The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-Analysis Revisited: Evidence of Genetic Moderation

By Katja Karg, Margit Burmeister, Kerby Shedden, Srijan Sen. Archives of General Psychiatry, 2011

1,388 citations recorded by the source corpus.

Context The initial report of an interaction between a serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the development of depression is perhaps the best-known and most cited finding in psychiatric genetics. Two recent meta-analyses explored the studies seeking to replicate this initial report and concluded that the evidence did not support the presence of the interaction. However, even the larger of the meta-analyses included only 14 of the 56 studies that have explored the relationship between 5-HTTLPR, stress and depression. Objective We sought to perform a meta-analysis including all relevant studies assessing whether 5-HTTLPR moderates the relationship between stress and depression. Data Sources We identified relevant articles from previous meta-analyses and reviews and a PubMed database search. Study Selection We excluded two studies presenting data that were included in other, larger, studies already included in our meta-analysis to avoid duplicate counting of subjects. Data Extraction In order to perform a more inclusive meta-analysis, we used the Liptak-Stouffer Z-score method to combine findings of primary studies at the significance test level rather than raw data level. Results We included 54 studies and found strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the 5-HTTLPR s allele associated with an increased risk of developing depression under stress (p<0.0001). When restricting our analysis to the studies included in the previous meta-analyses, we found no evidence of association (Munafo studies p=0.16; Risch studies p=0.11). This suggests that the difference in results between previous meta-analyses and ours was not due to the difference in meta-analytic technique but instead to the expanded set of studies included in this analysis. Conclusions Contrary to the results of the smaller earlier meta-analyses, we find strong evidence that 5-HTTLPR moderates the relationship between stress and depression in the studies published to date.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Pharmacology

View Paper: https://www.semanticscholar.org/paper/3861048d3f341b8e5673e114d093110e4dbe4780

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In Cellular and Molecular Neuroscience

1. Robin L. Carhart-Harris
2. David J. Nutt
3. A. Feder
4. C. Nemeroff
5. Dennis S. Charney

In Cognitive Neuroscience

1. Robin L. Carhart-Harris
2. A. Feder
3. David J. Nutt
4. C. Nemeroff
5. Dennis S. Charney

In Pharmacology

1. C. Nemeroff
2. Dennis S. Charney

Citations in the corpus

• The serotonin theory of depression: a systematic umbrella review of the evidence (2022, neutral): “The idea that depression is the result of a chemical imbalance also in fl uences decisions about whether to take or continue anti-depressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs [67, 68].”
• Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications (2013, background): “…in the promoter region of the serotonin transporter (5-HTTLPR) has been shown to moderate the influence of stress on the development of depression (Caspi et al., 2003, Karg et al., 2011) and to predict responsiveness to SSRIs (Smeraldi et al., 1998, Lotrich et al., 2008, Porcelli et al., 2012).”
• “The Biological Effects of Childhood Trauma” (2014, neutral): “An interaction showing that adults with histories of child maltreatment, who were also carriers of the short 5-HTTLPR allele were found in another metaanalysis to be at increased risk for depression.(159) On the other hand, in a forensic sample of 237 men with elevated levels of child abuse and negl”
• Understanding resilience (2013, background): “A particularly strong association between the s-allele and risk of developing depression was found in the group with a history of childhood maltreatment (Karg et al., 2011; Southwick and Charney, 2012).”
• Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect. (2016, background): “…in a large number of subsequent studies by Caspi and his collaborators (Uher et al., 2011), our group (Ressler et al., 2011), and others as regards depression vulnerability (Cutuli et al., 2013; Rocha et al., 2015), suicidality (Roy et al., 2007), and in a major meta-analysis (Karg et al., 2011).”
• Serotonin and brain function: a tale of two receptors (2017, background): “…that the (s/s) allele, associated with lower re-uptake and thus higher synaptic 5-HT (Lesch et al., 1996) is associated with a greater likelihood of depressive symptoms in response to stress (Caspi et al., 2003; Karg et al., 2011; Zammit and Owen, 2006) – although see (Mirkovic et al., 2016).”
• Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. (2012, neutral): “In summary, a recentmeta-analysis of the interaction of the 5-HTTLPR and stressful life events has shown that the timing and type of stress is important (Karg et al., 2011).”
• The Biological Underpinnings of Peer Victimization: Understanding Why and How the Effects of Bullying Can Last a Lifetime (2013, background): “A recent meta-analysis (Karg et al., 2011) documents the accumulated evidence of the moderating role of the serotonin transporter gene in the relationship between stress and depression.”