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R Hellweg

Publications and source records attributed to R Hellweg.

At least 19 recordsLinked to original sources

[Prevalence and role of psychiatric disorders in disability].

Common risk factors for the receipt of disability income (DI) are psychiatric diagnosis at the time of conscription, showing low personal responsibility and job satisfication, unemployment after graduation, low rating on an "IQ" test, low educational level, part-time employment, isolation, separation, smoking, problem drinking, poor subjective state of health and well-being. Psychiatric diagnoses are considered to be the main reason for disability income in women and rank third in men. With average retirement age of 39 for males and 42 for females, schizophrenia is the most important single reason for early retirement before age 40. Major depression has been shown to be the fourth leading cause of DI worldwide. Personality disorders, which display primarily antisocial, histrionic, emotionally unstable and narcissistic behaviour (Cluster B personality disorders) have been associated with an earlier age of work disability, and borderline personality has been associated with failure to return to work. A dependent, schizoid, paranoid and antisocial personality tends to be associated with an increased risk of developing disability. A subtype of adaptation disorder that is characterised primarily by lasting embitterment after exceptional life events, which violate basic beliefs, namely post-traumatic embitterment disorder, shows up highly the development of DI. However, most of the patients applying for a DI have neither been sufficiently diagnosed nor received adequate psychiatric and/or psychotherapeutic treatment when they claim on their DI policy. Thus, the prognosis of the diseases listed above could well be improved at least for some patients depending on their disease (10-80 %).

Comorbidity↗

Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness.

Stress-induced helplessness in rodents constitutes a well-defined model to investigate neurobiological mechanisms of depression. Neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have both been shown to be involved in neurobiological changes of physiological and pathological reactions to stress. In this study we investigated NGF and BDNF protein levels in the frontal cortex and hippocampus in mice treated with an established model of inducible helplessness via electric footshocks compared to untreated controls at various times (0 h up to 14 days after treatment). NGF levels were transiently decreased by one forth in the frontal cortex of shocked mice at 6 h after the stress treatment, whereas BDNF levels remained unchanged in the brain areas investigated throughout the time course. In addition, frontal cortex BDNF levels showed a significantly higher concentration in the right compared to the left hemisphere (up to 3-fold). This effect was detectable independently of treatment, namely in shocked and control mice at any time point measured. In conclusion, a transient decrease of frontal NGF constitutes the most striking correlate of neurobiological changes in this animal model of stress-induced change of behaviour. Interhemispherical differences of BDNF content in the frontal cortex are a new finding that might reflect intracerebral side dominance. Thus, subsequent studies of frontal cortex BDNF expression should carefully consider an interhemispherical variance to avoid misinterpretation.

Animals↗

Chronic alcohol intoxication in rats leads to a strong but transient increase in NGF levels in distinct brain regions.

Nerve growth factor (NGF), a member of the neurotrophin family, is an essential mediator of neuronal activity and synaptic plasticity of basal forebrain cholinergic neurons. In this study NGF-protein levels were determined in areas of the basal forebrain cholinergic system, its projection areas as well as the striatum and the cerebellum after long-term exposure (6 and 9 months) to ethanol and a phase of withdrawal in male Sprague-Dawley rats. 6-month alcohol treatment led to an increase of NGF to 650-850% of controls in the basal forebrain and the septum and to a 210-485% increase in the cholinergic projection areas (anterior cortex, hippocampus and olfactory bulb). After 9 months exposure to ethanol, a decrease of NGF by 16% in the frontal cortex was observed compared to controls. In the other brain regions no differences in NGF expression were detectable at this time-point. These results support the idea of an endogenous neuroprotective mechanism acting through a transient NGF induction followed by a decrease in NGF-levels during the course of further neuronal degeneration.

Acetylcholine↗

Regional selectivity of amyloid mRNA expression and neurotrophins on repetitive inhibition of oxidative phosphorylation.

Previously we showed that repetitive inhibition of oxidative phosphorylation impairs synaptic transmission and induces overexpression of amyloid precursor protein mRNA (APP-mRNA) in the hippocampus (Hellweg et al., 2003). Here we show that APP-mRNA remains alike in murine frontal cortex and cerebellum on repetitive treatment with 3-nitropropionate. However, nerve growth factor and brain-derived neurotrophic factor decreased by 28 to 38% in frontal cortex. Taken together, the pattern of change resembles genetic models of Alzheimer's disease with less susceptibility for overexpression of amyloid mRNA in frontal cortex than in hippocampus and reduced neurotrophin levels in frontal cortex. Given the similarity of this pattern to the one observed in human Alzheimer's disease the present model in future may give further insight into the pathophysiology of sporadic Alzheimer's disease.

Alzheimer Disease↗

Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development.

Serotonergic neurones are among the first to develop in the central nervous system. Their survival and maturation is promoted by a variety of factors, including serotonin itself, brain-derived neurotrophic factor (BDNF) and S100beta, an astrocyte-specific Ca(2+) binding protein. Here, we used BDNF-deficient mice and cell cultures of embryonic raphe neurones to determine whether or not BDNF effects on developing serotonergic raphe neurones are influenced by its action on glial cells. In BDNF-/- mice, the number of serotonin-immunoreactive neuronal somata, the amount of the serotonin transporter, the serotonin content in the striatum and the hippocampus, and the content of 5-hydroxyindoleacetic acid in all brain regions analysed were increased. By contrast, reduced immunoreactivity was found for myelin basic protein (MBP) in all brain areas including the raphe and its target region, the hippocampus. Exogenously applied BDNF increased the number of MBP-immunopositive cells in the respective culture systems. The raphe area displayed selectively reduced immunoreactivity for S100beta. Accordingly, S100beta was increased in primary cultures of pure astrocytes by exogenous BDNF. In glia-free neuronal cultures prepared from the embryonic mouse raphe, addition of BDNF supported the survival of serotonergic neurones and increased the number of axon collaterals and primary dendrites. The latter effect was inhibited by the simultaneous addition of S100beta. These results suggest that the presence of BDNF is not a requirement for the survival and maturation of serotonergic neurones in vivo. BDNF is, however, required for the local expression of S100beta and production of MBP. Therefore BDNF might indirectly influence the development of the serotonergic system by stimulating the expression of S100beta in astrocytes and the production MBP in oligodendrocytes.

Animals↗

No nerve growth factor response to treatment with memantine in adult rats.

Nerve growth factor (NGF) is the most widely examined neurotrophin in the experimental models of Alzheimer's disease (AD) and has been shown to prevent the retrograde degeneration of cholinergic neurons. In this study we examined NGF and cholineacetyltransferase (ChAT) changes in several rat brain regions after excitotoxic lesion of the entorhinal cortex with quinolinic acid and tested the effect of memantine on spatial learning in the radial maze after lesion. We observed a significant increase (+26%, p=0.02) of NGF concentrations in the hippocampus of the lesioned rats when compared to sham-lesioned rats. Chronic treatment with memantine showed no significant effect on the NGF increase in the hippocampus (p=0.72). The ChAT activity was significantly increased in the lesioned rats when compared to controls (+16%, p<0.05) and did not depend on treatment with memantine. In spite of this, memantine improved performance of the radial maze. This indicates that memory improving effects of memantine observed in experimental animals and in clinical studies are probably not related to changes in brain NGF content, whereas the observed NGF increase in the denervated hippocampus is probably trauma-related reflecting impaired retrograde transport of hippocampal NGF.

Animals↗

State of the art of the neurotrophin hypothesis in psychiatric disorders: implications and limitations.

The neurotrophin hypothesis proposes that repetitive neuronal activity enhances the expression, secretion and actions of neurotrophins to modify synaptic transmission and connectivity thereby providing a connection between neuronal activity and synaptic plasticity. Moreover, there is ample evidence that neurotrophins have numerous neuroprotective effects under pathological conditions, which might be important in particular for neurodegenerative diseases such as Alzheimer' disease. Current research postulates that effects during brain development lead to defective neural connectivity and altered biochemical functioning resulting in cognitive, emotional and intentional dysfunction later in life. This implicates a possible role in most psychiatric diseases including affective and schizophrenic disorders. This hypothesis is mainly based on new experimental evidence showing that psychiatric disorders are associated with neuronal atrophy and cell loss, impairments of structural plasticity and cellular resilience due to neurodevelopmental disturbances and morphological abnormalities of the brain. Thus, the potential role of neurotrophins in psychiatric disorders has been studied in different ways. Animal studies indicate the involvement of neurotrophins in psychopharmacological therapies and they show that gene expression of cerebral neurotrophins is changed in animal models of several psychiatric disorders. Whether such alterations are causatively associated with increased neural plasticity, improved cognitive function and decreased depressive mood states remains to be elucidated in further studies including man (e.g. in postmortem studies of patients). Association studies tried to link different variants in genes coding for neurotrophins, they have not been conclusive however. They partially allow to separate different subgroups of patients with differing therapy response profiles or indicate an increased vulnerability for a specific disorder. Finally, neurotrophin serum changes have been observed in most psychiatric disorders. The question remains though whether these alterations represent primary-causal or secondary-reactive changes.In conclusion, the issue of neuroprotection and neurotrophins is recognised as an important new lead in the quest for a deeper understanding of psychiatric disorders and the mechanisms of action of psychopharmacological interventions.

Alzheimer Disease↗

Nerve growth factor response to excitotoxic lesion of the cholinergic basal forebrain is slightly impaired in aged rats.

Nerve growth factor (NGF) promotes survival and function of basal forebrain cholinergic neurons. We studied NGF and choline acetyltransferase (ChAT) activity after partial quisqualic acid induced lesions of the basal forebrain in 3 and 27 months-old rats, in order to investigate whether NGF-related regeneration is disturbed in old age. 2 weeks post lesion, ChAT activity decreased by 25 to 32% in adult and old rats. 3 months post lesion, the ChAT deficit receded in adult rats, but remained unchanged in old rats. 2 weeks post lesion, NGF levels were reduced by 36 to 44%, but there was no significant difference between adult and old rats. 3 months post lesion, we found increased NGF levels by 44% in the posterior cortex of adult rats. These results indicate that the compensatory NGF increase in the posterior cortex after partial cholinergic lesion of the basal forebrain is slightly impaired in old age.

Acetylcholine↗

Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation.

Repetitive inhibition of oxidative phosphorylation is an established model of neurodegeneration. In contrast, a single mild treatment can be neuroprotective-chemical preconditioning. Repetitive chemical inhibition of oxidative phosphorylation may thus be a tool to study deterioration and improvement of cellular hypoxic tolerance and subsequent differential regulation of cellular responses in the same model. We investigated murine hippocampal function upon repetitive intraperitoneal injections of 3-nitropropionate (3-NP; 20 mg/kg body weight), an inhibitor of mitochondrial complex II. With a 2-day interval of repetitive in vivo treatment with 3-NP, posthypoxic recovery of population spike amplitude was below control. In contrast, even after nine in vivo treatments with 3-NP at 4-day intervals, an almost complete recovery of population spike amplitude was observed. Nerve growth factor (NGF) as assessed by ELISA and expression of beta-amyloid precursor protein (APP) mRNA increased upon nine treatments at 2-day intervals, but remained at control levels with 4-day intervals. In contrast, brain-derived neurotrophic factor (BDNF) as assessed by ELISA increased with the latter treatment. Expression of mRNA for adenosine-A1 and -A3 receptors and endothelial and neuronal nitric oxide synthase remained at control level for both treatment intervals. We conclude that the time interval between mild, subclinical repetitive inhibition of oxidative phosphorylation determines hippocampal neuronal impairment and integrity and modulates NGF and BDNF differently. Decreased hypoxic tolerance and increased APP expression upon repetitive inhibition of oxidative phosphorylation at short time intervals may thus trigger a vicious cycle and be a cofactor for neuronal dysfunction in cerebral hypoxia and neurodegenerative diseases.

Action Potentials↗

Platelet counts in depressed patients treated with amitriptyline or paroxetine.

OBJECTIVE: To assess whether therapy with two widely used antidepressants influences platelet counts. SUBJECTS AND METHODS: In 90 patients hospitalized for treatment of a major depressive episode according to DSM-IV, platelet counts were performed after a 6 d antidepressant-free run-in period and again after 35 d of active standardized treatment with amitriptyline (n = 40) or paroxetine (n = 50). RESULTS: There was a trend for platelet counts to increase during treatment with amitriptyline (from 245.5 +/- 68.6 to 256.8 +/- 69 cells x 10(9) L(-1), P < 0.06); no change was observed during treatment with paroxetine (from 232.6 +/- 58.3 to 234.6 +/- 68.9 cells x 10(9) L(-1), n.s). CONCLUSION: Treatment with amitriptyline tends to be associated with elevated platelet counts. The cause for this increase is not known, but may be relevant in terms of patients' long-term thromboembolic risk.

Amitriptyline↗

Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats.

There is compelling evidence that withdrawal of neurotrophins can lead to impaired neuronal function and even apoptotic death of neurons. Recent experimental evidence suggests that antidepressant drugs and electroconvulsive treatment might work by enhancing CNS levels of neurotrophins. In addition, Lithium (LI) has been shown to exert robust neuroprotective effects apart from its well known mood-stabilizing effects in humans. In this study we investigated the effects of subchronic (14 days) treatment with various doses of LI on the NGF content of several regions of the adult rat brain. LI treatment, which resulted in prophylactic LI serum concentrations (0.72 +/- 0.08 mMol l(-1)), induced a significant (P < 0.05) increase in NGF concentrations in the frontal cortex (+23.2%), hippocampus (+72%), amygdala (+74%) and limbic forebrain (+46.7%) compared to untreated controls, whereas no effects on NGF concentrations were observed in the striatum, the hypothalamus or the midbrain, even using various LI doses. Moreover, no significant change in NGF concentrations in the frontal cortex was observed after acute (1 day) treatment with LI. Our findings lend support to the notion that an enhancement of NGF production may be specifically involved in the mechanisms of action of antibipolar treatments.

Animals↗

Serotonergic lesion of median raphe nucleus alters nerve growth factor content and vulnerability of cholinergic septohippocampal neurons in rat.

About 45% of the serotonergic raphe neurons are reported to express nerve growth factor (NGF) receptors. We therefore investigated whether selective serotonergic lesions of the median or dorsal raphe nuclei are associated with changes in NGF protein levels of the brain and whether the loss of serotonergic function alters the vulnerability of cholinergic septohippocampal neurons. In adult rats the hippocampal NGF content changed in a biphasic way after lesion of the median raphe nucleus by 5,7-dihydroxytryptamine (5,7-DHT), with a significant increase after 2-3 weeks of up to 35%, followed by a significant reduction of 22% below control levels after 7 weeks, and a return to control levels within the following 4 weeks. By contrast, the decrease in hippocampal serotonin and 5-hydroxyindoleacetic acid remained throughout the observation period of 11 weeks, being still reduced to 15 and 30% of the control levels, respectively. In the frontal cortex the partial loss of the serotonergic innervation projecting from the median raphe was associated 5 weeks after 5,7-DHT injection with an increase in NGF protein of 39.7+/-9.6% (P<0.05), which remained elevated up to 11 weeks. At 9 weeks after 5,7-DHT, the lesion of the septohippocampal cholinergic neurons induced by the cholinotoxin ethylcholine aziridinium (AF64A) was exaggerated (P<0.05) as compared to AF64A-treated rats with intact serotonergic innervation. The present data indicate that a serotonergic lesion of the median raphe nucleus results in biphasic changes of NGF protein content and in a delayed increase in the vulnerability of septohippocampal cholinergic neurons.

5,7-Dihydroxytryptamine↗

Regulation of apolipoprotein E secretion in rat primary hippocampal astrocyte cultures.

Apolipoprotein E isoforms may have differential effects on a number of pathological processes underlying Alzheimer's disease. Recent studies suggest that the amount, rather than the type, of apolipoprotein E may also be an important determinant for Alzheimer's disease. Therefore, understanding the regulated synthesis of apolipoprotein E is important for determining its role in Alzheimer's disease. We show here that in rat primary hippocampal astrocyte cultures, dibutyryl-cAMP increased apolipoprotein E secretion with time in a dose-dependent manner (to 177% at 48 h) and that retinoic acid potentiated this effect (to 298% at 48 h). Dibutyryl-cAMP also gave a rapid, albeit transient, increase of apolipoprotein E mRNA expression (to 200% at 1 h). In contrast, the protein kinase C activator phorbol 12-myristate 13-acetate decreased both apolipoprotein E secretion (to 59% at 48 h) and mRNA expression (to 22% at 1 h). Phorbol 12-myristate 13-acetate also reversed the effects of dibutyryl-cAMP. Apolipoprotein E secretion was also modulated by receptor agonists for the adenylyl cyclase/cAMP pathway. Isoproterenol (50 nM, a beta-adrenoceptor agonist) enhanced, while clonidine (250 nM, an alpha2-adrenoceptor agonist) decreased, secreted apolipoprotein E. We also analysed the effects of agonists for the phospholipase C/protein kinase C pathway. Arterenol (1 microM, an alpha1-adrenoceptor agonist) and serotonin (2.5 microM) enhanced, whereas carbachol (10 microM, an acetylcholine muscarinic receptor agonist) decreased secreted apolipoprotein E. The effects of these non-selective receptor agonists were modest, probably due to effects on different signalling pathways. Arterenol also potentiated the isoproterenol-mediated increase. We also show that phorbol 12-myristate 13-acetate and dibutyryl-cAMP have opposite effects on nerve growth factor, as compared to apolipoprotein E, secretion, suggesting that the results obtained were unlikely to be due to a general effect on protein synthesis. We conclude that astrocyte apolipoprotein E production can be regulated by factors that affect cAMP intracellular concentration or activate protein kinase C. Alterations in these signalling pathways in Alzheimer's disease brain may have consequences for apolipoprotein E secretion in this disorder.

Alzheimer Disease↗

Genetic determinants of drug-induced agranulocytosis: potential risk of olanzapine?

Whether or not olanzapine causes bone marrow toxicity is still a matter of debate. In spite of pre-marketing and post-marketing clinical trials, and although there have been no cases in animals of olanzapine-induced neutropenia or agranulocytosis, the risk of bone marrow toxicity cannot be excluded. The present paper addresses the following questions: what is the potential background of drug-induced agranulocytosis? Are there any case reports supporting the view that olanzapine has relevant bone marrow toxicity? What strategies might be helpful in identifying the pathological mechanisms underlying this side effect?

Adult↗

["Catatonic dilemma". Therapy with lorazepam and clozapine].

We are reporting on a patient with a schizoaffective disorder (ICD 10:F25.1), whose catatonic symptoms deteriorated while receiving high-potency neuroleptic drugs in combination with anticholinergic medication. Initially there was a "catatonic dilemma", i.e. it was not possible to differentiate between the morbigenous and pharmacogenic (malignant neuroleptic syndrome) etiology of the catatonic symptoms. Catatonic symptoms were successfully treated with a combination of lorazepam and clozapine. The severe catatonic syndrome was found to be a neuroleptic-induced deterioration of a primary morbogenous catatonic syndrome. Thus, this case also suggests that the malignant neuroleptic syndrome and neuroleptic non-responsive catatonia may not be two different disease entities but that catatonia under neuroleptic medication is caused by the interaction of individual disposition, morbigenous and pharmacogenic factors.

Adult↗

[High dosage thyroxine treatment in therapy and prevention refractory patients with affective psychoses].

The following review summarizes current knowledge on the treatment of therapy-resistant patients with affective disorders with supraphysiological doses of thyroxine (T4). Several groups have reported independently of each other that administration of 200-500 micrograms T4/day has excellent effects in 50-65% of patients a) with bipolar disorder, with or without, "rapid cycling" course, who were previously resistant to all prophylactic drugs and b) in the treatment of therapy-resistant depression. T4 is effective only in combination with an antidepressant or a prophylactic drug. Side effects are minimal, even when T4 is administered over several years. These results now justify to recommend high dose T4-augmentation as "last-resort" treatment also beyond research purposes, i.e. in psychiatric wards and in private practice. Recommendations for clinical applications are given and hypotheses on possible mechanisms underlying the efficacy of T4 treatment are discussed.

Bipolar Disorder↗

The time course of nerve growth factor content in different neuropsychiatric diseases--a unifying hypothesis.

Nerve growth factor (NGF) is the prototype of related neurotrophic proteins, the so-called neurotrophins. NGF is essential for proper development of sympathetic and neural crest-derived sensory neurons of the peripheral nervous system (PNS) as well as of the neurons in the cholinergic basal forebrain (CBF). In the mature peripheral and central nervous system (CNS) NGF is also biologically active; NGF facilitates neuronal plasticity and regulates synaptic transmission and connectivity. Besides this well established neurotrophic function, recent findings suggest a role of NGF in neuroimmune and stress-associated processes, which NGF imparts not only as the classical "target-derived messenger", that is retrogradely transported within NGF-sensitive neurons, but also as para- and autocrine cytokine modulating the function of non-neuronal cells. Since neurotrophins are produced in very small amounts in vivo, NGF-sensitive cells have to compete for the limited NGF even under physiological conditions, so that normally only less than 10% of NGF receptors (NGFR) are saturated with their endogenous ligand. Consequently, it is feasable that minute changes in NGF concentrations can influence neuronal function in an extensive way. Hence, one plausible pathomechanism of disease(s) may be that a deficiency in NGF leads to malfunction of NGF-sensitive neurons. The change in NGF concentrations in the course of several diseases, namely during alcoholic and diabetic neuropathy as well as in Alzheimer's disease (AD) and several lesion-models of the CBF, indicates that fluctuations of endogenous NGF concentrations in PNS and CNS follow a distinctive pattern. An initial deficit of NGF at the onset of pathological processes is typically followed by its temporary elevation, during which some neuronal deficits may be partially ameliorated. However, if the disease progresses a decrease of NGF is typically observed, which appears to be a "normalization" of formerly elevated NGF concentrations. In our hypothesis we postulate that after acute or chronic injuries NGF is up-regulated as an intrinsic attempt to regenerate NGF-sensitive neurons. After long-term exposure to noxious processes, however, this compensatory increase of NGF cannot be maintained and eventually breaks down. The extent of such a compensatory up-regulation may depend on age and condition of NGF-sensitive neurons as well as on the type of lesion (acute or chronic). Furthermore, we also postulate that an exceeding level of NGF or its chronic elevation could even be detrimental to neuronal functioning under certain conditions. Thus, endogenous NGF has the capacity to modulate and even to compensate different kinds of harmful processes and in this way it may reinstate the homeostatic equilibrium. In our view, it seems to be a more appropriate approach to regard NGF changes as independent of classical constructs of neuropsychiatric diseases. Perhaps our understanding of NGF may even model for a new approach to the aetiology of multifactorial neuropsychiatric disorders.

Brain Diseases↗

Treatment of refractory depression with high-dose thyroxine.

In an open clinical trial we investigated whether addition of supraphysiological doses of thyroxine (T4) to conventional antidepressant drugs has an antidepressant effect in therapy-resistant depressed patients. Seventeen severely ill, therapy-resistant, euthyroid patients with major depression (12 bipolar, five unipolar) were studied. The patients had been depressed for a mean of 11.5 +/- 13.8 months, despite treatment with antidepressants and, in most cases, augmentation with lithium, carbamazepine, and neuroleptics. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 +/- 72 micrograms/day. The patients' scores on the Hamilton rating Scale for Depression (HRSD) declined from 26.6 +/- 4.7 prior to the addition of T4 to 11.6 +/- 6.8 at the end of week 8. Eight patients fulfilled the criteria for full remission (a 50% reduction in HRSD score and a final score of < or = 9) within 8 weeks and two others fully remitted within 12 weeks. Seven patients did not remit. The 10 remitted patients were maintained on high-dose T4 and followed up for a mean of 27.2 +/- 22.0 months. Seven of these 10 remitted patients had an excellent outcome, two had milder and shorter episodes during T4 augmentation treatment, and one failed to profit from T4 treatment during the follow-up period. Side effects were surprisingly mild, and no complications were observed at all. In conclusion, augmentation of conventional antidepressants with high-dose T4 proved to have excellent antidepressant effects in approximately 50% of severely therapy-resistant depressed patients.

Aged↗