Silexan does not cause withdrawal symptoms even when abruptly discontinued.

OBJECTIVE: Subsequent to a randomised, double-blind, double dummy clinical trial assessing the efficacy of silexan compared to placebo and paroxetine in patients suffering from generalised anxiety disorder (GAD), a 1week follow-up phase was added in order to assess possible withdrawal symptoms of silexan after abrupt discontinuation. METHODS: Participants received silexan 80 mg/d, silexan 160 mg/d, paroxetine 20 mg/d, or placebo at a ratio of 1:1:1:1. Study medication was discontinued after the 10 week active treatment phase of the original trial. Whereas paroxetine was tapered as indicated, silexan administration was discontinued abruptly. Assessment of possible withdrawal effects was done using the Physician Withdrawal Checklist questionnaire (PWC-20). RESULTS: During the 1 week down-titration phase, mean total PWC-20 scores had reduced by 0.19 in placebo, 0.23 in silexan 80, 0.65 in silexan 160, and 0.51 in paroxetine. The median change in all four groups was 0.00. In none of the treatment groups withdrawal effects occurred after discontinuation. CONCLUSIONS: Values assessed for the silexan groups indicate the absence of a dependency potential of this preparation.

[Cognitive disorders in schizophrenic patients]. / Kognitive Störungen bei schizophrenen Patienten.

Cognitive disorders have become a major topic not only in the scientific community but also among clinicians. Cognitive disorders are of special importance in schizophrenic patients. The present paper gives a survey over the basic definitions and the extent of these disturbances in schizophrenic patients, the main etiopathogenetic hypotheses and the development over time as well as treatment options with special regard to psychopharmacological treatment options.

[Therapeutic effects of venlafaxine extended release for patients with depressive and anxiety disorders in the German outpatient setting - results of 2 observational studies including 8500 patients]. / Klinische Effekte von retardiertem Venlafaxin (Trevilor retard) bei Patienten mit Depression und Angsterkrankungen in der ambulanten Behandlungspraxis in Deutschland - Ergebnisse von zwei Anwendungsbeobachtungen mit 8500 Patienten.

The therapeutic effects of venlafaxine extended release have been investigated by two prospective observational studies including 8506 patients in the outpatient setting of office based general practitioners and specialists. The efficacy has been documented by the Clinical Global Impression (CGI) scale and by the Hamilton depression (HAMD-21) scale. The tolerability has been assessed by the documentation of adverse events. About (2/3) of the patients were treated because of depression and about (1/3) mainly because of anxiety disorder. The patients of specialists did receive higher dosages and were more severely affected. The response rate on the CGI scale was 87.4 for the patients of general practitioners and 74.2 % for the patients of specialists. The results of the HAMD-21 scale, which has been used by specialists, showed a response rate of 71.8 and a remission rate of 56.3 %. These positive effects could be demonstrated even for the more severely and chronically affected patients. The incidence of adverse events was low in both studies and comparable to the tolerability profile of randomized studies. Importantly, the good tolerability profile was similar even for patients with concomitant cardiovascular disease. In conclusion, these results confirm the efficacy and good tolerability of venlafaxine extended release in the outpatient setting in Germany.

[Antidepressive pharmacotherapy. In slight and severe disease, young and old]. / Antidepressive Pharmakotherapie. Bei leichter und schwerer Erkrankung, bei jung und alt.

During the past decade a variety of promising new compounds launched onto the market not only enhancing serotonergic and noradrenergic neurotransmission, but also influencing the dopamine and the melatonergic receptor system. In spite of misleading discussions both in the specialized and in the lay press the clinical effectiveness of antidepressants still is indisputable. The main advantages of the newer drugs are the broadening of the spectrum treatments and a far better tolerability profile in comparison to older compounds. Predominantly depression of medium to high severity should be treated pharmacologically. Especially severe depression seems to respond better to dually acting antidepressants. In children effectiveness of Omega3-fatty acids has been shown, in adolescents SSRI treatment was efficacious. Older patients respond to all antidepressant mechanisms, but more selective substances should be preferred due to a better tolerability. The study of new treatment options is of major importance to provide better strategies for the clinical management of depression in the future, and is thus also of great socio-economic importance.

Continuation and long-term maintenance treatment with Hypericum extract WS 5570 after recovery from an acute episode of moderate depression--a double-blind, randomized, placebo controlled long-term trial.

The efficacy and safety of Hypericum extract WS 5570 in preventing relapse during 6 months' continuation treatment and 12 months' long-term maintenance treatment after recovery from an episode of recurrent depression were investigated in a double-blind, placebo controlled multicenter trial. Adult out-patients with a recurrent episode of moderate major depression, a 17-item Hamilton Depression Rating Scale (HAMD) total score > or =20 and > or =3 previous episodes in 5 years participated. After 6 weeks of single-blind treatment with 3 x 300 mg/day WS 5570 patients with score < or =2 on item 'Improvement' of the Clinical Global Impressions (CGI) scale and a HAMD total score decrease > or =50% versus baseline were randomized to 3 x 300 mg/day WS 5570 or placebo for 26 weeks. 426 patients were evaluated for efficacy. Relapse rates during continuation treatment were 51/282 (18.1%) for WS 5570 and 37/144 (25.7%) for placebo. Average time to relapse was 177+/-2.8 and 163+/-4.4 days for WS 5570 and placebo, respectively (time-to-event analysis; p=0.034; alpha=0.025 one-sided). Patients treated with WS 5570 showed more favorable HAMD and Beck Depression Inventory time courses and greater over-all improvement (CGI) than those randomized to placebo. In long-term maintenance treatment a pronounced prophylactic effect of WS 5570 was observed in patients with an early onset of depression as well as in those with a high degree of chronicity. Adverse event rates under WS 5570 were comparable to placebo. WS 5570 showed a beneficial effect in preventing relapse after recovery from acute depression. Tolerability in continuation and long-term maintenance treatment was on the placebo level.

Importance of open access to atypical antipsychotics for the treatment of schizophrenia and bipolar disorder: a European perspective.

OBJECTIVE: To assess European psychiatrists' prescribing behaviour and their perceived need for access to a wide range of atypical antipsychotics for patients with schizophrenia and bipolar disorder. METHODS: A blinded, internet survey of psychiatrists from the UK, Germany, Italy and the Netherlands occurred in 2007. Key inclusion criteria for psychiatrists: practising full time; practising for 5-35 years; prescribed atypical antipsychotics in prior 6 months to > or =20 patients with schizophrenia or bipolar disorder. Eligible psychiatrists selected records for four patients with schizophrenia or bipolar disorder for whom they prescribed > or =1 atypical antipsychotic since January 2004. RESULTS: Survey response rates were: UK, 14.8% (n = 107); Germany, 9.6% (n = 104); Italy, 8.9% (n = 101) and the Netherlands, 3.7% (n = 51); 363 psychiatrists reported on 1442 patients. Psychiatrists perceived a greater difference among atypical antipsychotics as a class (mean, 5.1 on a 7-point scale [7 = 'highly differentiated']) but not selective serotonin reuptake inhibitors (mean, 3.6). On average, psychiatrists used 6.8 different atypical antipsychotics across their patients with schizophrenia and 4.4 across their patients with bipolar disorder, with 2.5 and 2.4 changes required following first-line treatment to stabilise therapy, respectively. The most common reason for switching medication was lack of efficacy. Psychiatrists reported that expected consequences for patients should access to atypical antipsychotics be restricted would include illness deterioration, non-adherence and hospitalisation. CONCLUSIONS: Although this study is limited by potential selection biases, these data suggest that European psychiatrists tailor antipsychotic medications for patients with schizophrenia or bipolar disorder according to patients' needs and specific drug attributes.

Efficacy of St. John's wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials.

Based on the original data from two double-blind, randomized, placebo-controlled clinical trials and the acute phase of a long-term study that investigated the antidepressant efficacy of St. John's wort extract WS 5570, we present a re-analysis of a subset of patients suffering from an acute episode of mild depression according to DSM criteria. Out of a total of more than 1,200 patients included into these trials 217 had a pre-treatment total score < or =20 points on the 17-item Hamilton Rating Scale for Depression (HAMD) and were eligible for our re-analysis. They received 600, 900, or 1,200 mg/day WS 5570 or placebo for 6 weeks. In patients treated with WS 5570 the HAMD total score decreased by averages of 10.8 (600 mg/day), 9.6 (900 mg/day), and 10.7 (1,200 mg/day) points between the pre-treatment baseline value and the end of acute treatment, compared to 6.8 points in the placebo group (p < 0.01 for all pairwise comparisons of WS 5570 against placebo). This corresponded to average relative decreases by 49-57% for WS 5570 and by 36% for placebo. The rates of responders (i.e., patients with a HAMD total score decrease > or =50%) were 73%, 64%, 71%, and 37% for WS 5570 600 mg/day, 900 mg/day and 1,200 mg/day, and placebo, respectively. At the end of acute treatment 57% of the patients treated with WS 5570 600 mg/day, 33% in the 900 mg/day group and 62% in the 1,200 mg/day group, as well as 25% in the placebo group were in remission (HAMD total score < or =7 points). The analysis shows that St. John's wort extract WS 5570 has a meaningful beneficial effect during acute treatment of patients suffering from mild depression and leads to a substantial increase in the probability of remission.

Patterns and prevalence of antidepressant drug use in the German state of Baden-Wuerttemberg: a prescription-based analysis.

PURPOSE: Population-based data about patterns and prevalence of antidepressant drug use is limited in Europe and presently unavailable for Germany. Therefore, we have identified patterns and prevalence of antidepressant use among outpatients on a population-based scale in the German state of Baden-Wuerttemberg. METHODS: We conducted a historical cohort study using a computerised prescription database referring to all members of the major German public health insurance company AOK. We assessed the prevalence of antidepressant drug use over a 3-year period, calculated the number of prescription items purchased per patient and compared first-line and second-line treatments. RESULTS: The 1-year prevalence of antidepressant drug use among more than 4,000,000 health insurance members was 7.4% (male: 4.3%; female: 10.2%). Importantly, almost 40% of the patients received only a single prescription item from 2000 to 2002. Though the use of serotonin-reuptake inhibitors (SSRIs) markedly increased by about 65% within the study period, these are primarily used as second-line drugs and still much less frequently than St. John's wort or tricyclic antidepressants such as amitryptiline or doxepin. CONCLUSIONS: The prevalence of antidepressant drug use is higher than previously reported for other European countries. The preferred use of St. John's wort and tricyclics over SSRIs and other modern-type antidepressants in Germany is quite unique in Europe and different from the US. The identified drug use pattern leaves a major room for improvement in view of the numerous single prescription items purchased.

Reboxetine and cytochrome P450--comparison with paroxetine treatment in humans.

OBJECTIVES: The noradrenaline-selective antidepressant reboxetine in vitro is a weak inhibitor of both cytochrome P450 (CYP) 2D6 and CYP3A4. Thus, in this study the pharmacokinetics of reboxetine in relation to pharmacogenetics and the effects of reboxetine compared to paroxetine treatment on the CYP2D6 and CYP3A4 phenotype were analyzed in healthy control subjects. METHODS: Healthy male volunteers were treated with either 6 mg reboxetine (n = 26) or 30 mg paroxetine (n = 25). On Days 10/11 of treatment, serum concentrations of the antidepressants were measured and pharmacokinetic parameters calculated. Volunteers were phenotyped at the end of treatment and after at least 3 weeks washout (true phenotype) using 30 mg dextromethorphan (DM) hydrobromide given orally and measuring DM and metabolites in serum 2 h after intake. CYP2D6 and CYP2C19 genotypes were determined in parallel. RESULTS AND CONCLUSION: Reboxetine serum concentrations showed no correlation with the CYP2D6 genotype and the CYP2D6 phenotype, whereas paroxetine concentrations showed some dependence on CYP2D6. In contrast to in vitro investigations, indicating a major role of CYP3A4 in reboxetine metabolism, reboxetine concentrations in serum showed no correlation with the respective DM metabolic ratios. There was also no correlation between paroxetine concentrations and the CYP3A4 phenotype data. The CYP2C19 genotype (only heterozygosity) had no influence on reboxetine and paroxetine pharmacokinetics. There were only minor changes in the DM metabolite pattern on treatment with reboxetine and no evidence of enzyme inhibition was obtained. In contrast and as expected, paroxetine strongly inhibited CYP2D6. Thus, reboxetine treatment has no effect on the CYP2D6 genotype and no clinically relevant drug interactions involving CYP2D6 are anticipated.

Clinical trials with sigma ligands.

So far, sigma-ligands have been investigated for several indications in human studies in functional diarrhea as a model of somatoform disorder (igmesine), depression (igmesine, opipramol), anxiety (opipramol and--in animal models--siramisine), schizophrenia (panamasine, SL 82.0715, rimcazole, DuP 734, BMY 14 802), and somatoform disorders (opipramol). Results for schizophrenia failed to be clear cut and so investigations have apparently stopped for the time being. The Sigma-1-selective igmesine (200 mg) showed good results in a phase-1-model of functional diarrhea and some promising results in depressed patients. However, further development has been stopped due to marketing reasons, which is also true for siramasine, a selective sigma-2-ligand with anxiolytic properties. Opipramol, which, apart from a sigma-1- and 2-receptor liability, also possesses histamine-H(1)-antagonistic properties in connection with lower affinities for D(2) and 5-HT(2A) showed broad efficacy in generalized anxiety disorder and somatoform disorders. The receptor profile of opipramol and the results of studies of the selective sigma site ligands siramisine and igmesine suggest that opipramol acts pharmacologically and clinically via sigma receptors.

[Improvement in quality of life in the elderly. Results of a placebo-controlled study on the efficacy and tolerability of lecithin fluid in patients with impaired cognitive functions]. / Verbesserung der Lebensqualität im Alter. Ergebnisse einer plazebokontrollierten Studie zur Wirksamkeit und Verträglichkeit von Lecithin in flüssiger Darreichungsform bei Patienten mit Beeinträchtigung der kognitiven Funktionen.

Lecithin, a precursor of the neurotransmitter acetylcholine, has a positive effect on brain and memory functions. In a prospective, randomized, double-blind study, the effect of buerlecithin fluid (BLF) was investigated in comparison with placebo in patients with mild cognitive disorders. A total of 96 ambulatory patients (> 55 years) were admitted to the study. Treatment duration was 84 days. In both treatment groups, a clear improvement in all the cognitive parameters tested was seen. The main target measure, the overall Sandoz Clinical Assessment Geriatric (SCAG) score improved by 18.7 (test substance) and 16.4 (placebo) points (p = 0.1620). A statistically relevant improvement of the secondary target parameter, response in the SCAG score, was achieved with BLF (85.4%) in comparison with placebo (62.5%) (p = 0.018). Furthermore, BLF demonstrated significant superiority in a number of the other target measures. The study also confirmed the very good tolerability of BLF.

31P-MR spectroscopy in children and adolescents with a familial risk of schizophrenia.

Based on a previous report [9] on alterations of membrane phosphorus metabolism in asymptomatic family members of schizophrenic patients, the aim of the present study was to extend and improve the evaluation and data processing of (31)P spectroscopic data obtained from a larger study population by including an analysis of the broad spectral component (BC) of membrane phospholipids (PL). Eighteen children and siblings of patients with schizophrenia and a gender- and age-matched control group of 18 healthy subjects without familial schizophrenia were investigated with phosphorus magnetic resonance spectroscopy ((31)P-MRS) by using image selected in vivo spectroscopy (ISIS) in the dorsolateral prefrontal regions (DLPFR) of the brain. Spectral analysis was performed by using both the full and truncated FID to estimate metabolic peak ratios of different (31)P metabolites and the intensity and linewidth of the broad component. A significantly higher PDE level (p<0.01) and increased linewidth of the PDE components were observed for the high-risk group compared with the control group (p=0.02). No significant differences were observed for PME as well as for other (31)P-metabolites. No differences were observed between the left and right hemispheres for different normalised (31)P-metabolic levels. Decreased intensities (p=0.03) and smaller linewidths (p=0.01) were obtained for the broad component in the high-risk group. Impairments of membrane metabolism that are typical for schizophrenic patients are partially observed in adolescent asymptomatic family members of schizophrenics, including increased levels of low molecular PDE compounds indicating increased membrane degradation processes, no changes for PME, and decreased intensities and linewidths of the BC indicating changes in the composition and fluidity of membrane phospholipids. Despite limitations to completely suppress fast-relaxing components by dismissing initial FID data points, the spectroscopic results indicate additional changes in the membrane metabolism of high-risk subjects beyond changes of synthesis and degradation.

Cell-mediated side effects of psychopharmacological treatment.

Both antidepressants and neuroleptics are widely used in psychopharmacological treatment. In view of the often equal efficacy of substances belonging to the same class of drugs, potential side effects have become the most important criteria for the selection of a specific drug. The therapeutic effect of antidepressants is mediated by their inhibition of the reuptake of the neurotransmitters noradrenaline and of serotonin. Significant adverse effects may occur through the interaction of the antidepressants with other receptors believed not to be related to the therapeutic action, most importantly the muscarinic acetylcholine receptor (M), the histamine-1 (H1) receptor and the alpha-1 (alpha 1) adrenergic receptor. In contrast to the classical tricyclic antidepressants, the newly available selective serotonin reuptake inhibitors neither block the M1-, H1- nor the alpha 1 receptors. Although the rate of side effects is considerably lower compared to tricyclic antidepressants, adverse effects may, however, occur through the stimulation of different serotonin receptor subtypes (5-HT2A, 5-HT2B, and 5-HT3), leading to anxiety, sleep disturbances and nausea. Neuroleptics are often administered for years or even decades in the treatment of schizophrenia or schizoaffective disorder. The main adverse effects are extrapyramidal symptoms, including parkinsonism, akathisia, dystonic reactions, and tardive dyskinesias. With the introduction of the atypical neuroleptics (e.g. clozapine, risperidone, olanzapine) it became apparent that the antipsychotic effect and the extrapyramidal unwanted effect are not always and inextricably linked. The evidence for the hypotheses of the pathogenetic mechanisms leading to extrapyramidal side effects is reviewed. Both the dopamine receptor hypersensitivity hypothesis and the hypothesis of mitochondrial respiratory chain inhibition are as yet based on indirect evidence. However, if, as suggested by the analyses of mitochondrial energy metabolism, the antipsychotic effect and the adverse effects are unrelated properties of neuroleptics, new principles should be applied in the development of novel neuroleptics. Neuroleptics might then be developed that are effectively antipsychotic but are less likely to produce limiting extrapyramidal side effects.

[Repetitive transcranial magnetic stimulation (rTMS) in the acute and long-term therapy of refractory depression--a case report]. / Repetitive transkranielle Magnetstimulation (rTMS) in der Akut- und Langzeittherapie bei therapieresistenter Depression. Eine Falldarstellung.

We report on a patient with therapy-resistant major depression according to DSM-IV criteria who has been hospitalized for 60 months during the last 7 years. Not even five electroconvulsive therapy (ECT) series (61 single applications) brought lasting remission of symptoms. As cognitive deficits developed and prolonged postnarcotic recovery times were observed, further ECT was contraindicated. The left frontal cortex was chosen as the target site for repetitive transcranial magnetic stimulation (rTMS) treatment. For identification, a neuronavigational system was used that allows online monitoring of the position of the magnetic coil in relation to the individual cortex. The therapeutic progress was monitored by standardized psychiatric ratings (HAMD, BDI). In addition, cognitive performance was tested during the course of treatment. Only a few rTMS applications already caused an obvious brightening in mood, remission of depressive delusional symptoms, and an increase in personal interests and activities. After 4 weeks of daily treatment, the patient was discharged from the ward. The rTMS treatments and psychotherapeutic counseling have been continued on an outpatient basis. Thus, pharmaco- and psychotherapeutic interventions combined with rTMS led to persistent symptom remission and social reintegration.

[Psychiatric comorbidity in somatic disorders. Psychophytopharmaceuticals are worth a try]. / Psychiatrische Komorbidität bei somatischen Erkrankungen. Psychophytopharmaka lohnen den Versuch.

Somatic and psychiatric illnesses are commonly associated. Cardiovascular disorders, Parkinson's disease and stroke are especially often associated with depression as also anxiety and sleep disturbances. Psychophytopharmaceuticals, which are usually well tolerated, are highly suitable for this purpose. To treat mild to moderate episodes of depression, extracts of St. John's Wort are employed, but recently reported interactions with coumarin, theophylline and also estrogen preparations, need to be considered. Unspecific anxiety states can be treated with extracts of kava. At present, no herbal preparation can be recommended for the treatment of sleep disorders, as no unequivocal proof of efficacy in patients with such problems has yet been established.

Cerebral phosphate metabolism in first-degree relatives of patients with schizophrenia.

OBJECTIVE: Most phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) studies have described measures of lower membrane anabolism or greater catabolism in the frontal lobes of patients with schizophrenia. The purpose of the present study was to evaluate whether these findings can also be detected in young subjects at genetic risk for schizophrenia. METHOD: Fourteen children and siblings of patients with schizophrenia (mean age=16.7 years) and 14 comparison subjects (mean age=16.9 years) were included in a (31)P-MRS study of the frontal lobe. RESULTS: The high-risk subjects had significantly lower mean ratios of phosphomonoesters to phosphodiesters (0.25 versus 0.31) and higher mean phosphodiester values (37.59% versus 34.87%) than comparison subjects. CONCLUSIONS: These findings suggest greater phospholipid breakdown even in young first-degree relatives of patients with schizophrenia. This suggestion is discussed with respect to the membrane phospholipid hypothesis of schizophrenia.