H. Murck

Clinical and neurobiological effects of tianeptine and paroxetine in major depression

Selective serotonin reuptake inhibitors (SSRIs) are widely used as effective pharmacological agents to treat depressive disorders. In contrast to the SSRIs, which block the presynaptic serotonin (5-HT) transporter and by this route increase the concentration of serotonin in the synaptic cleft, the antidepressant tianeptine enhances the presynaptic neuronal reuptake of 5-HT and thus decreases serotonergic neurotransmission. Both SSRIs and tianeptine are clinically effective; however, their opposite modes of action challenge the prevailing concepts on the need of enhancement of serotonergic neurotransmission. To better understand the differences between these two opposite pharmacological modes of action, we compared the changes induced by tianeptine and paroxetine on psychopathology, the hypothalamic-pituitary-adrenocortical (HPA) system, and cognitive functions in a double-blind, randomized, controlled trial including 44 depressed inpatients over a period of 42 days. Depressive symptomatology significantly improved in all efficacy measures, with no significant differences between tianeptine and paroxetine. There was a trend toward better response to the SSRI among women. Assessment of the HPA system showed marked hyperactivity before the beginning of treatment, which then normalized in most of the patients, without significant differences between the two antidepressants. Cognitive assessments showed no significant differences between the two drugs investigated. The results of the current study suggest that the initial effect, i.e., enhancement or decrease of 5-HT release, is only indirectly responsible for antidepressant efficacy, and they support the notion that downstream adaptations within and between nerve cells are crucial. The normalization of the HPA system as a common mode of action of different antidepressants seems to be of special interest.

Elevated nocturnal profiles of serum leptin in patients with depression

Leptin, the protein product of the obese (ob) gene, has been suggested to play a role in the regulation of food intake. As depressive episodes are frequently characterized by loss of appetite, reduced food intake and weight loss, altered leptin secretion might also be expected in patients with depression. Therefore, we examined nocturnal (10.00 p.m. to 7.00 a.m.) secretion of leptin, cortisol, ACTH and growth hormone (GH) in a group of 15 patients with depression and age- and sex-matched controls (age range 23-71 years). In addition, the effects of pulsatile administration of growth hormone-releasing hormone (GHRH), thought to be an endogenous antagonist of corticotropin-releasing hormone (CRH), which in turn is believed to play a critical role for the pathophysiology of depression, on nocturnal hormone secretion were assessed. Patients with depression showed a trend towards elevated nocturnal cortisol secretion (F = 3.8, p < 0.05). Nocturnal serum leptin was significantly higher in patients, despite a reported weight loss (F = 8, p < 0.05), but showed the same sexual dimorphism as in controls (F = 20.9, p < 0.01). No significant differences were seen between patients and controls with regard to plasma GH and ACTH. GHRH treatment increased GH secretion in both patients and controls, while the other hormones were not affected. Furthermore, serum leptin was correlated with body mass index (BMI) in controls, but not in patients with depression, supporting an altered regulation of leptin secretion in depressive illness. Finally, we provide some evidence that in young female patients the normal nocturnal leptin surge is blunted. As glucocorticoids can prevent the fasting-induced decline in serum leptin, we propose that hypercortisolism in depression might counteract the reduction in leptin secretion caused by decreased food intake and weight loss. Elevated serum leptin in depression might in turn further promote CRH release, as shown in animals and, hence, contribute to HPA system hyperactivity seen in depression.

A double-blind, randomized trial of St John's wort, fluoxetine, and placebo in major depressive disorder

Objective: This study looks to compare the antidepressant efficacy and safety of a standardized extract of St Johns wort with both placebo and fluoxetine. Method: After a 1-week single-blind washout, patients with major depressive disorder diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were randomized to 12 weeks of double-blind treatment with LI-160 St Johns wort extract (900 mg/d), fluoxetine (20 mg/d), or placebo. The 17-item Hamilton Rating Scale for Depression (HAMD-17) was the primary efficacy measure, and analysis of covariance was used to compare differences in end point HAMD-17 scores across the 3 treatment groups, treating the baseline HAMD-17 as the covariate. Results: One hundred thirty-five patients (57% women; mean age, 37.3 ± 11.0; mean HAMD-17, 19.7 ± 3.2) were randomized to double-blind treatment and were included in the intent-to-treat analyses. Analysis of covariance analyses showed lower mean HAMD-17 scores at end point in the St Johns wort group (n = 45; mean ± SD, 10.2 ± 6.6) compared with the fluoxetine group (n = 47; 13.3 ± 7.3; P < 0.03) and a trend toward a similar finding relative to the placebo group (n = 43; 12.6 ± 6.4; P = 0.096). There was also a trend toward higher rates of remission (HAMD-17 <8) in the St Johns wort group (38%) compared with the fluoxetine group (30%) and the placebo group (21%). Overall, St Johns wort appeared to be safe and well tolerated. Conclusion: St Johns wort was significantly more effective than fluoxetine and showed a trend toward superiority over placebo. A (25%) smaller than planned sample size is likely to account for the lack of statistical significance for the advantage (indicating a moderate effect size, d = 0.45) of St Johns wort over placebo.

Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man.

The synthetic hexapeptide growth hormone-releasing peptide (GHRP-6) stimulates growth hormone (GH) release in animals and man. GH-releasing hormone (GHRH) has the same effect. In addition, pulsatile administration of GHRH in normal men results in increased slow-wave sleep (SWS) and blunted cortisol levels. The effect of GHRP on nocturnal hormone secretion and on the sleep electroencephalogram (EEG) is still unknown. We compared the effect of repetitive i.v. boluses (4 x 50 micrograms) of GHRP and placebo (PL) on the sleep EEG (23.00 to 07.00 h) and on the secretion profiles of GH, ACTH and cortisol (20.00 to 07.00 h) in normal male controls. After GHRP, the GH concentration (22.00 to 03.00 h) increased (15.4 +/- 9.6 ng/ml after GHRP vs. 5.5 +/- 4.0 ng/ml after PL, p < 0.02), as did the ACTH level (22.00 to 02.00 h: 21.0 +/- 5.3 pg/ml after GHRP vs. 16.6 +/- 3.1 pg/ml after PL, p < 0.02). During the total night, and particularly during the first half of the night, cortisol secretion was enhanced (22.00 to 03.00 h: 56.0 +/- 31.0 ng/ml after GHRP vs. 25.2 +/- 9.0 ng/ml after PL, p < 0.02). Stage 2 sleep increased (270.1 +/- 25.3 min after GHRP vs. 245.4 +/- 25.8 min after PL, p < 0.02), whereas other sleep-EEG variables including SWS remained unchanged. Our data demonstrate that GHRP stimulates not only GH release but also hypothalamic-pituitary-adrenocortical hormone secretion. The latter effect is opposite to the blunting of cortisol after GHRH. Both GHRP and GHRH promote sleep. However, GHRP enhances stage 2 sleep and does not affect SWS.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men

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.

Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression.

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.

Effects of Hormones on Sleep

Administration of hormones to humans and animals results in specific effects on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. Studies with pulsatile administration of various neuropeptides in young and old normal controls and in patients with depression suggest they play a key role in sleep-endocrine regulation. Growth hormone (GH)-releasing hormone (GHRH) stimulates GH and slow wave sleep (SWS) and inhibits cortisol, whereas corticotropin-releasing hormone (CRH) exerts opposite effects. Changes in the GHRH:CRH ratio contribute to sleep-endocrine aberrations during normal ageing and acute depression. In addition, galanin and neuropeptide Y promote sleep, whereas, in the elderly, somatostatin impairs sleep. The rapid eye movement (REM)-nonREM cycle is modulated by vasoactive intestinal polypeptide. Cortisol stimulates SWS and GH, probably by feedback inhibition of CRH. Neuroactive steroids exert specific effects on the sleep EEG, which can be explained by γ-aminobutyric acidA receptor modulation.

Somatostatin impairs sleep in elderly human subjects

With increasing age, sleep becomes more shallow and fragmented and sleep-associated growth hormone (GH) release declines. GH secretion is regulated physiologically by opposite actions of GH-releasing hormone (GHRH) and somatostatin (SRIF). The administration of GHRH promotes sleep in both young and elderly controls, whereas SRIF does not induce sleep-EEG changes in young subjects. Because the influence of peripheral SRIF administration on sleep EEG in the elderly is unknown, we administered 50 μg SRIF-14 every hour between 2200 and 0100 hours to controls with an age range from 60 to 73 years (mean ± SD 67.4 ± 5.1 years). After SRIF administration, total sleep time and rapid eye movement (REM) sleep decreased significantly, and more time was spent awake in the first sleep cycle, suggesting that SRIF induces sleep deterioration in the elderly. The peptide may become more effective on sleep EEG in older than in younger subjects, because of the decline of GHRH–GH axis activity, which may contribute to sleep disturbances in aging. The increased efficacy of SRIF in the elderly also may be explained by enhanced leakage of the blood-brain barrier.

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.