[Treatment pathways in the care of patients with schizophrenia and depression]. / Behandlungspfade in der Versorgung von Patienten mit Schizophrenie und Depression.

BACKGROUND: In mental healthcare the concept of pathways addresses diverse issues and problem areas, such as heterogeneous health service offers, the regional variability of treatment concepts and clear-cut guidelines on how and where to obtain treatment for a particular mental disorder. The ambiguous aspects of the concept require international and national definitions and consensus which must also cover quality criteria. METHODS: This article gives an overview of currently available evidence for the analysis of clinical pathways and pathways to care in international mental healthcare, covering studies on schizophrenia and depression from 2010 to 2014. RESULTS AND DISCUSSION: The ambiguity of the concept impedes the overview and does not provide unequivocal results. The development, implementation and analyses of guidelines or clear-cut clinical and pathways to care must consider individual, clinical and care system aspects as well as the interplay of these factors. Results suggest that system aspects tend to dominate over clinical factors of schizophrenia and depression. As a consequence, the definition, implementation and evaluation of clinical pathways or pathways to mental healthcare is first and foremost a responsibility of the respective national mental healthcare system and must be understood on that level, before findings are summarized internationally and models of best practice are debated.

[Indicators of patient care in Psychiatric and Psychosomatic Facilities (VIPP project)--a database project]. / Versorgungsindikatoren in der Psychiatrie und Psychosomatik (VIPP)--Ein Datenbank-Projekt.

INTRODUCTION: In Germany a new and unique remuneration system for psychiatric and psychosomatic stationary treatments (PEPP system) was introduced in 2013 on an optional basis. From 2015 it will be mandatory for psychiatric and psychosomatic facilities. The introduction of the PEPP system brings up different questions regarding the possible incentives of the new remuneration system and its effects on the supply of psychiatric and psychosomatic treatments. To conduct these necessary analyses a reliable database is needed. MATERIAL AND METHODS: The goal of the project "Indicators of patient care in Psychiatric and Psychosomatic Facilities" (VIPP project) is to gather a representative database which reflects the situation of day-to-day patient care performed by German psychiatric and psychosomatic facilities. The §â€Š21 data set represents the basis of this database which will be complemented by other data sources (i. e., financial statements and other economic data). A number of more than 100 ,000 cases per year has already been exceeded. These case data were provided by a wide range of psychiatric hospitals, departments and universities that participate in this project. The dataset is anonymised and by pooling the data it is not possible to identify the cases of a specific clinic. Participants receive a web-based access and have the possibility to analyse the data independently. RESULTS: Using the examples of coding accuracy and rehospitalisation rates the variety as well as the enormous potential of this database can be demonstrated. DISCUSSION: On the base of the VIPP database valid patient care indicators can be identified and cross-sectional analyses can be conducted. From such results key data on health economic strategies can be derived and the incentives, strengths and limitations of this constantly changing system can be identified.

Thalamic volumes in patients with bipolar disorder.

There are several hypotheses on functional neuronal networks that modulate mood states and which might form the neuroanatomical basis of bipolar disorder. The thalamus has been reported to be a key structure within the circuits that modulate mood states and might thus play an important role within the aetiology of the bipolar affective disorder. Nevertheless, structural brain imaging studies on the thalamus volume of bipolar patients have shown heterogeneous results. Using structural MRI scanning, we compared the thalamus volume of 41 euthymic bipolar patients to the thalamus volume of 41 well-matched healthy controls. Taking the concomitant medication as a co-variable within the patient group, the analysis of variance revealed a significantly smaller relative volume of the right thalamus in patients not treated with lithium when compared with healthy controls. In contrast, there are no significant differences concerning the thalamus volume between all euthymic bipolar patients and healthy controls. The study only shows findings of a transverse section. No longitudinal analysis was performed. More detailed information on patients' pharmacological histories could not be obtained. In conclusion, this result may be interpreted as an indication of the impact of the thalamus in the pathogenesis of the bipolar I disorder and emphasises the need for further longitudinal studies in bipolar patients with special attention paid to the concomitant medication, in particular to the role of lithium.

Nocturnal urinary cortisol excretion over a randomized controlled trial with paroxetine vs. placebo combined with relaxation training or aerobic exercise in panic disorder.

INTRODUCTION: Data on basal hypothalamo-pituitary-adrenomedullary (HPA) function over controlled treatment trials with serotonergic drugs in anxiety disorders are still rare. METHODS: 29 patients with panic disorder participating in a 10 week randomized, controlled trial (paroxetine vs. placebo with exercise or relaxation; N=60) collected urine for cortisol excretion over 3 consecutive nights before start and before termination of the treatment episode. Urinary cortisol was measured by radioimmunoassay. Efficacy measures were the Clinical Global Impression Scale (CGI) and the Panic and Agoraphobia Scale (P&A). 83% were female (p<.05 vs. males). 55% received additional aerobic exercise, and 45% relaxation. 55% received paroxetine treatment, and 45% placebo. Significantly fewer males received placebo treatment (p<.05). RESULTS: All subjects improved significantly. Cortisol excretion did not differ between treatment groups or at pre-/post measurements. Females showed a significantly higher variability of cortisol excretion compared to males, at pre-(p<.005) and post (p=.015) assessments. Males displayed a trend to lower basal HPA function at end of treatment (p=.08). HPA variability after treatment showed a trend to be higher in the paroxetine (p=.052) -who clinically improved significantly better- compared to the placebo group. No relationship between HPA activity and treatment response or with exercise was detected. DISCUSSION: HPA function shows significant gender differences, with females having a higher HPA function variability. Future studies on HPA function in treatment trials should address gender and medication effects.

Behavioural alterations in rats following neonatal hypoxia and effects of clozapine: implications for schizophrenia.

INTRODUCTION: As a consequence of obstetric complications hypoxia has been discussed as a possible factor in the pathophysiology of schizophrenia. The present study investigated the effects of weak chronic neonatal hypoxia in rats on different behavioural animal models of schizophrenia. METHODS: (1) After neonatal hypoxia, half of the pups were fostered by normally treated nurse animals to control for possible maternal effects. (2) The animals were tested on postnatal days (PD) 36, 86, 120 and 150 by applying three different behavioural tests: prepulse inhibition (PPI), social interaction and recognition, and motor activity in an open field. (3) Before the PD 150 test, half of the animals had been chronically treated with the antipsychotic drug clozapine (45 mg/kg/day). RESULTS: Rats exposed to hypoxia as neonates exhibited a deficit in locomotor activity on PD 86, 120, and 150, as well as a PPI deficit on PD 120 and 150 but not before. Chronic treatment with clozapine reverses the hypoxia induced PPI deficit, but not the decreased locomotor activity. In a second experiment, clozapine was chronically administered before PD 120 and blocked the development of the PPI deficit in the animals exposed to hypoxia. DISCUSSION: The time course of the hypoxia-induced PPI deficit and reversibility by clozapine supports the validity of our animal model and the hypothesis that hypoxia as an obstetric complication is an important factor in the pathophysiology of schizophrenia.

Reduced cortical inhibition in first-episode schizophrenia.

Disturbances in cortico-cortical and cortico-subcortical circuits in schizophrenia have been described by previous neuroimaging and electrophysiological studies. Transcranial magnetic stimulation (TMS) provides a neurophysiological technique for the measurement of cortical excitability, especially of the motoneural system. Previous studies using paired-pulse TMS to investigate short-interval cortical inhibition (SICI) and intracortical facilitation (ICF), mainly involving chronic schizophrenia patients, have been inconsistent and only one study in first-episode patients has been conducted so far. We assessed SICI (interstimulus interval, ISI, 3 milliseconds, ms) and ICF (ISI 7 ms) in 29 first-episode schizophrenia patients (FE-SZ) with limited exposure to antipsychotic treatment against measures of 28 healthy controls (HC). Amplitudes of motor evoked potentials (MEPs) were measured from the left and right first dorsal interosseus muscle (FDI). The conditioning stimulus was set at 80% intensity of resting motor threshold (RMT) and the test stimulus (TS) was set at an intensity that produced an MEP amplitude of about 1 mV. For SICI conditions, FE-SZ demonstrated significantly higher MEP amplitudes from left motor cortex (right FDI) compared to HC, and for MEPs from right motor cortex (left FDI) a similar trend was observable (FE-SZ 41% vs. HC 21% of TS, p=0.017 for left motor cortex, and FE-SZ 59% vs. HC 31% of TS, p=0.059 for right motor cortex; Mann-Whitney U-test). No significant difference in MEPs could be detected for ICF on either hemisphere. In addition, there was no difference in left and right RMT comparing patients and control subjects. Our result of a reduced SICI in a large sample of well characterized first-episode schizophrenia patients suggests that a GABAergic deficit may be involved in schizophrenic pathophysiology, already early in the disease course, supporting the intracortical dysconnectivity hypothesis.

Neurochemical pathology in hippocampus in euthymic patients with bipolar I disorder.

OBJECTIVE: Subcortical regions such as hippocampus, thalamus and ventral putamen are assumed to be involved in the pathophysiology of mood regulation. Disturbed hippocampal neuronal function indicated by reduced N-acetyl-aspartate (NAA) levels in bipolar patients was shown by several studies. Results in thalamus and putamen are inconsistent. METHOD: N-acetyl-aspartate, choline (Cho), creatine (Cr) and myo-inositol (Ins) were measured in left hippocampus, left thalamus and left putamen using proton magnetic resonance spectroscopy in 13 euthymic patients with bipolar I disorder and 13 pairwise matched healthy control subjects. Metabolic ratios NAA/Cr, NAA/Cho, Cho/Cr and Ins/Cr were calculated. RESULTS: Patients with bipolar I disorder demonstrated significantly reduced NAA/Cr in the left hippocampus compared with healthy control subjects. No alterations were found in thalamus or putamen. CONCLUSION: We hypothesize that this NAA/Cr reduction might reflect neuronal dysfunction in the left hippocampus in patients with bipolar disorder.

Cerebrospinal fluid diagnostic markers correlate with lower plasma copper and ceruloplasmin in patients with Alzheimer's disease.

Increasing evidence links Alzheimer's disease (AD) with misbalanced Cu homeostasis. Recently, we have shown that dietary Cu supplementation in a transgenic mouse model for AD increases bioavailable brain Cu levels, restores Cu, Zn-super oxide-1 activity, prevents premature death, and lowers A beta levels. In the present report we investigated AD patients with normal levels of A beta 42, Tau and Phospho-Tau in the cerebrospinal fluid (CSF) in comparison with AD patients exhibiting aberrant levels in these CSF biomarkers. The influence of these cerebrospinal fluid (CSF) diagnostic markers with primary dependent variables blood Cu, Zn and ceruloplasmin (CB) and secondary with CSF profiles of Cu, Zn and neurotransmitters was determined. Multivariate tests revealed a significant effect of factor diagnostic group (no AD diagnosis in CSF or AD diagnosis in CSF) for variables plasma Cu and CB (F=4.80; df=2, 23; p=0.018). Subsequent univariate tests revealed significantly reduced plasma Cu (-12.7%; F=7.05; df=1, 25; p=0.014) and CB (-14.1%; F=9.44; df=1, 24; p=0.005) levels in patients with aberrant CSF biomarker concentrations. Although only AD patients were included, the reduced plasma Cu and CB levels in patients with a CSF diagnosis of advanced AD supports previous observations that a mild Cu deficiency might contribute to AD progression.

[The role of copper in the pathophysiology of Alzheimer's disease]. / Zur Bedeutung von Kupfer für die Pathophysiologie der Alzheimer-Krankheit.

Alzheimer's dementia (AD) is a chronically progressive neurodegenerative disease. The key protein in the pathophysiology of AD is the amyloid precursor protein (APP) which releases the amyloid-beta peptide (Abeta) by proteolytic cleavage. APP is probably involved in the homeostasis of cellular copper (Cu) metabolism, because significantly changed Cu levels in the brain were found in AD patients as well as in mouse models. In vivo studies with transgenic mice showed that oral Cu supplements can restore lowered Cu levels in the brain to normal, can reduce Abeta production, and can reduce mortality of the animals. Currently, the influence of oral Cu supplementation (in addition to an established acetylcholinesterase inhibitor) on the progression of the disease is being studied in a prospective, double-blind, randomized and placebo-controlled longitudinal clinical trial in patients with mild AD.

[Homocysteine and dementia]. / Homozystein und Demenzerkrankungen.

Homocysteine is a vascular risk factor including cerebral macroangiopathy and microangiopathy. Furthermore, there might also be an association with cognitive disorders including vascular dementia and Alzheimer's disease. Hyperhomocysteinemia linked with cognitive impairment might be an indirect marker for low concentrations of vitamin B 12, vitamin B 6 or folate, resulting from low intake or from an impaired transport of the vitamins to the brain. Another possibility is a direct harmful effect of homocysteine to cognition via vascular and neurotoxic pathophysiologic mechanisms. Because hyperhomocysteinemia is a potentially reversible risk factor and can be identified early, it should be investigated by prospective intervention studies whether lowering homocysteine levels by vitamin supplementation could reduce incidence and progression of cognitive disorders.

Vagus nerve stimulation is associated with mood improvements in epilepsy patients.

Vagus nerve stimulation (VNS) has gained increasing acceptance for treatment of drug-resistant seizures. The aim of this study was to evaluate effects of VNS on depressed mood in epilepsy patients during the first 6 months after implantation of the stimulation device. This study was conducted as an addition to the international multisite randomized and double-blind controlled trial on anti-seizure effects of VNS (EO3). Only adult patients with >4/month medication-resistant complex-partial seizures were included (N=11). During the acute phase of the study (3 months after implantation), patients were randomly assigned to low (stimulation detection) versus high stimulation (maximal tolerability, maximum 1.75 mA). Mood and mood changes were recorded based on standardized psychiatric rating scales and self-report questionnaires. Patients were assessed 4 weeks before (baseline) as well as 3 and 6 months after implantation. Significant positive mood effects were observed in most scales and subscales at the 3-month follow-up (P<0.05). Mood improvements were sustained at the 6-month follow-up and were independent of effects on seizure activity (9/11 mood responders versus 2/11 seizure responders). Mood effects appeared more pronounced in the high stimulation group after the acute study phase, but findings were not significant (P<0.10). VNS is associated with mood improvements in patients with epilepsy, but to confirm VNS dose effects, studies with more statistical power are needed.

Antidepressant drug exposure is associated with mRNA levels of tyrosine receptor kinase B in major depressive disorder.

1. Recent studies have provided support for the notion that the high affinity neurotrophin receptor tyrosine receptor kinase B (trk B) may be involved in the treatment of depression. 2. Using a quantitative RT-PCR approach trk B mRNA levels were determined in brain material from cerebellum, temporal cortex, and frontal cortex of control specimen and patients with major depressive disorder, schizophrenia and bipolar disorder (15 subjects each). 3. Interestingly, elevated trk B mRNA levels were found in cerebellum (3.6-fold) in patients with major depressive disorder, reaching statistical significance (p=0.03). 4. The major depressive disorder-on drugs group differed from controls (p=0.006) in the cerebellum. 5. Since only patients with major depressive disorder received antidepressants, elevated trk B mRNA levels are possibly related to drug treatment.

Decreased frontal lobe ratio of N-acetyl aspartate to choline in familial schizophrenia: a proton magnetic resonance spectroscopy study.

Neuropathological and neuroimaging studies suggest neuronal dysfunction in schizophrenia. N-acetyl aspartate (NAA) is a useful marker of neuronal dysfunction that can be measured with magnetic resonance spectroscopy (MRS). In the present study NAA, choline (Cho), phospho-creatine ((P)Cr), inositol containing compounds and glutamine/glutamate (Glx) were assessed in the left frontal lobe and basal ganglia of subjects with familial schizophrenia, family members with mixed psychiatric diagnoses, unaffected family members, and community controls. Concentrations of metabolites were analyzed and expressed as ratios. NAA/Cho, NAA/(P)Cr and Glx containing compounds showed a negative correlation with age in the frontal lobe. After covarying for age, subjects with schizophrenia had a significant reduction in the left frontal lobe NAA/Cho ratio compared with unaffected family members (P=0.018) as well as with community non-familial (P=0.037) controls. These MRS observations support the hypothesis of a disease-related neuronal deficit in the frontal lobe of schizophrenic patients, and relatively normal basal ganglia.

Reduced tyrosine kinase receptor C mRNA levels in the frontal cortex of patients with schizophrenia.

Using a quantitative RNA-PCR approach tyrosine kinase receptor (trk) C mRNA levels were determined in brain material from the frontal cortex (BA10), temporal cortex (BA20) and cerebellum of control specimen and patients with schizophrenia, bipolar disorder or non-psychotic depression (15 subjects each). In the frontal cortex of schizophrenics there was a 5.8-fold reduction of trk C mRNA levels, which reached statistical significance (P < 0.05). Trk C levels in the cerebellum were positively correlated with lifetime fluphenazine equivalents (r = 0.54), suggesting that neuroleptics influence TRK C gene activity in the cerebellum. Moreover, the distinct medication-independent reduction of trk C mRNA may point to a disturbed neurotrophic gene activity in the frontal cortex of schizophrenic patients.

Compartmental volumetry of the superior temporal gyrus reveals sex differences in schizophrenia--a post-mortem study.

Brain imaging studies have shown superior temporal gyrus (STG) volume loss and abnormal patterns of asymmetry in schizophrenia; however, these are not consistent findings. Post-mortem volumetry of three different STG regions (defined by external landmarks) was used to compare 17 schizophrenics to 20 age- and sex-matched controls. Total STG volumes did not differ. A significant gray-matter volume reduction in schizophrenics was observed in the middle compartment (reaching from the mamillary body to the lateral geniculate body). This may have been related to reduced length of this region, particularly in schizophrenic females. These results reflect the problematic issue of defining boundaries of macroscopic brain structures.

Nitric oxide synthase-containing neurons in the human hypothalamus: reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics.

The neuroanatomical distribution of nitric oxide synthase-immunoreactive neurons was investigated in post mortem hypothalami of 10 patients suffering from schizophrenia, eight patients with depression and 13 matched control cases. Neuronal nitric oxide synthase containing nerve cells were detected in several hypothalamic nuclei including the medial preoptic region, the ventromedial, infundibular and suprachiasmatic nuclei and the lateral hypothalamus. The vast majority of hypothalamic nitric oxide synthase-immunoreactive neurons was found to be located in the paraventricular nucleus. Both magno and parvocellular paraventricular neurons contained the enzyme. A small subset of immunoreactive parvocellular paraventricular neurons co-expresses corticotropin-releasing hormone. The supraoptic nucleus did not contain nitric oxide synthase-immunoreactive neurons. Cell counts of paraventricular nitric oxide synthase-positive neurons in controls, schizophrenics and depressed patients revealed a statistically significant reduction of cell density in the right paraventricular nucleus of depressed patients and schizophrenics as compared to controls. The total amount of nitric oxide synthase-immunoreactive paraventricular neurons was smaller in depressive and schizophrenic patients than in normal cases. The putative pathophysiologic significance of the reduced expression of paraventricular nitric oxide synthase in depressive patients might be related to the supposed regulatory function of nitric oxide in the release of corticotropin-releasing hormone and arginine-vasopressin and/or oxytocin, which have been reported to be over-expressed in the so-called endogenous psychoses, especially in depression.