis was that such discrepancy can be explained considering time as moderating factor. We explored this hypothesis, exploiting a meta analytic approach. We searched PubMed, PsychoINFO, Scopus and EMBASE databases and 1096 studies were identified and screened, resulting in 22 studies to be included in the meta-analyses. The effect of the 5-HTTLPR x stress interaction on depression risk was found to be moderated by the following temporal factors: the duration of stress (i.e. chronic vs. acute) and the time interval between end of stress and assessment of depression (i.e. within 1 year vs. more than 1 year). When stratifying for the duration of stress, the effect of the 5-HTTLPR x stress interaction emerged only in the case of chronic stress, with a significant subgroup difference (p = 0.004). The stratification according to time interval revealed a significant interaction only for intervals within 1 year, though no difference between subgroups was found. The critical role of time interval clearly emerged when considering only chronic stress: a significant effect of the 5-HTTLPR and stress interaction was confirmed exclusively within 1 year and a significant subgroup difference was found (p = 0.01). These results show that the 5-HTTLPR x stress interaction is a dynamic process, producing different effects at different time points, and indirectly confirm that s-allele carriers are both at higher risk and more capable to recover from depression. Overall, these findings expand the current view of the interplay between 5-HTTLPR and stress adding the temporal dimension, that results in a three-way interaction: gene x environment x time.

HTR1A, TPH2, and 5-HTTLPR Polymorphisms and Their Impact on the Severity of Depressive Symptoms and on the Concentration of Tryptophan Catabolites during Hepatitis C Treatment with Pegylated Interferon-α2a and Oral Ribavirin (PEG-IFN-α2a/RBV)

“…On the one hand, Bleys et al [ 42 ] stated that their meta-analysis provided new evidence for the robustness of the interaction between stress and 5-HTTLPR in depression, but on the other hand, another meta-analysis published in the same year by Culverhouse et al [ 43 ] found no proof of a strong interaction between stress and the 5-HTTLPR genotype thats would contribute to the development of depression. One of the latest meta-analyses about the interaction among 5-HTTLPR, stress, and depression also added a temporal dimension, which resulted in a three-way interaction: gene x environment x time [ 44 ]. This meta-analysis revealed that the 5-HTTLPR and stress interaction was a dynamic process, producing different effects at different time points.…”

Uncovering the determinants of brain functioning, behavior and their interplay in the light of context

“…Accordingly, the combination of psychotherapy with antidepressants has been shown to be more effective than the drug alone . The key role of context is increasingly demonstrated also in studies concerning genetic polymorphisms affecting serotonin levels, such as the serotonin-transporter-linked promoter region (5HTTLPR) polymorphism, that makes individuals either more vulnerable or capable to recover from depression, according to their living conditions (Delli Colli et al, 2022). As a final telling example from rodent studies, a testosterone surge in the same individuals induces opposite behavioral outcomes according to social context, either facilitating prosocial responses if administered during affiliative encounters, or triggering aggression if administered during fights (Kelly et al, 2022).…”

Transition From Depression to Mental Health: Toward an Operationalization of Plasticity

“…By contrast, contextual factors, such as the living conditions or psychotherapeutic approaches, drive such change toward a beneficial outcome. Indeed, high plasticity is therapeutic in a favorable context [1][2][3] . For instance, the efficacy of plasticity-enhancing treatments such as selective serotonin reuptake inhibitors (SSRIs), psychedelics and ketamine-in promoting recovery from illness has been shown to be, at least in part, dependent on their combination with favorable environmental conditions [4][5][6][7][8] .…”