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1.
Nat Genet ; 36(12): 1319-25, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15565110

RESUMO

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.


Assuntos
Antidepressivos/uso terapêutico , Depressão/genética , Proteínas de Choque Térmico HSP90/genética , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores de Glucocorticoides/genética , Adulto , Análise de Variância , Antidepressivos/administração & dosagem , Western Blotting , Hormônio Liberador da Corticotropina/genética , Depressão/tratamento farmacológico , Fluorescência , Frequência do Gene , Genótipo , Alemanha , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Linfócitos/metabolismo , Neurofisinas/genética , Precursores de Proteínas/genética , Receptores de Glucocorticoides/metabolismo , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vasopressinas/genética
2.
BMC Neurol ; 10: 61, 2010 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-20630071

RESUMO

BACKGROUND: Animal and human studies suggest that stress experienced early in life has detrimental consequences on brain development, including brain regions involved in cognitive function. Cognitive changes are cardinal features of depression and posttraumatic stress disorder. Early-life trauma is a major risk factor for these disorders. Only few studies have measured the long-term consequences of childhood trauma on cognitive function in healthy adults. METHODS: In this pilot study, we investigated the relationship between childhood trauma exposure and cognitive function in 47 healthy adults, who were identified as part of a larger study from the general population in Wichita, KS. We used the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Wide-Range-Achievement-Test (WRAT-3) to examine cognitive function and individual achievement. Type and severity of childhood trauma was assessed by the Childhood Trauma Questionnaire (CTQ). Data were analyzed using multiple linear regression on CANTAB measures with primary predictors (CTQ scales) and potential confounders (age, sex, education, income). RESULTS: Specific CTQ scales were significantly associated with measures of cognitive function. Emotional abuse was associated with impaired spatial working memory performance. Physical neglect correlated with impaired spatial working memory and pattern recognition memory. Sexual abuse and physical neglect were negatively associated with WRAT-3 scores. However, the association did not reach the significance level of p < 0.01. CONCLUSIONS: Our results suggest that physical neglect and emotional abuse might be associated with memory deficits in adulthood, which in turn might pose a risk factor for the development of psychopathology.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Cognição , Adulto , Fatores Etários , Idoso , Criança , Maus-Tratos Infantis , Abuso Sexual na Infância , Escolaridade , Emoções , Feminino , Nível de Saúde , Humanos , Renda , Kansas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores Sexuais , Violência
3.
Psychosom Med ; 70(7): 829-36, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18606722

RESUMO

OBJECTIVE: To examine the neuropsychological function characterized in subjects with chronic fatigue syndrome (CFS) at the same time controlling for relevant confounding factors. CFS is associated with symptoms of neuropsychological dysfunction. Objective measures of neuropsychological performance have yielded inconsistent results possibly due to sample selection bias, diagnostic heterogeneity, comorbid psychiatric disorders, and medication usage. METHOD: CFS subjects (n = 58) and well controls (n = 104) from a population-based sample were evaluated, using standardized symptom severity criteria. Subjects who had major psychiatric disorders or took medications known to influence cognition were excluded. Neuropsychological function was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Compared with controls, CFS subjects exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task. CFS subjects also exhibited alterations in working memory as manifested by a less efficient search strategy on the spatial working memory task, fewer % correct responses on the spatial recognition task, and prolonged latency to a correct response on the pattern recognition task. A significantly higher percentage of CFS subjects versus controls exhibited evidence of neuropsychological impairment (defined by performance 1 standard deviation below the CANTAB normative mean) in tasks of motor speed and spatial working memory. Impairment in CFS subjects versus control subjects ranged from 20% versus 4.8% in five-choice movement time (p = .002) to 27.8% versus 10.6% in search strategy on the spatial working memory task (p = .006). CONCLUSIONS: These results confirm and quantify alterations in motor speed and working memory in CFS subjects independent of comorbid psychiatric disease and medication usage.


Assuntos
Síndrome de Fadiga Crônica/fisiopatologia , Síndrome de Fadiga Crônica/psicologia , Fadiga Mental/fisiopatologia , Testes Neuropsicológicos/estatística & dados numéricos , Adolescente , Adulto , Atenção , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/fisiopatologia , Transtorno Depressivo/psicologia , Síndrome de Fadiga Crônica/diagnóstico , Feminino , Humanos , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/fisiopatologia , Transtornos da Memória/psicologia , Memória de Curto Prazo , Fadiga Mental/diagnóstico , Fadiga Mental/psicologia , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Desempenho Psicomotor , Tempo de Reação , Reconhecimento Psicológico , Análise e Desempenho de Tarefas , Adulto Jovem
4.
Brain Behav Immun ; 22(6): 870-80, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18258414

RESUMO

Interferon (IFN)-alpha has been used to investigate pathways by which innate immune cytokines influence the brain and behaviour. Previous studies suggest that altered basal ganglia function may contribute to IFN-alpha-induced neuropsychological and behavioural changes. To further examine IFN-alpha effects on neuropsychological functions related to basal ganglia (as well as other brain regions), and explore the relationship between altered neuropsychological function and IFN-alpha-induced depression and fatigue, a selected subset of the Cambridge Neuropsychological Test Automated Battery was administered to 32 hepatitis C patients at baseline (Visit 1) and following approximately 12 weeks (Visit 2) of either no treatment (n=12) or treatment with IFN-alpha plus ribavirin (n=20). Symptoms of depression and fatigue were assessed using the Montgomery-Asberg Depression Rating Scale and the Multidimensional Fatigue Inventory. Compared to control subjects, patients treated with IFN-alpha/ribavirin exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task and slower response times in the rapid visual information processing task, a task of sustained attention. Decreased motor speed on the five-choice movement segments of the reaction time task was in turn correlated with increased symptoms of depression and fatigue (R=0.47, p<0.05 and R=0.48, p<0.05, respectively). IFN-alpha/ribavirin treatment had no effects on executive function, decision time in the reaction time task, or target detection accuracy in the sustained attention task. Motor slowing and its correlation with psychiatric symptoms suggest that altered basal ganglia function may contribute to the pathogenesis of IFN-alpha-induced behavioural changes.


Assuntos
Depressão/induzido quimicamente , Fadiga/induzido quimicamente , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Adulto , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/fisiopatologia , Depressão/fisiopatologia , Fadiga/fisiopatologia , Feminino , Seguimentos , Hepatite C Crônica/psicologia , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Tempo de Reação/efeitos dos fármacos , Análise de Regressão , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico
5.
Biol Psychiatry ; 62(4): 321-6, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17241618

RESUMO

BACKGROUND: Epidemiologic and clinical studies suggest comorbidity between major depressive disorder (MDD) and obesity. To elucidate the impact of weight on the course of depression beyond comorbidity, we investigated psychopathology, attention, neuroendocrinology, weight change, and treatment response in MDD patients, depending on their weight. METHODS: Four hundred eight inpatients with MDD participated in the Munich Antidepressant Response Signature Study, designed to discover biomarkers and genotypes that are predictive for clinical outcome. Psychopathology and anthropometric parameters were monitored weekly in 230 patients. In subsamples, combined dexamethasone-corticotropin-releasing hormone and attention tests were conducted at admission and discharge. One thousand twenty-nine diagnosed matched controls served for morphometric comparisons. RESULTS: Patients with MDD had a significantly higher body mass index (BMI) compared with healthy controls. Patients with high BMI (> or =25) showed a significantly slower clinical response, less improvement in neuroendocrinology and attention, and less weight gain than did patients with normal BMI (18.5 < or = BMI < 25) during antidepressant treatment. CONCLUSIONS: Our findings suggest that overweight and obesity characterize a subgroup of MDD patients with unfavorable treatment outcome.


Assuntos
Hormônio Adrenocorticotrópico/sangue , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Hidrocortisona/sangue , Obesidade/complicações , Sobrepeso/fisiologia , Adulto , Atenção/efeitos dos fármacos , Atenção/fisiologia , Índice de Massa Corporal , Estudos de Casos e Controles , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/complicações , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Sobrepeso/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiopatologia , Valores de Referência , Índice de Gravidade de Doença , Resultado do Tratamento
6.
BMC Neurol ; 7: 40, 2007 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-18053240

RESUMO

BACKGROUND: Complaints of unrefreshing sleep are a prominent component of chronic fatigue syndrome (CFS); yet, polysomnographic studies have not consistently documented sleep abnormalities in CFS patients. We conducted this study to determine whether alterations in objective sleep characteristics are associated with subjective measures of poor sleep quality in persons with CFS. METHODS: We examined the relationship between perceived sleep quality and polysomnographic measures of nighttime and daytime sleep in 35 people with CFS and 40 non-fatigued control subjects, identified from the general population of Wichita, Kansas and defined by empiric criteria. Perceived sleep quality and daytime sleepiness were assessed using clinical sleep questionnaires. Objective sleep characteristics were assessed by nocturnal polysomnography and daytime multiple sleep latency testing. RESULTS: Participants with CFS reported unrefreshing sleep and problems sleeping during the preceding month significantly more often than did non-fatigued controls. Participants with CFS also rated their quality of sleep during the overnight sleep study as significantly worse than did control subjects. Control subjects reported significantly longer sleep onset latency than latency to fall asleep as measured by PSG and MSLT. There were no significant differences in sleep pathology or architecture between subjects with CFS and control subjects. CONCLUSION: People with CFS reported sleep problems significantly more often than control subjects. Yet, when measured these parameters and sleep architecture did not differ between the two subject groups. A unique finding requiring further study is that control, but not CFS subjects, significantly over reported sleep latency suggesting CFS subjects may have an increased appreciation of sleep behaviour that may contribute to their perception of sleep problems.


Assuntos
Síndrome de Fadiga Crônica/fisiopatologia , Síndrome de Fadiga Crônica/psicologia , Percepção , Polissonografia , Transtornos do Sono-Vigília/fisiopatologia , Transtornos do Sono-Vigília/psicologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes/psicologia , Sono , Fases do Sono , Transtornos do Sono-Vigília/diagnóstico , Inquéritos e Questionários
7.
Biol Psychiatry ; 59(8): 681-8, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16580345

RESUMO

BACKGROUND: The most consistent biological finding in patients with depression is a hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis, which might be caused by impaired glucocorticoid signaling. Glucocorticoids act through the glucocorticoid receptor (GR) for which several polymorphisms have been described. The N363S and BclI polymorphisms have been associated with hypersensitivity to glucocorticoids, whereas the ER22/23EK polymorphism is related to glucocorticoid resistance. METHODS: We studied whether the susceptibility to develop a depression is related to these polymorphisms by comparing depressive inpatients (n = 490) and healthy control subjects (n = 496). Among depressed patients, we also investigated the relation between GR variants and dysregulation of the HPA-axis, as measured by the combined dexamethasone suppression/corticotropin-releasing hormone (CRH)-stimulation test, clinical response to antidepressive treatment, and cognitive functioning. RESULTS: Homozygous carriers of the BclI polymorphism and ER22/23EK-carriers had an increased risk of developing a major depressive episode. We found no genetic associations with functional HPA-axis measures in depressed patients. The ER22/23EK-carriers, however, showed a significantly faster clinical response to antidepressant therapy as well as a trend toward better cognitive functioning during depression. CONCLUSIONS: The BclI and ER22/23EK polymorphisms were associated with susceptibility to develop major depression. In addition, the ER22/23EK polymorphism is associated with a faster clinical response to antidepressant treatment. These findings support the notion that variants of the GR gene might play a role in the pathophysiology of a major depression and can contribute to the variability of antidepressant response.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético , Receptores de Glucocorticoides/genética , Adulto , Análise de Variância , Antidepressivos/uso terapêutico , Asparagina/genética , Estudos de Casos e Controles , Hormônio Liberador da Corticotropina/metabolismo , Análise Mutacional de DNA , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Dexametasona/administração & dosagem , Éxons/genética , Feminino , Humanos , Hidrocortisona/metabolismo , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Serina/genética , Índice de Gravidade de Doença , Fatores de Tempo
8.
Biol Psychiatry ; 57(4): 336-42, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15705348

RESUMO

BACKGROUND: One of the most demanding tasks in psychiatry is to protect patients from suicidal attempts. Preventive strategies could be improved by increasing our knowledge on the pathophysiologic disturbances underlying this behavior. More than 70-80% of suicides occur in the context of depressive disorders, in which dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most prominent neurobiological findings. So far data on the involvement of the HPA axis in the pathophysiology of suicidal behavior in depressed patients are controversial. METHODS: In this retrospective study, we administered the combined dexamethasone-suppression/CRH stimulation (Dex/CRH) test to 310 patients with a depressive syndrome characterized at admission for acute and past suicidal behavior within the first 10 days after hospitalization. RESULTS: Suicidal behavior in depressed patients, including past and recent suicide attempts as well as suicidal ideation, was associated with a lower adrenocorticotropin and cortisol response in the combined Dex/CRH test, with lowest hormone levels observed in patients with a recent suicide attempt. DISCUSSION: The findings suggest that suicidal behavior may alter HPA axis regulation in depressed patients. Large-scale prospective studies assessing neuroendocrine changes may help to develop predictors for an early identification of patients at risk for committing suicide.


Assuntos
Depressão/fisiopatologia , Depressão/psicologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Suicídio , Hormônio Adrenocorticotrópico/sangue , Adulto , Hormônio Liberador da Corticotropina , Depressão/diagnóstico , Dexametasona , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Estatísticas não Paramétricas , Suicídio/psicologia , Fatores de Tempo
9.
J Psychiatr Res ; 46(4): 500-6, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22336639

RESUMO

AIMS: Recent research has revealed that early life trauma (ELS), including abuse (sexual and/or physical) and neglect, produce lasting changes in the CNS. We posited that cognitive deficits, often observed in psychiatric patients, result, in part, due to the neurobiological consequences of ELS. Additionally, we hypothesized that the nature and magnitude of cognitive deficits would differ according to the subtype of ELS experienced. METHOD: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess neurocognitive functioning in 93 subjects (60 with ELS and 33 without). In the patients with a history of ELS, 35% and 16.7%, respectively, met criteria for current major depression and PTSD. RESULTS: Significant associations between ELS status and CANTAB measures of memory and executive and emotional functioning were found. CONCLUSIONS: These data suggest that exposure to ELS results in a cascade of neurobiological changes associated with cognitive deficits in adulthood that vary according to the type of trauma experienced.


Assuntos
Maus-Tratos Infantis/psicologia , Transtornos Cognitivos/etiologia , Transtorno Depressivo Maior/etiologia , Adolescente , Adulto , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Emoções , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Autorrelato , Estatística como Assunto , Inquéritos e Questionários , Adulto Jovem
10.
Biol Psychiatry ; 65(4): 296-303, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18801471

RESUMO

BACKGROUND: Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established. METHODS: Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after approximately 12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. RESULTS: Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r(2) = -.25, p < .05). CONCLUSIONS: These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.


Assuntos
Monoaminas Biogênicas/fisiologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Transtorno Depressivo/patologia , Inflamação/patologia , Interferon-alfa/farmacologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/patologia , Adulto , Antivirais/farmacologia , Monoaminas Biogênicas/líquido cefalorraquidiano , Biomarcadores/análise , Hormônio Liberador da Corticotropina/líquido cefalorraquidiano , Citocinas/líquido cefalorraquidiano , Transtorno Depressivo/líquido cefalorraquidiano , Feminino , Humanos , Inflamação/líquido cefalorraquidiano , Estudos Longitudinais , Masculino , Escalas de Graduação Psiquiátrica , Ribavirina/farmacologia
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