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Integrin α2β1, also known as very late antigen (VLA)-2, is a collagen-binding molecule expressed constitutively on platelets. Vatelizumab, a monoclonal antibody targeting the α2 subunit (CD49b) of VLA-2, was recently investigated for its safety and efficacy during a Phase 2 clinical study in multiple sclerosis patients, as integrin-mediated collagen binding at the site of inflammation is central to a number of downstream pro-inflammatory events. In the course of this study, we could show that VLA-2 is expressed ex vivo on platelets, platelet-T-cell aggregates, as well as a small population of highly activated memory T cells. Even though the clinical trial did not meet its primary clinical end-point (reduction in the cumulative number of new contrast-enhancing lesions on magnetic resonance imaging (MRI)), we observed enhanced frequencies of regulatory T cells (TREG) following vatelizumab treatment. Elevated TREG frequencies might be explained by the inhibition of p38 mitogen-activated protein kinase (MAPK) signaling, which is critically involved in the polarization of T helper 17 (TH17) cells and is activated by the α2 integrin cytoplasmic domain. Our findings suggest that blockade of VLA-2 might be a way to safely shift the TH17/TREG balance by inducing TREGin vivo., (© The Japanese Society for Immunology. 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The biological underpinnings of borderline personality disorder (BPD) and its psychopathology including states of aversive tension and dissociation is poorly understood. Our goal was to examine transcriptional changes associated with states of tension or dissociation within individual patients in a pilot study. Dissociation is not only a critical symptom of BPD but has also been associated with higher risk for self-mutilation and depression. We conducted a whole blood gene expression profile analysis using quantitative PCR in 31 female inpatients with BPD. For each individual, two samples were drawn during a state of high tension and dissociation, while two samples were drawn at non-tension states. There was no association between gene expression and tension states. However, we could show that Interleukin-6 was positively correlated to dissociation scores, whereas Guanine nucleotide-binding protein G(s) subunit alpha isoforms, Mitogen-activated protein kinase 3 and 8, Guanine nucleotide-binding protein G(i) subunit alpha-2, Beta-arrestin-1 and 2, and Cyclic AMP-responsive element-binding protein were negatively correlated to dissociation. Our data point to a potential association of dissociation levels with the expression of genes involved in immune system regulation as well as cellular signalling/second-messenger systems. Major limitations of the study are the the possibly heterogeneous cell proportions in whole blood and the heterogeneous medication.

Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study. They were genotyped for COX-2 and OXTR SNPs. Treatment resistance (according to two different definitions), response and remission were recorded. We did not observe any association between the genotypes or alleles of the selected SNPs within COX-2 and OXTR genes and treatment resistance, response and remission in the whole sample. Our results are consistent with those of some studies but not with those of other ones. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, and different definitions of treatment resistance., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies., (Copyright © 2012 S. Karger AG, Basel.)

Our study aims at replicating our previous finding of an association between COMT rs4680 G/A polymorphism and early onset major depression (MD). We included 462 MD, 147 bipolar disorders (BD) subjects and 295 healthy controls. We could partially replicate previous findings. In particular, rs4680 GG+AG genotypes were more represented in the subgroup of early onset MD patients (p=0.04). Additionally, we observed an association between rs737865 alleles and early onset MD (p=0.04). Rs4680 genotype was associated with early onset BD as well (p=0.01). In conclusion, we partially replicated our previous findings confirming a possible influence of COMT variants in MD and BD, particularly in early onset subjects, though not with the same risk genotypes., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In the present study, aimed at investigating whether a set of single nucleotide polymorphisms (SNPs) within PTGS2 gene (rs4648276, rs2066826 and rs689466) could be associated with antidepressant response, remission and treatment resistance in a sample of major depression patients, we did not find evidence supporting any of such associations., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has pivotal roles in neuronal survival, proliferation, and synaptic plasticity in the brain. Both clinical and pharmacological studies have implicated the common single nucleotide polymorphism (SNP) at position 196, Val66Met in the pathophysiology of major depressive disorder (MDD), and antidepressant response. However, inconsistent results were found between Val66Met (rs6265) polymorphism and treatment response phenotypes in genetic association studies. The functional Val66Met polymorphism and seven other tagging SNP markers selected to capture the major allelic variations across BDNF locus were analyzed in depressed patients, treated with antidepressants, and 76 control patients. Two hundred and six patients with Diagnostic and Statistical Manual of Mental Disorders-IV MDD were recruited for this study and genotyped for eight BDNF tagging SNPs (rs11030096, rs925946, rs10501087,rs6265, rs12273363, rs908867, rs1491850, and rs1491851)to investigate the functional impact of genotypes/haplotypes in the susceptibility of depression and on treatment response. None of the eight SNPs, including the rs6265, were significantly associated with MDD after permutation correction. However, we found an association for rs10501087, rs6265 with nonresponse to antidepressant treatment (corrected permutation P:0.03599; 0.0399 and power: 0.1420; 0.1492, respectively).Analysis of each two-marker, three-marker, and four-marker sliding window haplotypes showed significance in haplotype combinations. Especially rs10501087 (C), rs6265 (A), and rs149,1850 (C) together or with the other SNP haplotypes showed a similar pattern in all treatment response phenotypes. Despite the limited power of analysis, our results suggest that these three SNPs may play a role in antidepressant treatment response phenotypes in MDD.

Background: The transcription factor Cyclic adenosine monophosphate Response Element Binding (CREB) protein has been repeatedly involved in the aetiology and pharmacotherapy of major depression (MD). The aim of this study was to investigate the potential association of a set of single nucleotide polymorphisms (SNPs) in CREB1 gene and both MD and response, remission and treatment resistance to antidepressants., Methods: One hundred-ninety MD patients collected in the context of a resistant depression study and treated with antidepressants for at least 4weeks were genotyped for 5 CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). Response, remission and treatment resistance were recorded., Results: An allele of rs7569963 as well as rs2253206-rs7569963 A-A and rs7569963-rs4675690 A-C haplotypes were associated with the status of treatment resistance. Additionally, rs7569963 GG genotype was positively associated with remission. No further significant associations were observed., Limitations: Limitations of the present study include a relatively small sample size and the incomplete ascertainment of data which could influence the outcome., Conclusions: Our results preliminary suggest that some genetic polymorphisms in CREB1 could be associated to treatment resistance. Although such finding needs to be replicated in larger samples, it increases current knowledge about the genetic predictors of response to antidepressants that will probably lead to enhance treatment outcomes by addressing each individual to the most appropriate treatment strategy in the early stages of treatment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objectives: Dystrobrevin binding protein 1 (Dysbindin) is a plausible candidate gene for major depressive disorders (MDD) due to its involvement in synaptic signaling, plasticity and localization in the brain., Methods: Two intronic SNPs of DTNBP1; rs760761 (P1320) and rs2619522 (P1763) were analyzed in 206 patients with DSM-IV MDD to investigate the functional impact of genotypes on susceptibility for depression and some clinical phenotypes. The Sequenom iPLEX assay (Sequenom, Cambridge, MA) was used for genotyping., Results and Conclusions: Despite the limited power of analysis, our results showed that these two SNPs in DTNPB1 gene were not related to clinical phenotypes such as melancholia, age at onset, suicidality and co-morbid anxiety disorders, as well as to treatment response phenotypes.

The 5HT2A (5HTR2A) and 5HT1A receptor (5HTR1A) genes are plausible candidate genes for major depressive disorders. Two single nucleotide polymorphisms, the rs7997012 in 5HTR2A and the -1019C/G in 5HTR1A, were analyzed in 206 patients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder. Patients were retrospectively characterized for clinical response to antidepressant treatment. We found a significant difference in the rs7997012 allele frequency between resistant and nonresistant patients. However, following the Bonferroni correction we could not find any association between this single nucleotide polymorphism and treatment resistance phenotype. Nevertheless, given the limited power of our analysis, we are not able to conclude that these results reflect a lack of association. Additional studies are needed to confirm or to disprove our result.

It is increasingly acknowledged that the diagnosis of major depression encompasses patients who do not necessarily share the same disease biology. Though the diagnostic criteria allow the specification of different subtypes, e.g. melancholic and atypical features, a consensus still has to be reached with regard to the clinical symptoms that clearly delineate these subtypes. Beside clinical characteristics, biological markers may help to further improve identification of biologically distinct endophenotypes and, ultimately, to devise more specific treatment strategies. Alterations of the hypothalamus-pituitary-adrenal (HPA) axis and sleep architecture are not only commonly observed in patients with major depression, but the nature and extent of these alterations can help to identify distinct subtypes. Thus, a HPA overdrive, due to enhanced secretion of corticotropin-releasing hormone (CRH) and an impaired negative feedback via glucocorticoid receptors, seems to be most consistently observed in patients with melancholic features. These patients also show the clearest sleep-electroencephalogram (EEG) alterations, including disrupted sleep, low amounts of slow wave sleep (SWS), a short rapid eye movement (REM) latency and a high REM density. In contrast, patients with atypical features are characterized by reduced activity of the HPA axis and ascending noradrenergic neurons in the locus coeruleus. Though sleep-EEG alterations have been less thoroughly examined in these patients, there are data to suggest that SWS is not reduced and that REM sleep parameters are not consistently altered. While the atypical and melancholic subtypes of major depression may represent the extremes of a spectrum, the distinct clinical features provide an opportunity to further explore biological markers, as well as environmental factors, contributing to these clinical phenotypes. Moreover, dysregulations of the HPA axis and sleep-EEG alterations can also be induced in rodents, thereby allowing alignment of critical biological aspects of a human disease subtype with an animal model. Such "Translational Research" efforts should help to develop targeted therapies for distinct patient populations.

Preclinical and clinical studies suggest that neuropeptide Y (NPY) exerts functional corticotropin-releasing hormone (CRH) antagonistic effects. NPY activity appears to be blunted in depression. Recently, we have found in young normal male controls after repetitive administration of NPY a shortened sleep latency and a decrease of time awake and, in the second half of the night, EEG delta-power; cortisol and ACTH levels were blunted. Since during depression there is an overactivity of CRH, we tested the capacity of NPY to affect sleep endocrine activity in patients with depression compared with controls. After one night of adaptation we administered hourly IV injections of placebo (PL) during the second night and of 50 microg NPY during the third night between 22:00 and 01:00 h. Throughout the night ACTH, cortisol and prolactin levels were measured, simultaneously the sleep electroencephalogram (EEG) was recorded. Depressed patients as well as healthy controls exhibited significant shortening of sleep onset latency (SOL) (mean+/-SD; controls: 41.9+/-48.2 min PL vs 22.1+/-17.3 min NPY; patients: 31.8+/-19.8 min PL vs 24.7+/-20.1 min NPY; P<0.06) and REM latency (controls: 79.3+/-27.5 min PL vs 69.0+/-19.4 min NPY; patients: 79.8+/-45.5 min PL vs 52.4+/-51.2 min NPY; P<0.05). Both patients and controls showed a trend to an increase of prolactin during the night. In contrast to our recent observation in young normal subjects time awake, ACTH and cortisol remained unchanged in patients and controls in response to NPY. Whereas also an adaptation effect may contribute to the shortening of SOL, this change and the prolactin elevation are in line with a CRH antagonistic and GABA(A) agonistic/benzodiazepine-like effect of NPY. The lack of effects on time awake and HPA hormones may be explained by the higher CRH activity due to age and depression in the investigated samples in comparison to our recent study in young subjects.

CRH is known to enhance wakefulness and to reduce SWS. In addition, some but not all, studies suggest that CRH promotes REM sleep. Alpha-helical CRH exerts CRH-antagonistic effects in various studies. We studied its effect on sleep EEG and nocturnal secretion of ACTH, cortisol, GH (n = 7) in young normal male subjects. After administering the substance cortisol and ACTH levels were enhanced during the total night compared to placebo. We found an increase of the time spent awake for the first half. ACTH (2nd half of the night) and cortisol (total night and 1st half of the night) increased. The results of the present study correspond to a mixture of agonistic and antagonistic effects of alpha-helical CRH.

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.

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.

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.

Parturition is driven by a pulsatile pattern of oxytocin secretion, resulting from burst firing activity of supraoptic oxytocin neurones and reflected by induction of Fos expression. Rats were injected with progesterone on day 20 of pregnancy to investigate the role of the decreasing progesterone:ratio oestrogen ratio, which precedes delivery, in the activation of supraoptic neurones. Progesterone delayed the onset of birth by 28 h compared with vehicle (control) and prolonged the duration of delivery, which was overcome by pulsatile injections of oxytocin, indicating that the slow delivery may reflect impaired oxytocin secretion. Parturient rats pretreated with progesterone had fewer Fos immunoreactive nuclei in the supraoptic nucleus than did parturient rats pretreated with vehicle. The number of Fos immunoreactive nuclei was not restored after oxytocin injection, indicating that appropriate activation of oxytocin neurones is impaired by progesterone and also that there is a lack of stimulatory afferent drive. Fos expression increased in the nucleus of the tractus solitarius during parturition in rats pretreated with either vehicle or progesterone, but not in rats that had been pretreated with progesterone and induced with oxytocin, indicating that this input was inhibited. Endogenous opioids inhibit oxytocin neurones in late pregnancy and the opioid antagonist, naloxone, increases Fos expression in supraoptic nuclei by preventing inhibition. However, progesterone attenuated naloxone-induced Fos expression in the supraoptic nucleus in late pregnancy and naloxone administered during parturition did not accelerate the duration of births delayed by progesterone administration, indicating that progesterone does not act by hyperactivation of endogenous opioid tone. RU486, a progesterone receptor antagonist, enhanced supraoptic neurone Fos expression in late pregnancy, indicating progesterone receptor-mediated actions. Thus, progesterone withdrawal is necessary for appropriate activation of supraoptic and tractus solitarius neurones during parturition.

In depression and aging an increase in nocturnal cortisol secretion and a blunted nocturnal growth hormone (GH) surge have been described. In normal young men, growth hormone-releasing hormone (GHRH) promotes GH release and reduces plasma cortisol. Here, we examined whether GHRH could help to restore sleep-endocrine regulation in patients with depression and aging. GHRH (4x50 microgram, at 2200, 2300, 2400 and 0100 h) or saline (placebo) was injected intravenously to 42 patients with depression (19 females, 23 males) and matched controls (age range 19-76 years). Blood samples were withdrawn at 20 min intervals between 2200-0700 h and analysed using Manova (D.F. 1, 72). Patients compared to controls had significantly higher levels of ACTH and cortisol, particularly during the first half of the night (F=9 and F=11.8, each p<0.05). GHRH reduced ACTH during the first and cortisol secretion during the second half of the night in males, regardless of diagnosis, but enhanced it in females (F=5.1 and F=4.0, each p<0.05). ACTH and cortisol secretion were inversely related to NREM and stage 2 sleep in patients (r= -0.42, -0.42 and r= -0.36, -0.39, respectively, each p<0.05) but not in controls. Our data suggest that: 1) female gender, depression and aging add-on to enhance HPA activity, and 2) hyperactivity of the HPA system and the decrease in NREM and in particular stage 2 sleep in depression are interrelated. In men, GHRH can restore some of the sleep-endocrine alterations associated with depression and aging.

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.

Aging is associated with decreased sleep continuity, slow wave sleep (SWS), growth hormone (GH) release and an increased hypothalamo-pituitary-adrenocortical (HPA) system activity. Total sleep deprivation (TSD) is a strong stimulus for sleep. To determine if aging affects the response to TSD, for the first time the combined effects of TSD on conventional and spectral sleep electroencephalographic (EEG) parameters and GH, cortisol and prolactin secretion were compared in elderly (60-80 years; n = 7) vs. younger subjects (20-30 years; n = 7). MANOVA revealed a reduction of SWS in the elderly. TSD led to an increase in SWS, a decrease in sleep onset latency, rapid eye movement (REM) density and by trend REM-latency without a global group difference. GH was reduced, whereas prolactin was enhanced in the elderly. After TSD GH was unchanged and prolactin secretion was enhanced without group difference. Thus, the plasticity of the sleep-endocrine system in response to TSD is sustained during aging. The possible involvement of the GABAergic system, that seems not to be severely impaired with age, is proposed.

Sleep-endocrine regulation in humans involves high activity of the somatotropic axis at the beginning of the night and an increase in the hypothalamic-pituitary-adrenocortical (HPA) system during the night. Gender differences were examined with regard to sleep-endocrine regulation in young healthy controls (10 men, 9 women). The sleep EEG was recorded (23:00-07:00 h) and plasma samples were collected and analyzed for GH, cortisol and ACTH at 20-min intervals. Cortisol secretion was significantly higher in females during the first half of the night (F = 9.9, p < 0.05), while ACTH was not different. In women, sleep-EEG analysis showed less slow wave sleep (SWS) during the second half of the night (F = 4.5, p < 0.05) and a significantly greater decrease in SWS and delta activity from the first to the second half of the night (F = 3.7 and 7.4, respectively, p < 0.05). Sigma activity increased during the night in women only (F = 3.7, p < 0.05). Our data are compatible with the hypothesis that in women compared to men activity of hypothalamic CRH neurons and central CRH release is greater, but is not reflected by greater HPA activity.

After repeated intravenous (i.v.) boluses of growth hormone-releasing peptide-6 (GHRP-6) we found recently increases of growth hormone (GH), corticotropin (ACTH) and cortisol levels and of the amount of stage 2 sleep. In clinical use, oral (p.o.), intranasal (i.n.) and sublingual (s.l.) routes of administration have advantages over i.v. administration. We compared the sleep-endocrine effects of 300 microg/kg of body weight (b.w.) GHRP-6 in enteric-coated capsules given p.o. at 21.00 h and of 30 microg/kg GHRP-6 i.n. or 30 microg/kg GHRP-6 sl. given at 22.45 h in normal young male controls with placebo conditions. After GHRP-6 p.o. secretion of GH, ACTH and cortisol remained unchanged. The only effect of GHRP-6 s.l. was a trend toward an increase in GH in the first half of the night. GHRP-6 i.n. prompted a significant increase in GH concentration during the total night and a trend toward an increase in ACTH secretion during the first half of the night, whereas cortisol secretion remained unchanged. Furthermore, after GHRP-6 i.n., sleep stage 2 increased in the second half of the night by trend, and spectral analysis of total night non-rapid eye movement (REM) sleep revealed a decrease of delta power by trend. In contrast sleep stage 2 decreased during the second half of the night after GHRP-6 p.o. Our data demonstrate that GHRP-6 is capable of modulating GH and ACTH secretion as well as sleep. However, the effects depend upon dosage, duration and route of administration.

During slow wave sleep (SWS) pituitary responsiveness to CRH is reduced. Since GHRH is involved in the promotion of SWS in humans and rats, it was examined whether the blunted CRH-induced ACTH and cortisol release during SWS could be mimicked by systemic GHRH. Young healthy men (n = 7) participated in 4 sleep-endocrine protocols: (A) lights off at 23.00 h, intravenous injection of 50 microgram CRH during the first SWS period; (B) lights off at 01.00 h, injection of 100 microgram GHRH at 23.00 h, followed by 50 microgram CRH at 23.30 h; (C) lights off at 01.00 h, injection of 50 microgram CRH at 23.30 h, and (D) lights off at 23.00 h, saline treatment only (= baseline condition). The sleep EEG was recorded during the lights off period and blood samples, collected every 20 min between 22.00 and 07.00 h, were assayed for GH, cortisol and ACTH. There was no significant difference in the sleep-associated GH peak between protocols. Plasma ACTH was significantly higher following CRH administration during wakefulness compared with CRH administration during SWS (protocols B and C vs. A; area under the curve (AUC) 23. 00-03.00 h: 9.6 +/- 4.8 and 7.3 +/- 2.0 vs. 6.1 +/- 1.1 ng/ml x min; p < 0.05), while there was no significant difference in plasma ACTH concentration between the baseline condition and protocol A (CRH administration during SWS). Similarly, cortisol was significantly enhanced compared with baseline following CRH during wakefulness only. CRH induced an increase in EEG activity in the sigma frequency range, both when it was administered during wakefulness and SWS, while this effect was reduced by pre-treatment with GHRH. In summary, our data suggest that (1) the blunted CRH-induced release of ACTH and cortisol during SWS is not mimicked by systemic GHRH administration, and (2) CRH enhances sigma EEG activity possibly via modulation of afferent pathways from the median eminence to the thalamus and this effect is reduced by pre-treatment with GHRH.

With the introduction of the non-benzodiazepine hypnotics zopiclone and zolpidem it was expected to have hypnotics without side effects and risks characteristically seen with benzodiazepines. We report two cases with high-dose usage and dependency of non-benzodiazepine hypnotics. Both patients were prescribed the drugs to treat sleep disturbances occurring during a depressive episode. While one patient had a polysubstance abuse there was no evidence for an abuse history in the other patient. To reduce withdrawal symptoms long-acting benzodiazepines were given to both patients. Thus, it seems that not only patients with a history of substance abuse but also patients with a psychiatric disorder are at risk for abuse of non-benzodiazepine hypnotics. Considering the increasing number of case reports with abuse and dependence of zopiclone and zolpidem it seems necessary to reevaluate the dependency risk of the currently available non-benzodiazepine hypnotics.

Panamesine (PAN) is a nearly specific sigma ligand. Recently, we showed that PAN in doses up to 90 mg/day improved psychometric variables in patients with an acute episode of schizophrenia. No side effects connected to the extrapyramidal motoric system occurred; there was even an absence of daytime sedation. We investigated the effects of PAN on plasma cytokine and soluble cytokine receptor levels and blood cell counts during 4 weeks in ten patients out of the previous study sample. Under PAN treatment, tumor necrosis factor (TNF)-alpha, soluble TNF receptors p55 and p75, and soluble interleukin-2 receptor levels were not increased and neither were monocyte and lymphocyte counts affected. This absence of immunomodulation is in contrast to clozapine, but similar to haloperidol treatment. In a second study, a single dose of PAN (30 mg) or placebo was administered at 2200 hours to ten young male controls in order to investigate changes in the sleep EEG under the substance. Sleep efficiency index increased, whereas time spent awake decreased. No significant changes in rapid eye movement (REM) sleep or non-REM parameters occurred. The sleep-EEG investigation showed sleep-consolidating effects of the drug, comparable to those of classical neuroleptics. Our results support the hypothesis that the sigma ligand PAN, which has antipsychotic properties, shares biological aspects with haloperidol.

The concept of a posttraumatic stress disorder (PTSD) has become important for psychiatric diagnosis and research, particularly following US-american studies on Vietnam war veterans. Recently, studies on traindrivers involved in suicide accidents have shown symptoms of anxiety and depression in more than 30% of concerned drivers and typical symptoms of a PTSD in 15%. Here, we present the case of a traindriver who was involved in 6 suicide accidents within 17 years of traindriving (the average is 2 suicide accidents). Following the 3rd accident, the driver developed increasingly symptoms like anxiety, sleep disturbances, flashbacks and irritability. Following the 6th accident, he has been unable to work. A former expert opinion saw no relationship between the symptoms of the driver and the suicide accidents. Therefore, further information about the concept of a PTSD seems necessary to ensure early psychotherapeutic and pharmacological treatment of patients with such a disorder.

Bidirectional interactions between nocturnal hormone secretion and sleep regulation are well established. In particular, a link between PRL and rapid eye movement (REM) sleep has been hypothesized. Short-term administration of PRL and even long-term hyperprolactinemia in animals increases REM sleep. Furthermore, sleep disorders are frequent symptoms in patients with endocrine diseases. We compared the sleep electroencephalogram of seven drug-free patients with prolactinoma (mean PRL levels 1450 +/- 1810 ng/mL; range between 146 and 5106 ng/mL) with that of matched controls. The patients had secondary hypogonadism but no other endocrine abnormalities. They spent more time in slow wave sleep than the controls (79.4 +/- 54.4 min in patients vs. 36.6 +/- 23.5 min in controls, P < 0.05). REM sleep variables did not differ between the samples. Our data suggest that chronic excessive enhancement of PRL levels exerts influences on the sleep electroencephalogram in humans. Our result, which seems to be in contrast to the enhanced REM sleep under hyperprolactinemia in rats, leads to the hypothesis that both slow wave sleep and REM sleep can be stimulated by PRL. These findings are in accordance with reports of good sleep quality in patients with prolactinoma, which is in contrast to that of patients with other endocrine diseases.

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 gamma-aminobutyric acid(A) receptor modulation.

1. Intravenous administration of cholecystokinin (CCK) results in a transient activation of oxytocin neurones in the rat, and hence to oxytocin secretion: this activation is followed by expression of c-fos mRNA and of Fos-like immunoreactivity (Fos-LI) in magnocellular oxytocin neurones. Fos-like immunoreactivity is also induced in the regions of the brainstem that are thought to relay information from the periphery to the hypothalamus. 2. Administration of the selective CCKA receptor antagonist MK-329, but not the CCKB receptor antagonist L-365,260, prior to CCK injection, prevented oxytocin release as measured by radioimmunoassay and oxytocin neuronal activation as measured by electrophysiology and by the lack of induction of c-fos mRNA. 3. MK-329 abolished the release of adrenocorticotrophic hormone (ACTH) following injection of CCK. 4. MK-329 prevented the expression of Fos-LI in the hypothalamic magnocellular nuclei and in the area postrema and dorsal vagal complex of the brainstem. 5. L-365,260 had no effect on the expression of Fos-LI in the brainstem, but attenuated that seen in the hypothalamic magnocellular nuclei. 6. We conclude that CCK acts on CCKA receptors, either in the area postrema or on peripheral endings of the vagus nerve, to cause the release of hypothalamic oxytocin and ACTH. Information may be carried to the hypothalamus in part by CCK acting at CCKB receptors.