Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction.

BACKGROUND: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. AIMS: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. METHODS: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine's effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. RESULTS: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. CONCLUSION: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.

Reversible Hypothermia in a Drug-naive Inpatient with Alzheimer's Disease Receiving Pipamperone.

Hypothermia is a potentially life-threatening side effect of antipsychotic drugs, especially those with strong 5-HT2 antagonist properties. However, the exact underlying mechanism is still under debate. We discuss a case of hypothermia following pipamperone treatment in an elderly female inpatient with Alzheimer's disease, which occurred at day 4 after medication onset and vanished after dose reduction. Thus, this case demonstrates 1) the importance of monitoring body temperature even in low-potency antipsychotics, at least in the elderly, and 2) that in some cases, dose reduction may be a sufficient countermeasure.

Attention and CERAD test performances in cognitively impaired elderly subjects.

OBJECTIVES: Attention plays a fundamental role in cognitive performance and is closely interrelated with all major cognitive domains. In this retrospective study, we correlated different measures of attention with standard cognitive parameters in 85 cognitively impaired elderly individuals presenting with cognitive complaints to a memory clinic. MATERIALS AND METHODS: Z-scores of all relevant cognitive parameters of a extended Consortium to Establish a Registry for Alzheimer's disease (CERAD-Plus) neuropsychological battery were correlated with tonic and phasic alertness, inhibition, and divided attention, assessed by a computerized test battery of attention. The pooled sample consisted of 36 patients with the diagnosis of mild AD, 30 patients with mild cognitive impairment, and 19 patients with major depressive disorder. RESULTS: Subjects of all diagnostic groups exhibited normal results in all subtests of attention. Reaction times of neither the tonic nor the phasic alertness task were correlated with any parameter of memory and global cognition. However, significant correlations were obtained between reaction times in the alertness tasks and the trail-making tests. Omissions in the divided attention task yielded the strongest correlations with deficits in cognitive performance, particularly in the verbal learning tasks, the Boston naming test, and the trail-making tests. CONCLUSIONS: Our data demonstrate the relative independency of the CERAD-Plus on the variability of attention and particularly alertness suggesting its robustness in psychiatric memory clinic settings. Moreover, CERAD-Plus subtests correlated considerably with failure rates in divided attention, suggesting that impairment in divided attention tasks may be early markers of cognitive impairment.

["Extended suicide". Homicide-suicide under psychopathological and criminological aspects]. / Der "erweiterte Suizid". Vollendete Homizid-Suizide unter psychopathologischen und kriminologischen Aspekten.

BACKGROUND: Homicide-suicide is a rare and serious phenomenon which mainly occurs in intimate relationships and families. MATERIALS AND METHODS: In this study ten cases of murder-suicide during the period 2006-2011 in the greater area of Düsseldorf were investigated. Data were obtained from coroner and prosecution files. RESULTS: All perpetrators were male. In accordance with the literature the results of the analysis revealed male sex, higher age, intimate partnership, access to firearms and special personality traits, mainly emotionally unstable, narcissistic traits and aggressiveness as the main risk factors. In all cases, at least three risk factors were identified. Breakdown of the marital relationship and social descent emerged as probable leading motives. Shooting was the most frequent method of killing followed by sharp force. CONCLUSIONS: Compared with homicide and suicide, homicide-suicide appears to be a distinct phenomenon. The knowledge and understanding of relevant risk factors could help mental health professionals, police and public authorities to intervene in time.

[Vascular factors in the pathogenesis of Alzheimer's disease]. / Vaskuläre Faktoren in der Pathogenese der Alzheimer-Krankheit.

According to the amyloid hypothesis of Alzheimer's disease (AD), the amyloid ß (Aß) peptide, as the primary neurotoxic species, plays a key role in the pathogenesis of the disease. However, many lines of recent evidence also point towards a major importance of early cerebrovascular dysfunction at least for the most common form of the disease, sporadic AD. In the preclinical course not only neuronal but also vascular damage frequently occurs. Cerebral hypoperfusion, blood-brain barrier dysfunction and vascular oxidative stress are typical features of this stage of the disease. Most importantly, such alterations precede the classical pathological hallmarks, such as parenchymal deposition of extracellular amyloid and intracellular neurofibrillary tangles. In this article recent epidemiological, clinical pathological and experimental evidence for an integrative vascular neuronal pathogenetic model of sporadic AD is reviewed.

[Psychopharmacotherapy in patients with cardiovascular diseases]. / Psychopharmakotherapie bei Herz-Kreislauf-Erkrankungen.

Increased cardiometabolic morbidity and increased overall mortality has been observed in patients with severe mental disorders. Therefore, cardiometabolic safety is an important issue in the treatment of patients with psychiatric disorders, in particular in patients with comorbid cardiometabolic diseases. Frequent adverse side effects include disturbances of lipid and glucose metabolism, body weight changes and alterations of the QTc interval. Dependent on the particular substance used and on factors concerning individual vulnerability, these side effects vary in relative frequency. Therefore, regular monitoring is recommended including ECG. Furthermore, interactions between different medicaments may occur, either leading to enhanced or decreased drug concentrations. Prior to psychopharmacological treatment, proper cardiological treatment is recommended. The management of cardiovascular risks under psychopharmacology requires interdisciplinary cooperation between the cardiologist, general practitioner and psychiatrist.

[Antidepressant therapy in coronary artery disease]. / Antidepressive Therapie bei koronarer Herzkrankheit.

Depression is considered an independent risk factor for coronary artery disease (CAD) and other vascular conditions. Moreover, comorbid depressive disorder in CAD patients carries an increased risk of cardiac events and mortality. Among survivors of acute myocardial infarction, up to 20% meet diagnostic criteria for major depression, the presence of which carries a fivefold increased risk of cardiac death within 6 months. Heart patients with depressive comorbidity require particular care for both adequate treatment of their affective disorder and reduction of their cardiac risk. Antidepressant treatment must follow established guidelines; special care is needed to avoid cardiac side effects. In this review, we discuss the pathophysiological and prognostic significance of comorbid depression in CAD and weigh risks and benefits of available treatment options - particularly different drug classes and psychotherapy - in light of recent study results.

[Therapeutic options for weight management in schizophrenic patients treated with atypical antipsychotics]. / Möglichkeiten des Gewichtsmanagements in der Behandlung schizophrener Psychosen mit atypischen Antipsychotika.

Extensive, selective literature review of 2500 articles from the last years (up to December 2007) predominantly from Medline and Cochrane, using as search terms "antipsychotic or schizophrenia or individual drug names (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone)" and the terms "BMI, weight gain, metabolic syndrome, diabetes, lipid(s), cholesterol, triglycerides" was conducted. Regardless of the advantages ascribed to atypical antipsychotics and the special effectiveness of clozapine in patients resistant to therapy and at risk for suicide, the probability of weight gain is considerably increased for some of these substances. Patients with schizophrenia have a considerably reduced life expectancy associated with an increased prevalence of cardiovascular risk factors. There is a lack of practical guidelines integrated into clinical psychiatric care for the management of cardiovascular risk factors. The monitoring of patients treated with atypics, which has been recommended in the APA/ADA Consensus Paper in light of these facts, is insufficiently established in clinical practice. A regular monitoring can convey self control and motivation to the patient. In the case of corresponding risk constellations further decisions regarding indication and therapy have to be considered. Especially patients with a high cardiovascular risk profile are highly recommended to participate in a weight-management program for prevention purposes. Such a special program should include elements of dietetic treatment and behaviour and exercise therapy. First controlled studies suggest an effective prevention of weight gain and metabolic changes when applying such a structured program. The practice oriented step by step concept presented here is meant to provide points of reference for the implementation of required medical and psychoeducative measures facilitating the management of weight and further cardiovascular risk factors in the context of psychiatric care in patients with schizophrenia.

Spatial performance in a complex maze is associated with persistent long-term potentiation enhancement in mouse hippocampal slices at early training stages.

Long-term potentiation (LTP) and long-term depression (LTD) are principal reflections of synaptic plasticity that have been implicated in learning and memory. We have previously shown that spatial learning in a newly validated complex maze is accompanied by depression of hippocampal CA1 synaptic activity in hippocampal slices of trained mice ("behavioral LTD"). In the present study, we investigated whether behavioral LTD is accompanied by alterations of subsequent LTP induced by high-frequency stimulation (HFS). Moreover, we were interested in the time course of such alterations in relation to training stage. Animals underwent 1, 2, and 8 days of spatial training in the complex maze, respectively. Hippocampal slices were taken 24 h after the last training session. We found a simultaneous decrease of basal synaptic response and increase of HFS induced LTP magnitude compared with slices of untrained animals. Synaptic plasticity was not influenced by repeated running wheel exercise in an additional control group without spatial learning. The mentioned alterations occurred already after day 2 of maze exploration parallel to the most pronounced improvement of behavioral performance but did not change thereafter until day 8 despite further learning progress. They were also found when animals were trained for 2 days and kept at rest for a subsequent 6 days. In conclusion, spatial learning may be reflected by distinct and persistent measurable alterations of synaptic plasticity in hippocampal CA1 neurons at early training stages.

[Autoimmune functional disorders of the thyroid during interferon-beta-1b treatment in patients with multiple sclerosis. Case report and literature review]. / Autoimmune Funktionsstörungen der Schilddrüse unter Interferon-beta-1b-Therapie bei Patienten mit Multipler Sklerose. Kasuistik und Literaturübersicht.

Occurrence of thyroid autoimmunity and dysfunction following interferon alpha treatment of viral hepatitis and other diseases are known adverse effects and have been ascribed to the cytokine's general immunomodulatory and -activating properties. However, in spite of its extensive application, there have been few reports of such incidents during interferon beta (IFN-beta-1a/b) therapy, which is considered the standard treatment of relapsing-remitting multiple sclerosis (MS), and prospective studies have been published only recently. Here we present the case of a 38-year-old woman with Graves' disease including massive thyroid-associated ophthalmopathy appearing de novo following IFN-beta-1b therapy for MS. A literature search revealed an 11% (5% clinically overt) overall incidence of de novo thyroid dysfunction in IFN-beta-treated MS patients, mostly autoimmune hyperthyroidism. (Large-scale comparative studies for IFN-beta-1a are not available at present). Specific treatment but not necessarily discontinuation of IFN-beta-1b therapy was required in most cases. Female gender, pre-existing thyroid autoimmunity, and family history of thyroid disorders are presumable risk factors for thyroid dysfunction de novo during IFN-beta-1b treatment.

[18F]Fluoroethylflumazenil: a novel tracer for PET imaging of human benzodiazepine receptors.

5-(2'-[18F]Fluoroethyl)flumazenil ([18F]FEF) is a fluorine-18 labelled positron emission tomography (PET) tracer for central benzodiazepine receptors. Compared with the established [11C]flumazenil, it has the advantage of the longer half-life of the fluorine-18 label. After optimisation of its synthesis and determination of its in vitro receptor affinities, we performed first PET studies in humans. PET studies in seven healthy human volunteers were performed on a Siemens ECAT EXACT whole-body scanner after injection of 100-280 MBq [L8F]FEF. In two subjects, a second PET scan was conducted after pretreatment with unlabelled flumazenil (1 mg or 2.5 mg i.v., 3 min before tracer injection). A third subject was studied both with [18F]FEF and with [11C]flumazenil. Brain radioactivity was measured for 60-90 min p.i. and analysed with a region of interest-oriented approach and on a voxelwise basis with spectral analysis. Plasma radioactivity was determined from arterial blood samples and metabolites were determined by high-performance liquid chromatography. In human brain, maximum radioactivity accumulation was observed 4 +/- 2 min p.i., with a fast clearance kinetics resulting in 50% and 20% of maximal activities at about 10 and 30 min, respectively. [18F]FEF uptake followed the known central benzodiazepine receptor distribution in the human brain (occipital cortex >temporal cortex >cerebellum >thalamus >pons). Pretreatment with unlabelled flumazenil resulted in reduced tracer uptake in all brain areas except for receptor-free reference regions like the pons. Parametric images of distribution volume and binding potential generated on a voxelwise basis revealed two- to three-fold lower in vivo receptor binding of [18F]FEF compared with [11C]flumazenil, while relative uptake of [18F]FEF was higher in the cerebellum, most likely owing to its relatively higher affinity for benzodiazepine receptors containing the alpha6 subunit. Metabolism of [18F]FEF was very rapid. Polar metabolites represented about 50%-60% of total plasma radioactivity at 5 min and 80%-90% at 20 min p.i. Although [11C]flumazenil has some advantages over [18F]FEF (higher affinity, slower metabolism, slower kinetics), our results indicate that [18F]FEF is a suitable PET ligand for quantitative assessment of central benzodiazepine receptors, which can be used independently of an on-site cyclotron.