Assessment of Pharmacological Treatment Quality: Comparison of Symptom-triggered vs. Fixed-schedule Alcohol Withdrawal in Clinical Practice.

Introduction: Despite the fact, that symptom-triggered alcohol withdrawal treatment is recommended by German guidelines on alcoholism, many hospitals continue to use fixed-schedule protocols, as they have been successfully applied for many years. Methods: This retrospective study compared all patients' records of alcohol withdrawal treatment from October 2010 to November 2011 at Magdeburg's University Department of Psychiatry (n=120). A symptom-triggered protocol with clomethiazole (AESB, n=46) was used in parallel with the existing fixed-schedule protocol with diazepam (n=74). Results: The symptom-triggered group showed less need of pharmacological treatment duration (p<0.001) and cumulative dosage of medication compared to the fixed-schedule protocol (p<0.006). No difference was observed regarding the need of clonidine or haloperidol (to treat blood pressure derailment or delirium) and the incidence of epileptic seizures. Discussion: Based on the shorter treatment duration and a similar rate of complications our department has switched to the symptom-triggered protocol to improve the quality of patient care.

[Neonaticide: A classification of female perpetrators in an east-west comparison]. / Neonatizid : Täterinnentypologie und Ost-West-Vergleich.

BACKGROUND: The term neonaticide describes the act of killing a newborn child by a parent (mostly by the mother) within 24 h after birth. The aim of this study was to establish a classification of female perpetrators using psychopathological, mental, social and biographical characteristics and to make a comparison of the frequency between the old and new federal states in Germany. MATERIAL AND METHODS: In this study a total of 63 female German perpetrators who killed at least one newborn between 1986 and 2009 are portrayed and classified by epidemiological and psychopathological characteristics and personality profiles. After obtaining consent from the public prosecutors responsible, data were collected from forensic psychiatric expert opinions and legally valid court verdicts. A questionnaire was established to answer the questions on the psychopathological, e.g. do the women suffer from a mental disease when killing their newborn(s), mental, e.g. can personality accentuations be elicited, social, e.g. are the women unemployed and biographical characteristics of the women, e.g. how old are the women? Finally, an investigation was carried out using significance tests to find out if there was a significant statistical difference in the frequency of neonaticide between the eastern and western federal states. RESULTS: A cluster analysis based on the descriptive analysis was developed. The cluster analysis provided a foundation for a dichotomous classification of the perpetrators depending on five criteria. The first category contained 32 perpetrators who were on average 21 years old, who were primiparous and who hid, ignored or did not perceive their pregnancy. Most of them still lived with their parents. The perpetrators either did not have a mental disease or suffered from an acute stress disorder. The second category contained 31 perpetrators who were on average 25 years old, who were pluriparous, who hid their pregnancy and who lived with their partner. These women either did not have a mental disease or suffer from a personality disorder. A statistically significant higher incidence was found in the eastern federal states of Germany. CONCLUSION: The presented categorization of female perpetrators into two groups, where the features only show a small degree of overlap, should be taken into consideration in the assessment of the reasons for neonaticide. The typology of female perpetrators is more heterogeneous than previously assumed. The presented typologies and knowledge of conditional constellations involved in neonaticide achieve better prerequisites to be able to recognize persons at risk earlier and to instigate preventive measures.

Nardilysin in human brain diseases: both friend and foe.

Nardilysin is a metalloprotease that cleaves peptides, such as dynorphin-A, α-neoendorphin, and glucagon, at the N-terminus of arginine and lysine residues in dibasic moieties. It has various functionally important molecular interaction partners (heparin-binding epidermal growth factor-like growth factor, tumour necrosis factor-α-converting enzyme, neuregulin 1, beta-secretase 1, malate dehydrogenase, P42(IP4)/centaurin-α1, the histone H3 dimethyl Lys4, and others) and is involved in a plethora of normal brain functions. Less is known about possible implications of nardilysin for brain diseases. This review, which includes some of our own recent findings, attempts to summarize the current knowledge on possible roles of nardilysin in Alzheimer disease, Down syndrome, schizophrenia, mood disorders, alcohol abuse, heroin addiction, and cancer. We herein show that nardilysin is a Janus-faced enzyme with regard to brain pathology, being probably neuropathogenic in some diseases, but neuroprotective in others.

Differential topochemistry of three cationic amino acid transporter proteins, hCAT1, hCAT2 and hCAT3, in the adult human brain.

The cellular uptake of L-arginine and other cationic amino acids (such as L-lysine and L-ornithine) is mainly mediated by cationic amino acid transporter (CAT) proteins. Despite the important roles of cationic amino acid transporters for normal brain functioning and various brain diseases there is currently only fragmentary knowledge about their cellular and regional distribution patterns in the human brain. We mapped the immunohistochemical localization of human cationic amino acid transporters 1, 2 and 3 (hCAT1, 2, and 3) throughout five adult human brains and found a wide but uneven distribution of these transporters. All three hCAT1s were mainly localized in neurons, but were also found in numerous astrocytes, oligodendrocytes, plexus choroideus epithelial cells, and small blood vessels. The highest density of hCAT expressing neurons was observed in the hypothalamus, in some areas of the cerebral cortex, the thalamic reticular nucleus and the caudate nucleus, whereas weak to moderate expression was detected in the hippocampus, the prefrontal cortex (hCAT1 only), pons, brain stem and cerebellum. In contrast to what has been found in rodent brain, we detected hCAT2 and hCAT3 also in astrocytes. Overall, each hCAT has its characteristic, individual cerebral expression patterns, which, however, overlap with the others.

CPB-K mice a mouse model of schizophrenia? Differences in dopaminergic, serotonergic and behavioral markers compared to BALB/cJ mice.

Schizophrenia is characterized by disturbances in social behavior, sensorimotor gating and cognitive function, that are discussed to be caused by a termination of different transmitter systems. Beside morphological alterations in cortical and subcortical areas reduced AMPA- NMDA-, 5-HT2-receptor densities and increased 5-HT1-receptor densities are found in the hippocampus.The two inbred mouse strains CPB-K and BALB/cJ are known to display considerable differences in cognitive function and prepulse inhibition, a stable marker of sensorimotor gating. Furthermore, CPB-K mice exhibit lower NMDA-, AMPA- and increased 5-HT-receptor densities in the hippocampus as compared to BALB/cJ mice. We investigated both mouse strains in social interaction test for differences in social behavior and with immuncytochemical approaches for alterations of dopaminergic and serotonergic parameters. Our results can be summarized as follows: compared to BALB/cJ, CPB-K mice showed:(1) significantly reduced traveling distance and number of contacts in social interaction test, (2) differences in the number of serotonin transporter-immunoreactive neurons and volume of raphe nuclei and a lower serotonergic fiber density in the ventral and dorsal hippocampal subfields CA1 and CA3, (3) no alterations of dopaminergic markers like neuron number, neuron density and volume in subregions of substantia nigra and ventral tegmental area, but a significantly higher dopaminergic fiber density in the dorsal hippocampus, the ventral hippocampus of CA1 and gyrus dentatus, (4) no significant differences in serotonergic and dopaminergic fiber densities in the amygdala.Based on our results and previous studies, CPB-K mice compared to BALB/cJ may serve as an important model to understand the interaction of the serotonergic and dopaminergic system and their impact on sensorimotor gating and cognitive function as related to neuropsychiatric disorders like schizophrenia.

Region-specific alteration of GABAergic markers in the brain of heterozygous reeler mice.

Heterozygous reeler mice (HRM), haploinsufficient for reelin, have been proposed to be a genetic mouse model of schizophrenia. Beside behavioural similarities, HRM also demonstrate several neuroanatomical traits similar to patients suffering from schizophrenia. In the present study using immunocytochemical procedures, we investigated HRM and wild-type mice (WT) for differences in the numbers and densities of glutamic acid decarboxylase (GAD)67 and parvalbumin (PARV)-immunoreactive (IR) neurons in the hippocampus, tyrosine hydroxylase (TH)-IR neurons in the ventral tegmental area (VTA) and substantia nigra (SN), and serotonin transporter (5-HT-T)-IR neurons of the raphe nuclei. We found that HRM, compared with WT, show a significant decrease of GAD67-IR neurons in hippocampal subregion CA1 [stratum pyramidale (SP)], CA2 [stratum oriens (SO), stratum pyramidale (SP) and stratum radiatum (SR)] and dentate gyrus [granule cell layer (GL)], and also a significant decrease of PARV-containing neurons in CA1 (SO, SP) and CA2 (SP). No morphological differences were found in the SN/VTA or raphe nuclei. In conclusion, these results support a hippocampal γ-aminobutyric acid (GABA)ergic dysfunction in HRM as previously described by other authors, and may be based on a downregulation of GAD67 and PARV expressions. In summary, the reelin haploinsufficient mouse may provide a useful model for studying the interaction between reelin and hippocampal GABAergic system, its effect on dendritic spine maturation and plasticity related to schizophrenia.

Reduction of Prepulse Inhibition (PPI) after neonatal excitotoxic lesion of the ventral thalamus in pubertal and adult rats.

BACKGROUND: Growing evidence indicates the role of the thalamus in schizophrenia. The ventral part of the thalamus has been investigated in a few post-mortem studies, suggesting a possible neurodevelopmental etiology of the reduced neuron number. METHODS: Here we adapt a neurodevelopmental animal model, the neonatal excitotoxic brain lesion, to the ventral thalamus (VT) of Sprague-Dawley rats. At postnatal day (PD) 7 male pups were bilaterally infused into the VT using ibotenic acid (IBA) or artificial cerebrospinal fluid. Repeated measurements of prepulse inhibition (PPI) of the acoustic startle response, reviewed as a measure of sensorimotor gating deficits in neuropsychiatric disorders such as schizophrenia, were performed during puberty and adulthood. RESULTS: IBA animals showed lower PPI (p<0.001) compared to controls. The extent of VT lesions correlated negatively with PPI levels (p<0.001). PPI deficits in IBA animals were observed at PD 43 and PPI levels increased significantly after puberty without reaching control levels. Acute or subchronic clozapine treatment did not significantly restore low PPI in IBA rats. CONCLUSION: The present data suggest that the VT may be involved in the PPI deficits observed in schizophrenia.

Evidence for structural abnormalities of the human habenular complex in affective disorders but not in schizophrenia.

BACKGROUND: The habenular complex is composed of important relay nuclei linking the limbic forebrain to the midbrain and brain stem nuclei. Based on clinical observations, experiments with animals and theoretical considerations, it has been speculated that this brain area might be involved in psychiatric diseases (i.e. schizophrenia and depression). However, evidence in favour of this hypothesis is still lacking because the human habenular complex has rarely been studied with regard to mental illness. METHOD: We examined habenular volumes in post-mortem brains of 17 schizophrenia patients, 14 patients with depression (six patients with major depression and eight patients with bipolar depression) and 13 matched controls. We further determined the neuronal density, cell number and cell area of the medial habenular nuclei of the same cohorts using a counting box and a computer-assisted instrument. RESULTS: Significantly reduced habenular volumes of the medial and lateral habenula were estimated in depressive patients in comparison to normal controls and schizophrenia patients. We also found a reduction in neuronal cell number and cell area in depressive patients for the right side compared to controls and schizophrenia patients. No such changes were seen in schizophrenia. CONCLUSIONS: Our anatomical data argue against prominent structural alterations of the habenular nuclei in schizophrenia but demonstrate robust alterations in depressive patients. We are currently applying immunohistochemical markers to better characterize neuronal subpopulations of this brain region in schizophrenia and depression.

The resting brain and our self: self-relatedness modulates resting state neural activity in cortical midline structures.

The resting brain shows high neural activity in various regions, the default-mode network, chief among them the cortical midline structures (CMS). The psychological correlate of high resting state neural activity in CMS remains however unclear though speculatively it has been associated with processing of internally-oriented self-relatedness. We used functional MRI to examine internally-oriented self-relatedness during the resting state period. This was indirectly done by letting subjects perceive emotional pictures followed by a fixation cross; the very same pictures were then rated subjectively according to their degree of self-relatedness in a postscanning session. This allowed us to correlate the picture ratings of self-relatedness with signal changes in the subsequent resting state period, i.e. fixation period. The emotional pictures' degree of self-relatedness parametrically modulated subsequent resting state signal changes in various CMS, including ventro- and dorsomedial prefrontal cortex and posterior cingulate cortex. This modulation could be distinguished from effects of emotion dimensions (e.g. valence, intensity) and evoked effects of self-relatedness during the stimulus period itself the latter being observed rather in subcortical regions, e.g. amygdala, ventral striatum, and tectum. In sum, our findings suggest that resting state neural activity in CMS is parametrically and specifically modulated by the preceding stimulus's degree of self-relatedness. This lends further support to the presumed involvement of these regions in processing internally-oriented self-relatedness as distinguished from externally-oriented self-relatedness.

Histochemical evidence for wide expression of the metalloendopeptidase nardilysin in human brain neurons.

Nardilysin is a metalloendopeptidase that in vitro cleaves peptides such as dynorphin-A, somatostatin-28, alpha-neoendorphin and glucagon at the N-terminus of arginine and lysine residues in dibasic moieties. The enzyme is highly expressed in many endocrine tissues. Nardilysin has also been found in the brain. Previously, we have detected that nardilysin interacts with brain-specific proteins, i.e. p42(IP4)/centaurin-alpha1 [Stricker R, Chow KM, Walther D, Hanck T, Hersh LB, Reiser G (2006) Interaction of the brain specific protein p42(IP4)/centaurin-alpha1 with the peptidase nardilysin is regulated by the cognate ligands of p42(IP4), PtdIns(3,4,5)P(3) and Ins(1,3,4,5)P(4), with stereospecificity. J Neurochem 98:343-354]. However, very little is known about the distribution of nardilysin in the brain. The aim of the present study was to reveal its regional distribution and cellular localization in developing and adult human brain. Using immunohistochemistry and Western blot analysis we demonstrate that the enzyme is widely, but unevenly, expressed in the human brain. We found high staining intensity in the hypothalamus, neocortex and brain stem nuclei. The cellular localization is almost exclusively confined to neurons. In pre- and perinatal human brain cortex, most neurons express the enzyme. In cortical neurons nardilysin protein was found to be partially co-localized with parvalbumin but not calretinin. No co-expression was seen with somatostatin-28 immunoreactivity. A considerable overlap was revealed between p42(IP4) and nardilysin. Our data support the hypothesis that nardilysin might possibly play a role in brain development, whereas its putative function in brain peptide metabolism remains to be clarified further.

Hypothalamic nitric oxide synthase in affective disorder: focus on the suprachiasmatic nucleus.

Depression is frequently associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to repeated episodes of hypercortisolemia. Hypothalamic paraventricular neurons are believed to trigger these processes by aberrant generation and/or release of corticotropin releasing hormone, oxytocin, vasopressin, and nitric oxide (NO). Recent findings from two independent laboratories have demonstrated that the suprachiasmatic nucleus, which in part controls the cellular activity of paraventricular neurons (PVN), is also involved in affective disorder. The aim of the present study was to elucidate by stereological analysis, whether suprachiasmatic nucleus (SCN) nitric oxide synthase and neurophysin generating neurons are affected in neuropsychiatric disorders. We show that compared to controls the number of nitric oxide synthase immunoreactive neurons is greatly reduced both in depression and in schizophrenia. In subjects with affective disorder there was a correlation between the number of NOS-expressing cells and duration of treatment with antidepressants. The number of neurophysin-expressing SCN neurons was also fewer in cases with mood disorder. It is concluded that SCN-derived NO may be a relevant pathophysiological factor in neuropsychiatric disorders.

The Alzheimer disease-related calcium-binding protein Calmyrin is present in human forebrain with an altered distribution in Alzheimer's as compared to normal ageing brains.

The EF-hand calcium binding protein Calmyrin (also called CIB-1) was shown to interact with presenilin-2 (PS-2), suggesting that this interaction might play a role in the pathogenesis of Alzheimer's disease (AD). Here we have investigated the distribution of Calmyrin in normal human and AD brain. In normal brain Calmyrin immunoreactivity was unevenly distributed with immunostaining in pyramidal neurones and interneurones of the palaeo-cortex and neocortex, cerebellar granule cells and hypothalamic neurones of the paraventricular, ventromedial and arcuate nuclei. Moderate immunoreactivity was present in hippocampal pyramidal cells and stronger in dentate gyrus neurones. Thalamic and septal neurones were devoid of immunoreactivity. No apparent differences were visible between stainings of brain sections from younger and older nondemented patients. In AD brain a substantial loss of Calmyrin-immunopositive neurones was observed in all regions, especially in cortical areas. Still immunoreactive neurones, however, displayed stronger staining that was especially concentrated in perinuclear regions. Calmyrin immunosignals were in part associated with diffuse and senile plaques. Thus, although protein levels of Calmyrin are low in human forebrain, its cellular localization as well as its altered distribution in AD brain suggest that it may be involved in the pathogenesis of AD.

Mechanisms of action in the prevention of recurrent mood disorders.

BACKGROUND: Since long-term treatment is a need in many patients with mood disorders, knowledge on mechanisms of action in the prevention of recurrence is of major relevance. METHODS: Follow-up studies, which are best suited to prove the linkage of causal factors and mechanisms with the clinical course of the disorders, are rare. Another approach to search for preventive mechanisms is to address actions of pharmacological agents, which are effective in prophylactic treatment of mood disorders. Studies over the past several years have indicated that intracellular signaling cascades mediate long-term pharmacological effects via modulation of transcription factors and gene expression of neurotrophic and neuroprotective factors which may interfere with recurrence of affective illness. RESULTS: The impact of treatment on stress responsive systems varies with different therapeutic strategies and the relevance of a treatment-related modification of stress reliability for the course of the disease is not clear. Functional and structural actions of mood stabilizers and of antidepressants on mood-relevant anatomical circuits and modulation of chronobiological alterations also appear to be involved in preventive mechanisms in mood disorders. Moreover, cognitive mediators of prophylactic effects have been described. CONCLUSION: Combined clinical and biological studies should assess the relevance of those modes of action for the long-term course of mood disorders.