RESUMEN
BACKGROUND: Self-ratings of psychotic experiences might be biased by depressive symptoms. METHOD: Data from a large naturalistic multicentre trial on depressed inpatients (n=488) who were assessed on a biweekly basis until discharge were analyzed. Self-rated psychotic symptoms as assessed with the 90-Item Symptom Checklist (SCL-90) were correlated with the SCL-90 total score, the SCL-90 depression score, the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale 21 item (HAMD-21) total score, the Montgomery Åsberg Depression Rating Scale (MADRS) total score and the clinician-rated paranoid-hallucinatory score of the Association for Methodology and Documentation in Psychiatry (AMDP) scale. RESULTS: At discharge the SCL-90 psychosis score correlated highest with the SCL-90 depression score (0.78, P<0.001) and with the BDI total score (0.64, P<0.001). Moderate correlations were found for the MADRS (0.34, P<0.001), HAMD (0.37, P<0.001) and AMDP depression score (0.33, P<0.001). Only a weak correlation was found between the SCL-90 psychosis score and the AMDP paranoid-hallucinatory syndrome score (0.15, P<0.001). Linear regression showed that change in self-rated psychotic symptoms over the treatment course was best explained by a change in the SCL-90 depression score (P<0.001). The change in clinician-rated AMDP paranoid-hallucinatory score had lesser influence (P=0.02). CONCLUSIONS: In depressed patients self-rated psychotic symptoms correlate poorly with clinician-rated psychotic symptoms. Caution is warranted when interpreting results from epidemiological surveys using self-rated psychotic symptom questionnaires as indicators of psychotic symptoms. Depressive symptoms which are highly prevalent in the general population might influence such self-ratings.
Asunto(s)
Depresión/complicaciones , Trastorno Depresivo/complicaciones , Pacientes Internos/psicología , Trastornos Psicóticos/diagnóstico , Adulto , Lista de Verificación , Depresión/psicología , Trastorno Depresivo/psicología , Autoevaluación Diagnóstica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Psicometría , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/psicologíaRESUMEN
OBJECTIVES: The involvement of an immune process in the pathophysiology of major depression disorder (MDD) was substantiated by studies demonstrating elevated levels of proinflammatory cytokines and prostaglandin E(2) (PGE(2)). Cyclooxygenase-2 (COX-2) inhibitors lead to a reduced production of PGE(2) and have been shown to improve depressive symptoms. We investigated the three immune parameters macrophage migration inhibitory factor (MIF), transforming growth factor-ß (TGF-ß) and soluble CD14 (sCD14) in a randomized, placebo-controlled trial of the COX-2 inhibitor celecoxib as add-on therapy in patients with MDD treated with reboxetine. METHODS: Thirty-two patients with depression and 20 healthy controls participated in the study. The patients were treated with reboxetine and celecoxib or placebo. Immune parameters were measured from serum at baseline, after three and five weeks using ELISA. RESULTS: Celecoxib as add-on strategy resulted in a significant reduction of Hamilton Depression Scale scores compared to placebo. Depressed patients showed significantly elevated MIF (p < 0.001) and reduced TGF-ß (p = 0.006) concentrations at baseline. There was no difference in sCD14-concentrations. There was no difference between the placebo and the celecoxib group and no change over time. LIMITATIONS: Limitations of the study are the relatively small sample size and lack of functional assessment of HPA axis in parallel. CONCLUSIONS: MIF is a promising new candidate in the neuro-immune interplay that may link depressive symptoms, altered immune state and HPA-axis dysregulation. Reduced levels of TGF-ß replicate previous findings and support the importance of this regulatory cytokine in major depressive disorder.
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Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Trastorno Depresivo Mayor/inmunología , Oxidorreductasas Intramoleculares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Anciano , Antidepresivos/uso terapéutico , Celecoxib , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/farmacología , Depresión , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Quimioterapia Combinada , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Morfolinas/uso terapéutico , Escalas de Valoración Psiquiátrica , Pruebas Psicológicas , Reboxetina , Adulto JovenRESUMEN
PURPOSE: To develop and evaluate a self- and observer-rating scale on quality of life in patients suffering from schizophrenia with regard to the efficacy of atypical antipsychotics based on different dimensions and to apply within a pilot study. METHODS: Following review of existing scales and a prevalidation phase, the Riedel-Spellmann-Musil (RSM) scale was developed comprising 36 items assigned to different subscales. As reference scales, the Quality of Life Scale (QLS) and the Subjective Well-being Under Neuroleptic Treatment Scale-short version (SWN-K) were performed, psychopathology and adverse events were measured at all visits. Reliability was assessed using Cronbach's alpha, Pearson's correlation coefficients were used to assess construct validity, and Intraclass Correlation Coefficients (ICCs) were used for test-retest reliability. T tests were performed in normal distributed samples; otherwise Wilcoxon tests were used. RESULTS: One hundred and thirty-six patients were included in the study. Cronbach`s α was 0.917 for the self-rating and 0.915 for the interviewer-rating part. ICCs were >0.70 for all subscales. The self-rating part correlated strongly with the SWN-K and the observer part with the QLS. Changes in psychopathology over the study period and different levels of functioning were detected. CONCLUSION: The RSM-scale is a new scale to assess the quality of life in different dimensions of patients with schizophrenia treated with antipsychotics and shows good internal consistency, test-retest reliability, construct and discriminant validity.
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Antipsicóticos/uso terapéutico , Calidad de Vida , Esquizofrenia , Índice de Severidad de la Enfermedad , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Observación , Proyectos Piloto , Reproducibilidad de los Resultados , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND: To examine influencing variables of neurocognition in patients with schizophrenia and to predict cognition during antipsychotic treatment. METHODS: Data were obtained from patients with an acute episode of schizophrenia participating in two double-blind and one open label trial comparing the effects of different atypical antipsychotics on cognition. In total, 129 patients were enrolled in this analysis. Cognitive function was assessed at admission, week 4 and 8. Efficacy and tolerability were assessed weekly using the Positive and Negative Syndrome Scale (PANSS) and the Simpson Angus Sale (SAS). Patients were treated with aripirazole, olanzapine, quetiapine and risperidone. Regression analysis including mixed effect models was performed. RESULTS: A significant improvement in all cognitive domains was observed from baseline to week 8. Regarding the antipsychotic treatment applied quetiapine seemed to achieve the most favourable cognitive improvement. Negative and depressive symptoms, the patient's age and the concomitant and antipsychotic treatment applied were observed to significantly influence and predict neurocognition. CONCLUSION: The results may indicate that schizophrenia is a static disorder with trait and state dependent cognitive components especially in the memory domains. The influence of negative and depressive symptoms should be considered in daily clinical routine.
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Antipsicóticos/uso terapéutico , Trastornos del Conocimiento/complicaciones , Cognición/efectos de los fármacos , Neuronas/efectos de los fármacos , Esquizofrenia/complicaciones , Esquizofrenia/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Envejecimiento , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Trastornos del Conocimiento/fisiopatología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Interacciones Farmacológicas , Humanos , Memoria/efectos de los fármacos , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/fisiopatología , Persona de Mediana Edad , Esquizofrenia/fisiopatología , Esquizofrenia/terapia , Índice de Severidad de la Enfermedad , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: The aim of this study was to assess the cognitive effects of aripiprazole in inpatients with schizophrenia. METHODS: This was an investigator-initiated, open label eight-week trial evaluating 56 inpatients with the DSM-IV diagnosis of schizophrenia. Efficacy was assessed weekly using the Positive and Negative Syndrome Scale (PANSS) and tolerability was assessed each week using the Udvalg for Klinske Undersogelser side effect rating scale (UKU). Cognitive function was assessed at baseline, week 4 and week 8. RESULTS: Aripiprazole showed significant improvement in PANSS total score and all subscores between baseline and endpoint visit. The substance was very well tolerated. Patients improved significantly in verbal memory, reaction time and reaction quality/attention from baseline to week eight. Furthermore, mean z-values of individual cognitive domains summarized in a global cognitive index improved significantly from baseline to week eight. DISCUSSION: Our results suggest that aripiprazole provides a valuable treatment option for patients with schizophrenia.
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Antipsicóticos/uso terapéutico , Cognición/efectos de los fármacos , Piperazinas/uso terapéutico , Quinolonas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/efectos adversos , Aripiprazol , Atención/efectos de los fármacos , Humanos , Pacientes Internos , Memoria/efectos de los fármacos , Pruebas Neuropsicológicas , Piperazinas/efectos adversos , Escalas de Valoración Psiquiátrica , Quinolonas/efectos adversos , Tiempo de Reacción/efectos de los fármacos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Working memory as a part of higher-order executive functions is defined by the parallel storage and processing of information. Recent functional fMRI studies have revealed a functional, interregional disintegration of a neuronal network connecting cortical, subcortical and cerebellar regions in schizophrenic patients (SZ). Cognitive impairment in working memory is a core psychopathological correlate of schizophrenic symptoms. Atypical neuroleptics such as quetiapine have shown good efficacy in treating positive and negative symptoms. The presented study evaluated the impact of a neuroleptic steady state treatment with quetiapine on the altered working memory activation patterns in schizophrenia. METHODS: Patients were examined by fMRI at baseline and after 12 weeks of steady state treatment with quetiapine. Matched healthy controls (HC) underwent baseline examination. In the scanner, stimuli were presented in a 2-back and 0-back condition of a working memory (wm) paradigm, whereby a degraded and a non-degraded version were used each time. Additionally, behavioural responses (reaction time to target stimuli and error ratio) were measured. RESULTS: At baseline, healthy controls revealed increased activity in the frontal lobe, especially in regions of the prefrontal cortex. Compared to HC, SZ showed hypoactivation in the right dorsolateral prefrontal cortex (DLPFC) and the ventrolateral prefrontal cortex (VLPFC) bilaterally for the 2-back condition. In the 2-back degraded condition there was a hypoactivation in both, the right DLPFC and the VLPFC. Additionally, patients showed bilaterally decreased activation in the basalganglia in the 2-back and in the right caudatus in the 2-back degraded condition compared to healthy controls. After treatment with quetiapine, patients activations patterns were increased. The pre-post comparison of the 2-back condition revealed a significant increase of activation in the left VLPFC at a significance level of 0.001 (uncorrected). The 2-back degraded condition led to a significant activation pattern in the lingual gyrus and the right precuneus. In both wm conditions, at baseline there were no differences in reaction time but only a worse performance in SZ. After treatment, behavioural measurement of responses, including reaction time and performance, showed slight improvements in SZ, although these did not reach statistical significance. CONCLUSIONS: The neuronal networks underlying working memory are clearly altered in schizophrenia. After 12 weeks of treatment with quetiapine monotherapy, patients showed significant clinical improvement and revealed increased BOLD activity in the VLPFC during a working memory task, although there was no improvement of cognitive performance.
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Antipsicóticos/uso terapéutico , Ganglios Basales/efectos de los fármacos , Cerebelo/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Dibenzotiazepinas/uso terapéutico , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Imagen por Resonancia Magnética , Memoria a Corto Plazo/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Oxígeno/sangre , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Adulto , Antipsicóticos/efectos adversos , Ganglios Basales/fisiopatología , Cerebelo/fisiopatología , Corteza Cerebral/fisiopatología , Dibenzotiazepinas/efectos adversos , Aprendizaje Discriminativo/efectos de los fármacos , Aprendizaje Discriminativo/fisiología , Dominancia Cerebral/fisiología , Femenino , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/fisiología , Humanos , Masculino , Memoria a Corto Plazo/fisiología , Persona de Mediana Edad , Red Nerviosa/fisiopatología , Reconocimiento Visual de Modelos/efectos de los fármacos , Reconocimiento Visual de Modelos/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Fumarato de Quetiapina , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Esquizofrenia/fisiopatología , Resultado del TratamientoRESUMEN
Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E(2) (PGE(2)), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE(2) production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4-10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.
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Antidepresivos/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Dinoprostona/biosíntesis , Morfolinas/uso terapéutico , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Inhibidores de Captación Adrenérgica , Adulto , Ansiolíticos/administración & dosificación , Ansiolíticos/uso terapéutico , Antidepresivos/administración & dosificación , Antidepresivos/farmacología , Celecoxib , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/farmacología , Trastorno Depresivo/fisiopatología , Dinoprostona/análisis , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Interleucina-6/biosíntesis , Lorazepam/administración & dosificación , Lorazepam/uso terapéutico , Masculino , Persona de Mediana Edad , Morfolinas/administración & dosificación , Pacientes Desistentes del Tratamiento , Proyectos Piloto , Pruebas Psicológicas , Pirazoles/administración & dosificación , Pirazoles/farmacología , Reboxetina , Serotonina/metabolismo , Índice de Severidad de la Enfermedad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacologíaRESUMEN
INTRODUCTION: 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. METHODS: 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. RESULTS: Eighty-two patients were recruited. Mean oral dose of risperidone was 4.3 +/- 0.9 mg. 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 (> or = 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). DISCUSSION: 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.