Asunto(s)

Aldosterona/metabolismo , Corticosterona/metabolismo , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/metabolismo , Aldosterona/biosíntesis , Animales , Biomarcadores/metabolismo , Corticosterona/biosíntesis , Modelos Animales de Enfermedad , Femenino , Masculino , Ratas , Factores de Tiempo

RESUMEN

INTRODUCTION: Neuroendocrine changes in depression have long been recognized, with a focus mainly on hypercortisolism. The other hormone of the hypothalamus-pituitary adrenocortical system, aldosterone, has been widely neglected. METHODS: Here we summarize the involvement of the renin-angiotensin-aldosterone system (RAAS) and the regulation of aldosterone in health with a particular focus on sleep-related changes and its role in stress-related conditions, like major depression. RESULTS: We highlight its role in functional systems which could be relevant in the therapy for refractory depression, like inflammatory mechanisms, the monoaminergic and the glutamatergic systems. Furthermore, anatomic areas which specifically mediate the action of aldosterone have been identifi ed. In particular the nucleus of the solitary tract (NTS) seems to have an important role and appears to be a target for antidepressive manipulations, like vagus nerve stimulation. Clinical data demonstrating the efficacy of aldosterone-reducing strategies for specific depressive syndromes are reviewed. DISCUSSION: In particular aspects of differentiation between melancholic vs. atypical depression spectrum disorders are discussed.

Asunto(s)

Depresión/fisiopatología , Hormonas/fisiología , Sistema Renina-Angiotensina/fisiología , Trastornos del Sueño-Vigilia/fisiopatología , Estrés Psicológico/fisiopatología , Humanos

RESUMEN

Sub-chronic tryptophan depletion (SCTD) is proposed as an animal model for depression. Aims were to test the hypothesis and optimise the time of SCTD-induced depression-related behaviour and associated biochemical changes. Sprague Dawley rats were treated with a low tryptophan (TRP) containing diet for 0, 7 or 14 days. Peripheral and central neurochemical markers were measured. SCTD-induced depression-related behaviour was assessed by the forced swim test (FST). Model sensitivity to antidepressants was tested by concomitant treatment with paroxetine. SCTD-induced significant reductions in weight gain and measures of peripheral and central TRP. Corticosterone, aldosterone and kynurenine (K), increased whilst kynurenic acid (KA), an NMDA antagonist decreased. 5-HT(2) receptor binding Bmax was enhanced but was reversed by paroxetine. Corticosterone and aldosterone were significantly negatively-correlated to weight gain. SCTD increased floating time and reduced swimming time in the FST but were reversed by paroxetine. Aldosterone was increased at 7 and 14 days, whereas other changes maximised at 14 days. Aldosterone may be an early marker or causal link for depression development. Increased corticosterone and brain tissue 5-HT-receptor density may be correlates of depressive behaviour. Consequential increases in NMDA signalling through increased K/KA ratios suggest the model may be useful for testing novel antidepressants.

Asunto(s)

Depresión/etiología , Triptófano/deficiencia , Aldosterona/sangre , Análisis de Varianza , Animales , Peso Corporal/fisiología , Encéfalo/metabolismo , Proteínas de Unión al Calcio/sangre , Catecolaminas/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Corticosterona/sangre , Proteínas de Unión al ADN/sangre , Depresión/patología , Dieta/efectos adversos , Modelos Animales de Enfermedad , Ácido Quinurénico/metabolismo , Quinurenina/metabolismo , Quinurenina/farmacocinética , Masculino , Proteínas del Tejido Nervioso/sangre , Nucleobindinas , Paroxetina/uso terapéutico , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Natación/psicología , Factores de Tiempo , Tritio/farmacocinética

RESUMEN

A dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis represents a prominent finding in major depression, possibly related to a dysfunction of the corticosteroid receptor system. Antidepressants are involved in the restoration of the altered feed-back mechanism of the HPA-axis, probably via normalization of corticosteroid receptor functions. Since Hypericum perforatum has antidepressive properties, we here examined its putative actions on glucocorticosteroid receptor mRNA levels in human blood cells as a peripheral model for neuroendocrine effects in human brain cells. Our data show that Hypericum (LI 160) affects the cellular mRNA levels of both, the glucocorticoid receptor (GR)-α and its inhibitory counterpart, the GR-ß, at clinically-relevant concentrations. Under these conditions, a bimodal effect was observed. Dose-response studies suggest a rather small effective concentration range and time-effect data show a primary and transient up-regulation of GR-α mRNA levels and a down-regulation of GR-ß mRNA levels after 16 h of treatment. The sodium channel blocker benzamil neutralized the effects of Hypericum, pointing to an at least partial mechanism of action via this pathway. In conclusion, Hypericum treatment differentially affects GR-mRNA levels in the human system. Our data suggest a bimodal effect on GR, resulting in a time-and dose-related modification of GR-mediated cellular effects. Such a mechanism has been alleged as an important way of action for a number of antidepressants. It is the first time that a specific effect on both receptors, especially on the subtype of GR-ß, is shown under antidepressive treatment in a human system under in vitro conditions.

Asunto(s)

Regulación de la Expresión Génica/efectos de los fármacos , Hypericum/química , Monocitos/efectos de los fármacos , Extractos Vegetales/farmacología , ARN Mensajero/metabolismo , Receptores de Esteroides/genética , Amilorida/análogos & derivados , Amilorida/farmacología , Línea Celular Transformada , Coccidiostáticos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Monensina/farmacología , Receptores de Esteroides/clasificación , Receptores de Esteroides/metabolismo , Bloqueadores de los Canales de Sodio/farmacología

RESUMEN

OBJECTIVE: This multicenter, cross-sectional study was conducted to determine the sensitivity and specificity of a 9-item Wearing-off Questionnaire (WOQ-9) compared with assessment by a clinician. METHODS: Patients with a diagnosis of Parkinson's disease (PD) for 5 or=90 days, completed the WOQ-9 before independent evaluation by the physician. RESULTS: One hundred fifty-seven patients reported WO using the WOQ-9; only 79 had been previously diagnosed with WO by a physician. The most frequent items used by physicians to diagnose WO included type of symptoms (69.6%), symptom response (63.3%), and timing of symptom response (58.2%) to medication. Physician assessment of WO and WOQ-9 results corresponded in 76 of 79 cases; physicians disagreed with WO identification in 81 of 157 cases. Sensitivity of the WOQ-9 was 96.2% and specificity was 40.9%. CONCLUSION: The WOQ-9 is a useful screening tool to aid diagnosis of WO in PD patients.

Asunto(s)

Evaluación de la Discapacidad , Resistencia a Medicamentos/fisiología , Evaluación de Resultado en la Atención de Salud , Enfermedad de Parkinson/fisiopatología , Encuestas y Cuestionarios , Anciano , Antiparkinsonianos/uso terapéutico , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Estudios Retrospectivos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad

RESUMEN

OBJECTIVE: The aim of the present study was to measure the effect of two doses of extracts from Hypericum perforatum (HP), Jarsin, on evening salivary cortisol and NA-mediated melatonin in healthy male volunteers. METHODS: Twenty healthy male volunteers were randomly given a low or high dose of Jarsin for 7 days. Saliva samples for cortisol and melatonin, and overnight urine samples were collected for cortisol and 6-sulfatoxymelatonin and measured by specific radioimmunoassays. RESULTS: Treatment significantly increased salivary cortisol throughout the whole collection period in the low dose group but had no discernable effect in the high dose group. Salivary melatonin was not increased in either dose group following treatment. CONCLUSION: Salivary cortisol was enhanced in the low dose group only and melatonin was not affected by either treatment. We suggest that HP may enhance salivary cortisol via a U-shaped dose-response relationship and that this may be mediated through a 5-HT2 mechanism.

Asunto(s)

Hidrocortisona/metabolismo , Hypericum , Melatonina/metabolismo , Saliva/metabolismo , Adulto , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Melatonina/análogos & derivados , Melatonina/sangre , Proyectos Piloto , Extractos Vegetales/farmacología , Radioinmunoensayo , Saliva/efectos de los fármacos

RESUMEN

BACKGROUND: Changes in the activity of the renin-angiontensin-aldosterone system (RAAS) in depression have recently been reported. Renin and aldosterone secretion are coupled to sleep in healthy subjects. As total sleep deprivation (TSD) leads to a rapid mood improvement in patients with depression, it is of interest to investigate its effect on the response of the RAAS in the recovery night in this population as a possible probe for the neurobiological effects of TSD and potentially other rapid acting antidepressive interventions. Additionally we explored the HPA-system and the sleep-EEG-changes. METHODS: We compared the sleep related activity of the RAAS before and after TSD in seven depressed patients. After an accommodation night, a polysomnographic examination was performed between 23.00 h and 7.00 h. This was followed by 40 h of TSD and a second polysomnography. During the examination blood samples were taken in the night every 20 min for analysis of renin, aldosterone, ACTH and cortisol. RESULTS: During recovery-sleep renin was significantly increased (p < 0.05). Aldosterone showed no change. ACTH and cortisol were decreased by trend in the first half of the night. REM-density and intermittent wakefulness was significantly decreased (p < 0.05), whereas slow wave sleep increased by trend in the first half of the night. CONCLUSION: TSD in patients with depression leads to an increase in renin secretion and a concomitant trend for a decrease in HPA axis activity in the recovery night. These changes could be a "fingerprint" of a rapidly antidepressive treatment.

Asunto(s)

Trastorno Depresivo/fisiopatología , Trastorno Depresivo/terapia , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Sistema Renina-Angiotensina/fisiología , Privación de Sueño/fisiopatología , Hormona Adrenocorticotrópica/sangre , Adulto , Anciano , Aldosterona/sangre , Trastorno Depresivo/sangre , Electroencefalografía , Femenino , Hormonas/sangre , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Renina/sangre , Sueño/fisiología

RESUMEN

BACKGROUND: Preliminary evidence suggests beneficial effects of pure ethyl-eicosapentaenoate (ethyl-EPA) in Huntington disease (HD). METHODS: A total of 135 patients with HD were randomized to enter a multicenter, double-blind, placebo-controlled trial on the efficacy of 2 g/d ethyl-EPA vs placebo. The Unified Huntington's Disease Rating Scale (UHDRS) was used for assessment. The primary end point was outcome at 12 months on the Total Motor Score 4 subscale (TMS-4). Analysis of covariance (ANCOVA) and a chi2 test on response, defined as absence of increase in the TMS-4, were performed. RESULTS: A total of 121 patients completed 12 months, and 83 did so without protocol violations (PP cohort). Intent-to-treat (ITT) analysis revealed no significant difference between ethyl-EPA and placebo for TMS-4. In the PP cohort, ethyl-EPA proved better than placebo on the chi2 test on TMS-4 (p < 0.05), but missed significance on ANCOVA (p = 0.06). Secondary end points (ITT cohort) showed no benefit of ethyl-EPA but a significantly worse outcome in the behavioral severity and frequency compared with placebo. Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats. Reported adverse events were distributed equally between treatment arms. CONCLUSIONS: Ethyl-eicosapentaenoate (ethyl-EPA) (purity > 95%) had no benefit in the intent-to-treat cohort of patients with Huntington disease, but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort, treated with ethyl-EPA, showed stable or improved motor function. Further studies of the potential efficacy of ethyl-EPA are warranted.

Asunto(s)

Ácido Eicosapentaenoico/análogos & derivados , Enfermedad de Huntington/tratamiento farmacológico , Fármacos Neuroprotectores/administración & dosificación , Adulto , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Estudios de Cohortes , Método Doble Ciego , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/efectos adversos , Femenino , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/fisiopatología , Masculino , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Movimiento/efectos de los fármacos , Movimiento/fisiología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/prevención & control , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Efecto Placebo , Resultado del Tratamiento

RESUMEN

BACKGROUND: Reboxetine is a novel selective noradrenaline reuptake inhibitor. The antidepressive properties of the substance are established. METHODS: The influence of reboxetine on the sleep-EEG of eight patients with depression HAMD (mean +/- SD) 19.7 +/- 1.5 (5 women, 3 men; age range 31 to 75 years) was investigated. Sleep EEG was examined twice. The first examination was performed before starting active medication. The second examination was subsequently performed when patients received 8 to 10 mg reboxetine per day. RESULTS: Conventional sleep-EEG analysis showed a significant increase in intermittent wakefulness and sleep stage 2 and a decrease in sleep efficiency and REM time. Under reboxetine no significant changes were observed in sleep-EEG spectral analysis. CONCLUSION: Our results indicate, that reboxetine induces sleep-EEG changes similar to those after selective serotonin reuptake inhibitors (SSRI's) by increasing intermittent wakefulness and decreasing REM time.

Asunto(s)

Inhibidores de Captación Adrenérgica/farmacología , Inhibidores de Captación Adrenérgica/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Electroencefalografía/efectos de los fármacos , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Morfolinas/efectos adversos , Morfolinas/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Fases del Sueño/efectos de los fármacos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reboxetina , Vigilia/efectos de los fármacos

RESUMEN

Well documented changes of sleep electroencephalogram (EEG) in patients with depression include rapid eye movement (REM) sleep disinhibition, decreases of slow-wave-sleep (SWS) and increase in wakefulness. Twenty-seven inpatients with major depression were admitted subsequently to a clinical trial with the CRH(1)-receptor-antagonist R121919 administered in two different dose escalation panels. A random subgroup of 10 patients underwent three sleep-EEG recordings (baseline before treatment, at the end of the first week and at the end of the fourth week of active treatment). SWS time increased significantly compared with baseline after 1 week and after 4 weeks. The number of awakenings and REM density showed a trend toward a decrease during the same time period. Separate evaluation of these changes for both panels showed no significant effect at lower doses, whereas in the higher doses after R121919 REM density decreased and SWS increased significantly between baseline and week 4. Furthermore positive associations between HAMD scores and SWS at the end of active treatment were found. Although these data might indicate that R121919 has a normalizing influence on the sleep EEG, the design of the study does not allow to differentiate genuine drug effects from those of clinical improvement and habituation to the clinical setting.

Asunto(s)

Trastorno Depresivo/complicaciones , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Trastornos del Sueño-Vigilia/etiología , Administración Oral , Adulto , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento

RESUMEN

The long-acting somatostatin (SRIF) analogue octreotide decreased nonrapid eye movement sleep (NREMS) in the rat. This effect is opposite to the promotion of sleep after growth hormone (GH)-releasing hormone (GHRH) in various species including humans. Therefore, it appears likely that GHRH and SRIF, besides their opposite action on pituitary GH release, interact reciprocally in sleep regulation. In previous studies, SRIF impaired sleep in elderly subjects, although sleep in young men remained unchanged. We hypothesized that octreotide is a useful tool to study the role of SRIF in human sleep regulation. We examined the effect of subcutaneous administration of 0.1 mg octreotide at 2245 on the sleep EEG of seven young male controls (age, mean+/-SD, 22.3+/-3.0 years). In comparison to placebo, octreotide administration prompted decreases of sleep stage 4 during the total night and of rapid eye movement sleep (REMS) density during the first half of the night. Intermittent wakefulness increased during the second half of the night. The spectral analysis of total night NREMS revealed a significant decrease of sigma power. Similar to the effect of the short-acting SRIF in the elderly, the long-acting SRIF analogue octreotide impaired sleep in young healthy subjects. Obviously, the influence of octreotide on sleep is superior to that of short-acting SRIF, which did not affect sleep in young men. We suggest a reciprocal interaction of GHRH and SRIF in sleep regulation.

Asunto(s)

Electroencefalografía/efectos de los fármacos , Octreótido/farmacología , Trastornos del Sueño-Vigilia/inducido químicamente , Adolescente , Adulto , Método Doble Ciego , Humanos , Masculino , Octreótido/efectos adversos , Fases del Sueño/efectos de los fármacos , Somatostatina/análogos & derivados , Factores de Tiempo

RESUMEN

Aging and menopause are associated with alterations of the sleep EEG, while age-related changes of the hypothalamo-pituitary-adrenal (HPA) axis remain controversial. Major depression is also associated with typical sleep-endocrine changes, including enhanced activity of the HPA axis, while an influence of age and gender on these alterations is less clear. To test the hypothesis that after menopause sleep-endocrine alterations associated with major depression are accentuated, we examined the sleep EEG and nocturnal hormone secretion (ACTH, cortisol, GH, estradiol, LH, FSH, and leptin) in 16 drug-free female patients, mostly with the first episode of a major depressive disorder (seven pre- and nine postmenopausal subjects) and 19 female controls (10 subjects in the early follicular phase and nine postmenopausal subjects). Nocturnal cortisol secretion was increased in postmenopausal patients with depression, while a decrease was noted in postmenopausal controls. Sleep alterations typically associated with depression, namely a reduction in sleep continuity and slow wave sleep (SWS) and an increase in REM density, were prominent in post- but not in premenopausal patients. An inverse correlation was noted between the decline in SWS and sleep continuity and FSH secretion in patients with depression, suggesting a role of menopause for these sleep-endocrine alterations typically associated with major depression. In contrast, in premenopausal patients we noted primarily a shift in SWS and delta-EEG activity from the first to the second non-REM period, which was not related to age or hormone secretion. Though the relatively small number of subjects per group precludes a definitive conclusion, our data open up the possibility that the sleep-endocrine changes typically associated with major depression are most prominent in postmenopausal patients. Whether the predominant alteration of the distribution of SWS and delta EEG activity in younger patients with a first episode of major depression has a predictive value for the future course of the disease remains to be investigated.

Asunto(s)

Trastorno Depresivo Mayor/fisiopatología , Hidrocortisona/sangre , Menopausia/fisiología , Hormonas Adenohipofisarias/sangre , Trastornos del Sueño-Vigilia/fisiopatología , Hormona Adrenocorticotrópica/sangre , Adulto , Anciano , Trastorno Depresivo Mayor/complicaciones , Electroencefalografía , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Hormona de Crecimiento Humana/sangre , Humanos , Leptina/sangre , Hormona Luteinizante/sangre , Análisis por Apareamiento , Menopausia/psicología , Persona de Mediana Edad , Polisomnografía , Trastornos del Sueño-Vigilia/complicaciones , Sueño REM/fisiología , Estadística como Asunto

RESUMEN

Tianeptine enhances while paroxetine inhibits serotonin reuptake into neurons; however, both show an antidepressive action. A subgroup of 38 depressed patients from a drug trial comparing the efficacy of tianeptine with that of paroxetine was studied with regard to their effects on sleep regulation, especially in relation to treatment response. We recorded sleep EEGs at day 7 and day 42 after the start of treatment with either compound, which allows measurement of changes due to the antidepressive medication in relation to the duration of treatment. Spectral analysis of the non-REM sleep EEG revealed a strong decline in the higher sigma frequency range (14-16 Hz) in male treatment responders independent of medication, whereas nonresponders did not show marked changes in this frequency range independent of gender. The patients receiving paroxetine showed less REM sleep and more intermittent wakefulness compared to the patients receiving tianeptine. REM density after 1 week of treatment was a predictor of treatment response in the whole sample. Psychopathological features with regard to the score in single items of the HAMD revealed predictive markers for response, some of which were opposite in the gender groups, especially those related to somatic anxiety. Changes in REM density were inversely correlated to the changes in HAMD in the paroxetine, but not the tianeptine, group. Our data suggest the importance of taking gender into account in the study of the biological effects of drugs. The study further points to the importance of the higher sigma frequency range in the sleep EEG of non-REM sleep and REM density as a marker of treatment response.

Asunto(s)

Trastorno Depresivo Mayor/tratamiento farmacológico , Electroencefalografía/efectos de los fármacos , Paroxetina/uso terapéutico , Sueño/fisiología , Tiazepinas/uso terapéutico , Adulto , Anciano , Análisis de Varianza , Biomarcadores , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/psicología , Electroencefalografía/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paroxetina/farmacología , Pacientes/estadística & datos numéricos , Factores Sexuales , Sueño/efectos de los fármacos , Tiazepinas/farmacología

RESUMEN

Atypical depression, somatoform disorder, neurasthenia and fibromyalgia seem to form a spectrum of disorders, who share a common biological basis, i.e. a reduced activity of the hypothalamus-pituitary-adrenocortical (HPA)-system. This is similar to the situation in Cushing's disease, where the central part of the hypothalamus-pituitary-adrenocortical-system is decreased by an increased feedback via increased intracerebral cortisol concentration. Cushing's disease is accompanied by features of atypical depression and of somatisation. Treatment with hypericum seems to disinhibit the hypothalamus-pituitary-adrenocortical-system in healthy subjects and patients with a depression. Furthermore it decreases intracerebral corticosteroids, possibly by increasing the expression of p-glycoprotein at the blood brain barrier. Therefore hypericum might be especially effective in patients with a symptom cluster of atypical depressive features and somatisation. Clinical studies with patients with depression with atypical features like the seasonal affective disorder (SAD) and with patients with a depressive syndrome accompanied by somatic complaints or fatigue support this view.

Asunto(s)

Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Fibromialgia/tratamiento farmacológico , Hypericum , Neurastenia/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Trastornos Somatomorfos/tratamiento farmacológico , Antidepresivos/efectos adversos , Ensayos Clínicos como Asunto , Trastorno Depresivo/psicología , Fibromialgia/psicología , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Neurastenia/psicología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Extractos Vegetales/efectos adversos , Trastornos Somatomorfos/psicología , Resultado del Tratamiento

RESUMEN

The process of normal aging is accompanied by changes in sleep-related endocrine activity. During aging, an increase in cortisol at its nadir and a decrease in renin and aldosterone concentration occur. In aged subjects, more time is spent awake and slow-wave sleep is reduced: there is a loss of sleep spindles and accordingly a loss of power in the sigma frequency range. Previous studies could show a close association between sleep architecture, especially slow-wave sleep, and activity in the glutamatergic and GABAergic system. Furthermore, recent studies could show that the natural N-methyl-D-aspartate (NMDA) antagonist and GABA(A) agonist Mg(2+) seems to play a key role in the regulation of sleep and endocrine systems such as the HPA system and renin-angiotensin-aldosterone system (RAAS). Therefore, we examined the effect of Mg(2+) in 12 elderly subjects (age range 60-80 years) on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. A placebo-controlled, randomised cross-over design with two treatment intervals of 20 days duration separated by 2 weeks washout was used. Mg(2+) was administered as effervescent tablets in a creeping dose of 10 mmol and 20 mmol each for 3 days followed by 30 mmol for 14 days. At the end of each interval, a sleep EEG was recorded from 11 p.m. to 7 a.m. after one accommodation night. Blood samples were taken every 30 min between 8 p.m. and 10 p.m. and every 20 min between 10 p.m. and 7 a.m. to estimate ACTH, cortisol, renin and aldosterone plasma concentrations, and every hour for arginine-vasopressin (AVP) and angiotensin 11 (ATII) plasma concentrations. Mg(2+) led to a significant increase in slow wave sleep (16.5 +/- 20.4 min vs. 10.1 +/- 15.4 min, < or =0.05), delta power (47128.7 microV(2) +21417.7 microV(2) vs. 37862.1 microV(2) +/- 23241.7 microV(2), p < or =0.05) and sigma power (1923.0 microV(2) + 1111.3 microV(2) vs. 1541.0 microV(2) + 1134.5 microV(2), p< or =0.05 ). Renin increased (3.7 +/- 2.3 ng/ml x min vs. 2.3 +/- 1.0 ng/ml x min, p < 0.05) during the total night and aldosterone (3.6 +/- 4.7 ng/ml x min vs. 1.1 +/- 0.9 ng/ml x min, p < 0.05) in the second half of the night, whereas cortisol (8.3 +/- 2.4 pg/ml x min vs. 11.8 +/- 3.8 pg/ml x min, p < 0.01) decreased significantly and AVP by trend in the first part of the night. ACTH and ATII were not altered. Our results suggest that Mg(2+) partially reverses sleep EEG and nocturnal neuroendocrine changes occurring during aging. The similarities of the effect of Mg(2+) and that of the related electrolyte Li+ furthermore supports the possible efficacy of Mg(2+) as a mood stabilizer.

Asunto(s)

Envejecimiento/sangre , Electroencefalografía/efectos de los fármacos , Hormonas/sangre , Compuestos de Magnesio/farmacología , Sueño/efectos de los fármacos , Administración Oral , Hormona Adrenocorticotrópica/sangre , Anciano , Envejecimiento/efectos de los fármacos , Aldosterona/sangre , Angiotensina II/sangre , Arginina Vasopresina/sangre , Estudios Cruzados , Suplementos Dietéticos , Esquema de Medicación , Femenino , Humanos , Hidrocortisona/sangre , Compuestos de Magnesio/administración & dosificación , Masculino , Persona de Mediana Edad , Renina/sangre , Fases del Sueño/efectos de los fármacos , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Trastornos del Sueño-Vigilia/etiología , Resultado del Tratamiento

RESUMEN

There are several findings on the action of magnesium ions supporting their possible therapeutic potential in affective disorders. Examinations of the sleep-electroencephalogram (EEG) and of endocrine systems point to the involvement of the limbic-hypothalamus-pituitary-adrenocortical axis as magnesium affects all elements of this system. Magnesium has the property to suppress hippocampal kindling, to reduce the release of adrenocorticotrophic hormone (ACTH) and to affect adrenocortical sensitivity to ACTH. The role of magnesium in the central nervous system could be mediated via the N-methyl-D-aspartate-antagonistic, gamma-aminobutyric acidA-agonistic or a angiotensin II-antagonistic property of this ion. A direct impact of magnesium on the function of the transport protein p-glycoprotein at the level of the blood-brain barrier has also been demonstrated, possibly influencing the access of corticosteroids to the brain. Furthermore, magnesium dampens the calciumion-proteinkinase C related neurotransmission and stimulates the Na-K-ATPase. All these systems have been reported to be involved in the pathophysiology of depression. Despite the antagonism of lithium to magnesium in some cell-based experimental systems, similarities exist on the functional level, i.e. with respect to kindling, sleep-EEG and endocrine effects. Controlled clinical trials examining the effect of Mg in affective disorder are warranted.

Asunto(s)

Magnesio/fisiología , Trastornos del Humor , Glándulas Suprarrenales , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/fisiología , Electroencefalografía , Hipocampo , Homeostasis , Humanos , Hipotálamo , Excitación Neurológica , Litio/uso terapéutico , Locus Coeruleus , Magnesio/administración & dosificación , Magnesio/uso terapéutico , Trastornos del Humor/tratamiento farmacológico , Hipófisis , Sueño

RESUMEN

RATIONALE: EMD 68843 (EMD) has properties of a serotonin (5-HT)-reuptake inhibitor and a partial 5-HT1A agonist in one molecule in order to combine antidepressive and anxiolytic properties. OBJECTIVE: We investigated the effects of EMD on the sleep EEG in order to characterize how the complex interaction between these two properties influences the sleep EEG. METHODS: We performed a randomized crossover study in ten young normal male controls (20-30 years), receiving a single dose of 20 mg EMD or placebo orally at 2100 hours. Sleep EEG was recorded from 2300 to 0700 hours. RESULTS: After EMD, rapid eye movement (REM) sleep was nearly totally abolished. In the course of the night other effects on the sleep EEG occurred in distinct intervals. Slow wave sleep and EEG delta power increased in the first and third one-third of the night, whereas wakefulness was enhanced in the second and third one-third of the night. CONCLUSION: The sleep EEG effects of EMD fit with its pharmacological profile, which might lead to adaptive changes suggested to characterize an antidepressive substance.

Asunto(s)

Benzofuranos/farmacología , Electroencefalografía/efectos de los fármacos , Indoles/farmacología , Receptores de Serotonina/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Adulto , Benzofuranos/efectos adversos , Estudios Cruzados , Método Doble Ciego , Humanos , Indoles/efectos adversos , Masculino , Piperazinas , Receptores de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Factores de Tiempo , Clorhidrato de Vilazodona

RESUMEN

Anxiolytic and sedative effects of neuropeptide Y (NPY) are thought to involve inhibition of corticotropin-releasing hormone (CRH). Enhanced secretion of CRH plays a critical role in the pathophysiology of major depression, characterized by sleep disturbances, anxiety and loss of appetite. We examined for the first time in young men effects of intravenous injections of NPY (4x50 or 100 microg, n = 9 and 11, respectively, at 22.00, 23.00, 24. 00 and 01.00 compared to saline) on the sleep electroencephalogram (EEG; recorded from 23.00 to 07.00) and nocturnal secretion of adrenocorticotrophic hormone (ACTH), cortisol, growth hormone (GH), prolactin and leptin. Repeated measures MANOVA showed that ACTH secretion during the first half of the night was reduced by the lower dose of NPY only (F = 8.7, p<0.05), while cortisol secretion during the second half of the night was reduced regardless of the dose (F = 7.9, p<0.05). Regardless of the dose, NPY enhanced sleep period time and stage 2 sleep (F = 12.8 and 5.4, each p<0.05), and also reduced sleep latency and time awake (F = 4.9 and 4.4, each p<0.05) and modulated REM sleep. In summary, NPY promotes sleep and inhibits the hypothalamo-pituitary-adrenocortical (HPA) axis in humans, pointing to a possible role of NPY agonists for the development of novel treatment strategies for affective disorders.

Asunto(s)

Hormona Adrenocorticotrópica/efectos de los fármacos , Hidrocortisona/sangre , Neuropéptido Y/farmacología , Fases del Sueño/efectos de los fármacos , Hormona Adrenocorticotrópica/sangre , Adulto , Apetito/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Ritmo Circadiano , Electroencefalografía , Hormona del Crecimiento/sangre , Hormona del Crecimiento/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Leptina/sangre , Masculino , Prolactina/sangre , Prolactina/efectos de los fármacos , Fases del Sueño/fisiología

RESUMEN

The process of the human non-rapid eye movement (non-REM) sleep period has not been clarified. Time-based analysis on sleep EEG may provide an explanation. We focused on chronological aspects of initiation and termination of non-REM episodes, using spectral analysis of sleep EEG. The subjects were healthy male volunteers (n14 Hz) and longer in lower frequency ranges (<14 Hz). There were significant differences in the rise and decay latencies between low and high sigma ranges, indicating that the whole frequency ranges were clearly separated at the middle of the sigma range (14 Hz). The rise and decay latencies were significantly different in lower frequency ranges. The clock time of the night significantly affected only the rise latencies of the delta (0.78-3.9 Hz), alpha (8.2-11.7 Hz) and low sigma (12.1-13.7 Hz) ranges. In conclusion, initiation and termination of non-REM sleep was represented by higher frequency ranges, whereas further evolution and devolution of non-REM sleep was represented by lower frequency ranges, and only the evolution process was affected by the clock time of the night.

Asunto(s)

Electroencefalografía , Sueño/fisiología , Adulto , Análisis de Varianza , Humanos , Masculino

RESUMEN

In patients with depression, enhanced secretion of ACTH and cortisol, a reduction in slow wave sleep (SWS) and a blunted nocturnal growth hormone (GH) surge have been described and attributed, at least partly, to an elevation of corticotropin-releasing hormone (CRH), hence a shift in the ratio between growth hormone-releasing hormone (GHRH) and CRH. We investigated the effects of pulsatile administration of GHRH (4x50 microgram, at hourly intervals between 2200 and 0100 h) on the sleep EEG (2300-0700 h) in patients with depression (16 females, 19 males, age range 19-76 years) and matched controls (20 females, 20 males). In patients compared with controls, NREM sleep and in particular stage 2 sleep was greatly decreased at baseline. GHRH treatment enhanced NREM sleep, and in particular stage 2 sleep in men, regardless of diagnosis, while decreasing it in women (F=6.0 and 7.1, p<0.05). In controls, aging was associated with a decrease in NREM sleep, including both SWS and stage 2 sleep (r= -0.45 r= -0.39, p<0.05), while in patients only SWS declined with age (r= -0.49, p<0.05). The significant decrease in NREM sleep including stage 2 sleep in patients with depression and elderly control subjects is compatible with the suggested role of sleep continuity and stage 2 sleep in cognitive functioning. GHRH promoted NREM sleep, stage 2 sleep and sleep continuity and might prove beneficial for improvement of cognitive function, at least in men. These data support the hypothesis that female gender, aging and depression are associated with a shift in the GHRH/CRH ratio towards CRH.

Asunto(s)

Depresión/fisiopatología , Electroencefalografía/efectos de los fármacos , Hormona Liberadora de Hormona del Crecimiento/administración & dosificación , Sueño/efectos de los fármacos , Adulto , Anciano , Envejecimiento/fisiología , Demografía , Depresión/diagnóstico , Depresión/tratamiento farmacológico , Sistema Endocrino/efectos de los fármacos , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Polisomnografía , Factores Sexuales , Procesamiento de Señales Asistido por Computador , Fases del Sueño/efectos de los fármacos , Vigilia/efectos de los fármacos