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Biomedical subjects

R Rupprecht

Publications and source records attributed to R Rupprecht.

At least 19 recordsLinked to original sources
PubMed2006

Neuropsychological profile of adult patients with Niemann-Pick C1 (NPC1) mutations.

Niemann-Pick type C disease is a fatal neurovisceral disorder linked to dysregulation in cholesterol processing. A medication for this disease is currently being tested in clinical trials. However, there is a lack of information on neuropsychological testing parameters for this disease. One aim of this pilot study was to evaluate a test battery that could be used to assess cognitive deficits in different stages of the disease. A second aim was to determine whether specific functional deficits are associated with certain disease stages. Eight men and two women (19-40 years of age) harbouring mutations in the gene coding for the cholesterol trafficking protein NPC1 were put through the same test battery independently of their disease stage. The external staging criterion was based on a five-step clinical scale. Trail Making tests A & B and verbal fluency were sensitive indicators at early stages of NPC. Corsi Block-Tapping, Mini Mental Status, Find Similarities and Clock Drawing showed abnormal results in patients with advanced disease. The Grooved Pegboard, Trail Making and Mosaic tests were unsuitable in advanced disease due to impaired fine motor skills. We observed that visuospatial working memory was less affected by the neurodegenerative process than verbal working memory. The series of tests used here could be supplemented by the severe impairment battery and Raven matrices tests for patients with advanced disease.

Adult↗
PubMed2006

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism.

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.

Adult↗
PubMed2006

Neuroactive steroids and affective disorders.

Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of such neuroactive steroids have been observed during major depression and in several anxiety disorders, suggesting a pathophysiological role in such psychiatric conditions. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Furthermore, alterations of 3alpha-reduced pregnane steroids during major depression were corrected by successful treatment with antidepressant drugs. However in contrast, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. In addition, changes in neuroactive steroid concentrations after mirtazapine therapy occurred independently from the clinical response, thereby suggesting that changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of antidepressants rather than clinical improvement in general. Nevertheless, the effects of antidepressant pharmacotherapy on the composition of neuroactive steroids may contribute to the alleviation of certain depressive symptoms, such as amelioration of anxiety, inner tension or sleep disturbances. Moreover, first studies investigating the therapeutical effects of dehydroepiandrosterone revealed promising results in the treatment of major depression. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.

Animals↗
PubMed2006

Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity.

Concentrations of 3alpha-reduced neuroactive steroids are altered in depression and normalize after antidepressant pharmacotherapy with selective serotonin re-uptake inhibitors (SSRIs). We investigated the impact of mirtazapine on the activity of a key neurosteroidogenic enzyme, the 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), and on the levels of neuroactive steroids in relation to clinical response. A total of 23 drug-free in-patients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/day). Plasma samples were taken weekly at 0800 and quantified for neuroactive steroids by means of combined gas chromatography/mass spectrometry analysis. Enzyme activity was determined by assessment of steroid conversion rates. Irrespective of clinical outcome, there were significant increases in 3alpha,5alpha-tetrahydroprogesterone, 3alpha,5beta-tetrahydroprogesterone, 5alpha-dihydroprogesterone, and 5beta-dihydroprogesterone after mirtazapine treatment, whereas 3beta,5alpha-tetrahydroprogesterone levels were significantly decreased. In vitro investigations demonstrated a dose-dependent inhibitory effect of mirtazapine on the activity of the microsomal 3alpha-HSD in the oxidative direction (conversion of 3alpha,5alpha-tetrahydroprogesterone to 5alpha-dihydroprogesterone). Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3alpha-HSD is compatible with an enhanced formation of 3alpha-reduced neuroactive steroids. However, the changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of this antidepressant rather than clinical improvement in general.

3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)↗
PubMed2005

Neuroactive steroids as modulators of depression and anxiety.

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3alpha-reduced pregnane steroids are potent positive allosteric modulators of the GABA type A-receptor. During major depression there is a dysequilibrium of 3alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment we studied the impact of non-pharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroids observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder changes in neuroactive steroid composition have been observed opposite of those seen in depression. These changes may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimental panic induction with either cholecystokinin-tetrapeptide or sodium lactate there was a pronounced decline in the concentrations of 3alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3alpha, 5alpha-tetrahydrodeoxycorticosterone, allotetrahydrodeoxycorticosterone. The modulation of GABA type A-receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds.

Animals↗
PubMed2005

[Electroconvulsive therapy at the Department of Psychiatry and Psychotherapy, University of Munich. Development during the years 1995-2002].

BACKGROUND: So far, electroconvulsive therapy (ECT) has been proven to be a reliable and the most effective somatic treatment of depression or schizophrenia. This holds especially true for disturbances, which are refractory to pharmacological treatments. PATIENTS AND METHODS: We evaluated 4803 treatments in 445 patients. Main outcome criteria were efficacy and tolerability of treatment. Moreover, prospectively recorded neurophysiological parameters that might influence treatment outcome and treatment modalities and were assessed in a retrospective study design. RESULTS: During the last 7 years developmental changes show an increasing call for ECT treatment. Despite not being able to satisfy all demands the number of treatments more than doubled during the time period investigated. According to the latest scientific knowledge, especially in unipolar ECT, higher stimulation energy has been used to provide better treatment efficacy. Nevertheless, this was accompanied by a lower incidence of cognitive side effects. Due to the better tolerability of the treatment and the prospective neurophysiological indices, it appears that treatment quality has improved in recent years. Overall treatment efficacy was not improved, but could be maintained on a stable high level. This is presumably due to a stronger negative selection of patients with more pharmacotherapy-refractory disturbances. CONCLUSION: ECT still represents an important option in the treatment of therapy-resistant depression and schizophrenia despite recent progress in neuropsychopharmacology.

Adult↗
PubMed2004

[Diagnosis and treatment of panic disorder].

Panic disorder is defined as, recurrent, unexpected panic attacks. Panic attack means a period of intensive fear or discomfort, accompanied by a range of physical or psychological symptoms. Subsequently, anticipatory anxiety and avoidance behavior often develop. Panic disorder may or may not be accompanied by agoraphobia. Panic disorder can be treated both by psychotherapeutic and pharmacological measures. An ideal approach is combination therapy in the sense of a multimodal concept; with regard to cognitive behavioral therapy in particular, its effectiveness in the treatment of panic disorder is well documented. For pharmacotherapy, antidepressive agents, in particular selective serotonin reuptake inhibitors, are the drugs of first choice. Benzodiazepines should be given for only a few weeks until the antipanic effect of the antidepressants kicks in. With appropriate treatment, the prognosis is favorable.

Anti-Anxiety Agents↗
PubMed2004

[Considerations in the combination of clozapine and benzodiazepines].

Serious adverse events and even sudden death have been reported during administration of the combination of clozapine and benzodiazepines. However, this combination does not necessarily result in increased frequency of serious adverse events. Thus it is not regarded as an absolute contraindication and might be useful in distinct clinical situations, e.g., during the occurrence of a malignant neuroleptic syndrome, "catatonic dilemma," or severe agitation during clozapine treatment. In the following report, certain suggestions on how to deal with this combination therapy are provided which may provide a basis for discussion that ultimately may lead to the formulation of guidelines for this combination therapy. Such guidelines may help psychiatrists in dealing with this combination in clinical situations. Moreover, the formulation of such guidelines would help with forensic issues in case of serious adverse events occurring during this combination therapy.

Adverse Drug Reaction Reporting Systems↗
PubMed2004

Alpha-thujone reduces 5-HT3 receptor activity by an effect on the agonist-reduced desensitization.

The convulsant effects of alpha-thujone, the psychotropic component of absinthe, were attributed to inhibitory actions at the GABAA receptor. Here, we investigated for the first time the 5-HT3 receptor as a potential site of the psychotropic actions of alpha-thujone. This cation permeable ligand-gated ion channel shows considerable homology to the GABAA receptor. We previously demonstrated that in homomeric assemblies of cloned human 5-HT,A receptor subunits. the endogenous agonist 5-HT induced desensitization via channel blockade. When the 5-HT3 B receptor subunit was co-expressed, the resulting heteromeric assemblies desensitized independent from channel blockade. In the present study, patch-clamp experiments revealed an inhibitory action of alpha-thujone on both homomeric and heteromeric 5-HT3 receptors. This inhibitory action was mediated via channel blockade. However, it was not alpha-thujone itself which blocked the channel. The present experiments suggested that, in homomeric receptors, alpha-thujone enhanced the inherent channel-blocking potency of the natural ligand. 5-HT. In heteromeric receptors, alpha-thujonerecruited an additional channel-blocking component of the agonist. By means of kinetic modeling, we simulated possible mechanisms by which alpha-thuljone decreased the 5-HT-induced responses. It is suggested that alpha-thujone reduced 5-HT3 receptor activity by an effect on mechanisms involved in receptor desensitization, which depend on receptor subunit composition. It remains to be shown if this inhibitory action on serotonergic responses contributes to behavioral effects of alpha-thujone.

Bicyclic Monoterpenes↗
PubMed2004

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner.

The serotonin type 3 (5-HT(3)) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT(3) receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT(2)) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT(3) receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na(+)-inward currents through 5-HT(3) receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT(3) receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca(2+) influx, measured as a change in intracellular Ca(2+) concentrations ([Ca(2+)](i)). All neuroleptic drugs, but not risperidone, antagonized Na(+)- and Ca(2+)-inward currents evoked by 5-HT (10 microM for 2 s and 1 microM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC(50) values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT(3) receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na(+) and Ca(2+) currents. Since 5-HT(3) receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT(3) receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

Animals↗
PubMed2004

SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression.

Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P=0.0012, global P=0.0051) and MD. Haplotype analysis produced additional support for association (P<0.0001, global P=0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.

Adult↗
PubMed2004

Results of a surveillance programme for patients at high risk of malignant melanoma using digital and conventional dermoscopy.

Patients with a high number of atypical naevi and a personal and/or family history of melanoma are at high risk of malignant melanoma. The objective of this study was to design a special documentation and surveillance programme using epiluminescence microscopy (ELM) and digital epiluminescence microscopy (DELM) to improve the surveillance of these patients. High-risk patients (n=212) were categorized by the number and phenotype of their naevi and their personal and family history of melanoma. Then patients were screened by the unaided eye, conventional photography, ELM and, in selected cases of atypia, DELM. Median follow-up was 18 months, and 2939 pigmented lesions were followed by DELM. Examination on the first visit identified 17 cutaneous melanomas. During the following observation period, another 17 melanomas were identified. Fifteen of these follow-up melanomas were exclusively identified based upon DELM. In these cases, subtle lesional changes occurred over time, and ELM diagnostic algorithms for differentiating benign melanocytic lesions from melanoma did not score a suspicion of melanoma. All melanomas, either pre-existing or developing during follow-up, were identified in an early, curable phase of tumour growth. We conclude that DELM follow-up for patients at high risk allows the early detection of melanomas that have not yet acquired melanoma-typical ELM features.

Adult↗
PubMed2003

[Significance of GABAA receptors for the pathophysiology and therapy of panic disorders].

Gamma aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system. Its action is exerted in the brain through GABA(A) receptors which belong to the family of ligand-gated ion channels. These GABA(A) receptors consist of various subunits and are targets for benzodiazepines, barbiturates, neuroactive steroids, and distinct anticonvulsive agents. Meanwhile, there is considerable evidence that a dysfunction of GABA(A) receptors plays an important role in the pathophysiology of panic disorder. The anxiolytic effects of benzodiazepines are widely used in the treatment of panic disorder. Nevertheless, side effects of benzodiazepines, e.g., dependency and withdrawal symptoms, limit their use as a long-term treatment. In the meantime, antidepressants, especially selective serotonin reuptake inhibitors, comprise first-line treatment in the pharmacotherapy of panic disorder. They interfere with the synthesis of endogenous neuroactive steroids that allosterically modulate GABA(A) receptor function. With regard to experimentally evoked panic attacks in patients with panic disorder and healthy controls, recent investigations demonstrated that enhancing endogenous GABA through the blockade of the GABA transaminase by vigabatrin or inhibition of GABA transporters by tiagabine may exert anxiolytic effects. This novel strategy targeting the GABA binding site of the GABA(A)/benzodiazepine receptor complex and specific agonists for the benzodiazepine binding site present interesting perspectives for the future pharmacotherapy of panic disorder.

Animals↗
PubMed2003

[New developments in pharmacotherapy of depression].

In spite of recent progress in the pharmacotherapy of depression, major issues are still unresolved. These include the nonresponse rate of approximately 30% to conventional antidepressant pharmacotherapy, side effects of available antidepressants, and the latency period of several weeks until clinical improvement. Current treatment strategies aim to enhance serotonergic and/or noradrenergic neurotransmission. However, in the meantime, several new pharmacological principles are under investigation with regard to their antidepressant potency. Placebo-controlled, double-blind studies have been performed with 5-HT(1A) receptor agonists and tachykinin receptor antagonists which point towards antidepressant efficacy. While there is some evidence for putative antidepressant properties of various interventions within the hypothalamic-pituitary-adrenal system such as CRH(1) receptor antagonists, steroid synthesis inhibitors, and glucocorticoid receptor antagonists in animal studies, case series, open studies, and small placebo-controlled studies, no definite proof for their antidepressant efficacy has been furnished. Nevertheless, follow-up of new pharmacological strategies is of major importance to provide even better strategies for the clinical management of depression, which also has great socioeconomic impact.

Animals↗
PubMed2003

Effects of alprazolam on cholecystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study.

Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 microg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system.

Adrenocorticotropic Hormone↗
PubMed2003

[Current aspects of attachment theory and development psychology as well as neurobiological aspects in psychiatric and psychosomatic disorders].

This review covers basic principles of attachment research and its relationship to and implications for psychiatric and psychosomatic disorders. A great number of studies deal with the importance of attachment theory in the development of these disorders associated with distinct attachment styles. The most well-known concept is the attachment theory created by John Bowlby (1907-1990), which has strengthened our knowledge on early mother-infant relationships and influenced guidelines for child care. Within this concept, family structure is of great importance for the psychological development of the child and later the adult. Attachment research indicates that disturbances of patients with psychosomatic, e.g., somatoform disorders, in establishing relations must be seen in a developmental genetic context. A model of vulnerability is introduced which describes the development of psychopathology concerning the formation of representations taking advantage of attachment theory. Additionally, recent progress in cognitive neurosciences addresses attachment theory. During the last decade, neurobiological studies in rodents, primates, and humans indicate that early influences of psychosocial factors could have permanent consequences for brain structure and function. Besides the psychoanalytical and behavioral view concerning psychiatric and especially psychosomatic disorders, the integration of neurobiological findings will be a major challenge for the generation of further concepts.

Animals↗