M. Ziegenbein

Intravenous administration of the neuropeptide galanin has fast antidepressant efficacy and affects the sleep EEG

OBJECTIVE Recently, we demonstrated that the intravenous administration of the neuropeptide galanin acts on the sleep EEG of healthy young subjects similar to sleep deprivation. As this effect could imply an antidepressive potency we studied the effect of intravenous galanin administration on psychopathology and sleep EEG in patients with depression. METHODS Galanin was administered to 10 patients with depression, who were on a stable dose of trimipramine. A placebo controlled double blind randomized design was used. Intravenous boli of galanin in a dose of 4 x 50 microg or placebo were administered hourly between 09:00 and 12:00 h. Galanin or placebo, respectively were administered on 2 days each. The sequence of the galanin or placebo days was randomized, allowing for various crossovers. The Hamilton depression rating scale score (HAMD) was performed 30 min before the first and 30 min after the last injection. The mean of the HAMD change between 08:30 and 12:30 h was chosen as primary efficacy variable. Sleep EEGs were recorded once post placebo treatment and once post verum treatment. In this case, recordings started at 23:00 h and ended at 07:00 h the next morning. RESULTS The HAMD-difference between 08:30 and 12:30 h was significantly greater at the days of galanin-treatment compared to placebo-treatment. MANOVA revealed a significant change in sleep-EEG parameters (p < 0.05), mainly due to an increase in REM-latency (p < 0.06). CONCLUSION The data provide preliminary evidence for an acute antidepressive efficacy of galanin, probably by a mechanism related to that of therapeutic sleep deprivation.

The Renin-Angiotensin-Aldosterone system in patients with depression compared to controls - a sleep endocrine study

BackgroundHypercortisolism as a sign of hypothamamus-pituitary-adrenocortical (HPA) axis overactivity and sleep EEG changes are frequently observed in depression. Closely related to the HPA axis is the renin-angiotensin-aldosterone system (RAAS) as 1. adrenocorticotropic hormone (ACTH) is a common stimulus for cortisol and aldosterone, 2. cortisol release is suppressed by mineralocorticoid receptor (MR) agonists 3. angiotensin II (ATII) releases CRH and vasopressin from the hypothalamus. Furthermore renin and aldosterone secretion are synchronized to the rapid eyed movement (REM)-nonREM cycle.MethodsHere we focus on the difference of sleep related activity of the RAAS between depressed patients and healthy controls. We studied the nocturnal plasma concentration of ACTH, cortisol, renin and aldosterone, and sleep EEG in 7 medication free patients with depression (1 male, 6 females, age: (mean +/-SD) 53.3 ± 14.4 yr.) and 7 age matched controls (2 males, 5 females, age: 54.7 ± 19.5 yr.). After one night of accommodation a polysomnography was performed between 23.00 h and 7.00 h. During examination nights blood samples were taken every 20 min between 23.00 h and 7.00 h. Area under the curve (AUC) for the hormones separated for the halves of the night (23.00 h to 3.00 h and 3.00 h to 7.00 h) were used for statistical analysis, with analysis of co variance being performed with age as a covariate.ResultsNo differences in ACTH and renin concentrations were found. For cortisol, a trend to an increase was found in the first half of the night in patients compared to controls (p < 0.06). Aldosterone was largely increased in the first (p < 0.05) and second (p < 0.01) half of the night. Cross correlations between hormone concentrations revealed that in contrast to earlier findings, which included only male subjects, in our primarily female sample, renin and aldosterone secretion were not coupled and no difference between patients and controls could be found, suggesting a gender difference in RAAS regulation. No difference in conventional sleep EEG parameters were found in our sample.ConclusionHyperaldosteronism could be a sensitive marker for depression. Further our findings point to an altered renal mineralocorticoid sensitivity in patients with depression.

The somatostatin analogue octreotide impairs sleep and decreases EEG sigma power in young male subjects

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.

Structure and activity of the only human RNase T2

Mutations in the gene of human RNase T2 are associated with white matter disease of the human brain. Although brain abnormalities (bilateral temporal lobe cysts and multifocal white matter lesions) and clinical symptoms (psychomotor impairments, spasticity and epilepsy) are well characterized, the pathomechanism of RNase T2 deficiency remains unclear. RNase T2 is the only member of the Rh/T2/S family of acidic hydrolases in humans. In recent years, new functions such as tumor suppressing properties of RNase T2 have been reported that are independent of its catalytic activity. We determined the X-ray structure of human RNase T2 at 1.6 Å resolution. The α+β core fold shows high similarity to those of known T2 RNase structures from plants, while, in contrast, the external loop regions show distinct structural differences. The catalytic features of RNase T2 in presence of bivalent cations were analyzed and the structural consequences of known clinical mutations were investigated. Our data provide further insight into the function of human RNase T2 and may prove useful in understanding its mode of action independent of its enzymatic activity.

266. Treatment with the presynaptic 5-HT1A-antagonist pindolol in patients with panic disorder

SSRIs like paroxetine play an important role in the treatment of patients with panic disorder. It is striking to observe that at the beginning of the treatment an exacerbation of the symptoms occurs, usually in the form of an increase in the number of spontaneous attacks. It is known that at the beginning of the treatment with SSRIs the activity of serotonergic neurons in the nucleus raphe dorsalis (DRN) is suppressed via 5-HT 1A autoreceptors, therefore inhibiting serotonin (5HT) tone in projection areas (Romero et al., 1996). As locus coeruleus (LC) neurons are suppressed by 5-HT from the DRN and their activation accompanies anxiety, the increase in anxiety in panic disorder could be mediated via the inhibition of DRN-neurons. We therefore studied the effect of the presynaptic 5-HT1A/b-adrenergic antagonist pindolol on the clinical response in 3 inpatients (2 male, 1 female) with spontaneous panic attacks. All were diagnosed as suffering from panic disorder according to the DSM-IV criteria. It was ensured that these patients did not have a history of asthma or low blood pressure. We gave pindolol, 2.5mg three times daily in combination with an SSRI (10 mg paroxetine or citalopram at the beginning). The patients took the pindolol and SSRI regimen without reporting untoward side effects. An increase of spontaneous panic attacks was not found. All patients had a marked improvement of panic symptoms and remitted quickly. Our results indicate that pindolol addition to SSRIs is highly effective in reducing panic symptomatology.

Sleep-endocrine effects of growth hormone-releasing hormone (GHRH) in patients with schizophrenia

Changes in sleep-EEG after endocrine stimulation tests in patients with schizophrenia include reduced sleep efficiency, prolonged sleep latency and increased awaking after sleep onset Findings on sleep associated growth hormone (GH) secretion were ambiguous. The aim of this study was to elucidate the sleep-endocrine activity especially in the GH system of patients with schizophrenia after repeated administration of GHRH. The effect of repetitive injections of 4 × 50 μg GHRH between 22.00 and 01.00 h on sleep endocrine parameters was investigated in 9 patients diagnosed for schizophrenia. Patients did not receive any medication for one week. Concentrations of ACTH, cortisol, prolactin and GH were determined. Patients spent three consecutive nights in the sleep laboratory. Blood was taken every 20min. Results were compared with matched healthy controls. A non-significant prolonged sleep onset latency and increased time awake was found in patients compared to controls. Sleep stage 2 was significantly reduced in patients. No significant difference in ACTH and cortisol was detected, whereas the GH secretion in patients following GHRH stimulation was significantly elevated compared to controls. Our results in drug free patients confirm already known changes in sleep-EEG in these patients. The GH response to GHRH-stimulation indicates a different regulatory sensitivity of the system between daytime and night-time.