Dataset Information

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression.

ABSTRACT:

Background

Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.

Methods/design

To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.

Study eligibility criteria

Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.

Data sources

This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.

Discussion

Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.

SUBMITTER: Culverhouse RC

PROVIDER: S-EPMC3840571 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression.

Culverhouse Robert C RC Bowes Lucy L Breslau Naomi N Nurnberger John I JI Burmeister Margit M Fergusson David M DM Munafò Marcus M Saccone Nancy L NL Bierut Laura J LJ

BMC psychiatry 20131112

<h4>Background</h4>Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.<h4>Meth ...[more]

PMID: 24219410

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Project description:The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38?802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Project description:BACKGROUND: Depression and coronary heart disease (CHD) are frequently comorbid and portend higher morbidity, mortality and poorer quality of life. Prior systematic reviews of depression treatment randomized controlled trials (RCTs) in the population with CHD have not assessed the efficacy of collaborative care. This systematic review aims to bring together the contemporary research on the effectiveness of collaborative care interventions for depression in comorbid CHD populations. METHODS/DESIGN: Electronic databases (Cochrane Central Register of Controlled Trials MEDLINE, EMBASE, PsycINFO and CINAHL) will be searched using a sensitive search strategy exploding the topics CHD, depression and RCT. Full text inspection and bibliography searching will be conducted, and authors of included studies will be contacted to identify unpublished studies. Eligibility criteria are: population, depression comorbid with CHD; intervention, RCT of collaborative care defined as a coordinated model of care involving multidisciplinary health care providers, including: (a) primary physician and at least one other health professional (e.g. nurse, psychiatrist, psychologist), (b) a structured patient management plan that delivers either pharmacological or non-pharmacological intervention, (c) scheduled patient follow-up and (d) enhanced inter-professional communication between the multiprofessional team; comparison, either usual care, enhanced usual care, wait-list control group or no further treatment; and outcome, major adverse cardiac events (MACE), standardized measure of depression, anxiety, quality of life, cost-effectiveness. Screening, data extraction and risk of bias assessment will be undertaken by two reviewers with disagreements resolved through discussion. Meta-analytic methods will be used to synthesize the data collected relating to the outcomes. DISCUSSION: This review will evaluate the effectiveness and cost-effectiveness of collaborative care for depression in populations primarily with CHD. The results will facilitate integration of evidence-based practice for this precarious population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014013653.

Project description:ContextSubstantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression.ObjectiveTo conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data.Data sourcesSearch of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis.Study selectionCriteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data.Data extractionLogistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression.ResultsIn the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data.ConclusionThis meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.

Project description:ObjectStudies have suggested that depression was accompanied by oxidative stress dysregulation, including abnormal total antioxidant capacity (TAC), antioxidants, free radicals, oxidative damage and autoimmune response products. This meta-analysis aims to analyse the clinical data quantitatively by comparing the oxidative stress markers between depressed patients and healthy controls.MethodsA search was conducted to collect the studies that measured the oxidative stress markers in depressed patients. Studies were searched in Embase, Medline, PsychINFO, Science direct, CBMDisc, CNKI and VIP from 1990 to May 2015. Data were subjected to meta-analysis by using a random effects model for examining the effect sizes of the results. Bias assessments, heterogeneity assessments and sensitivity analyses were also conducted.Results115 articles met the inclusion criteria. Lower TAC was noted in acute episodes (AEs) of depressed patients (p<0.05). Antioxidants, including serum paraoxonase, uric acid, albumin, high-density lipoprotein cholesterol and zinc levels were lower than controls (p<0.05); the serum uric acid, albumin and vitamin C levels were increased after antidepressant therapy (p<0.05). Oxidative damage products, including red blood cell (RBC) malondialdehyde (MDA), serum MDA and 8-F2-isoprostanes levels were higher than controls (p<0.05). After antidepressant medication, RBC and serum MDA levels were decreased (p<0.05). Moreover, serum peroxide in free radicals levels were higher than controls (p<0.05). There were no differences between the depressed patients and controls for other oxidative stress markers.ConclusionThis meta-analysis supports the facts that the serum TAC, paraoxonase and antioxidant levels are lower, and the serum free radical and oxidative damage product levels are higher than controls in depressed patients. Meanwhile, the antioxidant levels are increased and the oxidative damage product levels are decreased after antidepressant medication. The pathophysiological relationships between oxidative stress and depression, and the potential benefits of antioxidant supplementation deserve further research.

Project description:ObjectiveTo conduct a meta-analysis of all published genetic association studies of 5-HTTLPR polymorphisms performed in PTSD cases.Methods data sourcesPotential studies were identified through PubMed/MEDLINE, EMBASE, Web of Science databases (Web of Knowledge, WoK), PsychINFO, PsychArticles and HuGeNet (Human Genome Epidemiology Network) up until December 2011.Study selectionPublished observational studies reporting genotype or allele frequencies of this genetic factor in PTSD cases and in non-PTSD controls were all considered eligible for inclusion in this systematic review.Data extractionTwo reviewers selected studies for possible inclusion and extracted data independently following a standardized protocol.Statistical analysisA biallelic and a triallelic meta-analysis, including the total S and S' frequencies, the dominant (S+/LL and S'+/L'L') and the recessive model (SS/L+ and S'S'/L'+), was performed with a random-effect model to calculate the pooled OR and its corresponding 95% CI. Forest plots and Cochran's Q-Statistic and I(2) index were calculated to check for heterogeneity. Subgroup analyses and meta-regression were carried out to analyze potential moderators. Publication bias and quality of reporting were also analyzed.Results13 studies met our inclusion criteria, providing a total sample of 1874 patients with PTSD and 7785 controls in the biallelic meta-analyses and 627 and 3524, respectively, in the triallelic. None of the meta-analyses showed evidence of an association between 5-HTTLPR and PTSD but several characteristics (exposure to the same principal stressor for PTSD cases and controls, adjustment for potential confounding variables, blind assessment, study design, type of PTSD, ethnic distribution and Total Quality Score) influenced the results in subgroup analyses and meta-regression. There was no evidence of potential publication bias.ConclusionsCurrent evidence does not support a direct effect of 5-HTTLPR polymorphisms on PTSD. Further analyses of gene-environment interactions, epigenetic modulation and new studies with large samples and/or meta-analyses are required.

Project description:Background and aimThe collaborative care (CC) is emerging as an effective method in treating patients with multimorbidity, but evidence whether this model is effective for people with comorbid depression and diabetes is unclear. This study aimed to investigate whether CC could improve depression outcomes and HbA1c in patients with depressive symptoms and diabetes, and assess its effects on Quality of Life (QoL).MethodThe author searched Embase, Scopus, PubMed, Cochrane, PsycINFO and CINAHL to identify randomized controlled trials (RCTs) and cluster RCTs published up to October 21, 2020. Studies were required to assess CC in patients with depressive symptoms and diabetes. The primary outcomes were depression treatment response rate and HbA1c and secondary outcome was Quality of Life (QoL). Available individual patient data was collected from all eligible studies. Studies were independently screened by two reviewers and critically appraised using the Cochrane Risk of Bias tool. This study conducted a systematic review and meta-analysis, and the fixed effects and random effects model were used to pool Relative Risks (RRs) and Standard Mean Differences (SMDs).ResultsOur research identified 7906 articles, and finally 12 RCTs were included. Study sample sizes ranged from 58 to 417. The total follow-up period ranged from 12 weeks to 24 months. At follow-up, depression treatment response rate had a significant increase (RR = 1·31, 95% CI 1·23 to 1·39, I2 = 0%) in CC patients compared to controls. There was no statistically significant difference in HbA1c between CC group and the control group (SMD = 0·15, 95% CI -0·35 to 0·65, I2 = 97·6%). Overall QoL at follow-up was greater (SMD = 0·12, 95% CI 0·03 to 0·21, I2 = 54·2%) in CC patients compared to controls but the difference was minor.ConclusionThis systematic review and meta-analysis supported the effectiveness of CC in reducing depression and improving QoL in people with comorbid depression and diabetes.

Project description:BACKGROUND:Despite the growing consensus that collaborative care is effective, limited research has focused on the importance of collaborative care fidelity as it relates to mental health clinical outcomes. OBJECTIVE:To assess the relationship of collaborative care fidelity on symptom trajectories and clinical outcomes among military service members enrolled in a multi-site randomized controlled trial for the treatment of depression and posttraumatic stress disorder (PTSD). DESIGN:Study data for our analyses came from a two-parallel arm randomized trial that evaluated the effectiveness of a centralized collaborative care model compared to the existing collaborative care model for the treatment of PTSD and depression. All patients were included in the analyses to evaluate how longitudinal trajectories of PTSD and depression scores differed across various collaborative care fidelity groupings. PARTICIPANTS:A total of 666 US Military Service members screening positive for probable PTSD or depression through primary care. MAIN MEASURES:Disease registry data from a web-based clinical management support tool was used to measure collaborative care fidelity for patients enrolled in the trial. Participant depression and PTSD symptoms were collected independently from research survey assessments at four time points across the 1-year trial period. Treatment utilization records were acquired from the Military Health System administrative records to determine mental health service use. KEY RESULTS:Consistent and late fidelity to the collaborative care model predicted an improving symptom trajectory over the course of treatment. This effect was more pronounced for patients with depression than for patients with PTSD. CONCLUSIONS:Long-term fidelity to key collaborative care elements throughout care episodes may improve depression outcomes, particularly for patients with elevated symptoms. More controlled research is needed to further understand the influence of collaborative care fidelity on clinical outcomes. TRIAL REGISTRATION:Clinicaltrials.gov Identifier NCT01492348.

Dataset Information

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression.

Background

Methods/design

Study eligibility criteria

Data sources

Discussion

Publications

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression.

Similar Datasets

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