Neurobiological understanding of suicide

Suicide is a complex phenomenon resulting from interactions between individual vulnerabilities and socio-environmental factors. The current review primarily focuses on research into the serotonin system, hypothalamic-pituitary-adrenal axis, neurotrophic factors, lipid metabolism, and functional neuroimaging studies. It has been found that dysfunctions in the serotonin system, hypothalamic-pituitary-adrenal axis abnormalities, and low brain-derived neurotrophic factor and cholesterol levels may be linked to suicide. Additionally, recent neuroimaging studies have suggested that structural and functional abnormalities in brain areas related to cognitive and emotional regulation may be associated with suicide. More research incorporating advanced methodological approaches may shed further light on the neurobiological basis of suicide.

Nueva teoría sobre la depresión: un equilibrio del ánimo entre el sistema nervioso y el inmunológico, con regulación de la serotonina-quinurenina y el eje hipotálamo-hipófiso-suprarrenal / A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamic-pituitary-adrenal axis

La hipótesis sobre las causas de la depresión basada en la acción de la serotonina y del sistema inmunológico, propone que ciertos tipos de estrés distorsionan la relación entre la actividad del sistema inmunitario innato y la del sistema nervioso central. El estrés causado por una infección o el estrés psicológico excesivo activan receptores de tipo toll, como el TLR-4, el factor de transcripción NF-kB, el inflamasoma NLRP3, así como la secreción de interleucina 1 beta (IL-1ß) e interleucina 6 (IL-6); esto causa, en primer lugar, los síntomas generales de enfermedad que aparecen con cualquier infección, pero también los síntomas característicos de la depresión como disforia y anhedonia. Las evidencias indican que, si el estímulo persiste o se repite en las siguientes 24 horas, se activa la enzima indolamina 2,3-dioxigenasa (IDO) de la vía metabólica de la quinurenina, lo cual incrementa la síntesis del ácido quinolínico y reduce la síntesis de serotonina. El ácido quinolínico activa los receptores de N-metil-D-aspartato (NMDA) en el sistema nervioso central y estimula la secreción de, entre otras, las interleucinas IL-6 e 1L-1ß, las cuales promueven la hiperactividad del eje hipotálamohipófiso-suprarrenal y refuerzan la desviación del metabolismo del triptófano hacia la producción de ácido quinolínico, así como de las interleucinas de la inmunidad innata, con lo cual se reduce más la síntesis de serotonina y se consolida el proceso depresivo. Este proceso puede ser iniciado por las interleucinas estimuladas por una infección, así como por algunas vacunas o por un estrés psicológico excesivo que active el eje hipotálamo-hipófiso-suprarrenal simultáneamente con la respuesta inmunológica innata, con lo que se provocaría un proceso de inflamación estéril en el sistema nervioso central.

The serotonergic and immunological hypothesis of depression proposes that certain types of excessive stress distort the relationship between the activities of the innate immune and central nervous systems, so that the stress caused by an infection, or excessive psychological stress, activate toll-like receptors such as the TLR-4, the transcription factor NF-kB, the inflammasome NLRP3, as well as the secretion of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and other factors of the innate immune response, causing first, the general symptoms of the disease which appear with any infection, but also those characteristic of depressive illness such as dysphoria and anhedonia. The evidence indicates that, if the stimulus persists or recurs within 24 hours, the indole-2, 3-dioxygenase enzyme (IDO) of the kynurenine metabolic pathway, which increases the synthesis of quinolinic acid, is activated with an associated reduction of serotonin synthesis. Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1ß, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system.

Basal cortisol levels and the relationship with clinical symptoms in multiple sclerosis: a systematic review / Níveis de cortisol basal e a relação com sintomas clínicos na esclerose múltipla: uma revisão sistemática

ABSTRACT Multiple sclerosis (MS) is a demyelinating, progressive and neurodegenerative disease. A disturbance on the hypothalamic-pituitary-adrenal axis can be observed in patients with MS, showing altered cortisol levels. We aimed to identify basal cortisol levels and verify the relationship with clinical symptoms in patients with MS. A systematic search was conducted in the databases: Pubmed, Web of Science and SCOPUS. Both higher and lower cortisol levels were associated with MS. Higher cortisol levels were associated with depression and anxiety, while lower levels were associated with depression, fatigue and urinary dysfunction. Higher cortisol levels may be associated with the progression and severity of MS.

RESUMO A esclerose múltipla (EM) é uma doença desmielinizante, progressiva e neurodegenerativa. Um distúrbio no eixo hipotálamo-hipófise-adrenal pode ser observado em pacientes com EM, mostrando níveis alterados de cortisol. Nosso objetivo foi identificar os níveis basais de cortisol e verificar a relação com os sintomas clínicos em pacientes com EM. Uma busca sistemática foi realizada nas bases de dados: Pubmed, Web of Science e SCOPUS. Ambos os níveis de cortisol elevado e baixo foram associados com a EM. Níveis mais elevados de cortisol foram associados à depressão e ansiedade, enquanto níveis mais baixos foram associados à depressão, fadiga e disfunção urinária. Níveis altos de cortisol podem estar associados à progressão e gravidade da EM.

Effects of endogenous glucocorticoid deprivation on immune response of allergic rhinitis in mice / 中华耳鼻咽喉头颈外科杂志

Objective@#To study the effect of dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis on the pathogenesis of allergic rhinitis (AR) by the mouse model of decreased endogenous glucocorticoid (GC) after adrenalectomy, and further explore the mechanism of neural-endocrine regulation.@*Methods@#According to literatures, adrenalectomized (ADX) mice and AR model were established. Eighty mice were randomly divided into four groups (n=20 per group) including control group, AR group of normal mice (AR group), AR group of bilateral ADX (bilateral ADX/AR group) and AR group of unilateral ADX (unilateral ADX/AR group). In order to assess the model of ADX, adrenal gland tissue was assayed by HE staining and the plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) concentrations were measured by enzyme-linked immunosorbent assay (ELISA). The behavioral observation, OVA-sIgE assessments and count of eosinophils/mast cells by the HE/Toluidine Blue staining of nasal septum mucosa tissue were performed to evaluate the AR model. The expression of peripheral blood CD4+ IL4+ T cells (Th2 cells) and CD4+ IFN-γ+ T cells (Th1 cells), splenocytes of CD4+ CD25+ Treg cells (Treg cells) were measured by flow cytometry to study the influence of endogenous GC on immunological indexes in different groups of mice. SPSS 16.0 software was used to analyze the data.@*Results@#The concentrations of OVA-sIgE in control group, AR group, bilateral ADX/AR group and unilateral ADX/AR group mice were (28.86±3.62) ng/ml, (76.27±16.47) ng/ml, (48.37±8.89) ng/ml, (49.86±7.19) ng/ml, respectively. There was statistically significant difference between control group and AR group (t=7.09, P<0.05), AR group and bilateral ADX/AR group (t=4.81, P<0.05), AR group and unilateral ADX/AR group (t=5.21, P<0.05). The level of Th2 cells in different four groups were (0.71±0.24)%, (7.03±1.95)%, (2.44±2.06)%, (3.20±1.21)%, respectively. There was statistically significant difference between control group and AR group (t=-2.93, P<0.05), AR group and bilateral ADX/AR group (t=-4.67, P<0.05), AR group and unilateral ADX/AR group (t=-3.61, P<0.05). The expression of Th2 in bilateral ADX/AR group is lower than that in unilateral ADX/AR group without significant difference (t=4.39, P>0.05). Meanwhile, the level of Th1 cells in different four groups was (0.58±0.76)%, (0.57±0.59)%, (0.72±0.34)%, (1.03±0.32)%, respectively, with no significant difference among these groups. The proportion of Treg cells was (11.10±2.18)%, (4.10±1.07)%, (7.15±0.92)%, (4.58±1.05)%, respectively, with significant difference between control and other groups (t value was -7.171, -8.273, -8.360, respectively, all P<0.05). Compared with AR group, Treg cells increased significantly in bilateral ADX/AR group (t=-2.607, P<0.05). In addition, lower expression of eosinophil and mast cell were detected in the local nasal tissue of bilateral ADX/AR group, and mast cell degranulation wasn′t be observed.@*Conclusion@#Unilateral or bilateral ADX leads to HPA axis dysfunction and endogenous GC deprivation, possibly regulating the mechanism of AR through Th1/Th2 immune bias and Tregs cell′ activity.

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.

La separación materna durante la lactancia altera los niveles basales del sistema neuroendocrino en ratas adolescentes y adultas / Maternal separation during nursing alters basal neuroendocrine levels in juvenile and adult rats

Introducción. En diversos modelos animales, incluido el de la separación materna durante la lactancia, se ha demostrado que las experiencias tempranas adversas, como el maltrato, el abandono materno y el estrés psicosocial, pueden favorecer el desarrollo de algunas enfermedades mentales, pero no se han descrito completamente varios de los cambios que se producen en el sistema neuroendocrino. Objetivo. Determinar si la separación materna durante la lactancia modificaba los niveles basales de neurohormonas como la corticosterona, la corticotropina (ACTH), la oxitocina y la vasopresina (ADH), en ratas jóvenes (35 días) y adultas (90 días). Materiales y métodos. Se separaron ratas Wistar de sus madres durante dos periodos de tres horas diarias a lo largo de los 21 días de lactancia. A los 35 y 90 días se tomaron muestras de los grupos de las ratas de control y de las separadas de la madre, para obtener el suero y posteriormente medir cada una de las hormonas mediante un ensayo inmunoenzimático. Resultados. Las concentraciones de corticosterona fueron mayores en las hembras adultas de control que en el resto de los grupos, y menores en los machos adultos de control. Las de ACTH fueron mayores en los machos y hembras jóvenes separadas de la madre que en los grupos de adultos. Los niveles de oxitocina fueron significativamente mayores en las hembras adultas separadas de la madre que en los otros grupos y significativamente menores en los machos adultos. En cuanto a la vasopresina, los grupos separados de la madre tuvieron concentraciones menores, en comparación con los grupos de jóvenes y adultos de control. Conclusiones. Estos resultados muestran que el estrés temprano al que fueron sometidas las ratas, produjo cambios en las respuestas del eje hipotálamo-hipófisis-suprarrenal, las cuales variaron según el sexo y la edad.

Introduction: Work with different animal models including that of maternal separation during nursing has shown that early adverse experiences such as abuse, maternal abandonment and psychosocial stress may favor the development of various psychopathologies. However, several neuroendocrine changes have not been completely described yet. Objective: To establish whether maternal separation during nursing modifies the basal levels of neurohormones such as corticosterone, ACTH, oxytocin and vasopressin in juvenile and adult rats (aged 35 and 90 days, respectively). Materials and methods: Wistar rats were separated from their mothers for two periods of 3 hours per day during the 21 days of nursing. Once these rats had reached 35 and then 90 days of age, blood samples were taken from both the separated and control groups to obtain serum for immunoenzymatic assays and measure the levels of each of the hormones. Results: Concentrations of corticosterone were higher in control adult females in comparison with the rest of the groups and lower in the control adult males. Those of ACTH were higher in the separated young males and females than in the adult groups. Oxytocin levels were significantly higher in the separated adult females in comparison with the other groups and significantly lower in the adult males. With respect to vasopressin, the separated groups had lower concentrations than the young and adult control groups. Conclusions: These results show that the early stress to which rats were submitted produced changes in the basal responses of the hypothalamic-pituitary-adrenal axis, that these responses were distinct in males and females and that they also differed according to age.

Evaluación de la función del eje hipotálamo-hipófisis-adrenal en niños tratados con esteroides / Evaluation of hypothalamic-pituitary-adrenal axis function in children treated with steroids

El uso frecuente de medicamentos esteroideos constituye un riesgo de supresión del eje hipotálamo-hipófisis-adrenal, en particular si el tratamiento se usa por más de cuatro semanas. El retiro planeado del medicamento y la evaluación oportuna mediante la prueba corta de estimulación con hormona adrenocorticotrópica permiten identificar los niños en riesgo de presentar una crisis o una insuficiencia adrenal, como también establecer la necesidad de suplementar a los pacientes con esteroides durante situaciones de estrés. En este artículo de revisión se describen los efectos de los esteroides sobre el eje hipotálamo-hipófisis-adrenal en pacientes pediátricos, los esquemas de retiro gradual de los esteroides y las pruebas para evaluar la función del eje hipotálamo-hipófisis-adrenal en dichos pacientes.

The frequent use of steroid drugs is considered a risk for suppression of the hypothalamic-pituitary-adrenal axis, especially if the treatment is given for longer than four weeks. Planned withdrawal of the drug and timely assessment with a short adrenocorticotropic hormone stimulation test can aid in the identification of patients at risk for adrenal crisis or insufficiency, and also helps establish if patients need steroid supplementation during periods of increased stress. In this review article the effects that steroids have over the hypothalamic-pituitary-adrenal axis are described as well as the various schemes of graduated steroid withdrawal, and the laboratory tests to evaluate the function of the hypothalamic-pituitary-adrenal axis in such patients.

Evaluation of hypothalamic-pituitary-adrenal axis in patients with atopic dermatitis.

Background: Most of the research on atopic dermatitis (AD) has focused on the pathophysiological role of the immune system in AD, and the role of endocrine signals in the pathology of AD has not been explored. Current research has shown a link between the neuroendocrine and immune functions. Aim: The aim was to measure the serum basal cortisol levels and cortisol levels following a low-dose ACTH stimulation test in patients with AD before and after treatment with corticosteroids. Methods: Three groups of patients with AD were evaluated: mild, moderate, and severe. Basal cortisol levels following an ACTH stimulation test were measured before and after treatment with topical steroids when an improvement in the disease activity by 75% as determined by the SCORAD index was observed. Results: Eighteen patients of the severe group at baseline showed an impaired hypothalamic-pituitary-adrenal (HPA) axis with cortisol levels <250 nmol/l during their first visit. A total of 13 of 18 patients regained their HPA axis activity when the baseline cortisol was measured after using topical corticosteroids which resulted in 75% improvement in the disease activity. Conclusions: The disease activity rather than the use of topical costicosteroids is responsible for the low basal levels in patients with severe AD.

The role of psychological stress and the hypothalamic pituitary adrenal axis in the pathophysiology of central serous chorioretinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

Central serous chorioretinopathy (CSC) is characterized by serous detachment of the sensory retina as a consequence of the focal leakage of fluid from the choriocapillaries to subretinal space through a defect of the retinal pigment epithelium(RPE). The exact cause of CSC is not well unknown. Psychological stress is thought to contribute to CSC, but the physiologic mechanisms are unclear. It is hypothesized that psychological stress can induce CSC through the mechanism of the hypothalamic-pituitary-adrenal (HPA) system. Psychological stress can adversely affect HPA axis and causes glucocorticoid levels to elevate. Increased glucocorticoids constrict choroid vessels, which leads to ischemia of choroids and damage vascular endothelial cells, thus causing vasopermeability to increase. RPE dysfunction will occur as a result of abnormalities in the choroidal circulation. The large molecules including protein may enter the subretinal space through the damaged vessels and RPE.

Neuroimunomodulação: sobre o diálogo entre os sistemas nervoso e imune / Neuroimmunomodulation: the cross-talk between nervous and immune systems

OBJETIVO: Trabalhos de pesquisa provenientes do campo da neuroimunomodulação vêm tornando explícitas as intrincadas relações existentes entre o sistema nervoso central e o sistema imune. Uma revisão bibliográfica foi realizada com o objetivo de descrever as bases de estudo da neuroimunomodulação. MODELOS EXPERIMENTAIS: Sabe-se, hoje, que estados emocionais como ansiedade e depressão são capazes de modificar a atividade do sistema imune como também o fazem o estresse e fármacos com ação no sistema nervoso central. COMPORTAMENTO DOENTIO: Os comportamentos apresentados por um organismo doente devem ser encarados como decorrência de estratégias homeostáticas de cada indivíduo. POSSÍVEIS MECANISMOS DE SINALIZAÇÃO DO SISTEMA IMUNE PARA O SISTEMA NERVOSO CENTRAL: Grande destaque tem sido atribuído para a participação do eixo hipotálamo-pituitária-adrenal, do sistema nervoso autônomo simpático e das citocinas nas sinalizações entre o sistema nervoso central e o sistema imune. CONCLUSÃO: O presente artigo pretende mostrar a relevância dos fenômenos de neuroimunomodulação; ele faz uma análise crítica das influências do sistema nervoso central sobre o sistema imune e vice-versa.

OBJECTIVE: Several papers arriving from the neuroimmunomodulation field are showing the relevant relationships between the nervous and the immune systems. A review of studies was carried out to describe the bases of the studies on neuroimmunomodulation. EXPERIMENTAL MODELS: It is clear nowadays that emotional states such as anxiety and depression change immune system activity, an affect also observed after both stress and use of nervous system acting drugs. SICK BEHAVIOR: The behavior displayed by sick organisms might be thought as being a consequence of homeostatic strategies. POSSIBLE MECHANISM OF THE ACTION BY MEANS OF IMMUNE SYSTEM TO NERVOUS SYSTEM: A very big emphasis is being given to Hipothalamus-pituitary-adrenal axis, simpathetic nervous system and cytokines participation on nervous system and immune system relationships. CONCLUSION: The present revision intend to show some essential studies in the neuroimmunomodulation field; it makes a critical analysis of the mutual relationships between nervous system and immune system.