[Oxytocin in schizophrenia : Evidence for an etiological and therapeutic relevance of the social neuromodulator]. / Oxytocin bei Schizophrenie : Evidenz für eine ätiologische und therapeutische Relevanz des sozialen Neuromodulators.

Neurobiological results from animal models as well as biochemical and genetic findings in patients indicate that the oxytocin (OT) system may be dysfunctional in schizophrenia. On this pathogenetic basis transnasally administered OT (tnOT) could be an innovative treatment option for schizophrenia. Experimental data from animal studies are also suggestive of a particular effectiveness in treatment-resistant schizophrenia. To date, clinical data on tnOT treatment of schizophrenia patients does not unequivocally support a general therapeutic effect on the psychopathology but suggests positive effects on higher integrated social cognitive performance, such as empathy and mentalization. In particular, tnOT augmentation of a social cognitive skills training resulted in a marked and lasting treatment effect; however, numerous person- and context-dependent variables can potentially moderate individual effects of OT and may even reverse effects in certain constellations. Most clinical studies so far have not systematically accounted and controlled for these factors with the probable result of larger variance of recorded treatment effects and lower likelihood of ascertaining positive effectiveness. Furthermore, there is still a gap of knowledge on dose response relations and central nervous system (CNS) permeation in man following tnOT administration. This review aims to give a concise overview on the evidence for the etiological relevance of the neurohormone OT and its treatment potential in schizophrenia.

Reversible Amisulpride-induced Elevation of Creatine Kinase (CK): A Case Series from the German AMSP Pharmacovigilance Project.

The elevation of creatine kinase (CK) levels without neuroleptic malignant syndrome has been reported for several antipsychotics. We present here 4 cases with CK elevation induced by amisulpride, which have been registered for the German pharmacovigilance project, Arzneimittelsicherheit in der Psychiatrie (AMSP). The magnitude of the CK elevation ranged between 1, 498 IU/L and 21,018 IU/L. All 4 patients reported myalgia. In each case CK returned to normal after amisulpride discontinuation. In the fourth case, fluids were administered intravenously in order to prevent acute renal failure. None of the cases showed deterioration of renal function. Finally, we present recommendations for clinical practice.

[Pilot study on a modular outpatient treatment programme following public order placements because of endangerment in patients with psychotic disorders]. / Pilot-Anwendung eines modularen ambulanten Therapieprogramms im Anschluss an PsychKG-Unterbringungen wegen Fremdgefährdung bei Patienten mit Psychose-Erkrankungen.

Patients with psychotic disorders who were detained by public order because of endangerment, can be regarded as a population at risk of further endangerment, public order placements and a forensic course. Concepts of specific aftercare for this subgroup are lacking thus far. The present pilot study explores the feasibility of a modular therapeutic outpatient programme that is tailored to specific subgroup needs and is applied over six months. Readmission rates during the intervention period are regarded exploratively.Consecutive screening of all patients placed in general psychiatry by public order during 05 to 11/2012. Included patients received baseline measurements followed by six-month intervention. Individual utilisation of treatment modules and number of readmissions, differentiated according to legal bases were assessed.Inclusion rate: 17.4 % of all screened subjects (115) and 57 % of all potentially includable subjects, dropout rate: 15 %. Mean utilisation rate: 23.5 therapeutic contacts per 6 months. Readmission rate: 50 %, of these 60 % on voluntary legal basis.Study inclusion, mean utilisation and dropout rates attest the feasibility and acceptance of the intervention in the population under study. A preponderance of voluntary vs. compulsory readmissions to hospital during the intervention indicates that in the majority of patients a higher degree of therapeutic cooperativeness can be reached. Further study on reduction of compulsory readmissions and on avoidance of a forensic course by application of the here introduced intervention in combination with methods of risk assessment in a consecutive main project seems justified.

A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI.

OBJECTIVES: Mild cognitive impairment (MCI) is etiologically heterogeneous, and a substantial proportion of MCI subjects will develop different dementia disorders. One subtype of this syndrome, amnestic MCI, occurs preferentially but not exclusively in prodromal AD and is characterized by defined deficits of episodic memory. DESIGN, SETTING AND PARTICIPANTS: For a 2-year, double-blinded, placebo-controlled study MCI patients, presenting with an amnestic syndrome but not necessarily based on presumed prodromal AD were randomized. INTERVENTION: Patients received (a) a combination of 16 mg galantamine plus 20 mg memantine, or (b) 16 mg galantamine alone or (c) placebo. MEASUREMENTS: The primary objective was to explore the differential impact of these interventions on the progression to dementia and on cognitive changes as measured by the ADAScog. RESULTS: After recruitment of 232 subjects, the trial was halted before reaching the planned sample size, because safety concerns arose in other studies with galantamine in MCI. This resulted in a variable treatment duration of 2-52 weeks. The statistical analysis plan was amended for studying cognitive effects of discontinuing the study medication, which was done separately for galantamine and memantine, and under double-blind conditions. There was one death, no unexpected severe adverse events, and no differences of severe adverse events between the treatment arms. The cognitive changes on the ADAScog were not different among the groups. Only for the subgroup of amnestic MCI with presumed AD etiology, a significant improvement of ADAScog score over placebo before the discontinuation of medication was observed, while amnestic MCI presumably due to other etiologies showed no cognitive changes with broad variation. Cognitive improvement was numerically larger in the combination treatment group than under galantamine alone. Patients who received placebo declined as expected. Discontinuation of galantamine, either as part of the combination regimen or as mono treatment, resulted in a transient decline of the ADAScog score in amnestic MCI of presumed AD etiology, while discontinuation of Memantine did not change the cognitive status. CONCLUSION: In an interrupted trial with amnestic MCI subjects the combination of galantamine plus memantine were generally well tolerated. In the subgroup of MCI subjects with presumed AD etiology, a cognitive benefit of a short-term combination treatment of galantamine plus memantine was observed, and cognitive decline occurred after discontinuation of galantamine.

Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease.

OBJECTIVE: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). METHODS: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale-Revised. CSF was obtained from all patients. RESULTS: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aß(1-42)/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD- patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. CONCLUSIONS: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.

A novel MRI-biomarker candidate for Alzheimer's disease composed of regional brain volume and perfusion variables.

BACKGROUND: Earlier evidence indicates that regional cerebral volume (rVOL) and blood flow (rCBF) variables carry independent information on incipient and early Alzheimer's disease (AD) and combining these modalities may increase discriminant performance. We compared single variables and combinations regarding their power for optimizing diagnostic accuracy. METHODS: Twelve cognitively normal elderly controls (CN), 30 subjects with mild cognitive impairment (MCI) and 15 with mild AD were examined by structural and perfusion-weighted magnetic resonance imaging (MRI) in single sessions at 1.5 Tesla. rVOLs were measured by manual volumetry, and rCBFs were calculated with a ROI-based co-localization technique. RESULTS: Applying single MRI variables for the differentiation of AD versus CN, the area under curve (AUC) of receiver operating characteristic curves (ROCCs) was highest for rVOL variables (maximum of 0.972 for right amygdala). A composite marker selected and weighted by logistic regression containing left amygdalar rCBF, left hippocampal and right amygdalar rVOLs gave a diagnostic accuracy for AD versus CN of 100%. Internal cross-validation revealed a reliability of 88.9%. CONCLUSIONS: Whilst external revalidation is mandatory employing a naturalistic sample containing disease controls, our phase I/II findings demonstrate that deducing composite markers from multimodal MRI acquisitions can optimize diagnostic accuracy for AD.

Evolution of Abeta42 and Abeta40 levels and Abeta42/Abeta40 ratio in plasma during progression of Alzheimer's disease: a multicenter assessment.

OBJECTIVE: To better understand the seemingly contradictory plasma beta-amyloid (Abeta) results in Alzheimer's disease (AD) patients by using a newly developed plasma Abeta assay, the INNO-BIA plasma Abeta forms, in a multicenter study. METHODS: A combined retrospective analysis of plasma Abeta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. RESULTS: Detection modules based on two different amino (N)-terminal specific Abeta monoclonal antibodies demonstrated that Abeta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low Abeta42 plasma concentrations. Abeta40 and Abeta42 concentrations varied consistently with the ApoE genotype, while the Abeta42/Abeta40 ratio did not. Irrespective of the decrease of the Abeta42/Abeta40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). CONCLUSION: A highly robust assay for repeatedly measuring Abeta forms in plasma such as INNO-BIA plasma Abeta forms might be a useful tool in a future risk assessment of AD.

[Data supporting quality circle management of inpatient depression treatment]. / Datengestützte Qualitätszirkel in der stationären Depressionsbehandlung.

BACKGROUND: Several quality assurance initiatives in health care have been undertaken during the past years. The next step consists of systematically combining single initiatives in order to built up a strategic quality management. METHODS: In a German multicenter study, the quality of inpatient depression treatment was measured in ten psychiatric hospitals. Half of the hospitals received comparative feedback on their individual results in comparison to the other hospitals (bench marking). Those bench markings were used by each hospital as a statistic basis for in-house quality work, to improve the quality of depression treatment. RESULTS: According to hospital differences concerning procedure and outcome, different goals were chosen. There were also differences with respect to structural characteristics, strategies, and outcome. The feedback from participants about data-based quality circles in general and the availability of bench-marking data was positive. The necessity of carefully choosing quality circle members and professional moderation became obvious. CONCLUSIONS: Data-based quality circles including bench-marking have proven to be useful for quality management in inpatient depression care.

Untangling the human estrogen receptor gene structure.

Awareness of estrogen's neuroprotective and behavioral effects is broadening rapidly and has served as an incentive to investigate estrogen signaling in central nervous system disorders. The present analysis focuses on two human nuclear estrogen receptors, ER alpha and ER beta, which have been shown to play key roles in the complex integration of estrogen's genomic and non-genomic modes of action. The corresponding genes are estimated to have diverged from an ancestral ER gene over 450 million years ago and are candidate genes for a variety of brain disorders. Recent progress in the Human Genome Project has greatly aided our understanding of the molecular blueprint and provides the means for reassessing both genes' genomic organization. Analyses of multiple alternatively spliced transcripts, large untranslated sequences and neighbouring genes reveal several novel features which suggest an increasingly versatile transcriptional machinery. We outline additional exons in the genes' 5'- and 3'-untranslated regions, a new polymorphic ER alpha microsatellite and a nested gene which lend themselves to further evolutionary and functional studies.

Unaltered brain levels of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal in Alzheimer's disease.

In recent years, an important role for the pathogenesis of Alzheimer's disease (AD) has been ascribed to oxidative stress. Trans-4-hydroxy-2-nonenal, a product of lipid peroxidation, forms stable adducts with a variety of nucleophilic substituents such as thiols or amino moieties. Here, we report the quantification of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal (HNE-dGp) using the specific and very sensitive method of 32P-postlabeling of deoxyguanosine adducts derived from nuclear DNA in neuron rich areas of the hippocampus, the parietal cortex, and the cerebellum of postmortem brains from patients with AD and age matched controls. Adduct levels were highest in the hippocampus, followed by the cerebellum and parietal cortex irrespective of the disease. Neither age, postmortem delay time, gender, nor the extent of neurofibrillary deposits affected tissue adduct levels in the brain areas examined. Although distinctively present in the human brain, the level of HNE-dGp adducts appears not to be useful as a biomarker for AD.

Alzheimer's disease-like alterations in peripheral cells from presenilin-1 transgenic mice.

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Expression of PS1 mutations in cell culture systems and in primary neurons from transgenic mice increases their vulnerability to cell death. Interestingly, enhanced vulnerability to cell death has also been demonstrated for peripheral lymphocytes from AD patients. We now report that lymphocytes from PS1 mutant transgenic mice show a similar hypersensitivity to cell death as do peripheral cells from AD patients and several cell culture systems expressing PS1 mutations. The cell death-enhancing action of mutant PS1 was associated with increased production of reactive oxygen species and altered calcium regulation, but not with changes of mitochondrial cytochrome c. Our study further emphasizes the pathogenic role of mutant PS1 and may provide the fundamental basis for new efforts to close the gap between studies using neuronal cell lines transfected with mutant PS1, neurons from transgenic animals, and peripheral cells from AD patients.

Hippocampal level of neural specific adenylyl cyclase type I is decreased in Alzheimer's disease.

Previous studies reported disruption of adenylyl cyclase (AC)-cyclic AMP (cAMP) signal transduction in brain of Alzheimer's disease (AD). We also demonstrated that basal and stimulated AC activities in the presence of calcium and calmodulin (Ca(2+)/CaM) were significantly decreased in AD parietal cortex. In the present study, we examined the amounts of Ca(2+)/CaM-sensitive types I and VIII AC, and Ca(2+)/CaM-insensitive type VII AC in the postmortem hippocampi from AD patients and age-matched controls using immunoblotting. The specificities of the anti-type VII and VIII AC antibodies were confirmed by preabsorption with their specific blocking peptides. We observed a significant decrease in the level of type I AC and a tendency to decrease in the level of type VIII AC in AD hippocampus. On the other hand, the level of type VII AC showed no alteration between AD and controls. A body of evidence from the studies with invertebrates and vertebrates suggests that types I and VIII AC may play an essential role in learning and memory. Our finding thus firstly demonstrated that a specific disruption of the Ca(2+)/CaM-sensitive AC isoforms is likely involved in the pathophysiology in AD hippocampus.