The interaction of serotonin transporter gene polymorphisms and early adverse life events on vulnerability for major depression

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Suite 4000 WMRB, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Current Psychiatry Reports (Impact Factor: 3.24). 01/2007; 8(6):452-7. DOI: 10.1007/s11920-006-0050-y
Source: PubMed


Considerable literature supports the hypothesis of dysfunction in central nervous system serotonergic circuits in the pathophysiology of mood disorders, specifically major depression. Since the development of the selective serotonin (5-HT) reuptake inhibitors, a putative role for the 5-HT transporter (SERT) in the etiology of depression has been explored. The discovery of a functional SERT polymorphism has provided a novel tool to further scrutinize the role of serotonergic neurons in depression. This article reviews the burgeoning evidence of an interaction between early life stress and an SERT polymorphism on vulnerability to depression.

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Available from: Charles B Nemeroff, Oct 02, 2015
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    • "Whereas glutamatergic and GABAergic systems are implicated in anxiety, learning and memory processes (Roozendaal et al., 2009), serotonin (5-HT), due to the important functions it play mainly -but not only-within the amygdala , 5-HT has a regulatory role in the anxiety behaviors and among the fifteen serotonin receptors, 5-HT1A and 5-HT2C receptors are relatively abundant in the amygdala (Li et al., 2012). Moreover, polymorphisms of the gene coding for the serotonin transporter have been linked to stress induced depression (Caspi et al., 2003; Vergne and Nemeroff, 2006). In pharmacology, 5-HT1A receptor agonists, such as buspirone due to its anxiolytic effects, have constituted an anxiolytic drug (De Vry, 1995; Li et al., 2012). "
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    • "While the annual prevalence of depression as defined by the Diagnostic and Statistical Manual IV-TR (DSM-IV-TR)22 criteria is estimated to be 3.2%, the heritability of depression is thought to be 31%–42%.23 In 2003, a gene × environment (G × E) hypothesis was proposed, suggesting that because an association between 5-HTT genotype and response to stress in animals and humans had been demonstrated, and that stressful life events are known to affect the onset and course of depression,24 it was therefore logical to conclude that the 5-HTT genotype could contribute to the development of depression.7 These researchers sought to determine if 5-HTT genotype altered the serotonergic response to stress, thereby predisposing participants to a greater influence of stressful life events on depression.7 Caspi et al demonstrated a positive association between the number of stressful life events and the probability of depression that was statistically stronger in S carriers than L homozygotes.7 "
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    ABSTRACT: Serotonin (5-HT) regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR) polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele ("risk allele") may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles), and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (L(A)/L(G)/S) may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication.
    Pharmacogenomics and Personalized Medicine 01/2012; 5(1):19-35. DOI:10.2147/PGPM.S23462
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    • "These are the gene encoding the rate-limiting enzyme in the biosynthesis of serotonin, tryptophan hydroxylase [59] [60] [61], the serotonin transporter [62, 63], and the 5-HT 1A [64, 65] and 5-HT 2A [66] receptors. Genetically determined dysfunction of the serotonergic system increases the risk of developing depression and in particular, the genetic makeup seems to interact with environmental life-stressors [67] [68]. "
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