The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: A replication. Archives of General Psychiatry, 62, 529-535

Virginia Institute for Psychiatry and Behavioral Genetics, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA 23298, USA.
Archives of General Psychiatry (Impact Factor: 13.75). 06/2005; 62(5):529-35. DOI: 10.1001/archpsyc.62.5.529
Source: PubMed

ABSTRACT Prior evidence from twin studies suggested genetic moderation of the depressogenic effects of stressful life events (SLEs). Can the specific genes involved in this effect be identified?
To replicate and extend a recent study that a functional variant in the serotonin transporter (5-HTT) might in part explain these findings.
Characterizing risk for major depression and generalized anxiety syndrome in the last year as a function of 5-HTT genotype, sex, and the occurrence of SLEs and ratings of the SLE-associated level of threat.
A population-based sample of adult twins.
Five hundred forty-nine male and female twins with a mean age at participation of 34.9 years (SD 9.1).
Episodes of major depression and generalized anxiety syndrome in the last year with onset measured to the nearest month.
Individuals with 2 short (S) alleles at the 5-HTT locus were more sensitive to the depressogenic effects of all SLEs than were those with 1 or 2 long (L) alleles. When level of SLE-associated threat was examined, the interaction between genotype and SLE resulted from an increased sensitivity of SS individuals to the depressogenic effects of common low-threat events. These events had little impact on risk for those possessing the SL and LL genotypes. The 5-HTT genotype did not modify the effects of SLEs on risk for generalized anxiety syndrome.
Variation at the 5-HTT moderates the sensitivity of individuals to the depressogenic effects of SLEs largely by producing, in SS individuals, an increased sensitivity to the impact of mild stressors. Replication of these intriguing results is needed.

1 Follower
  • Source
    • "Given that prevalence of SS in European-ancestry populations is 17% (Clarke et al., 2010; Lesch et al., 1996), the numbers suggest that the low-risk group is depleted of SS rather than the high-risk group being enriched for it. Having two copies is associated with increased stress sensitivity (Kendler et al., 2005). Absence of SS may protect against psychobiological responses to stressful events, and is consistent with the lower rates of depressive and anxiety disorders in the low-risk group (Weissman et al., 2006; Weissman et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of the serotonin transporter promoter linked polymorphism (5HTTLPR) in depression, despite much research, remains unclear. Most studies compare persons with and without depression to each other. We show offspring at high (N=192) as compared to low (N=101) familial risk for major depressive disorder were almost four times as likely to have two copies of the short allele at 5HTTLPR, suggesting that incorporation of family history could be helpful in identifying genetic differences. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    04/2015; 228(1). DOI:10.1016/j.psychres.2015.04.015
  • Source
    • "Stressful life events were measured using the List of Threatening Experiences Questionnaire (LTE-Q). The LTE-Q was modified following previous studies of the G × E interaction [18] [19] [20] [21]. The time period was extended to the previous 5 years following evidence that the G × E interaction showed stronger effect for chronic stressors [7], and both severity and number of events were combined by summing the subjective rated impact of all events to create the 'LTE-Q Total' variable. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to test whether a specific serotonin transporter (5HTT) gene polymorphism interacting with life stress increased the risk of depression in patients with epilepsy.
    Epilepsy & Behavior 08/2014; 39C:33-37. DOI:10.1016/j.yebeh.2014.07.016 · 2.06 Impact Factor
  • Source
    • "In humans, depression consequent to early-life stress is influenced by polymorphisms of specific genes that confer a vulnerability diathesis (Kaufman et al., 2004, 2006; Kendler et al., 2005; Popova Nina and Naumenko Vladimir, 2013). The serotonin transporter protein gene, SLC6A4, encodes the serotonin transporter, a protein critical to the regulation of brain serotonin function (Lesch et al., 1995). "
    [Show abstract] [Hide abstract]
    ABSTRACT: First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are less than 50%. The authors examine the putative biological substrates underlying “Treatment Refractory Depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin (5-HT) system becomes impervious to the desired enhancement of 5-HT neurotransmission by SSRI’s. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple 5-HT deficit state but rather an excess of midbrain peri-raphe 5-HT and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in 5-HT-mediated neuroplasticity. Glutamate, 5-HT, noradrenaline and histamine are activated by stress and exert an inhibitory effect on 5-HT outflow, in part by “flooding” 5-HT1A autoreceptors by 5-HT itself. Certain factors putatively exacerbate this scenario- presence of the short arm of the serotonin transporter gene, early life adversity and comorbid bipolar disorder- each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing 5-HT neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on 5-HT neurons. Future studies are recommended to test this biologically based approach for TRD.
    Frontiers in Behavioral Neuroscience 05/2014; 8:189. DOI:10.3389/fnbeh.2014.00189 · 4.16 Impact Factor
Show more