Antidepressant-like and Beneficial Effects of a Neoponcirin-Beta-Cyclodextrin Inclusion Complex in Mice Exposed to Prolonged Stress.

Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/ßCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/ßCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/ßCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice's expression of stress-related inflammatory cytokines (IL-1ß, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/ßCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/ßCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1ß levels. The effects of the NEO/ßCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.

Stress and cortisol responses in men: differences according to facial symmetry.

Stress response is associated with increased activity in the hypothalamic-pituitary-adrenocortical axis. Chronic stress-induced elevation in cortisol may alter its own negative regulation with multiple long-term consequences for physical and psychological health. One of the most reliable physical traits associated with mental, apparent physical health, and competitiveness is the degree of facial fluctuating asymmetry. However, to our knowledge there are no studies regarding the relationship between cortisol levels, facial symmetry and male competitiveness, and how cortisol changes after a stressful test depending on these traits. Here, a group of 100 college men were photographed to obtain their facial asymmetry levels. They then, answered the perceived stress scale and the intrasexual competition test and donated two saliva samples (pre-and post-test sample) to measure the change in their cortisol levels after a stressful test. We found that basal cortisol levels were positively correlated with both perceived stress and competitiveness, but not with facial fluctuating asymmetry. Cortisol levels increased in most symmetrical men after a short stressful test, but it decreased in most asymmetrical men. The results suggest differences in endocrine responses according to facial fluctuating asymmetry in men and how these responses could be related to the maintenance of social status.

[Cortisol reactivity and adult mental health in adults exposed to early violence: a systematic reviewReatividade do cortisol e saúde mental em adultos com exposição precoce à violência: uma revisão sistemática]. / Reactividad del cortisol y salud mental en adultos expuestos a violencia temprana: revisión sistemática.

OBJECTIVE: Analyze results with respect to cortisol reactivity (CR) in experimental stress paradigms in adults with or without a psychiatric disorder who suffered violence in early developmental stages (infancy or early adolescence); and use these results to propose a clinical tool to determine biological stress indicators. METHODS: A systematic review was conducted using several databases and following PRISMA criteria; of a total of 231 articles, 16 satisfied the inclusion criteria and the results were analyzed qualitatively. RESULTS: Despite heterogeneity, the results suggested that the people who suffered violence at an early age present a pattern of low CR. In contrast, people who also developed symptoms of post-traumatic stress disorder and depression, regardless of the type of violence, showed increased CR. The majority of studies focused on people who suffered childhood sexual abuse and half of the articles supported the hypothesis that CR is more pronounced in men than in women. CONCLUSIONS: The results of this review suggest that cortisol hyperreactivity can be considered a biomarker for treatment and intervention in people with post-traumatic stress disorder and depression who suffered violence at an early age. The results also support evidence that experiencing violence alters stress response and mental health in the long term. However, it is necessary to conduct more studies, in particular studies on hyporeactivity and gender differences.

OBJETIVO: Analisar os resultados da reatividade do cortisol segundo um modelo de estresse experimental em adultos com ou sem transtorno psiquiátrico que foram precocemente expostos à violência durante o desenvolvimento (infância e início da adolescência) e propor um instrumento clínico para determinar indicadores biológicos de estresse. MÉTODOS: Uma revisão sistemática foi conduzida em diferentes bases de dados conforme os critérios PRISMA. Dos 231 artigos selecionados, 16 satisfizeram os critérios de inclusão. Foi realizada uma análise qualitativa dos resultados. RESULTADOS: Apesar de serem heterogêneos, os resultados indicam que adultos com exposição precoce à violência apresentam baixa reatividade do cortisol. De maneira oposta, os indivíduos que desenvolveram sintomas de transtorno de estresse pós-traumático e depressão, independentemente do tipo de violência sofrida, apresentaram elevada reatividade do cortisol. A maioria dos estudos se centrou em vítimas de abuso sexual na infância e, em metade dos artigos, sustentou-se a hipótese de que a reatividade do cortisol é mais acentuada no sexo masculino que no feminino. CONCLUSÕES: Os resultados deste estudo de revisão apontam que se pode considerar a hiper-reatividade do cortisol como biomarcador para o tratamento e a intervenção de pacientes que foram expostos precocemente à violência e que apresentam transtorno de estresse pós-traumático e depressão. Além disso, é reforçada a evidência de que sofrer violência afeta a resposta ao estresse e a saúde mental a longo prazo. Porém, fazem-se necessários mais estudos, sobretudo investigando hiporreatividade e diferenças de gênero.

The Comparative Effect of Occupational and Musical Enrichment on Fecal Glucocorticoid Metabolite Levels in a Captive Colony of Stumptail Macaques (Macaca arctoides).

Environmental enrichment improves captive animal welfare by reducing stress-related behaviors. Previous studies in a captive colony of stumptail macaques (Macaca arctoides) reported a reduction of aggression, coprophilia, and stereotypic behaviors after an occupational enrichment program; however, the effect on stress hormones such as glucocorticoids has not been investigated yet. The goal of this study was to compare the effect of sex, age, and social rank on changes in fecal glucocorticoid metabolites (fGCM) after applying two kinds of enrichments (occupational vs. musical) in a captive colony of stumptail macaques. We collected 234 fecal samples from 25 stumptail macaques under the following conditions: (1) basal (no enrichment), (2) three weeks of occupational enrichment, and (3) three weeks of relaxing/classical music. The Generalized Estimated Equation Model showed an increase in fGCM levels after the occupational enrichment only in adult subjects (p = 0.003 compared to basal). The fGCM levels reached by the adults after the occupational enrichment was higher than that of juveniles (p = 0.002) and subadults (p = 0.02). Occupational and musical enrichment decreased fGCM levels only in middle-ranking individuals (p < 0.001 and p = 0.013, respectively). No sex differences were found. In conclusion, there were age and rank differences in individuals' physiological reactivity to the effects of environmental enrichment which need to be considered when planning enrichment programs.

Testing the Challenge Hypothesis in Stumptail Macaque Males: The Role of Testosterone and Glucocorticoid Metabolites in Aggressive and Mating Behavior.

The "challenge hypothesis" predicts higher male-male aggressive behavior along with increases in testosterone levels during times of reproductive challenges and social instability. In addition, in some primate species, higher glucocorticoid levels can be observed as well, but this is usually modulated by dominance rank. We studied rank-related aggressive behavior, mating activity, and fecal testosterone and glucocorticoid metabolites (fTm and fGCm) in male stumptail macaques (Macaca arctoides) in order to test some predictions of the "challenge hypothesis". Over a 20-month period, we collected data on aggressive behavior and copulation, as well as fecal samples (n = 700) to quantify fTm and fGCm in seven adult stumptail males living in captivity. During periods of mating activity, male-to-male aggression increased in higher- and middle-ranking males. Neither fTm nor fGCm levels predicted male-to-male aggression. fGCm levels (but not fTm) were positively associated with male-to-female aggression; however, this association was pronounced during periods of mating activity. fGCm levels differed according to social rank, with middle-ranking males having the highest levels. Both hormones were higher during periods of mating activity, but only in higher- and middle-ranking males. Taken together, our findings partially support the challenge hypothesis in a non-seasonal primate and shed some light on the unique social and mating system of the stumptail macaque.

Psychopathology, cortisol and testosterone responses to traumatic images: differences between urban and suburban citizens in a middle-income country.

Background: Living in urban places has been associated with a higher risk of psychopathology as well as with altered hypothalamus-pituitary-adrenal (HPA) axis and consequently altered cortisol response, but studies have concentrated mainly in high-income countries population. The role of other hormones such as testosterone, implicated in stress response and with human social behaviors, have not yet been investigated. The aim of this study was to compare symptoms of psychopathology as well as cortisol and testosterone in response to traumatic images between urban and suburban people in a middle-income country. Methods: A sample of 67 women and 55 men (N = 122, 18-45 years) from urban and suburban places of Mexico participated in the study. We quantified salivary cortisol and testosterone in response to images with traumatic and violent content (basal, 15, 30, and 45 min after images). Participants answered a general information questionnaire and the Symptom Checklist-90-R to assess their psychopathological traits. We performed Generalized Estimating Equation Models to analyze hormonal levels and MANOVAs to compare differences in participants' psychopathology symptoms. Area under the curve respect to ground (AUCG) of hormonal levels and sex differences were also compared. Results: Suburban citizens showed no cortisol response, whereas urban people showed a cortisol peak 15 min after the image's exposure; however, suburban people had higher AUCG and basal levels compared to urban ones. Contrastingly, testosterone levels declined in all participants excepting the urban women, who showed no testosterone response. Although similar testosterone profile, AUCG levels were higher in urban than suburban men. Participants living in suburban areas had higher scores of somatizations, obsessive-compulsive, and interpersonal sensitivity, as well as more sleep disorders than participants living in urban areas. Conclusion: This study offers novel evidence about differences in cortisol and testosterone responses to a social stressor and in mental health indicators between a population of urban and suburban citizens, highlighting the impact of urbanization process on physiological and psychological outcomes in a middle-income country.

Antidepressant-like effects of a methanol extract of Leonotis nepetifolia in mice.

This study evaluated the antidepressant-like effects of a methanol extract of Leonotis nepetifolia in behavioural tests in mice. Our results showed that a single administration of the extract significantly reduced immobility behaviour in the tail suspension test, while three administrations were necessary to diminish immobility behaviour in the forced swimming test. A daily dose of the extract for 28 days improved body weight gain and significantly reduced corticosterone levels of mice exposed to chronic unpredictable mild stress. Metabolic profiling of the extract revealed that nepetaefolin, methoxynepataefolin, and 7-O-ß-glucoside luteolin were the main products. Acute and repeated administration of the extract produced antidepressant-like effects in animals subjected to chronic stress. Our results suggest the hypothalamus-hypophysis-adrenal axis participates in the antidepressant actions of the extract. These results show that alterations in behaviour elicited by stress can be prevented with L. nepetifolia treatment.

Increased Cortisol Response and Low Quality of Life in Women Exposed to Intimate Partner Violence With Severe Anxiety and Depression.

Background: Intimate partner violence (IPV) is one of the most prevalent forms of violence against women globally and it is considered a public health problem. Because the experience of IPV is stressful and traumatic for victims, they are at high risk of developing alteration of the Hypothalamus-Pituitary-Adrenal (HPA) axis functioning as well as anxiety and depression symptoms. The aim of this study was to compare the quality of life and changes in cortisol response to an acute stressor between women exposed to IPV and non-exposed women. Differences according to symptoms of anxiety and depression including the risk of suicide thoughts, were also analyzed. Method: Our sample size consisted of 130 women (ages 18-68) grouped as follows: 71 women experiencing IPV and 59 women without history of IPV as control group. All participants completed a battery of questionnaires including IPV exposure, anxiety, and depression symptoms (Beck Inventories), as well as quality of life (WHOQOL-BREF). Salivary cortisol levels in response to a cognitive test with verbal, mathematical, and abstract reasoning were measured at four time points. Results: Women exposed to IPV, with severe anxiety and depression symptoms as well as suicide thoughts, exhibited heightened cortisol response after the cognitive test and reported lower quality of life compared to (i) women experiencing IPV with moderate symptoms of anxiety and depression, who showed a blunted response, and (ii) women without history of IPV with minimal to moderate symptoms, who showed a decreased cortisol profile. Social relationships dimension was in particular the most affected aspect of quality of life. Conclusions: Our findings highlight the role of cortisol responses as a complementary biological marker to be associated with severe psychiatric disturbances in women exposed to IPV.

Chronic Social Defeat During Adolescence Induces Short- and Long-Term Behavioral and Neuroendocrine Effects in Male Swiss-Webster Mice.

Chronic stress exposure during adolescence is a significant risk factor for the development of depression. Chronic social defeat (CSD) in rodents is an animal model of depression with excellent ethological, predictive, discriminative, and face validity. Because the CSD model has not been thoroughly examined as a model of stress-induced depression within the adolescence stage, the present study analyzed the short- and long-term behavioral and neuroendocrine effects of CSD during early adolescence. Therefore, adolescent male Swiss-Webster (SW) mice were exposed to the CSD model from postnatal day (PND) 28 to PND37. Twenty-four hours (mid-adolescence) or 4 weeks (early adulthood) later, mice were tested in two models of depression; the social interaction test (SIT) and forced swimming test (FST); cognitive deficits were evaluated in the Barnes maze (BM). Finally, corticosterone and testosterone content was measured before, during, and after CSD exposure, and serotonin transporter (SERT) autoradiography was studied after CSD in adolescent and adult mice. CSD during early adolescence induced enduring depression-like behaviors as inferred from increased social avoidance and immobility behavior in the SIT and FST, respectively, which correlated in an age-dependent manner with SERT binding in the hippocampus; CSD during early adolescence also induced long-lasting learning and memory impairments in the Barnes maze (BM). Finally, CSD during early adolescence increased serum corticosterone levels in mid-adolescence and early adulthood and delayed the expected increase in serum testosterone levels observed at this age. In conclusion: (1) CSD during early adolescence induced long-lasting depression-like behaviors, (2) sensitivity of SERT density during normal brain development was revealed, (3) CSD during early adolescence induced enduring cognitive deficits, and (4) results highlight the vulnerability of the adolescent brain to social stressors on the adrenal and gonadal axes, which emphasizes the importance of an adequate interaction between both axes during adolescence for normal development of brain and behavior.

Calea zacatechichi Schltdl. (Compositae) produces anxiolytic- and antidepressant-like effects, and increases the hippocampal activity during REM sleep in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.

Choosing Fighting Competitors Among Men: Testosterone, Personality, and Motivations.

Higher testosterone levels have been positively related to a variety of social behaviors and personality traits associated with intrasexual competition. The aim of this study was to evaluate the role of testosterone levels and personality traits such as aggressiveness, competitiveness, and self-esteem on the task of choosing a fighting competitor (a rival) with or without a motivation to fight. In Study 1, a group of 119 men participated in a task for choosing a rival through pictures of men with high-dominant masculinity versus low-dominant masculinity. Participants completed three personality questionnaires and donated two saliva samples (pre-test and post-test sample) to quantify their testosterone levels. We found that the probability of choosing high-dominant masculine men as rivals increased with higher aggressiveness scores. In Study 2, the task of choosing rivals was accompanied by motivations to fight (pictures of women with high or low waist-to-hip ratio [WHR]). In this context, we observed that the probability of choosing dominant masculine men as rivals depended on the WHR of the women. Overall, average levels of post-test testosterone, aggressiveness, and high self-esteem increased the probability to fight for women with low WHR independently of the dominance masculinity of the rivals. Our results indicate that human decisions, in the context of intrasexual competition and mate choice, are regulated by physiological and psychological mechanisms allowing men to increase their biological fitness. We discuss our results in the light of the plasticity of human behavior according to biological and environmental forces.

Comparison of two psychotherapies in cortisol response and their efficacy in reducing symptoms of anxiety and depression in women victims of intimate partner violence / Comparación de dos psicoterapias en la respuesta del cortisol y en su eficacia para reducir los síntomas de ansiedad y depresión en mujeres víctimas de violencia de pareja

Abstract Introduction There is a growing need to implement evidence-based psychological treatments for women victims of intimate partner violence (IPV) who commonly experience stress-related disorders such as anxiety, depression, or suicide risk, as well as altered cortisol reactivity. Objective 1. To compare the changes in depressive and anxious symptomatology, quality of life, and cortisol reactivity after two different interventions, Acceptance and Commitment Therapy (ACT, based on psychological flexibility) or Interpersonal Therapy (IPT, based on empowerment) in women exposed to IPV. 2. To compare the changes in relation to the presence of suicide thoughts. Method A clinical sample of 50 women (ages 21-74) randomly assigned to attend ACT or IPT, completed pre- and post-intervention questionnaires about intimate partner violence, quality of life, depression, anxiety, and measurements of salivary cortisol reactivity (basal, 15, 30, and 45 minutes after a cognitive challenge). We used Generalized Estimating Equation Models for data analysis. Results There was a significant improvement post-intervention in all variables, regardless of the type of psychotherapy or the presence of suicide thoughts. Before interventions, women that reported suicide thoughts had severe symptoms of depression, anxiety, worse quality of life, and a cortisol hyper-response profile, in contrast to women without suicide thoughts who had moderate symptoms and no cortisol response. Cortisol response to the cognitive test decreased in all women after both therapies. Discussion and conclusion Although different psychological approach, ACT, and IPT effectively improved mental health, quality of life, and changed cortisol reactivity of women exposed to IPV, including women at suicide risk.

Resumen Introducción Son necesarios tratamientos basados en evidencia para mujeres víctimas de violencia de pareja (IPV), con trastornos relacionados con estrés como ansiedad, depresión y riesgo suicida y alteraciones en la reactividad del cortisol. Objetivo Comparar los cambios en la sintomatología depresiva, ansiosa, calidad de vida y reactividad del cortisol después de aplicar Terapia de Aceptación y Compromiso (ACT, basada en la flexibilidad psicológica) o Terapia Interpersonal (IPT, basada en el empoderamiento) en mujeres expuestas a IPV y compararlos en función al pensamiento suicida. Método Una muestra clínica de 50 mujeres (entre 21 y 74 años) fueron asignadas aleatoriamente a recibir ACT o IPT, completaron antes y después, cuestionarios sobre IPV, calidad de vida, depresión y ansiedad, y mediciones de cortisol (basal, 15, 30 y 45 minutos después de un reto cognitivo) en saliva en respuesta a un reto cognitivo. Utilizamos modelos de Ecuaciones de Estimación generalizada para analizar los datos. Resultados Mejoraron significativamente todas las variables, independientemente del tipo de psicoterapia y del pensamiento suicida. Antes de la intervención, las mujeres con ideación suicida presentaron depresión y ansiedad severas, peor calidad de vida e hiper-respuesta de cortisol, en contraste con las mujeres sin ideación, quienes presentaron síntomas moderados y una respuesta de cortisol plana. El cortisol disminuyó en todas las mujeres después de ambas terapias. Discusión y conclusión Ambas terapias IPT y ACT mejoraron la salud mental y calidad de vida de las mujeres con IPV y modificaron la reactividad del cortisol, incluyendo a las pacientes que reportaron ideación suicida.

Reactividad del cortisol y salud mental en adultos expuestos a violencia temprana: revisión sistemática / Cortisol reactivity and adult mental health in adults exposed to early violence: a systematic review / Reatividade do cortisol e saúde mental em adultos com exposição precoce à violência: uma revisão sistemática

RESUMEN Objetivo Analizar los resultados con respecto a la reactividad del cortisol (RC) ante un paradigma de estrés experimental en adultos con o sin algún trastorno psiquiátrico que sufrieron violencia en etapas tempranas de desarrollo (infancia y adolescencia temprana) y con ello proponer una herramienta clínica para el establecimiento de indicadores biológicos de estrés. Métodos Se realizó una revisión sistemática en diversas bases de datos, siguiendo los criterios PRISMA; de un total de 231 artículos, 16 cumplieron los criterios de inclusión y los resultados fueron analizados de manera cualitativa. Resultados A pesar de la heterogeneidad, los resultados sugieren que las personas que sufrieron violencia temprana presentan un patrón de baja RC. Contrariamente, la población que además desarrolló síntomas de trastorno de estrés postraumático y depresión, independientemente del tipo de violencia, mostró incrementada RC. La mayoría de los trabajos se centraron en población que sufrió abuso sexual en la infancia y la mitad de los artículos apoya la hipótesis de que la RC es más pronunciada en hombres que en mujeres. Conclusiones Los resultados de esta revisión nos permiten sugerir que es posible considerar la hiperreactividad del cortisol como un biomarcador para el tratamiento e intervención de población con trastorno de estrés postraumático y depresión que sufrieron violencia temprana. Además, apoyan la evidencia de que sufrir violencia altera la respuesta del estrés y la salud mental a largo plazo. Sin embargo, es necesario realizar más estudios principalmente los que se refieren a la hiporreactividad y a las diferencias de género.

ABSTRACT Objective Analyze results with respect to cortisol reactivity (CR) in experimental stress paradigms in adults with or without a psychiatric disorder who suffered violence in early developmental stages (infancy or early adolescence); and use these results to propose a clinical tool to determine biological stress indicators. Methods A systematic review was conducted using several databases and following PRISMA criteria; of a total of 231 articles, 16 satisfied the inclusion criteria and the results were analyzed qualitatively. Results Despite heterogeneity, the results suggested that the people who suffered violence at an early age present a pattern of low CR. In contrast, people who also developed symptoms of post-traumatic stress disorder and depression, regardless of the type of violence, showed increased CR. The majority of studies focused on people who suffered childhood sexual abuse and half of the articles supported the hypothesis that CR is more pronounced in men than in women. Conclusions The results of this review suggest that cortisol hyperreactivity can be considered a biomarker for treatment and intervention in people with post-traumatic stress disorder and depression who suffered violence at an early age. The results also support evidence that experiencing violence alters stress response and mental health in the long term. However, it is necessary to conduct more studies, in particular studies on hyporeactivity and gender differences.

RESUMO Objetivo Analisar os resultados da reatividade do cortisol segundo um modelo de estresse experimental em adultos com ou sem transtorno psiquiátrico que foram precocemente expostos à violência durante o desenvolvimento (infância e início da adolescência) e propor um instrumento clínico para determinar indicadores biológicos de estresse. Métodos Uma revisão sistemática foi conduzida em diferentes bases de dados conforme os critérios PRISMA. Dos 231 artigos selecionados, 16 satisfizeram os critérios de inclusão. Foi realizada uma análise qualitativa dos resultados. Resultados Apesar de serem heterogêneos, os resultados indicam que adultos com exposição precoce à violência apresentam baixa reatividade do cortisol. De maneira oposta, os indivíduos que desenvolveram sintomas de transtorno de estresse pós-traumático e depressão, independentemente do tipo de violência sofrida, apresentaram elevada reatividade do cortisol. A maioria dos estudos se centrou em vítimas de abuso sexual na infância e, em metade dos artigos, sustentou-se a hipótese de que a reatividade do cortisol é mais acentuada no sexo masculino que no feminino. Conclusões Os resultados deste estudo de revisão apontam que se pode considerar a hiper-reatividade do cortisol como biomarcador para o tratamento e a intervenção de pacientes que foram expostos precocemente à violência e que apresentam transtorno de estresse pós-traumático e depressão. Além disso, é reforçada a evidência de que sofrer violência afeta a resposta ao estresse e a saúde mental a longo prazo. Porém, fazem-se necessários mais estudos, sobretudo investigando hiporreatividade e diferenças de gênero.