Serotonin-1A Receptor Gene HTR1A Variation Predicts Interferon-Induced Depression in Chronic Hepatitis C

Kraus, Michael R.; Al-Taie, Oliver; Schäfer, Arne; Pfersdorff, M.; Lesch, Klaus‐Peter; Scheurlen, Michael

doi:10.1053/j.gastro.2007.02.053

Cited by 97 publications

(86 citation statements)

References 33 publications

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“…Conversely, there was absolutely no association of the 5-HTTLPR polymorphism and worsening sadness (F 4,16.9 ¼ 0.1; P ¼ 0.98), suicidal thoughts (F 4,59.7 ¼ 0.5; P ¼ 0.7) nor feelings of worthlessness (F 4,44.8 ¼ 0.2; P ¼ 0.9). We also replicated a prior negative finding of no association between 5-HTTLPR and HADS scores during IFN-a treatment (Kraus et al, 2007)-though there was a trend for subjects with the S allele to have greater increase in HADS scores during IFN-a therapy (F 4,17.8 ¼ 2.6; P ¼ 0.07).…”

Section: Resultssupporting

confidence: 85%

“…Consistent with this, we replicated a prior negative finding that the S allele was not strongly associated with increased HADS scores during IFN-a treatment (Kraus et al, 2007), despite being associated with categorical DSM-IV-defined MDD (Bull et al, 2008;Lotrich et al, 2009). This may have treatment implications-(i) emergent neurovegetative symptoms during IFN-a therapy are less responsive to SSRI treatment (Capuron et al, 2002); (ii) neurovegetative symptoms are less response to SSRI treatment of MDD in general (McClintock et al, 2011;Morrow et al, 2003;Nierenberg et al, 2010;Targum and Fava, 2011); and (iii)the S allele (which increases risk for neurovegetative symptoms) has been associated with a poor response to SSRI treatment (Lotrich et al, 2008;Porcelli et al, 2012).…”

Section: Discussionsupporting

confidence: 88%

“…Consistent with this, we have found that polymorphisms affecting TNF-a and IL-28b are associated with specific mood-related symptom clusters in individuals receiving IFN-a (Lotrich et al, 2010;Lotrich et al, 2011). Also, we have found that a serotonin reuptake promoter polymorphism (5-HTTLPR) is associated with increased Beck Depression Inventory scores during IFN-a therapy ), but another group did not find an association using the Hospital Anxiety Depression Scale (Kraus et al, 2007). Thus, we explored the possibility that either BDNF genotype and/or 5-HTTLPR may each influence a specific subset of depression symptoms.…”

Section: Introductionsupporting

confidence: 63%

“…This clinical situation has become a paradigmatic model for prospectively examining vulnerability/resilience to inflammatory cytokine-associated depression, as MDD develops in about 30% of non-depressed subjects within a few months of initiating IFN-a treatment (IFN-MDD) (Lotrich, 2009;Raison et al, 2005). A number of putative vulnerability factors for subsequent IFN-MDD have been identified ranging from a 'short' (S) low-expression allele in the promoter of the serotonin transporter (5-HTTLPR) (Bull et al, 2008;Lotrich et al, 2009), a polymorphism in the serotonin 1A receptor (Kraus et al, 2007), increased interleukin-6 (IL-6) serum levels and an IL-6 polymorphism (Bull et al, 2008;Prather et al, 2009), pre-existing poor sleep quality (Franzen et al, 2009), high neuroticism traits (Lotrich et al, 2007), increased hypothalamic-pituitaryadrenal axis sensitivity, (Raison et al, 2008), elevated ratio of omega-6 fatty acids to omega-3 fatty acids , and increased sensitivity to activating the p38 mitogen-activated protein kinase (Felger et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Lotrich

Albusaysi

Ferrell

2012

Neuropsychopharmacol

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Depression has been associated with inflammation, and inflammation may both influence and interact with growth factors such as brainderived neurotrophic factor (BDNF). Both the functional Val66Met BDNF polymorphism (rs6265) and BDNF levels have been associated with depression. It is thus plausible that decreased BDNF could mediate and/or moderate cytokine-induced depression. We therefore prospectively employed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Montgomery-Asberg Depression Rating Scale (MADRS) in 124 initially euthymic patients during treatment with interferon-alpha (IFN-a), assessing serum BDNF and rs6265. Using mixed-effect repeated measures, lower pretreatment BDNF was associated with higher depression symptoms during IFN-a treatment (F 144,17.2 ¼ 6.8; Po0.0001). However, although the Met allele was associated with lower BDNF levels (F 1,83.0 ¼ 5.0; P ¼ 0.03), it was only associated with increased MADRS scores (F 4,8.9 ¼ 20.3; Po0.001), and not the BDI-II or HADS. An exploratory comparison of individual BDI-II items indicated that the Met allele was associated with suicidal ideation, sadness, and worthlessness, but not neurovegetative symptoms. Conversely, the serotonin transporter promoter polymorphism (5-HTTLPR) short allele was associated with neurovegetative symptoms such as insomnia, poor appetite and fatigue, but not sadness, worthlessness, or suicidal ideation. IFN-a therapy further lowered BDNF serum levels (F 4,37.7 ¼ 5.0; P ¼ 0.003), but this decrease occurred regardless of depression development. The findings thus do not support the hypothesis that decreasing BDNF is the primary pathway by which IFN-a worsens depression. Nonetheless, the results support the hypothesis that BDNF levels influence resiliency against developing inflammatory cytokine-associated depression, and specifically to a subset of symptoms distinct from those influenced by 5-HTTLPR. Neuropsychopharmacology (2013) 38, 985-995;

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Section: Resultssupporting

confidence: 85%

Section: Discussionsupporting

confidence: 88%

Section: Introductionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

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Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Lotrich

Albusaysi

Ferrell

2012

Neuropsychopharmacol

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“…Vulnerability, in the present context, refers to an innate or acquired predisposition to develop a given pathology when causal factors are present. Dysfunction in genes controlling key proteins in cytokine production (e.g., IL-6 [71]) and serotoninergic neurotransmission (e.g, activity of the serotonin transporter [71] or serotonin receptor subtype [72]) are identified as vulnerability factors for cytokineinduced depression. Vulnerability to cytokine-induced depression can be revealed by psychologic features.…”

Section: Pathophysiologic Implicationsmentioning

confidence: 99%

Cytokine, Sickness Behavior, and Depression

2006

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SummarySufficient evidence is now available to accept the concept that the brain recognizes cytokines as molecular signals of sickness. Clarifying the way the brain processes information generated by the innate immune system is accompanied by a progressive elucidation of the cellular and molecular components of the intricate system that mediates cytokine-induced sickness behavior. We are still far, however, from understanding the whole. Among the hundreds of genes that proinflammatory cytokines can induce in their cellular targets, only a handful has been examined functionally. In addition, a dynamic view of the cellular interactions that occur at the brain sites of cytokine production and action is missing, together with a clarification of the mechanisms that favor the transition toward pathology.Anyone who has experienced an episode of viral or bacterial infection knows well the subjective feelings of sickness, in the form of malaise, lassitude, fatigue, numbness, coldness, muscle and joint aches, and reduced appetite. Because they are common, these symptoms usually are ignored by physicians. They are considered uncomfortable, but banal, components of the pathogen-induced debilitation process that affects sick individuals.This simplistic view has turned out to be incorrect. The psychologic and behavioral components of sickness represent, together with fever response and associated neuroendocrine changes, a highly organized strategy of the organism to fight infection [1]. This strategy, referred to as "sickness behavior," is triggered by the proinflammatory cytokines produced by activated cells of the innate immune system in contact with specific pathogen-associated molecular patterns (PAMPs). These cytokines include mainly interleukin (IL) 1 (IL-1α and IL-1β), IL-6, and tumor necrosis factor α (TNF-α).The mechanisms that mediate the behavioral effects of peripherally released cytokines have been elucidated during the past fifteen years. IL-1 and other cytokines act on the brain via two main communication pathways: (1) a neural route represented by the primary afferent neurons that innervate the body site where the infectious process takes place and (2) a humoral pathway that involves the production of proinflammatory cytokines by phagocytic cells in the circumventricular organs (CVOs) and choroid plexus in response to circulating PAMPs or cytokines, followed by the propagation of these immune signals into the brain parenchyma (Fig. 1) [2]. The objective of this review is to present the current knowledge on the way this communication system is organized and regulated and the implications of these advances for understanding brain physiology and pathology.

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The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited

Karg¹,

Burmeister²,

Shedden³

et al. 2011

Arch Gen Psychiatry

1,259

1,090

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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.

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Serotonin-1A Receptor Gene HTR1A Variation Predicts Interferon-Induced Depression in Chronic Hepatitis C

Cited by 97 publications

References 33 publications

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Cytokine, Sickness Behavior, and Depression

The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited

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