Childhood maltreatment and adult psychopathology: pathways to hypothalamic-pituitary-adrenal axis dysfunction

OBJECTIVE: The aim of this paper was to examine the relationship between childhood maltreatment and adult psychopathology, as reflected in hypothalamic-pituitary-adrenal axis dysfunction. METHOD: A selective review of the relevant literature was undertaken in order to identify key and illustrative research findings. RESULTS: There is now a substantial body of preclinical and clinical evidence derived from a variety of experimental paradigms showing how early-life stress is related to hypothalamic-pituitary-adrenal axis function and psychological state in adulthood, and how that relationship can be modulated by other factors. DISCUSSION: The risk for adult psychopathology and hypothalamic-pituitary-adrenal axis dysfunction is related to a complex interaction among multiple experiential factors, as well as to susceptibility genes that interact with those factors. Although acute hypothalamic-pituitary-adrenal axis responses to stress are generally adaptive, excessive responses can lead to deleterious effects. Early-life stress alters hypothalamic-pituitary-adrenal axis function and behavior, but the pattern of hypothalamic-pituitary-adrenal dysfunction and psychological outcome in adulthood reflect both the characteristics of the stressor and other modifying factors. CONCLUSION: Research to date has identified multiple determinants of the hypothalamic-pituitary-adrenal axis dysfunction seen in adults with a history of childhood maltreatment or other early-life stress. Further work is needed to establish whether hypothalamic-pituitary-adrenal axis abnormalities in this context can be used to develop risk endophenotypes for psychiatric and physical illnesses.OBJETIVO: A meta deste artigo foi a de estudar as relações ente maus-tratos na infância e psicopatologia no adulto, como reflexo de uma disfunção do eixo hipotálamo-pituitária-adrenal. MÉTODO: Uma revisão seletiva da literatura relevante foi feita para identificar achados-chave e ilustrativos. RESULTADOS: Existe atualmente um volume significativo de achados científicos pré-clínicos e clínicos derivados de paradigmas experimentais, que demonstram que o estresse precoce está relacionado à função do eixo hipotálamo-pituitária-adrenal e a estados psicológicos no indivíduo adulto, e como esta relação pode ser modulada por outros fatores. DISCUSSÃO: O risco para o desenvolvimento de psicopatologia no adulto e disfunções do eixo hipotálamo-pituitária-adrenal está relacionado à complexa interação de múltiplos fatores vivenciais, assim como a genes que levam a uma susceptibilidade, que interagem com estes fatores. Embora as respostas agudas do eixo hipotálamo-pituitária-adrenal sejam geralmente adaptativas, as respostas excessivas podem levar a efeitos deletérios. O estresse precoce pode alterar a função do eixo hipotálamo-pituitária-adrenal assim como o comportamento, porém, o padrão da disfunção do eixo hipotálamo-pituitária-adrenal e a evolução psicológica na vida adulta refletem ambas as características do estressor e outros fatores modificadores. CONCLUSÃO: A pesquisa atual identificou múltiplos determinantes da disfunção do eixo hipotálamo-pituitária-adrenal encontrados em adultos com história de maus-tratos na infância ou outros estressores precoces. Trabalhos futuros são necessários para estabelecer se as anormalidades do eixo hipotálamo-pituitária-adrenal neste contexto podem ser usadas para o desenvolvimento de endofenótipos de risco para doenças físicas ou psiquiátricas.Universidade Federal de São Paulo (UNIFESP) Instituto PROVEBrown University Warren Alpert Medical School Butler HospitalUNIFESP, Instituto PROVESciEL

Mechanisms of Perceived Treatment Assignment and Subsequent Expectancy Effects in a Double Blind Placebo Controlled RCT of Major Depression

Objective: It has been suggested that patients' perception of treatment assignment might serve to bias results of double blind randomized controlled trials (RCT). Most previous evidence on the effects of patients' perceptions and the mechanisms influencing these perceptions relies on cross-sectional associations. This re-analysis of a double blind, placebo controlled RCT of pharmacological treatment of major depression set out to gather longitudinal evidence on the mechanism and effects of patients' perceived treatment assignment in the pharmacological treatment of major depression.Methods: One-hundred eighty-nine outpatients with DSM-IV diagnosed major depression were randomized to SAMe 1,600–3,200 mg/d, escitalopram 10–20 mg/days, or placebo for 12 weeks. Data on depressive symptoms (17-item Hamilton Depression Scale; HDRS-17), adverse events and patients' perceived treatment assignment was collected at baseline, week 6, and week 12. The re-analysis focused on N = 166 (out of the originally included 189 participants) with available data on perceived treatment assignment.Results: As in the parent trial, depressive symptoms (HDRS-17) significantly decreased over the course of 12 weeks and there was no difference between placebo, SAMe or escitalopram. A significant number of patients changed their perceptions about treatment assignment throughout the trial, especially between baseline and week 6. Improvement in depressive symptoms, but not adverse events significantly predicted perceived treatment assignment at week 6. In turn, perceived treatment assignment at week 6, but not actual treatment, predicted further improvement in depressive symptoms at week 12.Conclusions: The current results provide longitudinal evidence that patients' perception of treatment assignment systematically change despite a double blind procedure and in turn might trigger expectancy effects with the potential to bias the validity of an RCT.Parent study grant number: R01 AT001638 Parent study ClinicalTrials. gov Identifier: NCT0010145

Prenatal stress, fearfulness, and the epigenome: Exploratory analysis of sex differences in DNA methylation of the glucocorticoid receptor gene.

Exposure to stress in utero is a risk factor for the development of problem behavior in the offspring, though precise pathways are unknown. We examined whether DNA methylation of the glucocorticoid receptor gene, NR3C1, was associated with experiences of stress by an expectant mother and fearfulness in her infant. Mothers reported on prenatal stress and infant temperament when infants were 5 months old (n = 68). Buccal cells for methylation analysis were collected from each infant. Prenatal stress was not related to infant fearfulness or NR3C1 methylation in the sample as a whole. Exploratory sex-specific analysis revealed a trend-level association between prenatal stress and increased methylation of NR3C1 exon 1F for female, but not male, infants. In addition, increased methylation was significantly associated with greater fearfulness for females. Results suggest an experience-dependent pathway to fearfulness for female infants via epigenetic modification of the glucocorticoid receptor gene. Future studies should examine prenatal stress in a comprehensive fashion while considering sex differences in epigenetic processes underlying infant temperament

The Nicotinic Acetylcholine Receptor as a Target for Antidepressant Drug Development

An important new area of antidepressant drug development involves targeting the nicotinic acetylcholine receptor (nAChR). This receptor, which is distributed widely in regions of the brain associated with depression, is also implicated in other important processes that are relevant to depression, such as stress and inflammation. The two classes of drugs that target nAChRs can be broadly divided into mecamylamine- and cytisine-based compounds. These drugs probably exert their effects via antagonism at α4β2 nAChRs, and strong preclinical data support the antidepressant efficacy of both classes when used in conjunction with other primary antidepressants (e.g., monoamine reuptake inhibitors). Although clinical data remain limited, preliminary results in this area constitute a compelling argument for further evaluation of the nAChR as a target for future antidepressant drug development

Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults.

A history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans.We examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test.Disruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05).These findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology

Do measures of healthy eating differ in survivors of early adversity?

Early life adversity has been linked to poor health, including obesity. Understanding the role of unhealthy food intake, may elucidate the importance of self-soothing behaviors in explaining the association between early life adversity and poor health in adulthood. The purpose of this study was to assess the association between early life adversity and dietary quality in a sample of adults from the Lifestyle Influences of Family Environment study. Early life adversity, demographic, and dietary data were obtained for 145 participants using formal interviews and two days of interviewer-administered 24-h recalls. Dietary quality was measured using the 2015 Healthy Eating Index (HEI) scoring algorithm to compute total and component scores. The association between early life adversity and dietary quality was assessed through linear regression and in models adjusted for age and sex. The mean ± SD HEI score for all participants was 54.6 ± 12.8. Individuals with early life adversity had a 4.51 lower overall HEI score when compared to those without early life adversity, 95% CI (0.35, 8.68). After adjusting for age and sex, early life adversity was associated with a 4.6 lower HEI score, 95% CI (0.45, 8.73). HEI component scores indicated that individuals with early life adversity were significantly more likely to have lower whole grain (0.7 versus 2.4) and total dairy (4.3 versus 6.1) scores compared to those without early life adversity. ELA was associated with lower measures of dietary quality. Results warrant future research on dietary and behavioral factors that underly the association between early life adversity and poor health outcomes