Pharmakotherapie gehörloser schizophrener Patienten

Die vorliegende Untersuchung behandelt Teilaspekte des von 1994 bis 1999 an der psychiatrischen Universitätsklinik Münster durchgeführten, von der Deutschen Forschungsgemeinschaft geförderten Projekts "Schizophrenien Gehörloser". Ziel dieses Projekts war die Untersuchung des (Behandlungs-) Verlaufs schizophrener Psychosen in einer Stichprobe prälingual gehörloser Patienten, deren Umfang auch die Anwendung statistischer Verfahren ermöglicht. Die in dieser Dissertation zu behandelnde Fragestellung bezieht sich auf die besondere Problematik der neuroleptischen Psychopharmakotherapie gehörloser Patienten, die sich in vielerlei Hinsicht von derjenigen hörender unterscheidet. So werden u.a. die besondere "soziale Einbettung" der Gehörlosen, die daraus erwachsenden kulturellen wie sprachlichen Besonderheiten und deren Folgen für die psychiatrische Therapie diskutiert und der aktuelle Stand der therapeutischen Möglichkeiten vorgestellt

Diagnosis-specific effect of familial loading on verbal working memory in schizophrenia

Working memory disturbances are a frequently replicated finding in schizophrenia and less consistent also in schizoaffective disorder. Working memory dysfunctions have been shown to be heritable and have been proposed to represent a promising endophenotype of schizophrenic psychoses. In the present study, we investigated the effects of familial loading on performance rates in circuit-specific verbal and visuospatial working memory tasks in matched samples of schizophrenic patients (from multiply affected or uniaffected families), schizoaffective patients (from multiply affected or uniaffected families), and healthy subjects. We found a significant interaction effect between familial loading and diagnosis in terms of a diagnosis-specific detrimental effect of familial loading on the performance of schizophrenic (but not schizoaffective) patients in the articulatory rehearsal task. This finding of a circuit-specific verbal working memory deficit in schizophrenic patients with additional familial loading is consistent with prior studies, which provided evidence for the existence of specific subgroups of schizophrenic patients with selective working memory impairments and for diagnosis-specific dysfunctions of the articulatory rehearsal mechanism in schizophrenic, but not in schizoaffective patients. Together, these findings suggest that the genetic risk for (a subtype of) schizophrenia may be associated with dysfunctions of the brain system, which underlies the articulatory rehearsal mechanism, the probably phylogenetically youngest part of human working memory

Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks

Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer-based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia

Cognitive benefits of quetiapine versus risperidone in schizophrenia

Objective: This randomized, double-blind study compared the effect of quetiapine and risperidone on cognitive function in patients with schizophrenia. Methods: Patients (n=44) with predominantly negative symptoms were randomized to quetiapine (400–800mg/day) or risperidone (4–8mg/day) for 12 weeks. Cognitive function (reaction time and quality; executive function; working, verbal and visual memory) was assessed at baseline and Week 6. Between-group differences at Week 6 were analyzed using MANCOVA. The incidence of extrapyramidal symptoms (EPS) was also assessed. Results: Patients had impaired cognition at baseline. Twenty-six patients completed the study. At Week 6, 19 patients in the quetiapine group and 15 in the risperidone group had cognitive data available for analysis. Mean doses at Week 6 were 570.6mg/day for quetiapine and 5.1mg/day for risperidone. Cognitive scores improved from baseline to Week 6 in both groups. However, the improvement in working memory was significantly greater with quetiapine (p<0.01 risperidone). EPS and anticholinergic medication requirement were significantly lower in the quetiapine group. Conclusions: Although both quetiapine and risperidone improved cognition, quetiapine produced significantly greater improvements in working memory, with fewer EPS

Risperidone plasma levels, clinical response and side–effects

Assessment of the relation between oral risperidone dose, serum drug levels and clinical response may provide important information for rational treatment decisions. Inter–individual differences in the liver cytochrome P450 system, especially in the CYP2D6 subsystem, which account for a significant portion of risperidone metabolism, may also influence plasma drug levels and alter clinical response parameters. We thus prospectively investigated risperidone serum concentrations in relation to clinical efficacy and side–effects and genotyped major CYP2D6 polymorphisms to determine their effect upon these parameters.Neuroleptic monotherapy with risperidone was administered to schizophrenia patients in a 6–week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of risperidone and 9–OH–risperidone were carried out. In addition, major CYP2D6 polymorphisms including alleles *4, *6 and *14 were genotyped.Eighty–two patients were recruited. Mean oral dose of risperidone was 4.3 ± 0.9mg. Mean plasma level of both risperidone and 9–OH–risperidone together (“active moiety”) was 41.6 ± 26.6 ng/ml. Significant improvements in PANSS scales and the various subscales ensued. There was a positive linear correlation between active moiety plasma levels and dose (r = 0.291, p = 0.015) and between risperidone and 9–OH–risperidone levels (r = 0.262; p = 0.016). Nonresponders to pharmacotherapy (PANSS–Improvement < 30%) showed significantly higher active moiety plasma levels (49.9 ± 30.7 ng/ml) than responders (38.2 ± 17.0 ng/ml; p = 0.045) without significantly higher oral doses (p = 0.601). Patients with longer illness duration (≥ 3 years) had significantly higher plasma drug levels than those with a shorter course (< 3 years; p = 0.039). Extrapyramidal side effects (EPS) and plasma levels were not correlated (r = 0.028; p = 0.843), but higher plasma levels at week 2 predicted an incidence for EPS (p < 0.050). Accordingly, patients initially receiving higher oral doses of risperidone were significantly more likely to respond with EPS in the trial course. Eight patients (9.8%) were heterozygous carriers of the CYP2D6 allele *4. CYP2D6 polymorphisms did not predict clinical response, but predicted a tendential increase in the plasma risperidone to 9–OH–risperidone ratio (0.5 ± 0.6 vs. 1.9 ± 1.8; p = 0.120).The major finding was that responders to risperidone treatment had significantly lower blood levels of risperidone and 9–OH risperidone than patients who did not respond to the treatment despite administration of similar oral doses. The observed CYP2D6 polymorphisms did not contribute to altered clinical efficacy, but affected risperidone to 9–OH–risperidone ratios. Increased plasma levels of the active moiety in patients with longer illness may represent general aging effects. Conversely, the observed higher plasma levels in nonresponders may derive from unaccounted genetic metabolism abnormalities or Phase II metabolism disturbances. Patients initially receiving higher oral risperidone doses were more likely to respond with extrapyramidal side effects which reaffirms the need for careful titration. The high inter–individual variability in risperidone and 9–OH–risperidone metabolization and the relationship between clinical outcome and plasma levels warrants regular plasma level monitoring of both compounds to assess for the clinically relevant active moiety

Risperidone Plasma Levels, Clinical Response and Side-Effects

Introduction: Assessment of the relation between oral neuroleptic dose, serum drug levels and clinical response may provide important information for rational treatment decisions. Methods: Risperidone mono-therapy was administered to 82 schizophrenia patients in a 6-week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of Risperidone and 9-OH-Risperidone were carried out. Additionally, major CYP2D6 polymorphisms were genotyped. Results: Mean oral dose of risperidone was 4.4±1.0mg. Mean plasma level of both risperidone and 9-OH-Risperidone together („active moiety“) was 41.6±26.6 ng/ml. There was a positive linear correlation between risperidone plasma levels and dose (r=0.308, p≤.05). Therapy non-responder (PANSS improvement <30%) showed significantly higher plasma levels (p=.032) than responder (PANSS improvement ≥30%) without higher dosages (p=.258). Patients with a duration ≥ 5 years had significantly higher plasma levels than those with a duration <5 years (p=.028). EPS and plasma levels were not correlated (r=.028; p=.843). Patients initially receiving higher oral doses of risperidone were significantly more likely to develop extrapyramidal side effects later in the trial course. Eight of the patients (9.8%) were heterozygous for the CYP2D6 polymorphism. CYP2D6 polymorphisms did not predict clinical response, but tended to predict an increase in the Risperidone/9-OH-Risperidone-Ratio (p=0.095). Discussion: Several aspects of our study have an important implication for the clinical use: The higher incidence of EPMS is related to a faster up-titration of Risperidone and higher plasma levels; Non-responders to risperidone treatment showed higher plasma levels, indicating that a further increase in the daily dose is not recommended; patients with a longer duration of illness showed higher plasma levels, although receiving the same oral dose. The therapeutic monitoring of risperidone and 9-OH-risperidone blood levels is thus highly recommended

Remission in schizophrenia - What are we measuring? Comparing the consensus remission criteria to a CGI-based definition of remission and to remission in major depression

Background: Despite being recommended for use in clinical trials, the consensus remission criteria were found to leave patients with persisting symptoms, relevant areas of functional impairment and a decreased sense of wellbeing. Therefore, to evaluate the appropriateness of the schizophrenia consensus criteria, a definition of remission based on the Clinical Global Impression Scale (CGI) was developed and remitter subgroups were compared. Methods: 239 patients with a schizophrenia spectrum disorder were evaluated regarding their remission status after inpatient treatment. Remission in schizophrenia was defined according to the symptom-severity component of the consensus criteria by Andreasen et al. and a CGI based definition was calculated using sensitivity and specificity using receiver operating curves (asymptomatic remitter). Both remitter groups (schizophrenia consensus versus asymptomatic remitters) were compared regarding different clinical variables at discharge as well as the likelihood to relapse within a 1-year follow-up period. Both schizophrenia remitter subgroups were compared to remitters in major depression as a reference value. Results: Following the consensus criteria, 63% of the schizophrenia patients were in remission compared to only 18% following the asymptomatic criterion. The schizophrenia consensus remitters were less likely to be concurrent treatment responders (p < 0.0001), had a significantly greater illness severity (p < 0.0001) and less functioning (p = 0.0358) as well as a significantly greater risk to relapse (p = 0.0174) compared to the schizophrenia asymptomatic remitters as well as the depressed remitters. Conclusion: It should be critically re-evaluated if the currently proposed consensus criteria are adequate to measure what is traditionally understood to be remission. (C) 2019 Elsevier B.V. All rights reserved