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Rolf R Engel

Publications and source records attributed to Rolf R Engel.

16 recordsLinked to original sources
PubMed2006

Is the superior efficacy of new generation antipsychotics an artifact of LOCF?

It has been argued that the efficacy superiority found in meta-analyses for some of the atypical antipsychotics is an artifact of higher dropout rates due to side effects in the haloperidol group combined with last-observation-carried-forward (LOCF) analyses. We therefore reanalyzed a number of pivotal studies comparing new generation antipsychotics (NGAs) and conventional antipsychotics (CAs). A total of 5 studies (n = 1271) comparing amisulpride and 3 studies (n = 2454) comparing olanzapine with CAs were reanalyzed using original patient data. We applied 4 different models: LOCF, completer analysis, LOCF but excluding dropouts due to adverse events, and LOCF but excluding all dropouts with the exception of dropouts related to efficacy. Effect sizes expressed as standardized mean differences between NGAs and CAs based on the 4 different analysis models were compared. The overall results were not different irrespective of the model used. Single studies, however, showed higher effect sizes when LOCF instead of other models was used. Overall, it does not seem that higher dropout rates due to side effects in the haloperidol groups together with LOCF analyses consistently biased the results in favor of amisulpride and olanzapine. Because the results of the single studies, however, showed that this may occasionally be the case, future studies should look at the data from different angles applying sensitivity analyses, and they may use alternative statistics such as mixed models, which need to be developed further. Ultimately, strategies to reduce dropout rates are needed.

Amisulpride↗
PubMed2006

Linking the PANSS, BPRS, and CGI: clinical implications.

To understand what given scores of the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) mean from a clinical point of view is important for the translation of research results into practice. We therefore (a) compared the absolute change of the BPRS/PANSS with the Clinical Global Impressions Ratings (CGI) -improvement score and the change of the CGI severity score, (b) analyzed whether the severity of illness at baseline had an impact on the latter association, and (c) attempted to replicate previous BPRS findings using a completely different data set based upon the PANSS-derived BPRS. The method used was equipercentile linking of BPRS and CGI ratings from 14 drug trials in acutely ill patients with schizophrenia (n=5970). An absolute reduction of the BPRS/PANSS by approximately 10/15 points corresponded to a CGI change of 'minimally improved' and to a change of the CGI severity score by one severity step. However, the latter associations depended on the severity of symptoms at baseline. Less severely ill patients required less BPRS/PANSS total score reduction to achieve the same CGI-improvement score than more severely ill patients. This effect of initial severity was attenuated using percentage rather than absolute BPRS/PANSS reduction scores. The linking analysis between the absolute BPRS/PANSS reduction and the CGI may have an implication for the interpretation of efficacy differences found in clinical trials, and for sample size estimations. Clinicians seem to base CGI ratings on relative change rather than on absolute change of symptoms.

Adult↗
PubMed2006

The relative sensitivity of the Clinical Global Impressions Scale and the Brief Psychiatric Rating Scale in antipsychotic drug trials.

Although the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS) are both frequently used in drug trials for schizophrenia, their relative sensitivity in detecting differences between antipsychotics has not yet been examined. We therefore reanalyzed original patient data from all four pivotal, randomized controlled studies (n = 1205) that compared amisulpride with haloperidol in patients with schizophrenia. The sensitivity of the BPRS vs the CGI-improvement and the CGI-severity scales in detecting between-drug differences was estimated by calculating effect sizes and their 95% confidence intervals for both continuous (standardized mean differences) and dichotomous outcomes (odds ratios). The primary end points were the last observation carried forward results at study end points pooling all studies, but the results of the observed cases at different study weeks and the results of the single studies were also examined. The effect sizes derived from the BPRS and from the CGI were similar. When the single studies were pooled, all outcomes analyzed showed a statistically significant superiority of amisulpride compared to haloperidol as early as 2 weeks after initiation of treatment. The CGI may be as sensitive as the BPRS in detecting efficacy differences between antipsychotic drugs, although specific studies with truly independent ratings would be needed for confirmation. The fact that it takes only 1-2 min to fill in the CGI justifies its use in addition to more specific scales in drug trials for schizophrenia. Further development and evaluation of the CGI is warranted.

Analysis of Variance↗
PubMed2006

Influence of prior assignment on refusal rates in a trial of supplemental oxygen for retinopathy of prematurity.

Investigators aware of prior treatment assignments may deliberately or subliminally influence rates of subsequent consent in randomised trials, thus introducing the possibility of bias. As a trial of Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) was not masked to health professionals other than ophthalmologists, this possibility was evaluated by comparing the incidence of refusal to participate in relation to the previous assignment. Over 5 years, the STOP-ROP trial enrolled 649 infants, while 394 eligible subjects refused. Enrolled infants were assigned to supplemental oxygen or control groups at 30 centres including 71 hospitals, and stratified into two severity strata of their retinopathy of prematurity. We studied whether the assignment of the previously enrolled infant to either the supplemental arm or the control arm of the study affected the incidence of refusal to participate in the study by the next eligible infant. We also evaluated the possibility that refusal based on the preceding assignment could have influenced either the baseline balance of eye severity and pulmonary status between the two arms of the study or the final outcome of the randomised trial. There was a significantly higher incidence of refusal if the prior enrollee had been assigned to the supplemental oxygen group (44%) as compared with the control group (34%, P = 0.004). This effect from the prior assignment was larger in the later half of the study. Irrespective of the prior enrollee's assignment, refusal was more likely for more mature infants and those with milder baseline disease. Selection bias did not influence the ophthalmic or pulmonary findings at baseline, or the study outcomes. In incompletely masked studies, monitoring the distribution of refusers in relation to the previous assignment can reveal selection bias. Despite evidence of unequal refusal rates, the results of the STOP-ROP trial were not affected.

Age Factors↗
PubMed2006

Psychoeducation and compliance in the treatment of schizophrenia: results of the Munich Psychosis Information Project Study.

OBJECTIVE: The present study examined whether psychoeducational groups for patients with schizophrenic disorders and for their families can reduce rehospitalization rates and improve compliance. METHOD: 236 inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and who had regular contact with at least 1 relative or other key person were randomly assigned to 1 of 2 treatment conditions. In the intervention condition, patients and their relatives were encouraged to attend psychoeducational groups over a period of 4 to 5 months. The patients' and relatives' psychoeducational programs were separate, and each consisted of 8 sessions. Patients in the other treatment condition received routine care. Outcomes were compared over 12-month and 24-month follow-up periods. The study was conducted from 1990 to 1994. RESULTS: It was possible to significantly reduce the rehospitalization rate after 12 and 24 months in patients who attended psychoeducational groups compared with those receiving routine care (p < .05). Patients who attended psychoeducational groups showed better compliance than patients under routine care without psycho-education. CONCLUSIONS: The results suggest that a relatively brief intervention of 8 psychoeducational sessions with systematic family involvement in simultaneous groups can considerably improve the treatment of schizophrenia. Psychoeducation should be routinely offered to all patients with schizophrenia and their families.

Adult↗
PubMed2005

Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms.

Atypical antipsychotics are generally thought to be more effective than conventional agents in treating the negative symptoms of schizophrenia; however, there have been few direct comparisons among atypicals. We therefore investigated risperidone and quetiapine with respect to their efficacy against negative symptoms in a 12-week,double-blind, comparative pilot study involving 44 patients with schizophrenia with predominantly negative symptoms, as defined by Positive and Negative Syndrome Scale (PANSS) scores. Other efficacy measures included the Scale for the Assessment of Negative Symptoms (SANS) and the Clinical Global Impression (CGI) rating scale. Antipsychotic tolerability was assessed using the Simpson-Angus Scale (SAS) and various laboratory measures. Mean doses were 589.7 mg/ day quetiapine and 4.9 mg/day risperidone (observed cases). Both antipsychotics produced significant decreases in PANSS total, positive and negative scores, and SANS scores. Patients receiving risperidone were significantly more likely to experience extrapyramidal symptoms (EPS) [p <0.05], or to require anticholinergic medication (p <0.05), and had significantly higher prolactin levels (p <0.001) than quetiapine-treated patients. In conclusion, there is no significant difference in efficacy between quetiapine and risperidone in alleviating the negative symptoms of schizophrenia. Quetiapine is also well tolerated, with a lower incidence of EPS and prolactin increase than risperidone.

Adult↗
PubMed2005

What does the PANSS mean?

OBJECTIVE: Despite the frequent use of the Positive and Negative Syndrome Scale (PANSS) for rating the symptoms of schizophrenia, the clinical meaning of its total score and of the cut-offs that are used to define treatment response (e.g. at least 20% or 50% reduction of the baseline score) are as yet unclear. We therefore compared the PANSS with simultaneous ratings of Clinical Global Impressions (CGI). METHOD: PANSS and CGI ratings at baseline (n = 4091), and after one, two, four and six weeks of treatment taken from a pooled database of seven pivotal, multi-center antipsychotic drug trials on olanzapine or amisulpride in patients with exacerbations of schizophrenia were compared using equipercentile linking. RESULTS: Being considered "mildly ill" according to the CGI approximately corresponded to a PANSS total score of 58, "moderately ill" to a PANSS of 75, "markedly ill" to a PANSS of 95 and severely ill to a PANSS of 116. To be "minimally improved" according to the CGI score was associated with a mean percentage PANSS reduction of 19%, 23%, 26% and 28% at weeks 1, 2, 4 and 6, respectively. The corresponding figures for a CGI rating "much improved" were 40%, 45%, 51% and 53%. CONCLUSIONS: The results provide a better framework for understanding the clinical meaning of the PANSS total score in drug trials of schizophrenia patients with acute exacerbations. Such studies may ideally use at least a 50% reduction from baseline cut-off to define response rather than lower thresholds. In treatment resistant populations, however, even a small improvement can be important, so that a 25% cut-off might be appropriate.

Adult↗
PubMed2005

Neuropsychological performance in adult attention-deficit hyperactivity disorder: meta-analysis of empirical data.

Attention-deficit hyperactivity disorder (ADHD) is increasingly recognized not only in children but also in adults. Neuropsychological tests are important tools to quantify the attentional and/or cognitive deficits of patients compared to controls. The present meta-analysis integrates 24 empirical studies reporting results of at least one of 50 standard neuropsychological tests comparing adult ADHD patients with controls. The 50 tests were categorized into the following 10 functional domains: verbal ability, figural problem solving, abstract problem solving, executive function, fluency, simple attention, sustained attention, focused attention, verbal memory, figural memory. For each domain a pooled effect size d' was calculated. Complex attention variables and verbal memory discriminated best between ADHD patients and controls. Effect sizes for these domains were homogeneous and of moderate size (d' between 0.5 and 0.6). In contrast to results reported in children, executive functions were not generally reduced in adult ADHD patients.

Adolescent↗
PubMed2004

Clinical effects of COX-2 inhibitors on cognition in schizophrenia.

An activation of pro-inflammatory cytokines in the central nervous system is associated with cognitive disturbances. This process is mediated by prostaglandins and cyclo-oxygenase-2 (COX-2). COX-2 inhibitors have been suggested to show beneficial effects in disorders associated with cognitive disturbance, although clinical effects on cognition have not been shown until today. Data from a schizophrenia study were reevaluated under the aspect whether an effect on the positive and negative syndrome scale (PANSS) factor cognition can be observed during therapy with the COX-2 inhibitor celecoxib add on to risperidone in comparison to riperidone alone. Beside the effect on the PANSS total score, the effect on the cognition factor was the most pronounced using the analysis of covariance compared to all other factors of the PANSS (p < 0.06). Although suggestions of basic research led to an expected therapeutic effect of COX-2 inhibitors on cognition, this effect could not yet be shown clinically. In schizophrenia, the effect on cognition contributes to the therapeutic effect of COX-2 inhibitors.

Adult↗
PubMed2004

Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression.

BACKGROUND: Substantial evidence supports a role for dysfunction of the serotonin transporter in the pathogenesis of major depression. Several studies have found reciprocal interactions between the serotonergic system and both brain-derived neurotrophic factor and glutamate, which are known to modulate or affect hippocampal morphologic characteristics. OBJECTIVE: To examine the influence of a polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene on hippocampal volumes in patients with major depression and healthy controls. DESIGN: Baseline investigation of a prospective magnetic resonance imaging study with a 4-year follow-up period. PATIENTS: We examined 40 inpatients with major depression as well as 40 healthy controls matched for age, sex, and handedness. MAIN OUTCOME MEASURES: Subjects underwent high-resolution magnetic resonance imaging. Furthermore, genotyping for the 5-HTTLPR biallelic polymorphism was performed, which consists of a 44-base pair insertion (L allele) or deletion (S allele). RESULTS: Patients with the L/L homozygous genotype had significantly smaller hippocampal gray matter (left hemisphere: P=.003; right hemisphere: P=.01) and white matter volumes (left hemisphere: P=.001; right hemisphere: P=.002) than controls with this genotype. No significant differences were found between patients and controls with the L/S or S/S genotype. Moreover, patients with the L/L genotype had significantly smaller hippocampal white matter volumes than those with the L/S or S/S genotype (P=.03). CONCLUSIONS: These findings suggest that homozygosity for the L allele is associated with decreased hippocampal volumes in patients with major depression but not in healthy controls. A possible explanation is that the interaction between the serotonergic system and neurotrophic factors as well as excitatory amino acid neurotransmission may affect hippocampal morphologic characteristics.

Adult↗
PubMed2003

Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials.

OBJECTIVE: The authors performed a systematic review and meta-analysis of studies of the potential of new-generation antipsychotic drugs to improve adherence and decrease relapse rates in patients with schizophrenia. METHOD: Randomized, controlled trials comparing new-generation antipsychotic drugs with placebo and/or conventional antipsychotics were identified. Data on relapse, general treatment failure, and dropout due to adverse events were extracted and combined in a meta-analysis. RESULTS: Because few trials were available for each individual drug, the effects of new-generation antipsychotic drugs as a group were analyzed. The analysis of six placebo comparisons, involving a total of 983 patients, clearly demonstrated that new-generation antipsychotic drugs are effective for relapse prevention. Eleven studies with a total of 2,032 patients provided comparative data on relapse/treatment failure for new-generation and conventional antipsychotics. The analysis revealed that rates of relapse and overall treatment failure were modestly but significantly lower with the newer drugs. Whether this advantage was partly mediated by improved adherence to treatment remains unclear. No significant superiority in terms of fewer dropouts due to adverse events was found for the newer drugs. Furthermore, a number of methodological problems were identified. CONCLUSIONS: Overall, the currently available data suggest that new-generation antipsychotics have the potential to reduce relapse rates. Methodological issues to be addressed in future trials include the choice of comparator, use of appropriate doses, application of clinically relevant relapse criteria, monitoring of adherence, and minimization of dropouts.

Antipsychotic Agents↗
PubMed2002

No association between the G308A polymorphism of the tumor necrosis factor-alpha gene and schizophrenia.

Several linkage analyses in schizophrenia research point to a locus on chromosome 6p22, where the gene coding for tumor necrosis factor-alpha (TNF-alpha) is located. A marked influence of antipsychotic medication on TNF-alpha has been described. As the involvement of an immune process in the pathophysiology of schizophrenia has been discussed, a functional TNF-alpha polymorphism appears to be a candidate in genetic schizophrenia research. The G308A polymorphism of the TNF-alpha gene was described to be associated with increased TNF-alpha production. Boin and colleagues have already described a significant association between the polymorphic allele and schizophrenia, investigating 84 schizophrenic patients (21 % polymorphic allele) and 138 healthy volunteers (11 % polymorphic allele), recruited in Northern Italy. We carried out a replication study including 157 schizophrenic patients and 186 healthy persons, who were recruited in Southern Germany. Psychopathology was additionally monitored by PANSS. We were not able to replicate the findings of Boin et al., as we did not find any difference in allele frequency or genotype distribution between our schizophrenic patients (13.7 % polymorphic allele) and healthy controls (16.9 % polymorphic allele). Moreover, we did not find any association between genotype and psychopathology, as measured by PANSS. The different results between these two studies may be due to ethnic differences.

Adult↗
PubMed2002

Value of event-related P300 subcomponents in the clinical diagnosis of mild cognitive impairment and Alzheimer's Disease.

Accurate and early diagnosis of Alzheimer's Disease (AD) with reliable and noninvasive methods is of great importance for clinical practice as effective and specific antidementive therapies become available. The aim of the study was to evaluate the clinical relevance of event-related P300 in the early diagnosis of AD. Thirty patients with AD, 26 patients with mild cognitive impairment (MCI) from our Memory Clinic and 26 age-matched healthy controls (HC) were studied with event-related P300 potentials. Amplitudes of temporo-basal dipoles (TB-P300) were significantly diminished in AD compared to HC and MCI. Furthermore, latencies of temporo-superior dipoles (TS-P300) were significantly prolonged in AD compared with HC. Sensitivity was 90.0% for the differentiation of patients with AD from HC (specificity 79.1%) using reduced TB-P300 amplitudes and prolonged TS-P300 latencies. Similar results were found using Pz amplitudes as well as Fz latencies. Our data suggest that TB-P300 amplitudes and TS-P300 latencies may be an accurate clinically available, nonexpensive, noninvasive, and reliable marker for AD.

Aged↗
PubMed2002

Amisulpride, an unusual "atypical" antipsychotic: a meta-analysis of randomized controlled trials.

OBJECTIVE: The "atypical" profile of the new antipsychotics clozapine, olanzapine, quetiapine, and risperidone has been linked to combined antagonism of serotonin 2 (5-HT(2)) and dopamine 2 (D(2)) receptors. Although amisulpride is a highly selective D(3)/D(2) receptor antagonist, it is assumed to have atypical properties as well. The purpose of this article was to compare the atypical profile of amisulpride with that of the 5-HT(2)/D(2) antagonists. METHOD: Randomized controlled trials that compared amisulpride with conventional antipsychotics or placebo for patients with schizophrenia were identified and included in a meta-analysis. The mean effect sizes found for amisulpride were compared with those of an updated meta-analysis of the 5-HT(2)/D(2) antagonists. RESULTS: Eighteen randomized controlled trials of amisulpride (N=2,214) were found. In 11 studies of acutely ill patients it proved to be consistently more effective than conventional antipsychotics for global schizophrenic symptoms (measured with the Brief Psychiatric Rating Scale) and negative symptoms. Amisulpride is to date the only atypical antipsychotic for which several studies of patients suffering predominantly from negative symptoms have been published. In four such studies amisulpride was significantly more effective than placebo. Three small studies with conventional antipsychotics as comparators showed only a trend in favor of amisulpride in this regard. Amisulpride was associated with clearly lower use of antiparkinsonian medication and with fewer dropouts due to adverse events than conventional antipsychotics. CONCLUSIONS: These results cast some doubt on the notion that combined 5-HT(2)/D(2) antagonism is the reason that the newer antipsychotic medications are effective for negative symptoms and have fewer extrapyramidal side effects.

Amisulpride↗
PubMed2002

Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.

OBJECTIVE: Abnormalities in the immune system in schizophrenia have been described. However, important findings such as high levels of activating cytokines in the CSF and signs of CNS inflammation have been controversial. The authors conducted a trial of the new selective cyclooxygenase-2 inhibitor celecoxib, an immunomodulatory drug, in schizophrenic patients to evaluate its therapeutic effects. METHOD: In a prospective, double-blind evaluation, 50 patients with an acute exacerbation of schizophrenia were randomly assigned to either risperidone plus celecoxib or risperidone plus placebo. After a washout period, 25 patients received 2-6 mg/day of risperidone plus placebo and 25 received risperidone plus 400 mg/day of celecoxib for 5 weeks. The treatment effect was calculated by analysis of covariance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or risperidone dose or plasma level. RESULTS: Over 5 weeks, both groups of patients showed significant improvement in scores on the Positive and Negative Syndrome Scale and on all subscales. However, the celecoxib group showed significantly greater improvement in the total score. CONCLUSIONS: Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug showed beneficial effects on schizophrenia symptoms indicates that immune dysfunction in schizophrenia is not just an epiphenomenon but is related to the pathomechanism of the disorder. However, a nonimmunological therapeutic effect of celecoxib mediated by the N-methyl-D-aspartic acid receptor has to be taken into account.

Adolescent↗