Dataset Information

A functional serotonin transporter gene polymorphism and depressive effects associated with interferon-alpha treatment.

ABSTRACT:

Background

Interferon-alpha (IFN-alpha) treatment frequently induces depression, potentially leading to early dose reductions or a shorter duration of treatment, which can adversely affect outcomes, including quality of life.

Objective

Defining relevant risk factors for IFN-alpha-induced depression is essential in order to identify prophylactic treatment strategies.

Method

The authors examined whether a functional polymorphism (5-HTTLPR) in the gene encoding the serotonin transporter moderates IFN-alpha-induced depressive symptoms in 1,015 patients with chronic hepatitis C (CHC) receiving pegylated IFN-alpha and ribavirin. Depressive symptoms were assessed at baseline, 12 weeks, and 20 weeks of treatment.

Results

Depression symptoms increased during antiviral treatment; 5-HTTLPR genotype moderated IFN-alpha-induced depression symptoms in both non-Hispanic Caucasians and Hispanic patients, although the opposite risk allele was associated with depression in the two populations.

Conclusion

5-HTTLPR may moderate risk for the development of depressive symptoms during IFN-alpha therapy for CHC in a population-specific manner.

SUBMITTER: Pierucci-Lagha A

PROVIDER: S-EPMC3746312 | biostudies-literature | 2010 Mar-Apr

REPOSITORIES: biostudies-literature

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Publications

A functional serotonin transporter gene polymorphism and depressive effects associated with interferon-alpha treatment.

Pierucci-Lagha Amira A Covault Jonathan J Bonkovsky Herbert L HL Feinn Richard R Abreu Christine C Sterling Richard K RK Fontana Robert J RJ Kranzler Henry R HR

Psychosomatics 20100301 2

<h4>Background</h4>Interferon-alpha (IFN-alpha) treatment frequently induces depression, potentially leading to early dose reductions or a shorter duration of treatment, which can adversely affect outcomes, including quality of life.<h4>Objective</h4>Defining relevant risk factors for IFN-alpha-induced depression is essential in order to identify prophylactic treatment strategies.<h4>Method</h4>The authors examined whether a functional polymorphism (5-HTTLPR) in the gene encoding the serotonin t ...[more]

PMID: 20332289

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Project description:Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.

Project description:BackgroundThe serotonin (5-HT) transporter-linked polymorphic region (5-HTTLPR) moderates the relationship between stressful life events and depression. Given the high prevalence of depression in chronic pain, the primary aim of this preliminary study was to investigate the associations between the 5-HTTLPR and the severity of depressive symptoms in a cohort of adults with chronic pain.MethodsAdults with chronic pain who were consecutively admitted to an outpatient pain rehabilitation program and met inclusion criteria were recruited for study participation (n=277). Individuals were genotyped for the 5-HTTLPR (including rs25531) and categorized as high, intermediate, or low expressors of the 5-HT transporter. The severity of depressive symptoms at admission was measured by using the Center for Epidemiologic Depression scale (CES-D).ResultsThe distribution of the high-, intermediate-, and low-expressing genotypes was 61 (22%), 149 (54%), and 67 (24%), respectively. The Hardy-Weinberg P-value was 0.204, which indicated no departure from equilibrium. A main effect of 5-HTTLPR was observed for depressive symptoms (P=0.040) where Center for Epidemiologic Depression scale (CES-D) scores were significantly greater in the low-expressing group compared to the high- (P=0.019) and intermediate (P=0.029)-expressing groups. In multivariate multinomial logistic regression analysis adjusted for age, sex, pain severity, pain catastrophizing, and pain anxiety, greater CES-D scores were significantly associated with the 5-HTTLPR low-expressing group compared to the high-expressing group (P=0.023), but not for the low-expressing group compared to the intermediate-expressing group (P=0.056).ConclusionThese preliminary findings suggest that the triallelic 5-HTTLPR could influence the severity of depressive symptoms in adults with chronic pain. Individuals with chronic pain may be particularly vulnerable to the moderating effects of 5-HTTLPR due to high levels of pain-related stress that are inherently present in this population.

Project description:ObjectiveInflammatory cytokines may influence both labile anger and depression. Both psychiatric conditions can occur during interferon alfa-based treatments. Evidence also indicates a central nervous system role for tumor necrosis factor alpha (TNF-alpha), whose expression may be increased by interferon alfa. A polymorphism in the promoter region of TNF-alpha has been associated with various inflammatory illnesses. We therefore hypothesized that this TNF-alpha polymorphism would influence susceptibility to psychiatric symptoms during interferon alfa therapy.MethodsOne hundred five patients with hepatitis C, initially without active major depression (major depressive disorder), were treated with interferon alfa and then prospectively monitored using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the Beck Depression Inventory II, the Anger Irritability and Assault Questionnaire, and circulating TNF-alpha levels. The A-308G polymorphism (rs1800629) was determined using the 5'-nuclease assay. Repeated-measure mixed-effect analyses compared changes in symptoms over time.ResultBeck Depression Inventory II score increased during interferon alfa therapy (F = 6.2; P < 0.001), with 27% developing MDD. The TNF-alpha A allele was associated with worsened labile anger (F = 2.5; P < 0.05) and fatigue (F = 2.9; P < 0.05) during treatment but not with major depression incidence (chi = 0.0; P = 0.99) or increased Beck Depression Inventory II (F = 1.2; P = 0.31). Labile anger was not predicted by the serotonin transporter polymorphism (F = 0.8; P = 0.59).DiscussionDuring treatment with an exogenous cytokine, vulnerability to worsening labile anger-distinct from major depression-is associated with genetic variability in TNF-alpha. This has implications both for patients being treated with interferon alfa and our understanding of genetic vulnerability for different subtypes of dysphoric and mood disorders.

Dataset Information

A functional serotonin transporter gene polymorphism and depressive effects associated with interferon-alpha treatment.

Background

Objective

Method

Results

Conclusion

Publications

A functional serotonin transporter gene polymorphism and depressive effects associated with interferon-alpha treatment.

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