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Gene-Environment Interaction in Youth Depression: Replication of the 5-HTTLPR Moderation in a Diverse Setting
Abstract and Figures
Replication of scientific findings is a major challenge in biomedical research. In psychiatry, the identification of measured gene-environment interactions (G×E) has promoted a heated debate over the past decade, with controversial results about its influence on disorders such as major depression. The authors sought to replicate a 2003 study on G×E in youth depression in a large birth cohort from a diverse setting.
Using data from the 1993 Pelotas Birth Cohort Study, and adopting a design as similar as possible to that of the original study, the authors tested whether the relationship between childhood maltreatment and a subsequent depressive episode diagnosis was moderated by 5-HTTLPR genotype. Of 5,249 individuals assessed at birth and followed up to age 18, data on the evaluation for depressive episodes in early adulthood, on childhood maltreatment, and on genotype were available for 3,558 participants, of whom 2,392 remained after conservative screening for previous depressive symptoms. Associations were investigated with logistic regression analyses and controlling for potential confounders.
The results replicated important findings of the original study, this time in a sample of young adults from a middle-income country: there was a differential dose-response relationship between childhood maltreatment and major depression according to 5-HTTLPR genotype.
After following a research strategy as comparable as possible to that of the original study, the results corroborated the existence of a measured G×E, now in a large sample from a different sociocultural context. These findings provide further evidence that a genetic variant in the 5-HTTLPR moderates the link between childhood maltreatment and youth depression.
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... For instance, Bakermans-Kranenburg et al. (2007) found that children carrying the 7-repeat DRD4 allele who were raised by insensitive mothers exhibited significantly more behavior disorders than those without the repeat allele, and yet when children with this allele were raised by sensitive mothers they exhibited the least behavior disorders. Caspi et al., (2003) and Rocha et al. (2015) found evidence of differential susceptibility in studies of serotonin-transporter-linked polymorphisms and depression in the context of childhood maltreatment. Individuals with homozygous short alleles were at a significantly increased risk of depression when there was a history of childhood maltreatment but were at a significantly decreased risk of depression when there was no history of childhood maltreatment. ...
A New Model for Understanding and Treating Borderline Personality Disorder
(Revised Edition) 2023
Lee Crandall Park, M.D. and Thomas J. Park, Ph.D.
Abstract: Borderline Personality Disorder is almost always a fully developmentally engendered disorder of the Social Intelligence faculty for Theory of Mind (ToM), in the absence of any inherent neurobiological deficits. Nonetheless, pre-borderline children do have a unique, but normal, neurobiological vulnerability that can lead to maldevelopment of the mind. This inherent vulnerability is exhibited behaviorally by their well-documented very high sensitivity, but this sensitivity is not a defect. Rather, it is the visible expression of an enhanced faculty for ToM, providing a high degree of “Epistemic Trust” (ET). This would be a major asset for the development of the mind in a normal, or especially in an enriched, Developmental Social Environment (DSE). Quite paradoxically, this neurobiological enhancement is also very “Differentially Susceptible” to the nature of the DSE, providing the same high degree of inherent Epistemic Trust in a poor or adverse DSE. Throughout the developmental years the sensitive pre-borderline “orchid” child experiences routine, everyday, often rather subtle, psychological/emotional adversity that directly interferes with and perverts proper development of the mind. This exceptional vulnerability to psychological adversity gradually leads to the severe mental illness that has been incorrectly labeled as Borderline Personality Disorder.
The co-occurrence in borderline patients of inherently enhanced yet developmentally impaired Theory of Mind provides for the complex and sometimes paradoxical symptomatology that uniquely identifies BPD. In particular, although borderline patients demonstrate severe impairments in mentalizing and in understanding self and others, they can also, surprisingly, demonstrate good or even exceptional mentalization and social perceptivity (Borderline Empathy Paradox). This perceptivity has enabled them to occasionally draw even experienced professionals into strong countertransferences and boundary violations.
To our knowledge, the possibility of a fully developmental source for Borderline Personality Disorder has never been explored or even seriously considered. This is remarkable considering that the mind and language do not even exist at birth as working faculties, but must be entirely and gradually constructed during childhood social development. This omission may be largely due to the incorrect conviction that neurobiological limitations or flaws have already been identified and confirmed as inherent and contributing to the occurrence of the disorder.
This new understanding of Borderline Personality Disorder as a developmentally engendered disorder of Theory of Mind that has been gradually “learned” during the childhood everyday social experience leads to new recommendations for preventing and treating BPD. First, new research must focus on developing guidelines for parenting highly sensitive children. Second, necessary modifications for current treatment models should resolve their persisting failures to provide either a sufficiently positive sense of self or successful intimacy with others. These modifications are presented in Chapter 2. Full text available at:
https://leecrandallparkmd.net/BPDmonograph
... In the latter case, a study may be as simple as analyzing a single outcome, single genetic variant, and single environmental exposure. A famous and enduring study of this type found that a serotonin transporter (5-HTT) gene promoter polymorphism moderated the effect of stressful life events on depression [157,158]. This design can be thought of as the simplest kind of whole person model as we have defined it above: a single outcome (in this case, a clinical variable) is being modeled as the product of one biological factor and one psychosocial factor (potentially in the presence of additional covariates). ...
The growing global burden of mental illness has prompted calls for innovative research strategies. Theoretical models of mental health include complex contributions of biological, psychosocial, experiential, and other environmental influences. Accordingly, neuropsychiatric research has self-organized into largely isolated disciplines working to decode each individual contribution. However, research directly modeling objective biological measurements in combination with cognitive, psychological, demographic, or other environmental measurements is only now beginning to proliferate. This review aims to (1) to describe the landscape of modern mental health research and current movement towards integrative study, (2) to provide a concrete framework for quantitative integrative research, which we call Whole Person Modeling, (3) to explore existing and emerging techniques and methods used in Whole Person Modeling, and (4) to discuss our observations about the scarcity, potential value, and untested aspects of highly transdisciplinary research in general. Whole Person Modeling studies have the potential to provide a better understanding of multilevel phenomena, deliver more accurate diagnostic and prognostic tests to aid in clinical decision making, and test long standing theoretical models of mental illness. Some current barriers to progress include challenges with interdisciplinary communication and collaboration, systemic cultural barriers to transdisciplinary career paths, technical challenges in model specification, bias, and data harmonization, and gaps in transdisciplinary educational programs. We hope to ease anxiety in the field surrounding the often mysterious and intimidating world of transdisciplinary, data-driven mental health research and provide a useful orientation for students or highly specialized researchers who are new to this area.
... In view of the above research differences, consider the role of gene-environment interaction between the two. Rocha et al. followed up 3,558 adolescents and showed that child abuse and 5-HTTLPR gene polymorphisms interacted in the development of adolescent depression, and 5-HTTLPR could reduce the link between child abuse and adolescent depression (19). Re-search on depression related to stress and 5-HTTLPR allelic variation is controversial, a meta-analysis supports that 5-HTTLPR can mediate the relationship between depression and stress (20); another meta-analysis shows that 5-HTTLPR There is no strong relationship between genotype and stress leading to the development of depression, and the interaction of 5-HTTLPR with stress and depression can only be observed in stressed individuals (21). ...
Biogenetics plays an important role in the pathogenesis of adolescent depression and the study of gene polymorphisms has updated the understanding of adolescent depression. However, under the influence of gene-environment interaction and adolescent developmental age factors, the impact of gene polymorphisms on adolescent depression is intricate. Studying and elucidating the relationship between depression-related gene polymorphisms and adolescent depression contributes to the study of the pathogenesis of depression and provides new clues for the prevention and treatment of depression in adolescents. This article reviews the related gene polymorphisms around adolescent depression.
... As three studies [35][36][37] considered overlapping populations, we excluded from the analyses those with the smallest samples (Supplementary Table 2). Characteristics of the 22 articles included in the meta-analysis [7,14,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] are summarized in Table 1. ...
The serotonin-transporter-linked promoter region (5-HTTLPR) has been widely investigated as contributing to depression vulnerability. Nevertheless, empirical research provides wide contrasting findings regarding its involvement in the etiopathogenesis of the disorder. Our hypothesis was that such discrepancy can be explained considering time as moderating factor. We explored this hypothesis, exploiting a meta analytic approach. We searched PubMed, PsychoINFO, Scopus and EMBASE databases and 1096 studies were identified and screened, resulting in 22 studies to be included in the meta-analyses. The effect of the 5-HTTLPR x stress interaction on depression risk was found to be moderated by the following temporal factors: the duration of stress (i.e. chronic vs. acute) and the time interval between end of stress and assessment of depression (i.e. within 1 year vs. more than 1 year). When stratifying for the duration of stress, the effect of the 5-HTTLPR x stress interaction emerged only in the case of chronic stress, with a significant subgroup difference (p = 0.004). The stratification according to time interval revealed a significant interaction only for intervals within 1 year, though no difference between subgroups was found. The critical role of time interval clearly emerged when considering only chronic stress: a significant effect of the 5-HTTLPR and stress interaction was confirmed exclusively within 1 year and a significant subgroup difference was found (p = 0.01). These results show that the 5-HTTLPR x stress interaction is a dynamic process, producing different effects at different time points, and indirectly confirm that s-allele carriers are both at higher risk and more capable to recover from depression. Overall, these findings expand the current view of the interplay between 5-HTTLPR and stress adding the temporal dimension, that results in a three-way interaction: gene x environment x time.
Biogenetics plays an important role in the pathogenesis of depressive disorder in adolescents. Various genetic polymorphism studies have updated the understanding of adolescent depressive disorder. However, due to the influence of gene-environment interaction and age of puberty, the influence of gene polymorphisms on adolescent depressive disorder is complicated to clarify. Investigating and clarifying the relationship between gene polymorphisms and adolescent depressive disorder will promote the research on the pathogenesis of this disorder and provide a reference for the prevention and treatment of this disorder. This article reviews the genetic polymorphisms related to adolescent depressive disorder.
We examined relationships between the serotonin system and stress in major depression and suicidal behavior. Twenty-five medication-free depressed participants (13 suicide attempters) underwent same-day [11C]DASB and [11C]CUMI-101 positron emission tomography (PET) imaging. Binding potential (BPND) to the serotonin transporter (5-HTT) and serotonin 1A (5-HT1A) receptor, respectively, was quantified using the NRU 5-HT atlas, reflecting distinct spatial distributions of multiple serotonin targets. Ecological momentary assessment (EMA) measured current stress over one week proximal to imaging. EMA stress did not differ between attempters and non-attempters. In all depressed participants, 5-HTT and 5-HT1A BPND were unrelated to EMA stress. There were region-specific effects of 5-HTT (p=0.002) and 5-HT1A BPND (p=0.03) in attempters vs. nonattempters. In attempters, region-specific associations between 5-HTT (p=0.03) and 5-HT1A (p=0.005) BPND and EMA stress emerged. While no post-hoc 5-HTT BPND correlations were significant, 5-HT1A BPND correlated positively with EMA stress in attempters in 9/10 regions (p-values<0.007), including the entire cortex except the largely occipital region 5. Brodmann-based regional analyses found diminished effects for 5-HTT and subcortically localized positive corrrelations between 5-HT1A and EMA stress, in attempters only. Given comparable depression severity and childhood and current stress between attempters and nonattempters, lower 5-HTT binding in attempters vs. nonattempters may suggest a biological risk marker. Localized lower 5-HTT and widespread higher 5-HT1A binding with stress among attempters specifically may suggest that a serotonergic phenotype might be a key determinant of risk or resiliency for suicidal behavior.
Introduction: Attenuated adult hippocampal neurogenesis may manifest in affective symptomatology and/or resistance to antidepressant treatment. While early-life adversity and the short variant (‘s’) of the serotonin transporter gene's long polymorphic region (5-HTTLPR) are suggested as interacting risk factors for affective disorders, no studies have examined whether their superposed risk effectuates neurogenic changes into adulthood. Similarly, it is not established whether reduced hippocampal volume in adolescence, variously identified as a marker and antecedent of affective disorders, anticipates diminished adult neurogenesis. We investigate these potential developmental precursors of neurogenic alterations using a bonnet macaque model.
Methods: Twenty-five male infant bonnet macaques were randomized to stressed [variable foraging demand (VFD)] or normative [low foraging demand (LFD)] rearing protocols and genotyped for 5-HTTLPR polymorphisms. Adolescent MRI brain scans (mean age 4.2y) were available for 14 subjects. Adult-born neurons were detected post-mortem (mean age 8.6y) via immunohistochemistry targeting the microtubule protein doublecortin (DCX). Models were adjusted for age and weight.
Results: A putative vulnerability group (VG) of VFD-reared ‘s’-carriers (all ‘s/l’) exhibited reduced neurogenesis compared to non-VG subjects. Neurogenesis levels were positively predicted by ipsilateral hippocampal volume normalized for total brain volume, but not by contralateral or raw hippocampal volume.
Limitations: No ‘s’-carriers were identified in LFD-reared subjects, precluding a 2 × 2 factorial analysis.
Conclusion: The ‘s’ allele (with adverse rearing) and low adolescent hippocampal volume portend a neurogenic deficit in adult macaques, suggesting persistent alterations in hippocampal plasticity may contribute to these developmental factors’ affective risk in humans.
Background
: Polygenic risk score (PRS) is a method of revealing multiple genes effect. The study of PRS and childhood trauma (CT) and resilience on adolescent depressive symptoms are fewer reported, especially the functional mechanism of resilience among them.
Methods
: 718 Chinese adolescents aged 10-14 years were surveyed including CT, resilience, depressive symptoms, and phenotype data in three years of the cohort study. PRS was calculated by the weighted accumulation effects of alleles on depressive symptoms. Their relationships were analyzed by the mediation and moderation models.
Results
: PRS and CT were risk factors for depressive symptoms. Interaction (PRS × CT) on depressive symptoms had no statistical significance. Resilience acted as the protective mediator from CT (emotional abuse, emotional neglect, physical neglect) to depressive symptoms and moderator from CT (emotional abuse) to depressive symptoms.
Limitations
: The sample size was a little small so that the inference were drawn prudently. Except gene data, other were collected by self-reported questionnaire instruments which inevitably brought recall bias.
Conclusions
: PRS and CT could have adverse impact on depressive symptoms, resilience could alleviate these risk effects as a moderator and a mediator. The findings have important implications for prevention and intervention in adolescent depressive symptoms.
There is strong evidence that childhood maltreatment has significant long-term mental health consequences, and these adverse childhood experiences have resulted in a serious public health crisis. Though they are highly prevalent, these early life stress (ELS) events contribute substantially to the risk of a variety of psychiatric and medical disorders including mood disorders, substance use, anxiety, suicidality, and common medical comorbidities such as obesity, diabetes, and cardiovascular disease. The consensus of most studies show that childhood maltreatment is associated with a higher incidence, worsened course, and poorer treatment response to both psychotherapy and psychopharmacology. Multiple genetic polymorphisms interact to increase risk for these disorders, increasing the likelihood of long-term consequence when children are exposed to the stressful events. Numerous animal studies report long lasting neurobiological consequences of ELS to include alterations in endocrine regulation and neural development. Substantial research supports that childhood maltreatment leads to elevated inflammatory markers in later life, and that these elevated biomarkers contribute toward the risk of inflammatory-linked disorders including autoimmune diseases, heart disease, diabetes, cancer, GI disorders, as well as other medical conditions. Imaging studies demonstrate persistent structural brain changes after individuals suffered physical, sexual, and emotional abuse. Many studies point toward epigenetic mechanisms causing heritable changes in gene expression as a causative mechanism by which ELS may influence gene expression. Other studies document advanced cellular aging in the form of shortened telomere length as another mechanism by which psychological stress and trauma contribute to both medical and psychiatric disorders. In this review, we examine the expanding body of research on the long-term biological and clinical consequences of child maltreatment, and the need for public health efforts to work toward reducing the incidence of this abuse, and the consequent lifelong morbidity it creates.
Objetivos: O MINI é uma entrevista diagnóstica padronizada breve (15-30 minutos), compatível com os critérios do DSM-III-R/IV e da CID-10, que é destinada à utilização na prática clínica e na pesquisa em atenção primária e em psiquiatria, e pode ser utilizada por clínicos após um treinamento rápido (de 1 a 3 horas). A versão Plus do MINI, mais detalhada, gera diagnósticos positivos dos principais transtornos psicóticos e do humor do DSM-IV. Este artigo apresenta os resultados de quatro estudos de validação do instrumento, realizados na Europa e nos EUA. Métodos: Os estudos 1 (França) e 2 (EUA) testaram a confiabilidade -entre avaliadores e teste-reteste -da versão DSM-III-R do MINI (n=84, sendo 42 pacientes psiquiátricos de cada centro) e sua validade com relação ao CIDI (n=346, sendo 296 pacientes psiquiátricos e 50 controles) e ao SCID-P (n=370, sendo 308 pacientes psiquiátricos e 62 controles), respectivamente. O estudo 3 testou a validade de diagnósticos gerados por clínicos gerais usando o MINI (DSM-IV) com relação aos diagnósticos clínicos habituais de psiquiatras, em 409 pacientes de centros de atenção primária de quatro países (França, Espanha, Itália e Reino Unido). O estudo 4 testou a confiabilidade entre avaliadores (n=20 pacientes psiquiátricos) e a validade dos módulos Transtornos Psicóticos, Depressão e Mania do MINI Plus - DSM IV (n=104 pacientes psiquiátricos) com relação a dois critérios de referência: diagnósticos do CIDI e diagnósticos clínicos de psiquiatras. Análises quantitativas (índices de concordância e de validade) e qualitativas (razões de discordância) foram realizadas. Resultados: Os índices de confiabilidade do MINI (estudos 1 e 2) e do MINI Plus (estudo 4) foram globalmente satisfatórios. Comparados a vários critérios de referência (CIDI, SCID-P, opinião de peritos), em diferentes contextos (unidades psiquiátricas e centros de atenção primária), o MINI e o MINI Plus mostraram qualidades psicométricas similares às de outras entrevistas diagnósticas padronizadas mais complexas, permitindo uma redução de 50% ou mais no tempo da avaliação. Análises qualitativas identificaram dificuldades e erros diagnósticos ligados aos casos, métodos de avaliação e critérios de diagnósticos estudados. Modificações foram introduzidas para corrigir os problemas identificados e otimizar as propriedades psicométricas do MINI e do MINI Plus. Conclusões: O MINI e sua versão Plus são adaptados ao contexto clínico e à avaliação de pacientes mais graves, e representam uma alternativa econômica para a seleção de pacientes, segundo critérios internacionais, em estudos clínicos e epidemiológicos. O MINI já está disponível em aproximadamente 30 idiomas, incluindo a versão brasileira. As perspectivas atuais de adaptação e aplicação transcultural do instrumento são discutidas.
Brazil never had segregation laws defining membership of an ethnoracial group. Thus, the composition of the Brazilian population is mixed, and its ethnoracial classification is complex. Previous studies showed conflicting results on the correlation between genome ancestry and ethnoracial classification in Brazilians. We used 370,539 Single Nucleotide Polymorphisms to quantify this correlation in 5,851 community-dwelling individuals in the South (Pelotas), Southeast (Bambui) and Northeast (Salvador) Brazil. European ancestry was predominant in Pelotas and Bambui (median = 85.3% and 83.8%, respectively). African ancestry was highest in Salvador (median = 50.5%). The strength of the association between the phenotype and median proportion of African ancestry varied largely across populations, with pseudo R(2) values of 0.50 in Pelotas, 0.22 in Bambui and 0.13 in Salvador. The continuous proportion of African genomic ancestry showed a significant S-shape positive association with self-reported Blacks in the three sites, and the reverse trend was found for self reported Whites, with most consistent classifications in the extremes of the high and low proportion of African ancestry. In self-classified Mixed individuals, the predicted probability of having African ancestry was bell-shaped. Our results support the view that ethnoracial self-classification is affected by both genome ancestry and non-biological factors.
b>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.
This manuscript is correspondence, there is no abstract.
In this paper we update the profile of the 1993 Pelotas (Brazil) Birth Cohort Study, with emphasis on a shift of priority
from maternal and child health research topics to four main categories of outcome variables, collected throughout adolescence:
(i) mental health; (ii) body composition; (iii) risk factors for non-communicable diseases (NCDs); (iv) human capital. We
were able to trace 81.3% (n = 4106) of the original cohort at 18 years of age. For the first time, the 18-years visit took place entirely on the university
premises, in a clinic equipped with state-of-the-art equipment for the assessment of body composition. We welcome requests
for data analyses from outside scientists. For more information, refer to our website (http://www.epidemio-ufpel.org.projetos_de_pesquisas/estudos/coorte_1993) or e-mail the corresponding author.
Kumanan Wilson and colleagues explain how the rapid response to XMRV as a novel pathogen has highlighted some challenges pertaining to policy-making and editorial responsibilities. The impact on policy and the propagation of the initial scientific information may not cease if the evidence is disproven and retracted from the peer-reviewed literature, which creates a challenge for regulators and scientific journals.
Please see later in the article for the Editors' Summary
Science advances on a foundation of trusted discoveries. Reproducing an experiment is one important approach that scientists use to gain confidence in their conclusions. Recently, the scientific community was shaken by reports that a troubling proportion of peer-reviewed preclinical studies are not reproducible. Because confidence in results is of paramount importance to the broad scientific community, we are announcing new initiatives to increase confidence in the studies published in Science . For preclinical studies (one of the targets of recent concern), we will be adopting recommendations of the U.S. National Institute of Neurological Disorders and Stroke (NINDS) for increasing transparency. * Authors will indicate whether there was a pre-experimental plan for data handling (such as how to deal with outliers), whether they conducted a sample size estimation to ensure a sufficient signal-to-noise ratio, whether samples were treated randomly, and whether the experimenter was blind to the conduct of the experiment. These criteria will be included in our author guidelines.
A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.