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Recent research on Flight-deck Interval Management (FIM), a modern technology for increasing safety and improving airspace and runway utilisation through self-spacing, has led to the development of a new rule-based logic for FIM, namely Interval Management – Speed Planning (IM-SP). In an initial benchmark study, IM-SP showed good spacing performance with a significant reduction in speed commands, a major area of concern with previous FIM logics, resulting in a lower burden on the flight crew during FIM operation. Nevertheless, there remains scope for improvement in other aspects, such as fuel burn. In this study, the internal cost function of IM-SP is further analysed and optimised using speed-constrained multi-objective particle swarm optimisation to improve the performance of IM-SP under the multiple objectives of FIM. The optimisation renders new settings that address the problem areas, improve the speed commands and enhance the overall quality of IM-SP. Two distinctive solutions, viz. a spacing performance optimised setting and a fuel burn optimised setting, are further analysed and discussed, and directions for follow-up research are explored.
Pharmacogenetics in schizophrenia comprises pharmacokinetical and pharmacodynamical aspects as well as an approach to identify candidate genes associated with therapy response or side effects. Firstly focussing on classical drug targets like dopaminergic or serotonergic receptors, currently also developmental and regulatory genes presumably associated with effects of antipsychotic therapy are identified. The aim of this study was to investigate associations between therapy response in schizophrenic patients and different polymorphisms previously been identified within a genome wide array in rodents treated with MK-801 and/or haloperidol combined with some well-known schizophrenia candidate genes. We genotyped for 200 different polymorphisms in 285 schizophrenic patients, who were treated with different antipsychotics within randomized controlled trials. Psychopathology was measured weekly using the PANSS scale. Correlations between psychopathology and genotypes were calculated by using a linear model (ANCOVA).
We found significant associations between some well-known candidate genes (e.g. D2-, 5HT1A-, and α1A-receptors) and different PANSS subscales at baseline and after four weeks of antipsychotic treatment considered as therapy response. Furthermore we also identified several significant associations between some genes introduced from the animal model and psychopathology at baseline and towards therapy response. Some of them were formerly described in the literature (e.g. Homer1, Phospholipase C and Transthyretin), but most of them have not been related to schizophrenia or antipsychotic treatment by now (e.g. PLEKHA6, CLIC6 and SOSTDC1).
This indicates an involvement of genes in the pathophysiology of schizophrenia apart from yet known candidate genes and might further help in detecting differential therapy response in individuals with schizophrenia.
Long-term lithium-treatment has been associated with deficits in several cognitive domains in euthymic bipolar patients. At the same time, long-term lithium treatment is also associated with an increase in parathyroid levels, often without a concomitant increase in calcium levels. Such an isolated increase in parathyroid levels has been linked to depressive symptoms and cognitive deficits in otherwise healthy individuals.
To investigate whether increased parathyroid levels are associated with cognitive deficits in euthymic bipolar patients.
We plan to recruit 30 euthymic bipolar patients on lithium treatment for this study. Patients will take part in several neuropsychological tests, covering executive functioning, memory and attention. In parallel, blood levels of lithium, parathyroid hormone, 25-hydroxyvitamin D, creatinine, calcium and phosphate will be assessed, besides clinical chemistry and blood cell count. In addition, to account for potential confounders, a variety of clinical variables will be recorded, including established mood rating scales and demographic variables as well as further parameters relevant to the course of the illness.
As the study is still ongoing results are not available yet at this moment.
Results will be discussed in the context of previous studies examining the impact of lithium and parathyroid hormone on mood and cognition in healthy individuals and patients with bipolar disorder, respectively. Dependent on the outcome of this study, potential future studies, including intervention trials aiming at lowering increased PTH levels in bipolar patients on lithium will be outlined.
Patients with impulse control deficits often show cognitive abnormalities especially in executive abilities. One possibility to examine the underlying neurophysiological mechanisms is to assess evoked potentials. In the present study an adapted go/nogo-paradigm was used to investigate electrophysiological correlates of voluntary selection and behaviour control processes in patients suffering from alcohol dependence and attention deficit hyperactivity disorder (ADHD).
15 patients with alcohol dependence, 15 adult patients with ADHD and 15 control persons were included into the study. Patients with alcoholism were examined twice: before and after an inpatient detoxification.
The participants performed a go/nogo task, comprising three different conditions:
Apart from the go-condition (button press required) and the nogo-task (inhibition of a behavioural response), a voluntary selection task was included in which participants were allowed to freely decide, whether to press the response button or not.
Results and discussion
Response inhibition and voluntary selection processes were related to a fronto-central negativity after 200 ms (N2) and a positivity after 300 ms (P3) in healthy subjects. In patients, the P3 amplitude was reduced compared to the controls. In addition, alcohol dependent patients did not show a N2 potential.
The results indicate fronto-central dysfunctions dysfunctions in either patient group. However, different neuronal processes seemed to be affected in patients with ADHD and patients with alcoholism.
Executive functions comprise various cognitive abilities including the inhibition of prepotent responses and voluntary decisions. Several studies showed medial-frontal activations in tasks with the free selection of responses. The inhibition of prepotent response tendencies seems to be associated with medial frontal as well as lateral frontal BOLD responses. The aim of this simultaneous EEG and fMRI study was to discriminate the neural correlates of behavioural control processes in ADHD.
8 adults with ADHD and 8 matched healthy subjects performed a go/nogo task comprising three different conditions: during the go condition, subjects were instructed to press a response button as fast as possible; during the nogo condition, this response was to be inhibited. In the voluntary selection task participants were allowed to freely decide, whether to press the response button or not.
The fMRI protocol used a gradient-echo EPI pulse sequence. Further analyses were done with using the BrainVoyager software package (Goebel, Maastricht). EEG signals were simultaneously recorded (Brain Products, Munich).
Electrophysiologically, the nogo task and voluntary decision task led to a negative decline especially in fronto-central brain regions (N2) in both groups. Regarding the functional MRI data we found inhibition-associated BOLD responses especially medial-frontal in the pre-SMA and activations in the medial part of BA 8 for the voluntary selection. ADHD patients showed a reduced contribution of frontal brain regions during free responses compared to controls.
The results may indicate that selection processes are related with dysfunctions predominantly in frontal brain regions in ADHD patients.
Aim was to evaluate influencing factors of response and symptomatic remission in first-episode schizophrenia patients treated with risperidone or haloperidol.
229 first-episode schizophrenic patients were examined within a double blind controlled trial of the German Study Group on first-episode schizophrenia with biweekly PANSS ratings. Response was defined according to the definition by Lieberman et al. (2003) and symptomatic remission as the severity component of the consensus remission criteria by the Remission in Schizophrenia Working Group. Sociodemographic, psychopathological and functional variables as well as the treatment applied were evaluated regarding their potential predictive validity for treatment outcome. Univariate tests, logistic regression and CART-analyses were consulted as statistical methods.
126 patients (55%) achieved response and 118 patients (52%) symptomatic remission at discharge with no significant differences between the risperidone (51%) and haloperidol (49%) treated patients. Better baseline functioning, early treatment response, less depressive symptoms and a shorter duration of untreated psychosis were revealed significant predictors of response. Patients with symptomatic remission also had a significantly shorter duration of untreated psychosis and significantly less depressive symptoms at baseline. Logistic regression and CART-analyses revealed low general psychopathology, early treatment response and a high score in the Strauss-Carpenter-Prognostic-Scale at admission to be significantly positive predictive for symptomatic resolution.
Early treatment response, depressive symptoms and the level of psychosocial functioning were revealed to significantly predict outcome, with no significant differences between risperidone and haloperidol. The importance of an early adequate symptom control and the implementation of early intervention programs is highlighted.
To test in first-episode schizophrenia (FES) patients whether early treatment improvement accurately predicts subsequent treatment outcome and to develop a valid definition for early improvement.
188 first episode schizophrenia inpatients were assessed with the Positive and Negative Syndrome Scale (PANSS) at admission and biweekly until discharge within a randomized, double-blind trial. 93 patients were treated with risperidone, 95 with haloperidol. Response was defined as a 40% improvement in PANSS total score from admission to discharge, remission according to the recently proposed consensus criteria and early improvement as an improvement in the PANSS total subscore after the second week. Receiver operator characteristic (ROC) analyses were used to evaluate predictive validity of early improvement and to find the most reasonable cutoff definition according to specificity and sensitivity. A confidence interval for the optimum cutoff was furthermore estimated.
ROC analyses revealed reasonable predictability for response (AUC=0.707) and remission (AUC=0.692) concerning early improvement as a predictor for response/remission. No significant differences were found between the two treatment groups. Early improvement defined as a 46% PANSS total score reduction for response and a PANSS total score reduction of 50% for remission obtained the best results in terms of sensitivity and specificity.
We were able to confirm that early improvement is a valid predictor of subsequent treatment response and remission. FES patients should at least improve up to 30% in the PANSS total score at week 2 to achieve treatment response and remission.
To investigate the association of early improvement and treatment emergent suicidal ideation in a large sample (N=705) of naturalistically treated inpatients with major depressive disorder
In line with previous reports early improvement was defined as a 20% HAMD improvement within the first two weeks of antidepressant treatment. Treatment emergent suicidal ideation was defined by a sudden increase from 0 or 1 to at least 3 on HAM-D item-3 and from 0,1 to at least 4 on MADR item 10 for suicidal ideation. Early improvers were compared with non-early improvers with respect to the occurrence of treatment emergent suicidality during treatment.
Early improvers were 3 (MADRS) to 3.4 (HAMD) times less likely to experience new emergence of suicidal ideation during the treatment course than non-improvers. In addition, early improvement was associated with significantly less pessimistic thoughts.
The analysis is based on secondary analysis of prospectively collected data. No controlled study design.
Early improvement is associated with significantly less treatment emergent suicidal ideation for it my may provide rapid symptom relief and reduce hopelessness.
Since the introduction of second generation antipsychotics (SGA) extrapyramidal-motor symptoms (EPS) have become a lesser problem in the treatment of schizophrenic patients. Yet, some SGAs display these adverse events and first generation antipsychotics are still widely used. Several genetic polymorphisms have been found to be associated with the occurance of EPS.
In this study we tried to identify genes related to EPS from an animal model and then replicated the findings in schizophrenic patients.
To identify new genes and show their relevance in the treatment of schizophrenic patients.
Rats were treated with haloperidol or saline and differential gene expression was assessed by using microarrays. We genotyped 285 schizophrenic patients for candidate genes and differentially expressed genes derived from the animal model. All patients were treated monotherapeutically with different antipsychotics within randomized controlled trials. EPS were assessed weekly using the ESRS and BAS. We used a linear model (ANCOVA) with PANSS total at baseline, type of medication and premedication as covariates for all investigated SNP's.
We found several SNPs to be associated with the occurance of EPS. The best results were obtained for SNPs within the genes of Phospholipase C epsilon 1 (PLCe1), Methionine Sulfoxide Reductase B3 (MSRB3), Chloride Intracellular Channel 6 (CLIC6), Prolactin Receptor (PRLR) and Dopamine Receptor D4 (DRD4). Effect sizes were between 1.7 and 4.9.
We could replicate some findings of the literature and identified four new genes possibly related to EPS. Some of these genes were recently related to schizophrenia.
Purpose of this study was to assess subjective well-being in schizophrenia inpatients and to find variables predictive for response and remission of subjective well-being.
The subjective well-being under neuroleptic treatment scale (SWN-K) was used in 232 schizophrenia patients within a naturalistic multicenter trial. Early response was defined as a SWN-K total score improvement of 20% and by at least 10 points within the first 2 treatment weeks, response as an improvement in SWN-K total score of at least 20% and by at least 10 points from admission to discharge and remission in subjective well-being as a total score of more or equal to 80 points at discharge. Logistic regression and CART analyses were used to determine valid predictors of subjective well-being outcome.
Twenty-nine percent of the patients were detected to be SWN-K early responders, 40% fulfilled criteria for response in subjective well-being and 66% fulfilled criteria for remission concerning subjective well-being. Among the investigated predictors, SWN-K early improvement and the educational status were significantly associated with SWN-K response. The SWN-K total score at baseline showed a significant negative predictive value for response. Baseline SWN-K total score, PANSS global subscore, and side effects as well as the educational status were found to be significantly predictive for remission.
Depressive symptoms should be radically treated and side effects closely monitored to improve the patient's subjective well-being. The important influence of subjective well-being on overall treatment outcome could be underlined.
Soluble Interleukin-6 receptor (sIL-6R) levels are strongly related to the levels of Interleukin-6 (IL-6), and sIL-6Rs increase the immune activating properties of IL-6. We estimated sIL-6R serum levels in 25 schizophrenic patients and 25 healthy controls. In the patients, SIL-6R-CSF levels were also measured. The psychopathology was rated according to the AMDP system. We found a significant correlation between serum and cerebrospinal fluid (CSF) levels of sIL-6R, suggesting that serum levels may be a meaningful marker for the central action of sIL-6R. Moreover, significant correlations between the paranoid-hallucinatory syndrome and sIL-6R levels both in serum and CSF were observed. This finding suggests that IL-6 plays a role in the paranoid-hallucinatory symptomatology in schizophrenia. This can be understood regarding the influence of IL-6 to the catecholaminergic neurotransmission. The downregulating effects of neuroleptic treatment to sIL-6R demonstrate that the sIL-6R levels are decreased in the whole group of schizophrenic patients compared to controls.
The primary objective of this randomised, active–controlled, parallel group, double-blind study was to evaluate the tolerability of treatment with either amisulpride or risperidone in elderly patients with schizophrenia aged over 65 years; evaluation of efficacy was a secondary objective.
The study included patients of either sex aged 65 years or older fulfilling DSM IV-diagnostic criteria for psychotic disorders and who presented psychotic symptoms severe enough to require antipsychotic medication. Subjects were randomly allocated to a flexible dose of either amisulpride (100–400 mg/day) or risperidone (1–4 mg/day) for six weeks following a three- to six-day placebo wash-out period. Safety assessment involved adverse event reporting, physical examination, blood pressure, heart rate and ECG monitoring, and laboratory tests. Extrapyramidal symptoms were evaluated with the Simpson–Angus Scale, Barnes Akathisia Scale and the AIMS. Efficacy parameters were changes in score on the PANSS, BPRS, CDS and MMSE scores.
Thirty-eight patients were randomised, 25 to amisulpride and 13 to risperidone. A total of 26 adverse events were experienced by 10 patients in the amisulpride group and five patients in the risperidone group. One patient in each group discontinued the study due to the emergence of a movement disorder. Changes in scores on the three measures of extrapyramidal symptoms were similar in the two groups. The PANSS total score decreased by 27.8% in the amisulpride group and by 29% in the risperidone group between inclusion and study end.
Amisulpride and risperidone are generally well tolerated in elderly patients with schizophrenia. Both drugs appeared to be efficacious in this study population, with no differences in efficacy being observed. However, the sample size was too low to reveal potential inter-group differences. Both these atypical antipsychotics thus appear to be suitable for the treatment of schizophrenia in the elderly.
Driving is a daily activity for most people in developed countries and is important in maintaining independence. Bipolar patients may have an impaired driving behavior because of the pathology itself, with psychomotor and cognitive disturbances. Additionally, adverse effects of pharmacologic treatment may be detrimental.
24 remitted bipolar outpatients diagnosed according to ICD-10 criteria were enrolled in the study, receiving either lithium (n = 12) or lamotrigine (n = 12). Participants were investigated under steady state plasma level conditions. According to the German Guidelines for road and traffic safety data were collected with the Wiener Testsystem (WTS) measuring visual perception, reactivity, stress tolerance, concentration and vigilance.
Psychopathologic symptoms were rated with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale - Clinician rated (YMRS-C).
About 40% of patients were without clinically relevant psychomotor disturbances. In 40% of cases mild to moderate impairments could be seen, and 20% of the patients were considered as severely impaired. Data show that patients under lamotrigine had an altogether better test performance than patients treated with lithium. Especially in visual perception and stress tolerance differences were most pronounced.
About 20% of remitted bipolar outpatients treated with lithium or lamotrigine must be considered unfit to drive. In 40% of the cases it seems justified to counsel patients individually, taking into account compensational factors. Analysis of our data point to an advantage for bipolar patients treated with lamotrigine when compared with lithium. However causal relationships can not be drawn from our data.
To examine the predictive validity of early improvement in a naturalistic sample of inpatients and to identify the criterion that best defines early improvement.
Two hundred and forty-seven inpatients who fulfilled ICD-10 criteria for schizophrenia were assessed with the Positive And Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the recently proposed consensus criteria, response as a reduction of at least 40% in the PANNS total score from admission to discharge.
Receiver operating characteristic (ROC) analyses showed that early improvement (reduction of the PANSS total score within the first 2 weeks of treatment) predicts remission (AUC = 0.659) and response (AUC = 0.737) at discharge. A 20% reduction in the PANSS total score within the first 2 weeks was the most accurate cut-off for the prediction of remission (total accuracy: 65%; sensitivity: 53%; specificity: 76%), and a 30% reduction the most accurate cut-off for the prediction of response (total accuracy: 76%; sensitivity: 47%; specificity: 90%).
The findings of clinical drug trials that early improvement is a predictor of subsequent treatment response were replicated in a naturalistic sample. Further studies should examine whether patients without early improvement benefit from an early change of antipsychotic medication.
In the multilayered treatment of bipolar patients, medication treatment is the basic component. The relevance of additional psychosocial treatment has been shown in several controlled and uncontrolled studies. In particular, psychoeducation and Cognitive Behavioural Therapy (CBT) seem to be effective concerning relapse prevention and symptom reduction. The aim of this 12 months randomised study was to examine the efficacy of a psychoeducation programme integrating cognitive behavioural elements in bipolar patients. We are presenting data at 3 months follow-up.
Medicated bipolar patients (CGI ≤ 3) were randomised to psychoeducation (intervention group) or waiting list (control group). The psychoeducation programme took place once a week over a period of 12 weeks, focusing on the following major topics: information on the origins of the illness, medical and psychological treatment options, how to detect symptoms and early warning signs, crisis management and how to maintain a regular lifestyle. The patients' knowledge of bipolar disorder, symptoms, social functioning, quality of life and medication compliance were assessed before and after the intervention and every three months for a total of 12 months. For the statistical analysis, mixed models were applied in order to evaluate group differences over time.
Forty patients have been randomised. On the outcome variables (symptoms, social functioning, knowledge), the patients receiving the early psychoeducation programme did numerically better on all variables than the control group. However, in terms of statistical significance, only trends could be detected.
Our findings support the benefits of psychoeducation in the management of bipolar disorder.
In the context of the development of DSM-V and ICD-11 it appears to be useful to get further data on the validity of the diagnostic differentiation between schizophrenic and affective disorders. This study investigated the relevance of the main diagnostic groups schizophrenia, schizoaffective psychosis and affective disorder in the context of different diagnostic systems (ICD-9, ICD-10, DSM –IV), assessing their time stability, long-term courses, types and functional outcome.
A total of 323 first hospitalized inpatients of the Psychiatric Department of the University Munich were recruited at index time. The full follow-up evaluation including standardized assessment procedures could be performed in 197 patients.
The re-diagnosis of the patients’ disorders shows that with the transition from ICD-9 to ICD-10 or DSM-IV, the group of affective disorders increased numerically while the diagnostic groups of schizophrenia and schizoaffective disorders decreased in size. The structured clinical interview for DSM-IV (SCID) analysis showed that altogether ICD-10 and DSM-IV had a relatively high diagnostic stability. Of the patients with an ICD-10 diagnosis of schizophrenia, 57% had a chronic course; 61% of the patients with a DSM-IV diagnosis of schizophrenia. Patients with affective disorders, according either to ICD-10 or DSM-IV, had in more than 90% of the cases an episodic-remitting course. In terms of prediction of long-term outcome regarding the differentiation between chronic and non-chronic course, the ICD-10 diagnoses did give a slightly better predictive result than a dimensional approach based on the key psychopathological syndrome scores.
The differentiation between schizophrenic and affective disorders seems meaningful especially under predictive aspects. A dimensional syndromatological description does not exceed the predictive power of the investigated main diagnostic categories, but might increase the clinically relevant information.