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BACKGROUND: Irritability in people with autism spectrum disorders (ASD) is common and impairing, yet its mechanisms remain understudied. We investigated symptom reporting and mechanisms of irritability in ASD, focusing on the relation between irritability and physiological stress responses. METHODS: Forty-seven unmedicated boys with high-functioning ASD (hfASD) and 23 typically developing boys aged 10-16 years completed a psychosocial stress test. Changes in cortisol, heart rate and heart rate variability throughout the test were recorded. Self- and parent-reported measures of irritability were obtained. Irritability symptom reporting in the hfASD group was compared to two groups of boys without ASD: highly irritable boys (severe mood dysregulation, SMD; n = 40) and healthy-control boys (HC; n = 30). RESULTS: Boys with hfASD scored significantly higher on irritability than HC boys, and they reported a pattern of irritability symptoms closely resembling that of boys with SMD. The internal consistency of irritability in hfASD was high by parent- and self-report. Although boys with hfASD showed significant stress-induced changes in cortisol and heart rate, those who rated themselves as highly irritable had lower cortisol levels throughout the test compared to those low on irritability. Participants rated as highly irritable by their parents showed blunted cortisol and heart rate responses to stress. The effects of irritability on heart rate, but not cortisol, were accounted for by trait anxiety. CONCLUSIONS: Irritability can be measured reliably in hfASD and is associated with distinct biological responses to stress.
Assuntos
Transtorno do Espectro Autista/fisiopatologia , Frequência Cardíaca/fisiologia , Hidrocortisona/metabolismo , Humor Irritável/fisiologia , Estresse Psicológico/fisiopatologia , Adolescente , Transtorno do Espectro Autista/metabolismo , Criança , Humanos , Masculino , Estresse Psicológico/metabolismoRESUMO
BACKGROUND: People with severe depressive illness have raised levels of cortisol and reduced glucocorticoid receptor function. AIMS: To obtain a physiological assessment of hypothalamic-pituitary-adrenal (HPA) axis feedback status in an in-patient sample with depression and to relate this to prospectively determined severe treatment resistance. METHOD: The prednisolone suppression test was administered to 45 in-patients with depression assessed as resistant to two or more antidepressants and to 46 controls, prior to intensive multimodal in-patient treatment. RESULTS: The patient group had higher cortisol levels than controls, although the percentage suppression of cortisol output after prednisolone in comparison with placebo did not differ. Non-response to in-patient treatment was predicted by a more dysfunctional HPA axis (higher cortisol levels post-prednisolone and lower percentage suppression). CONCLUSIONS: In patients with severe depression, HPA axis activity is reset at a higher level, although feedback remains intact. However, prospectively determined severe treatment resistance is associated with an impaired feedback response to combined glucocorticoid and mineralocorticoid receptor activation by prednisolone.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Glucocorticoides , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Prednisolona , Adolescente , Antidepressivos/uso terapêutico , Estudos de Casos e Controles , Transtorno Depressivo/fisiopatologia , Resistência a Medicamentos/efeitos dos fármacos , Inglaterra , Feminino , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Sistema Hipófise-Suprarrenal/fisiopatologia , Estudos Prospectivos , Receptores de Glucocorticoides/metabolismo , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
RATIONALE: Patients with major depression show hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, but the mechanisms underlying this abnormality are still unclear. OBJECTIVES: We have compared two synthetic glucorticoids, dexamethasone and prednisolone, in their ability to suppress the hypothalamic-pituitary-adrenal (HPA) axis in depressed patients. Dexamethasone probes glucocorticoid receptor (GR) function, while prednisolone probes both GR and mineralocorticoid receptor (MR) function. MATERIALS AND METHODS: We used a single-blind, repeated-measure design. We administered placebo, prednisolone (5 mg) or dexamethasone (0.5 mg), at 22:00, to 18 severe, treatment-resistant depressed inpatients (15 of them with a history of childhood trauma) and 14 healthy volunteers. On the following days, we collected salivary cortisol from 9:00 to 22:00. RESULTS: Depressed patients had higher salivary cortisol levels compared with controls, at baseline and after both prednisolone and dexamethasone (p<0.001). Consistent with previous studies, depressed inpatients showed impaired suppression by dexamethasone: based on the analysis of the areas under the curve (AUCs), suppression by dexamethasone (0.5 mg) was -85% in controls vs -46% in depressed patients (p=0.018). However, the same depressed patients showed normal suppression by prednisolone (5 mg): suppression was -41% in controls and -36% in depressed patients (p=0.6). CONCLUSIONS: We suggest that the additional effects of prednisolone on the MR explain the different responses to these glucocorticoids in the same depressed patients.
Assuntos
Transtorno Depressivo Maior/metabolismo , Dexametasona/farmacologia , Prednisolona/farmacologia , Área Sob a Curva , Dexametasona/sangue , Dexametasona/farmacocinética , Feminino , Glucocorticoides/farmacocinética , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Prednisolona/sangue , Prednisolona/farmacocinética , Receptores de Glucocorticoides/agonistas , Receptores de Mineralocorticoides/agonistas , Saliva/efeitos dos fármacos , Saliva/metabolismo , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/metabolismo , Método Simples-CegoRESUMO
We have developed a suppressive test for the hypothalamic-pituitary-adrenal (HPA) axis using prednisolone, which is similar to endogenous glucocorticoids. We used a single-blind, repeated-measure design in healthy volunteers. In the first phase of the study, we compared placebo or prednisolone 2.5 mg, 5 mg, or 10 mg; in the second phase of the study, we compared placebo or prednisolone 5 mg or dexamethasone.5 mg. On the following day, we collected plasma and salivary cortisol levels from 9 AM to 5 PM. Maximal average prednisolone plasma levels (at 9 AM after the 10-mg dose) were 30 to 35 ng/mL. At all doses, prednisolone caused a larger suppression of salivary cortisol (approximately 20% after 2.5 mg, 30% to 35% after 5 mg, and 70% to 75% after 10 mg) than of plasma cortisol (approximately 5% after 2.5 mg, 10% after 5 mg, and 35% after 10 mg). Dexamethasone.5 mg gave 80% suppression of plasma cortisol and 90% suppression of salivary cortisol. Plasma and salivary cortisol levels were more consistently correlated in each subject after prednisolone than after dexamethasone. We propose that prednisolone at the 5-mg dosage (which gave partial HPA suppression), together with the assessment of salivary cortisol, can be used to investigate both impaired and enhanced glucocorticoid-mediated negative feedback in large samples of patients with psychiatric disorders.
Assuntos
Glucocorticoides , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Prednisolona , Adulto , Dexametasona , Feminino , Glucocorticoides/metabolismo , Humanos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/metabolismo , Prednisolona/metabolismo , Saliva/metabolismo , Método Simples-CegoRESUMO
RATIONALE: Chronic antidepressant treatment increases glucocorticoid-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, and thus reduces HPA axis activity, in depressed patients and healthy controls. In contrast, acute antidepressant treatment induces an activation of basal HPA axis activity. OBJECTIVES: We examined the effects of 4 days of treatment with the selective serotonin reuptake inhibitor, citalopram, on basal salivary cortisol and on suppression of salivary cortisol by prednisolone. METHODS: We used a single-blind, placebo-controlled, repeated-measure design. Salivary cortisol was measured from 0900 to 1700 hours. In the first phase of the study, basal salivary cortisol secretion was measured on 2 study days, before and after 4 days of treatment with citalopram (orally, 20 mg/day). In the second phase, salivary cortisol secretion after suppression by prednisolone (5 mg, given at 2200 hours the night before) was measured on 2 study days, again before and after 4 days of treatment with citalopram (orally, 20 mg/day). Eight volunteers participated to the study. RESULTS: Citalopram increased basal salivary cortisol in the morning (0900-1100 hours) by approximately 47% (P=0.003). Moreover, citalopram increased suppression by prednisolone in the morning (0900-1100 hours): suppression was approximately 22% before citalopram and 45% after citalopram (P=0.05). CONCLUSIONS: Citalopram increases glucocorticoid-mediated negative feedback on the HPA axis after as little as 4 days of treatment. This effect could be due to an increased function of the corticosteroid receptors. Our findings further support the notion that one of the mechanisms by which antidepressants exert their therapeutic effects is by normalizing HPA axis hyperactivity in depressed patients.
Assuntos
Citalopram/administração & dosagem , Hidrocortisona/metabolismo , Prednisolona/farmacologia , Adulto , Análise de Variância , Sinergismo Farmacológico , Feminino , Humanos , Hidrocortisona/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/metabolismo , Método Simples-CegoRESUMO
Previous studies using plasma cortisol estimations have suggested that hypothalmo-pituitary-axis (HPA) activation occurs in alcohol-dependent patients during alcohol withdrawal. The present study set out to confirm this finding using salivary cortisol assays, which are a better indicator of plasma free cortisol, the fraction which exerts its physiological effects. Nine alcohol dependent patients provided four saliva samples (at 10 a.m., 2 p.m., 6 p.m. and 10 p.m.) on days 1, 3 and 7 of a medically assisted alcohol withdrawal (corresponding to 1, 3 and 7 days following the last drink, respectively).Withdrawal symptom severity, craving and mood disturbance were also measured. A group of non-alcohol-dependent individuals, without psychiatric or medical disorder, gave four samples at the same times on one day only. Mean daily cortisol levels in our alcohol-dependent population, as calculated by the area under the curve (AUC), decreased significantly over time (mean AUC (nmol/l/hour) on day 1 = 149, on day 7 = 85.7, p = 0.009) and were significantly higher than controls on each day (mean AUC in controls = 28.3, p = 0.001). The cortisol response showed a similar temporal trend to withdrawal symptom severity and mood disturbance. This is consistent with previous studies measuring plasma cortisol in alcohol withdrawal. However, the magnitude of the effect in our study was greater, and in contrast to some previous studies, levels were far from normal by day 7. The comparatively low cortisol response in our one mildly dependent patient suggests that there may be a relationship between dependence severity and the size of the cortisol response to withdrawal. Salivary cortisol sampling could prove to be a useful prognostic tool, with implications for subsequent withdrawal symptom severity, mood disturbances, risk of relapse and alcohol-related cognitive decline. There are implications for developing new treatments for alcohol withdrawal but more studies are needed.
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OBJECTIVE: This study examined cortisol in adolescents with chronic fatigue syndrome (CFS) compared to healthy adolescents and changes in cortisol after cognitive behavioural guided self-help treatment. Exploratory analyses investigated the association between cortisol output and psychological variables. METHODS: Salivary cortisol was measured upon awakening, at 15, 30, 45 and 60 min afterwards and at 12 noon, 4:00 p.m. and 8:00 p.m., in adolescents with CFS and healthy controls (HC). Groups were matched for age, gender, menarche status, menstrual cycle and awakening time. Twenty-four adolescents with CFS provided saliva samples six months after treatment. The main outcome measure was total salivary output over the day, calculated by area under the curve (AUC). The salivary awakening response was also assessed. RESULTS: Cortisol output over the day was significantly lower in the CFS group (n=46) than in healthy controls (n=33). Within the CFS group, lower daily cortisol output was associated with higher self-reported perfectionist striving and prosocial behaviour. There were no significant group differences in the awakening response (n=47 CFS versus n=34 HC). After treatment, adolescents with CFS (n=21) showed a significant increase in daily cortisol output, up to normal levels. CONCLUSION: The reduced daily cortisol output in adolescents with CFS is in line with adult findings. Associations between reduced cortisol output and two psychological variables-perfectionism and prosocial behaviour-are consistent with cognitive behavioural models of chronic fatigue syndrome. The mild hypocortisolism is reversible; cortisol output had returned to healthy adolescent levels by six months after cognitive behavioural guided self-help treatment.
Assuntos
Terapia Cognitivo-Comportamental , Síndrome de Fadiga Crônica/metabolismo , Síndrome de Fadiga Crônica/terapia , Hidrocortisona/metabolismo , Grupos de Autoajuda , Adolescente , Área Sob a Curva , Estudos de Casos e Controles , Síndrome de Fadiga Crônica/psicologia , Feminino , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Saliva/metabolismoRESUMO
Children and adolescents with autism spectrum disorder (ASD) have much higher rates of anxiety disorders relative to their typically developing peers. However, there have been few attempts to investigate what physiological parameters may be associated with this elevated rate of anxiety. Therefore, this study investigated the physiological correlates of anxiety in ASD, with a focus on whether measures of heart rate and cortisol responsiveness to psychosocial stress differentiate those participants with ASD with and without a co-occurring anxiety disorder. A total of 75 male participants aged 10-16 years with normal intellectual ability underwent a psychosocial stress test. The participants included healthy controls (n=23), ASD only (ASD; n=20) and ASD with a comorbid anxiety disorder (ASDanx; n=32). Heart rate, heart rate variability and salivary cortisol were compared by fitting a piecewise regression model to examine baseline levels and change over time within and between the rest, stress and recovery phases of the stress test. The ASDanx group had different response patterns from both the ASD and control groups. The ASDanx group was characterized by a blunted cortisol and heart rate response to psychosocial stress. Furthermore, in the ASDanx group, reduced heart rate and cortisol responsiveness were significantly related to increased anxiety symptoms. This is the first study to report a possible physiological basis for co-occurring anxiety disorders in children and adolescents with ASD. It is possible that a non-adaptive physiological response to psychosocial stress may be related to the high prevalence of co-occurring anxiety disorders in people with ASD.
Assuntos
Ansiedade/fisiopatologia , Ansiedade/psicologia , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Transtornos Globais do Desenvolvimento Infantil/psicologia , Frequência Cardíaca , Sistema Hipotálamo-Hipofisário , Meio Social , Estresse Psicológico/fisiopatologia , Adolescente , Ansiedade/complicações , Criança , Transtornos Globais do Desenvolvimento Infantil/complicações , Comunicação , Humanos , Hidrocortisona/metabolismo , Masculino , Escalas de Graduação Psiquiátrica , Saliva/metabolismoRESUMO
BACKGROUND AND AIMS: Childhood trauma may have longstanding effects on individuals' propensity to react adversely to stress, and also predisposes individuals to suffer from depression. The current study aimed to examine stress reactivity in individuals with and without a history of childhood trauma by measuring cortisol responses to the passive viewing of stressful images, specifically including images relevant to childhood trauma. In addition, participants with and without a diagnosis of current depression were studied to investigate whether cortisol stress reactivity may underlie resilience or vulnerability to depression. METHODS: The study involved 17 healthy participants with and 24 without a history of childhood trauma; and 21 depressed patients with and 18 without a history of childhood trauma. Salivary cortisol was measured before, during and after participants were shown affectively laden images, including standardised scenes from the International Affective Picture System and also images suggestive of childhood abuse. Cortisol stress reactivity to the passive image viewing was compared between groups. RESULTS: In those who had experienced childhood trauma, cortisol stress responses were overall low and the same in those who were depressed and those who were not (mean stress reactivity variable - depressed: 0.8 nmol/l; non-depressed: 0.72 nmol/l). In contrast, cortisol stress reactivity was raised in depressed subjects relative to those who were not depressed in those without a history of childhood trauma (mean stress reactivity variable - depressed: 3.75 nmol/l; non-depressed: 0.1 nmol/l). CONCLUSIONS: A history of childhood trauma has longstanding effects on adulthood cortisol responses to stress, particularly in that depressed individuals with a history of childhood trauma show blunted cortisol responses. However, there were no differences between abused depressed and abused non-depressed subjects on cortisol stress responses, suggesting that such a finding does not explain subsequent susceptibility to depression. On the other hand, patients who experience depression without a history of childhood trauma show enhanced cortisol stress reactivity, which could help explain the aetiology of their depressive illnesses. Differences between the current findings and those using other pharmacological and stress challenge paradigms may relate to the type of stimuli used and to dysfunction at different levels of the hypothalamic-pituitary-adrenal (HPA) axis.
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Transtorno Depressivo/fisiopatologia , Hidrocortisona/análise , Sistema Hipotálamo-Hipofisário/fisiopatologia , Acontecimentos que Mudam a Vida , Sistema Hipófise-Suprarrenal/fisiopatologia , Estresse Psicológico/fisiopatologia , Adulto , Transtorno Depressivo/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Saliva/química , Estresse Psicológico/complicaçõesRESUMO
BACKGROUND: Treatment-resistant depression patients show both reduced glucocorticoid receptor function and a hyperactive hypothalamic-pituitary-adrenal axis. However, few studies have examined the role of the mineralocorticoid receptor. This study aimed to evaluate the functional activity of the mineralocorticoid receptor system in regulating the hypothalamic-pituitary-adrenal axis in well-defined treatment-resistant depression patients. MATERIAL AND METHOD: We recruited 24 subjects divided into: (a) treatment-resistant depression; (b) healthy controls. We evaluated: (a) the effect of combined glucocorticoid receptor/mineralocorticoid receptor stimulation with prednisolone; (b) the effect of prednisolone with the mineralocorticoid receptor antagonist spironolactone; and (c) the effect of spironolactone alone. The response of the hypothalamic-pituitary-adrenal axis was measured using salivary cortisol and plasma levels of drugs were also measured. RESULTS: Treatment-resistant depression patients had higher cortisol compared with controls after all challenges. In controls, spironolactone increased cortisol compared to placebo. The co-administration of spironolactone with prednisolone in controls decreases the suppressive effects of prednisolone. In contrast, in treatment-resistant depression, spironolactone did not increase cortisol compared to placebo and spironolactone with prednisolone had no effect on the suppressive effects of prednisolone. Patients with treatment-resistant depression had a reduction in the conversation of spironolactone to the active metabolite canrenone. CONCLUSION: Our data confirmed that treatment-resistant depression is associated with hypercortisolism and these patients no longer show an hypothalamic-pituitary-adrenal response to the administration of a mineralocorticoid receptor antagonist, suggesting that there is a mineralocorticoid receptor malfunctioning, such as a down regulation, however, pharmacokinetics and pharmacodynamics in these subjects could also have had an effect on the lack of mineralocorticoid receptor response.
Assuntos
Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Prednisolona/farmacologia , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Canrenona/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Sistema Hipófise-Suprarrenal/metabolismo , Prednisolona/administração & dosagem , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/efeitos dos fármacos , Saliva/química , Método Simples-Cego , Espironolactona/administração & dosagem , Espironolactona/farmacocinética , Espironolactona/farmacologiaRESUMO
BACKGROUND: Abnormalities in hypothalamic-pituitary-adrenal (HPA) axis activity have been reported in patients with psychosis, but it is still unclear how these are related to the clinical symptomatology. Inconsistent findings have emerged from previous studies on the association between cortisol levels and clinical symptoms. Methodological and/or clinical factors, such as patients' diagnosis or illness phase, might partially account for these inconsistencies. The aim of this study was to investigate the association between HPA axis activity and clinical symptoms in first-episode psychosis, taking into account diagnosis and illness phase. METHOD: Saliva samples were collected in 55 subjects with first-episode psychosis to assess the Cortisol Awakening Response (CAR) and diurnal cortisol levels (AUC-DAY). Severity of symptoms was assessed with the Positive and Negative Syndrome Scale (PANSS). Scores for subscales and symptom dimensions were used as predictors in multivariate analyses in different diagnostic subgroups and in clinically remitted patients. In addition, a systematic review of the literature on this topic was conducted. RESULTS: In subjects with schizophrenia (n=36), the CAR was predicted by the severity of positive symptoms (beta=0.47, p=0.04); in subjects with depressive psychoses (n=8) the CAR was predicted by excitement (beta=0.58, p=0.005), disorganization (beta=0.39, p=0.007) and depressive symptoms (beta=0.32, p=0.005). In patients with bipolar psychoses (n=11) AUC-DAY was predicted negatively by disorganization (beta=-2.82, p=0.009) and positively by excitement (beta=2.06, p=0.009) and positive symptoms (beta=1.28, p=0.02). In the sample in clinical remission (n=9), the CAR was associated with the severity of positive symptoms (beta=1.34, p=0.009) and, negatively, with excitement (beta=-1.05, p=0.04). The systematic review (on a total of 28 papers, including n=1022 patients), found that in patients with psychosis cortisol levels have been associated with the severity of multiple symptom dimensions. CONCLUSIONS: HPA axis activity is associated with the severity of multiple types of symptoms in first-episode psychosis. Patients' diagnosis and clinical phase partially influence these associations.
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Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Antipsicóticos/uso terapêutico , Ritmo Circadiano/fisiologia , Depressão/fisiopatologia , Feminino , Humanos , Hidrocortisona/análise , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/psicologia , Saliva/química , Esquizofrenia/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
The weight of current evidence supports the presence of the following factors related to hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness. Furthermore, HPA axis changes seem clinically relevant, as they are associated with worse symptoms and/or disability and with poorer outcomes to standard treatments for CFS. Regarding etiology, women with CFS are more likely to have reduced cortisol levels. Studies published in the past 8 years provide further support for a multifactorial model in which several factors interact to moderate HPA axis changes. In particular, low activity levels, depression and early-life stress appear to reduce cortisol levels, whereas the use of psychotropic medication can increase cortisol. Addressing these factors-for example, with cognitive behavioral therapy-can increase cortisol levels and is probably the first-line approach for correcting HPA axis dysfunction at present, as steroid replacement is not recommended. Given what is now a fairly consistent pattern of findings for the type of HPA axis changes found in CFS, we recommend that future work focuses on improving our understanding of the cause and relevance of these observed changes.
Assuntos
Síndrome de Fadiga Crônica/complicações , Síndrome de Fadiga Crônica/fisiopatologia , Doenças Hipotalâmicas/etiologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Desidroepiandrosterona/sangue , Desidroepiandrosterona/metabolismo , Síndrome de Fadiga Crônica/epidemiologia , Humanos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Hidrocortisona/urina , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/epidemiologia , Metanálise como Assunto , Modelos BiológicosRESUMO
OBJECTIVE: Childhood adverse experiences are known to engender persistent changes in stress-related systems and brain structures involved in mood, cognition, and behavior in animal models. Uncertainty remains about the causal effect of early stressful experiences on physiological response to stress in human beings, as the impact of these experiences has rarely been investigated while controlling for both genetic and shared environmental influences. METHOD: We tested whether bullying victimization, a repeated adverse experience in childhood, influences cortisol responses to a psychosocial stress test (PST) using a discordant monozygotic (MZ) twin design. Thirty pairs (43.3% males) of 12-year-old MZ twins discordant for bullying victimization were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994-1995 cohort of families with twins. RESULTS: Bullied and nonbullied MZ twins showed distinct patterns of cortisol secretion after the PST. Specifically, bullied twins exhibited a blunted cortisol response compared with their nonbullied MZ co-twins, who showed the expected increase. This difference in cortisol response to stress could not be attributed to children's genetic makeup, their familial environments, pre-existing and concomitant individual factors, or the perception of stress and emotional response to the PST. CONCLUSION: Results from this natural experiment provide support for a causal effect of adverse childhood experiences on the neuroendocrine response to stress.
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Bullying/psicologia , Doenças em Gêmeos/sangue , Doenças em Gêmeos/genética , Hidrocortisona/sangue , Gêmeos Monozigóticos/genética , Nível de Alerta/genética , Nível de Alerta/fisiologia , Criança , Estudos de Coortes , Vítimas de Crime/psicologia , Doenças em Gêmeos/psicologia , Feminino , Humanos , Controle Interno-Externo , Estudos Longitudinais , Masculino , Relações Mãe-Filho , Fatores de Risco , Meio Social , Estresse Psicológico/complicações , Gêmeos Monozigóticos/psicologia , Reino UnidoRESUMO
BACKGROUND: Evidence from animal and human studies suggests that early-life stress such as physical maltreatment has long-lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis and is associated with blunted HPA axis reactivity in adulthood. Few studies have investigated whether blunted HPA axis reactivity observed in children exposed to early-life stress signals social, emotional, and behavioral problems. METHODS: Participants were 190 12-year-old children (50.5% males) recruited from the Environmental Risk Longitudinal Twin Study, a nationally representative 1994 to 1995 cohort of families with twins. Cortisol responses to psychosocial stress were measured in maltreated/bullied (n = 64) and comparison children (n = 126). We ascertained maltreatment and bullying victimization using mothers' reports and assessed children's social, emotional, and behavioral problems at ages 5 and 12 using mothers' and teachers' reports. RESULTS: Piecewise multilevel growth curve analyses indicated that maltreated/bullied and comparison children showed distinct cortisol responses to stress. Specifically, maltreated/bullied children had lower cortisol responses than comparison children who exhibited a significant increase. Lower cortisol responses were, in turn, associated with more social and behavioral problems among maltreated/bullied children. CONCLUSIONS: These findings provide support for the influence of childhood harm on blunted HPA axis reactivity and its potential impact on children's functioning. Our findings emphasize the need to integrate stress biomarkers in guiding prevention efforts for young victims.
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Maus-Tratos Infantis/psicologia , Transtornos do Comportamento Infantil/sangue , Transtornos do Comportamento Infantil/etiologia , Hidrocortisona/sangue , Estresse Psicológico/complicações , Criança , Estudos de Coortes , Emoções/fisiologia , Saúde da Família , Feminino , Humanos , Imunoensaio/métodos , Masculino , Modelos Psicológicos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Reduced brain-derived neurotrophic factor (BDNF) levels have been reported in the serum and plasma of patients with psychosis. The aim of this cross-sectional case-control study was to investigate potential causes and consequences of reduced BDNF expression in these patients by examining the association between BDNF levels and measures of stress, inflammation, and hippocampal volume in first-episode psychosis. METHOD: Brain-derived neurotrophic factor, interleukin (IL)-6, and tumor necrosis factor (TNF)-α messenger RNA levels were measured in the leukocytes of 49 first-episode psychosis patients (DSM-IV criteria) and 30 healthy controls, all aged 18 to 65 years, recruited between January 2006 and December 2008. Patients were recruited from inpatient and outpatient units of the South London and Maudsley National Health Service Foundation Trust in London, United Kingdom, and the healthy controls were recruited from the same catchment area via advertisement and volunteer databases. In these same subjects, we measured salivary cortisol levels and collected information about psychosocial stressors (number of childhood traumas, number of recent stressors, and perceived stress). Finally, hippocampal volume was measured using brain magnetic resonance imaging in a subsample of 19 patients. RESULTS: Patients had reduced BDNF (effect size, d = 1.3; P < .001) and increased IL-6 (effect size, d = 1.1; P < .001) and TNF-α (effect size, d = 1.7; P < .001) gene expression levels when compared with controls, as well as higher levels of psychosocial stressors. A linear regression analysis in patients showed that a history of childhood trauma and high levels of recent stressors predicted lower BDNF expression through an inflammation-mediated pathway (adjusted R(2) = 0.23, P = .009). In turn, lower BDNF expression, increased IL-6 expression, and increased cortisol levels all significantly and independently predicted a smaller left hippocampal volume (adjusted R(2) = 0.71, P < .001). CONCLUSIONS: Biological changes activated by stress represent a significant factor influencing brain structure and function in first-episode psychosis through an effect on BDNF.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/sangue , Hipocampo/patologia , Transtornos Psicóticos/patologia , Estresse Psicológico/patologia , Adulto , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Estudos de Casos e Controles , Estudos Transversais , Feminino , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Masculino , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/fisiopatologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
Depressed patients have reduced glucocorticoid receptor (GR) function, as demonstrated by resistance to the suppressive effects of the synthetic glucocorticoid hormone, and GR agonist, dexamethasone. We have developed a suppressive test with prednisolone, a synthetic glucocorticoid that is similar to cortisol in its pharmacodynamics and pharmacokinetics, and binds to both the GR and the mineralocorticoid receptor (MR). We have found that depressed patients suppress normally to prednisolone, unless they are particularly non-responsive to treatment. In the present study, we evaluated 28 inpatients with treatment-resistant depression (TRD), and compared salivary cortisol secretion (at 0900 h, 1200 h and 1700 h) after placebo or after prednisolone (5 mg), before and after an inpatient treatment admission. Half of the patients (n=14) reached treatment response. When comparing the assessment between admission and discharge, cortisol output after placebo fell (-26% of area under the curve; p=0.024) while the output after prednisolone did not change. Moreover, there was no change in the response to prednisolone (percentage suppression) between admission at discharge, and this was not influenced by treatment response. Finally, we could confirm and extend our previously published data with prednisolone (5 mg), showing that depressed patients (n=12) and controls (n=12) suppressed equally to both 5 and 10 mg doses of prednisolone. This study suggests that the response to prednisolone is similar in depressed patients and controls at different doses of prednisolone, and does not change with symptomatic improvement. This is in contrast with findings, from us and others, using other measures of hypothalamic-pituitary-adrenal axis function, such as basal cortisol levels or the response to dexamethasone. Thus, we propose that the prednisolone suppression test may offer specific biological and clinical information, related to its action at both the GR and the MR.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Glucocorticoides , Prednisolona , Transtorno Depressivo Maior/psicologia , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/administração & dosagem , Humanos , Pacientes Internados , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Escalas de Graduação Psiquiátrica , Saliva/metabolismoRESUMO
This study investigated the relationship between cortisol secretion and hippocampal volume in first-episode psychosis and healthy controls. Hippocampal volume was measured by magnetic resonance imaging (MRI) in 24 first-episode psychosis patients and in 18 healthy controls, together with diurnal cortisol levels. Twelve patients received a second MRI scan at 3-month follow-up. Diurnal cortisol levels were inversely correlated with left hippocampal volume in patients, both at baseline and at follow-up, while no correlation was found in controls. Our findings suggest that smaller hippocampal volume in first-episode psychosis can partly be explained by stress-related processes in the brain, as measured by cortisol hyper-secretion.
Assuntos
Transtorno Bipolar/sangue , Transtorno Bipolar/patologia , Hipocampo/patologia , Hidrocortisona/sangue , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Transtornos Psicóticos/sangue , Transtornos Psicóticos/patologia , Esquizofrenia/sangue , Esquizofrenia/patologia , Adulto , Nível de Alerta/fisiologia , Transtorno Bipolar/diagnóstico , Ritmo Circadiano/fisiologia , Dominância Cerebral/fisiologia , Feminino , Humanos , Masculino , Tamanho do Órgão/fisiologia , Transtornos Psicóticos/diagnóstico , Valores de Referência , Esquizofrenia/diagnósticoRESUMO
BACKGROUND: There is evidence that patients with chronic fatigue syndrome (CFS) have mild hypocortisolism. One theory about the aetiology of this hypocortisolism is that it occurs late in the course of CFS via factors such as inactivity, sleep disturbance, chronic stress and deconditioning. We aimed to determine whether therapy aimed at reversing these factors--cognitive behavioural therapy for CFS--could increase cortisol output in CFS. METHODS: We measured diurnal salivary cortisol output between 0800 and 2000 h before and after 15 sessions (or 6 months) of CBT in 41 patients with CDC-defined CFS attending a specialist, tertiary outpatient clinic. RESULTS: There was a significant clinical response to CBT, and a significant rise in salivary cortisol output after CBT. LIMITATIONS: We were unable to control for the passage of time using a non-treated CFS group. CONCLUSIONS: Hypocortisolism in CFS is potentially reversible by CBT. Given previous suggestions that lowered cortisol may be a maintaining factor in CFS, CBT offers a potential way to address this.
Assuntos
Terapia Cognitivo-Comportamental , Síndrome de Fadiga Crônica/terapia , Hidrocortisona/sangue , Adulto , Comorbidade , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/psicologia , Transtorno Depressivo Maior/terapia , Síndrome de Fadiga Crônica/sangue , Síndrome de Fadiga Crônica/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Saliva/química , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 muM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.