Pharmacokinetics and Safety of Bilastine 10 mg/d in Children Aged 2 to 5 Years With Allergic Rhinoconjunctivitis or Urticaria: A Phase 3 Clinical Trial.

BACKGROUND: Bilastine is a second-generation antihistamine for the symptomatic treatment of allergic rhinoconjunctivitis (ARC) and urticaria in adults, adolescents, and children. The pharmacokinetics and safety of oral bilastine 10 mg/d in children aged 2 to 5 years were evaluated. METHODS: This was a multicenter, open-label clinical trial in children aged 2 to 5 years with seasonal or perennial ARC or urticaria treated once daily with bilastine 10 mg orodispersible tablets. The safety evaluation included treatment-emergent adverse events (TEAEs), vital signs, and physical examination. Pharmacokinetic data were pooled with data from a prior pediatric study, and pharmacokinetic modeling was performed to assess consistency. RESULTS: A total of 37 children with ARC (81.1%), urticaria (8.1%), or both (10.8%) were included in the study, with a mean (SD) age of 3.7 (1.2) years. The highest plasma concentrations of bilastine were observed 1 hour after administration (634.91 ng/mL). Eight patients (21.6%) experienced 1 TEAE each, none of which was severe. Body weight and age were not covariates of variation in either systemic clearance or the volume of distribution in children aged 2 to 5 years and did not affect the pharmacokinetic parameters of bilastine. CONCLUSIONS: The pharmacokinetics of bilastine was linear and consistent with data from a previous trial, suggesting that a 10-mg dose may be used in children (2 to <12 years). No dose adjustments are deemed necessary. Oral once-daily bilastine 10 mg presented a good safety profile in children aged 2 to 5.

Different levels of lack of improvement at 4 weeks of escitalopram treatment as predictors of poor 8-week outcome in MDD.

BACKGROUND: Several post-hoc studies have shown that lack of early improvement reduces the chance of later response or remission. This post-hoc analysis evaluates different cut-off points of non-improvement at 4 weeks of escitalopram treatment to predict 8-week non-response and non-remission. METHOD: This study consisted of MDD patients with an absence of improvement (<30% reduction in baseline score of the HAMD-17) at Week 4 of escitalopram treatment (10mg/day) that continued escitalopram treatment (10-20mg/day) for a further 4-week period (n=251). Predictive, sensitivity and specificity values for the several definitions of non-improvement (≤ 25%, ≤ 20% and ≤ 15% reduction in the HAMD-17 baseline total score) at 4 weeks were calculated. RESULTS: Overall, 70.1% (176/251) of patients did not achieve response at Week 8 and 84.5% (212/251) did not achieve remission. The predictive value for non-response was high (71.4-74.3%) for all cut-off points of non-improvement tested. The respective values for non-remission were placed between 85.0% and 87.2%. LIMITATIONS: This was a post-hoc subgroup analysis. The only drug assessed was escitalopram. CONCLUSIONS: Our data indicate that an absence of improvement, <30% reduction in the HAMD-17, after 4 weeks of escitalopram treatment should prompt clinicians to consider a change in treatment strategy. Similar findings were previously reported for other antidepressants.

Validation of the translation of an instrument to measure reliability of written information on treatment choices: a study on attention deficit/hyperactivity disorder (ADHD).

INTRODUCTION: DISCERN is an instrument designed to help patients assess the reliability of written information on treatment choices. Originally created in English, there is no validated Spanish version of this instrument. This study seeks to validate the Spanish translation of the DISCERN instrument used as a primary measure on a multicenter study aimed to assess the reliability of web-based information on treatment choices for attention deficit/hyperactivity disorder (ADHD). METHODS: We used a modified version of a method for validating translated instruments in which the original source-language version is formally compared with the back-translated source-language version. Each item was ranked in terms of comparability of language, similarity of interpretability, and degree of understandability. Responses used Likert scales ranging from 1 to 7, where 1 indicates the best interpretability, language and understandability, and 7 indicates the worst. Assessments were performed by 20 raters fluent in the source language. RESULTS: The Spanish translation of DISCERN, based on ratings of comparability, interpretability and degree of understandability (mean score (SD): 1.8 (1.1), 1.4 (0.9) and 1.6 (1.1), respectively), was considered extremely comparable. All items received a score of less than three, therefore no further revision of the translation was needed. CONCLUSION: The validation process showed that the quality of DISCERN translation was high, validating the comparable language of the tool translated on assessing written information on treatment choices for ADHD.

Functioning and symptomatic outcomes in patients with bipolar I disorder in syndromal remission: a 1-year, prospective, observational cohort study.

BACKGROUND: Recent studies demonstrate that many Bipolar Disorder (BD) patients experience mild symptoms and/or suffer significant functional impairment during periods of syndromal remission, suggesting greater relapse risk and need for more intensive therapeutic strategies. However, most studies have cross-sectional designs and other methodological limitations. This study aimed to prospectively evaluate whether the presence of subsyndromal symptoms and level of functionality have long-term consequences in BD patients in syndromal remission. METHODS: A 1-year, prospective, observational cohort study of BD patients in syndromal remission assessed participants at study entry and 3, 6 and 12months after baseline on a range of clinical, social and functional outcomes. RESULTS: A total of 473 BD patients were screened at 51 study sites across Spain. Finally, 398 patients with bipolar I disorder in syndromal remission were included. After the 12-month, follow-up period, 87.6% of patients remained in syndromal remission, 79.9% of patients were free of subsyndromal symptoms, but only 53.5% had normal levels of functionality. Patients without subsyndromal symptoms and with normal levels of functionality at baseline had longer time to relapse, lower relapse risk, fewer changes on medication and hospitalizations, better employment, less medical/psychiatric leaves and better functional household membership. LIMITATIONS: Limitations of this study are related with its naturalistic design. CONCLUSIONS: In a prospectively assessed BD cohort with all patients in syndromal remission at baseline, syndromal remission was not always accompanied by normal functioning and/or the presence subsyndromal symptoms. Interventions, including medication and psychosocial approaches, should go beyond syndromal remission and target subsyndromal symptoms and functional recovery.

Social and occupational functioning impairment in patients in partial versus complete remission of a major depressive disorder episode. A six-month prospective epidemiological study.

PURPOSE: To evaluate social and occupational functioning in patients in partial remission (PR) compared with patients in complete remission (CR) of a major depressive disorder (MDD) episode. SUBJECTS AND METHODS: This is a six-month prospective study. PR was defined as a score more than 7 and less or equal to 15 in the Hamilton Depression Rating Scale, and CR as less or equal to 7. All patients had been on acute antidepressant treatment during the previous three months and no longer met criteria for MDD. Functioning was assessed by the Social and Occupational Functioning Assessment Scale (SOFAS). RESULTS: Mean (S.D.) patient age was 50.5 (14.5) years (N=292) and 77% were female. At baseline, partial remitters showed greater impairment in social and occupational functioning than complete remitters (62.8 [12.6] versus 80.4 [10.5], respectively; P<.0001). After six months, only 47% PR versus 77% CR reached normal functioning, and SOFAS ratings for PR were below normal range (76.2 [12.3] PR versus 84.6 [9.4] CR; P<.0001). PR reported three times more days absent from work due to sickness than CR (63 days versus 20 days; P<.001). CONCLUSION: We conclude that PR of an MDD episode is associated with significant functional impairment that persists even after nine months of antidepressant treatment. Our results underline the importance of treating the patient until achieving full remission.

[Attention deficit/hyperactivity disorder: burden of the disease according to subtypes in recently diagnosed children]. / Trastorno por déficit de atención/hiperactividad: impacto de la enfermedad de acuerdo al subtipo en niños con diagnóstico reciente.

INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with deterioration of several dimensions of quality of life (QoL) and with the development of comorbid psychiatric disorders. The objective of the present study is to evaluate the burden of illness of ADHD subtypes in untreated newly diagnosed children in Spain. METHODS: We recruited 124 children (80 combined, 25 inattentive and 19 hyperactive-impulsive subtype) aged 6-12 years with untreated newly diagnosed Diagnostic and Statistical Manual of Mental Disorders, 4th edition DSM-IV) ADHD. We collected socio-demographic, clinical (Attention-Deficit/Hyperactivity Disorder Rating Scale ADHD-RS], Conner's Parent Rating Scale-Revised: Short Form [CPRS:R-S], Clinical Global Impression-Severity [CGI-S], Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version [K-SADS-PL], intelligence Quotient [IQ]), Quality of Life (QoL), Child Health Questionnaire-Parent Form 50 CHQ-PF50), academic performance and health care resources utilization data. We investigated the correlations between ADHD symptom severity and QoL, academic performance and time from onset of symptoms to diagnosis. RESULTS: QoL of children with combined-type ADHD was rated as significantly worse in patients with predominance of hyperactivity/impulsivity for most of the domains. Inattentive-type children also had worse ratings than patients with hyperactivity/impulsivity predominance in most of the domains. The ADHD Index of Conner's Parent Rating Scale-Revised: Short Form (CPRS-R:S) was significantly lower in hyperactive/impulsive patients. We found no differences across subtypes in IQ, academic performance and health care resources utilization. Higher ADHD symptom severity was associated to poor QoL. CONCLUSIONS: Combined and inattentive subtypes are associated with greater disorder severity, more comorbid psychiatric disorders, and worse QoL than the subtype with hyperactivity/impulsivity predominance.

Trastorno por déficit de atención/hiperactividad: impacto de la enfermedad de acuerdo al subtipo en niños con diagnóstico reciente / Attention deficit/hyperactivity disorder: burden of the disease according to subtypes in recently diagnosed children

Introducción. El trastorno por déficit de atención/hiperactividad (TDAH) se asocia con un deterioro en varias dimensiones de calidad de vida (QoL) y el desarrollo de trastornos psiquiátricos comórbidos. El objetivo del presente estudio es evaluar el impacto de la enfermedad de los subtipos de TDAH en niños con diagnóstico inicial y sin tratamiento en España. Métodos. Reclutamos a 124 niños (80 de subtipo combinado, 25 inatento y 19 hiperactividad-impulsividad) entre 6 y 12 años de edad con nuevo diagnóstico de TDAH (Manual diagnóstico y estadístico de los trastornos mentales, 4.a ed., DSM-IV) y sin tratar. Recogimos datos sociodemográficos y clínicos (Attention Deficit/Hyperactivity Disorder-Rating Scale [Escala de evaluación para el trastorno por déficit de atención/hiperactividad, ADHD-RS], Conner’s Parent Rating Scale-Revised: Short Form [Escala de evaluación de Conner, versión para los padres revisada: versión breve, CPRS:R-S], Impresión Clínica Global-Severidad [ICG-S], Kiddie Schedule of Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetie Version [Inventario Kiddie para los trastornos afectivos esquizofrenia para niños en edad escolar, versión actual y a lo largo de la vida, K-SADS-PL] y coeficiente intelectual [CI]), de Qualite of Life (Calidad de vida, Qol), Child Health Questionnaire-Parent Form 50 (Cuestionario de Salud Infantil, versión para los padres de 50 ítems, CHQ-PF50), rendimiento académico y utilización de recursos sanitarios. Investigamos las correlaciones entre la gravedad del TDAH y QoL, rendimiento académico y tiempo transcurrido desde el inicio de los síntomas hasta el diagnóstico. Resultados. La QoL de niños con subtipo combinado de TDAH se valoró como significativamente peor que en pacientes con predominio de hiperactividad/impulsividad en la mayoría de los dominios. Los niños con subtipo inatento también puntuaron peor que los de predominio de hiperactividad/impulsividad en varios dominios. La puntuación de ADHD de la CPRS-R:S fue significativamente menor en los pacientes con predominio de hiperactividad/impulsividad. No encontramos diferencias entre los distintos subtipos respecto al CI, rendimiento académico y utilización de recursos sanitarios. Una mayor gravedad de los síntomas del TDAH se asoció con una peor QoL. Conclusiones. Los subtipos combinado e inatento se asociaron con mayor gravedad del trastorno, más trastornos psiquiátricos comorbidos y peor QoL que el subtipo con predominio de hiperactividad/impulsividad (AU)

Introduction. Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with deterioration of several dimensions of quality of life (QoL) and with the development of comorbid psychiatric disorders. The objective of the present study is to evaluate the burden of illness of ADHD subtypes in untreated newly diagnosed children in Spain. Methods. We recruited 124 children (80 combined, 25 inattentive and 19 hyperactive-impulsive subtype) aged6-12 years with untreated newly diagnosed Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) ADHD. We collected socio-demographic, clinical(Attention-Deficit/Hyperactivity Disorder Rating Scale[ADHD-RS], Conner’s Parent Rating Scale-Revised: Short Form [CPRS:R-S], Clinical Global Impression-Severity [CGI-S], Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version[K-SADS-PL], intelligence Quotient [IQ]), Quality of Life (QoL), Child Health Questionnaire-Parent Form 50(CHQ-PF50), academic performance and health care resources utilization data. We investigated the correlations between ADHD symptom severity and QoL, academic performance and time from onset of symptoms to diagnosis. Results. QoL of children with combined-type ADHD was rated as significantly worse in patients with predominance of hyperactivivity/impulsivity for most of the domains. Inattentive-type children also had worse ratings than patients with hyperactivity/impulsivity predominance in most of the domains. The ADHD Index of Conner’s Parent Rating Scale-Revised: Short Form (CPRS-R:S) was significantly lower in hyperactive/impulsive patients. We found no differences across subtypes in IQ, academic performance and health care resources utilization. Higher ADHD symptom severity was associated to poor QoL. Conclusions. Combined and inattentive subtypes are associated with greater disorder severity, more comorbid psychiatric disorders, and worse QoL than the subtype with hyperactivity/impulsivity predominance (AU)

Remisión y recaída en el tratamiento ambulatorio de los pacientes con esquizofrenia. Resultados a 3 años / Remission and relapse in the outpatient treatment of patients with schizophrenia. Outcomes at 3 years

Introducción. Los datos del seguimiento de 3 años realizado para el estudio SOHO en España se han empleado para evaluar los resultados del tratamiento antipsicótico en términos de incidencia y factores asociados a la remisión y la recaída. Métodos. El SOHO es un estudio observacional, prospectivo, longitudinal realizado en 10 países europeos sobre los resultados del tratamiento de la esquizofrenia en pacientes ambulatorios que inician o modifican su farmacoterapia antipsicótica con el objetivo particular de comparar olanzapina con los demás antipsicóticos. El presente artículo presenta la incidencia y los factores asociados a la remisión y recaída clínicas de la esquizofrenia (definidas según los criterios internacionales al uso) en la muestra española. Resultados. En España se reclutaron 2.020 pacientes. Casi dos tercios (60,1%) cumplieron los criterios de remisión clínica. Se identificaron varios factores relacionados con la probabilidad de remisión, tales como el sexo, el estado clínico y/o funcional basal, el tiempo de evolución desde el primer tratamiento para esquizofrenia, el tratamiento con olanzapina frente a antipsicóticos típicos orales y la prescripción concomitante de fármacos ansiolíticos. El 18,7% de los pacientes presentó alguna recaída. El tratamiento con quetiapina y el uso concomitante de anticolinérgicos se asociaron con un mayor riesgo de recaída. Conclusiones. Los resultados de este estudio señalan algunos factores asociados a la evaluación de la esquizofrenia y subrayan la importancia de una correcta elección del fármaco antipsicótico y su mantenimiento para lograr un resultado clínico favorable a largo plazo en la práctica clínica habitual (AU)

Introduction. Three year data collected in the frame of the SOHO study within Spain were used to evaluate antipsychotic treatment outcomes by analyzing remission and relapse as well as the factors influencing them. Methods. The SOHO was a prospective, long-term, observational study of the outcomes of schizophrenia treatment in ambulatory who initiated therapy or who changed to a new antipsychotic drug performed in10 European countries, with a focus on olanzapine. This article reports the attainment of international schizophrenia clinical remission and relapse criteria and the associated correlates in these patients. Results and conclusions. A total of 2,020 patients were recruited in Spain. Almost 2/3 (60.1%) of the patients met the criteria for clinical remission. Factors that influence the likelihood of remission were identified, such as gender, baseline clinical and/or functional status, time since treatment initiation, treatment with olanzapine versus oral typical antipsychotics, duration of treatment, gender or the need for concomitant anxiolytics. Relapse occurred in 18.7 % of patients. Treatment with quetiapine or the prescription of anticholinergics was associated with a greater risk of relapse. Conclusions. These results highlight some prognostic factors of the course of schizophrenia and underscore the importance of the antipsychotic choice and its maintenance to achieve favorable long-term clinical outcomes in routine practice (AU)

[Remission and relapse in the outpatient treatment of patients with schizophrenia. Outcomes at 3 years]. / Remisión y recaída en el tratamiento ambulatorio de los pacientes con esquizofrenia. Resultados a 3 años.

INTRODUCTION: Three year data collected in the frame of the SOHO study within Spain were used to evaluate antipsychotic treatment outcomes by analyzing remission and relapse as well as the factors influencing them. METHODS: The SOHO was a prospective, long-term, observational study of the outcomes of schizophrenia treatment in ambulatoty who initiated therapy or who changed to a new antipsychotic drug performed in 10 European countries, with a focus on olanzapine. This article reports the attainment of international schizophrenia clinical remission and relapse criteria and the associated correlates in these patients. RESULTS AND CONCLUSIONS: A total of 2,020 patients were recruited in Spain. Almost 2/3 (60.1%) of the patients met the criteria for clinical remission. Factors that influence the likelihood of remission were identified, such as gender, baseline clinical and/or functional status, time since treatment initiation, treatment with olanzapine versus oral typical antipsychotics, duration of treatment, gender or the need for concomitant anxiolytics. Relapse occurred in 18.7% of patients. Treatment with quetiapine or the prescription of anticholinergics was associated with a greater risk of relapse. CONCLUSIONS: These results highlight some prognostic factors of the course of schizophrenia and underscore the importance of the antipsychotic choice and its maintenance to achieve favorable long-term clinical outcomes in routine practice.

[Development and validation of the Social Functioning Scale, short version, in schizophrenia for its use in the clinical practice]. / Desarrollo y validación de la versión corta de la Escala de Funcionamiento Social en esquizofrenia para su uso enla práctica clínica.

INTRODUCTION: The Social Functioning Scale (SFS) was designed to evaluate social functioning essential to schizophrenic patients. Its length may be difficult to use in clinical practice. The objective of this study was to develop and validate a short version of the SFS. METHODS: Data from 445 patients with schizophrenia who came from two separate studies, one longitudinal (n=250) and one cross-sectional (n=195), were used to produce and validate the short form of the SFS. The two samples were combined and then randomly split into two subsamples. In the first subsample (n = 223), items were eliminated using classical, modern (item response theory) psychometric criteria, as well as clinimetric criteria. The short version was independently validated using data from the other subsample (n = 222), by comparing the level of association (correlation and Area Under the ROC Curve [AUC]) with the EQ-5D VAS and the Clinical Global Impression (CGI), with the original scale. RESULTS: The original 78 items were reduced initially to 19 and 13 items (respectively using classic and modern psychometric criteria) and then to 15, since 2 items related with the employment capacity were added for clinometric criteria. The short form of the SFS had a Cronbach's alpha of 0.76. Spearman correlation coefficients with the EQ-5D VAS and with the CGI score (0.46 and 0.42, respectively) were similar or even higher for the short version than for the original version. The AUC of the SFS and the dichotomous CGI were practically the same for both the original (AUC: 0.74) and the short (AUC: 0.73) versions. CONCLUSIONS: The short version of the SFS proved to be reliable and valid. It could be adequate for use in clinical practice.

Desarrollo y validación de la versión corta de la Escala de Funcionamiento Social en esquizofrenia para su uso en la práctica clínica / Development and validation of the Social Functioning Scale, short version, in schizophrenia for its use in the clinical practice

Introducción. La Social Functioning Scale (SFS) fue diseñada para evaluar el funcionamiento social de pacientes esquizofrénicos. Su longitud puede ser una dificultad para su uso clínico. El objetivo del trabajo fue desarrollar y validar una versión corta de la escala SFS. Métodos. Se analizaron los datos de 445 pacientes con esquizofrenia que provenían de dos estudios, un ensayo clínico(n = 250) y un estudio observacional (n = 195). Las dos muestras se combinaron para dividirlas posteriormente en dos submuestras aleatorizadas. La primera (n=223) fue analizada para reducir los ítems utilizando criterios psicométricos clásicos, modernos (teoría de respuesta al ítem) y clinimétricos. La versión corta obtenida fue validada en la segunda submuestra (n=222), estimando su asociación con la Escala Visual Analógica (EVA EQ-5D) y con la Impresión Clínica Global (ICG) y comparándola con la asociación de la versión larga. Resultados. Los 78 ítems originales se redujeron inicialmente a 19 y a 13 (criterios psicométricos clásicos y modernos, respectivamente) y finalmente a 15, al añadir 2 ítems relacionados con la «capacidad de empleo» (criterio clinimétrico). La versión corta de la SFS no contiene subdimensiones. El coeficiente alfa de Cronbach fue de 0,76. La correlación de la versión corta con la EVA-EQ y la ICG resultó semejante o superior (0,46 y –0,42, respectivamente) a la de la versión original larga. El área bajo la curva ROC (AUC) mostró una capacidad discriminativa prácticamente idéntica para ambas versiones de la SFS (AUC: 0,74 para la original y 0,73 para la corta) respecto a la escala ICG. Conclusiones. La versión corta de la SFS es fiable y válida, por lo que podría ser útil para la práctica clínica habitual (AU)

Introduction. The Social Functioning Scale (SFS) was designed to evaluate social functioning essential to schizophrenic patients. Its length may be difficult to use in clinical practice. The objective of this study was to develop and validate a short version of the SFS. Methods. Data from 445 patients with schizophrenia who came from two separate studies, one longitudinal (n=250) and one cross-sectional (n=195), were used to produce and validate the short form of the SFS. The two samples were combined and then randomly split into two subsamples. In the first subsample (n = 223), items were eliminated using classical, modern (item response theory) psychometric criteria, as well as clinimetric criteria. The short version was independently validated using data from the other subsample (n = 222), by comparing the level of association (correlation and Area Under the ROC Curve [AUC]) with the EQ-5D VAS and the Clinical Global Impression (CGI), with the original scale. Results. The original 78 items were reduced initially to 19 and 13 items (respectively using classic and modern psychometric criteria) and then to 15, since 2 items related with the employment capacity were added for clinometric criteria. The short form of the SFS had a Cronbach’s alpha of 0.76. Spearman correlation coefficients with the EQ-5D VAS and with the CGI score (0.46and 0.42, respectively) were similar or even higher for the short version than for the original version. The AUC of the SFS and the dichotomous CGI were practically the same for both the original (AUC: 0.74) and the short (AUC: 0.73) versions. Conclusions. The short version of the SFS proved to be reliable and valid. It could be adequate for use in clinical practice (AU)

Patrones de tratamiento farmacológico para el episodio maníaco en la práctica clínica. Resultados de la muestra española en el estudio EMBLEM / Patterns of drug treatment for manic episode in the clinical practice. Outcomes of the Spanish sample in the EMBLEM Study

Introducción. Aunque el tratamiento de la manía ha sido estudiado profusamente en ensayos clínicos aleatorizados, existen pocos datos respecto al manejo real de estos pacientes en términos clínicos, funcionales y económicos en la práctica psiquiátrica en España. Objetivo. Determinar, a través de la muestra española de pacientes bipolares en fase maníaca o mixta del estudio paneuropeo EMBLEM, los patrones de prescripción en España. Método. El estudio EMBLEM reclutó a 3.681 pacientes, 312 de los cuales (8.47 %) fueron incluidos en España. Los pacientes tenían que ser adultos con diagnóstico de trastorno bipolar que iniciaran tratamiento para una fase maníaca. Se les evaluó con las versiones españolas de escalas para la gravedad (Escala de Young, CGI-BP, Escala de Hamilton) y para la funcionalidad (LCM, SLICE of LIFE). Se recogió información sobre variables farmacológicas y de adherencia al tratamiento. Resultados. Antes de entrar en el estudio el 42% de los pacientes recibía politerapia, el 35% estaba en monoterapia y el 23% no tomaba ninguna medicación. Un 40% de los pacientes incumplía total o parcialmente el tratamiento prescrito. Durante la fase inicial del estudio el manejo agudo de la manía fue a expensas, como monoterapia, de dosis medias diarias de: olanzapina, 25 mg; risperidona, 6,6 mg; haloperidol, 9,5 mg; lamotrigina, 165 mg; valproato, 938,5 mg, y litio, 909 mg, mientras que cuando fueron empleados en combinación las dosis fueron: olanzapina, 22,1 mg; risperidona, 7,3 mg; haloperidol, 12,3 mg; lamotrigina, 175,1 mg; valproato, 1.038,4 mg, y litio, 1.012,6 mg. De los pacientes que al inicio del estudio estaban en monoterapia, el 51% fueron tratados con un solo fármaco y un 48% recibió tratamiento combinado. De entre los pacientes que iniciaron el estudio recibiendo tratamiento combinado, el 94 % continuo recibiendo tratamiento combinado. La gran mayoría de los pacientes (92%) mejoraron al término del estudio. En el caso de los pacientes hospitalizados, los cuales conformaron el 88% de la muestra, el tiempo medio hasta el alta del hospital fue de 24 días. Conclusiones. El tratamiento de la manía en España se sustenta fundamentalmente en tratamientos combinados, hospitalización y dosis de fármacos antimaníacos generalmente algo superiores a las recomendadas en las fichas técnicas, indicando que la realidad clínica es más compleja de lo que indican los ensayos clínicos realizados en condiciones experimentales

Introduction. Although treatment for mania has been studied extensively in randomized clinical trials, there are few data that address how these patients are truly managed in clinical, functional, and economic terms in the psychiatric practice in Spain. Objective. To determine prescribing patterns in Spain on the basis of the Spanish sample of bipolar patients in manic or mixed phase included as part of the pan-European EMBLEM Study. Method. The EMBLEM Study recruited 3,681 patients, 312 of whom (8.47%) were included in Spain. Patients had to be adults with a diagnosis of bipolar disorder who were initiating treatment for a manic phase. They underwent evaluation using the Spanish versions of scales that measure severity of mania (the Young Mania Rating Scale, CGI-BP and the Hamilton Scale) and functional level (LCM, SLICE of LIFE). Information was collected regarding drug and treatment adherence variables. Results. Prior to being admitted into the study, 42% of the patients were receiving polytherapy, 35% were on monotherapy, and 23% were not taking any medication whatsoever. Forty percent of the patients presented partial or total non-compliance with the treatment prescribed. During the first stage of the study, in the case of single-drug treatment, acute management for mania consisted of mean daily doses of 25 mg of olanzapine, 6.6 mg of risperidone, 9.5 mg of haloperidol, 165 mg of lamotrigine, 938.5 mg of valproate, and 909 mg of lithium, whereas when combined therapy was used, the following doses were used: olanzapine, 22.1 mg; risperidone, 7.3 mg; haloperidol, 12.3 mg; lamotrigine, 175.1 mg; valproate, 1,038.4 mg, and lithium, 1012.6 mg. Of those patients who were on monotherapy at the beginning of the study 51% were treated with a single drug, whereas 48 % were receiving polytherapy. Among the participants who were receiving combined treatment when they began the study, almost all of them, 94 %, were prescribed combined treatment. In the case of the hospitalized patients who made up 88% of the sample, the vast majority, 92%, had improved by the time the study was completed. Mean time to release from hospital was 24 days. Discussion. In Spain, treatment for mania is essentially based on combined treatments, hospitalization, and anti-mania drugs that are prescribed at somewhat higher doses than those recommended in the corresponding prescribing information documents, which indicates that the clinical reality of this entity is far more complex than clinical trials conducted in experimental conditions suggest

Patterns of drug treatment for manic episode in the clinical practice. Outcomes of the Spanish sample in the EMBLEM Study.

INTRODUCTION: Although treatment for mania has been studied extensively in randomized clinical trials, there are few data that address how these patients are truly managed in clinical, functional, and economic terms in the psychiatric practice in Spain. OBJECTIVE: To determine prescribing patterns in Spain on the basis of the Spanish sample of bipolar patients in manic or mixed phase included as part of the pan-European EMBLEM Study. METHOD: The EMBLEM Study recruited 3,681 patients, 312 of whom (8.47%) were included in Spain. Patients had to be adults with a diagnosis of bipolar disorder who were initiating treatment for a manic phase. They underwent evaluation using the Spanish versions of scales that measure severity of mania (the Young Mania Rating Scale, CGI-BP and the Hamilton Scale) and functional level (LCM, SLICE of LIFE). Information was collected regarding drug and treatment adherence variables. RESULTS: Prior to being admitted into the study, 42% of the patients were receiving polytherapy, 35% were on monotherapy, and 23% were not taking any medication whatsoever. Forty percent of the patients presented partial or total non-compliance with the treatment prescribed. During the first stage of the study, in the case of single-drug treatment, acute management for mania consisted of mean daily doses of 25 mg of olanzapine, 6.6 mg of risperidone, 9.5 mg of haloperidol, 165 mg of lamotrigine, 938.5 mg of valproate, and 909 mg of lithium, whereas when combined therapy was used, the following doses were used: olanzapine, 22.1 mg; risperidone, 7.3 mg; haloperidol, 12.3 mg; lamotrigine, 1,75.1 mg; valproate, 1,038.4 mg, and lithium, 1012.6 mg. Of those patients who were on monotherapy at the beginning of the study 51% were treated with a single drug, whereas 48% were receiving polytherapy. Among the participants who were receiving combined treatment when they began the study, almost all of them, 94%, were prescribed combined treatment. In the case of the hospitalized patients who made up 88% of the sample, the vast majority, 92%, had improved by the time the study was completed. Mean time to release from hospital was 24 days. DISCUSSION: In Spain, treatment for mania is essentially based on combined treatments, hospitalization, and antimania drugs that are prescribed at somewhat higher doses than those recommended in the corresponding prescribing information documents, which indicates that the clinical reality of this entity is far more complex than clinical trials conducted in experimental conditions suggest.

Novedad terapéutica: duloxetina en el tratamiento de la depresión en Atención Primaria / Therapeutic novelty: duloxetine in treatment of depression in Primary Health Care

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Use of olanzapine in dysphoric mania.

BACKGROUND: The simultaneous presentation of both manic and depressive symptoms has long been recognized. Nevertheless, a variable prevalence of dysphoric mania has been reported. The aim of this study was to estimate the prevalence of dysphoric mania among hospitalized patients and to assess the effectiveness of olanzapine in this type of patients. METHODS: Eighty-six patients who met DSM-IV criteria for mania were evaluated at admission with a protocol that included McElroy's criteria for dysphoric mania [Am. J. Psychiatry 149 (1992) 1633]. Treatment was administered according to clinical need, using mood stabilizers combined with antipsychotics. Sequential assessments were conducted throughout the study. RESULTS: Forty-four patients (51.2%) fulfilled McElroy's criteria for dysphoric mania. Fourteen of these dysphoric patients were treated with olanzapine in combination with mood-stabilizers. All patients improved in manic symptoms but patients treated with olanzapine improved significantly more than those treated with other antipsychotics in depressive symptoms. LIMITATIONS: The lack of randomization is a methodological limitation of this study, so these findings should be considered as preliminary. CONCLUSIONS: Dysphoric symptoms are common in this population of manic patients. Olanzapine in combination with mood-stabilizers may be effective in these patients. Additional controlled studies are needed to replicate these results.

Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar disorder.

The aim of this study was to estimate the long-term effectiveness of olanzapine as adjunctive therapy in patients with bipolar disorder who exhibited an inadequate response to mood stabilizers. Twenty-three Research Diagnostic Criteria (RDC) patients with bipolar I and II were assessed by means of the Schedule for Affective Disorders and Schizophrenia and entered if they gave their consent to participate. All of them had experienced frequent relapses, residual subsyndromal symptoms, and inadequate responses to other drugs, such as lithium, valproate, or carbamazepine. While maintaining other drugs, they all received open-label, increasing doses of olanzapine, until achieving clinical response. Other drugs were maintained. The patients were assessed several consecutive times from baseline to the endpoint with the Clinical Global Impressions (CGI) scale for use in bipolar illness. Records of recurrences, hospitalizations, and side effects were also collected. The last-observation-carried-forward analysis showed that there was a significant reduction of CGI scores after the introduction of olanzapine, either in manic symptoms (p = 0.0015), depressive symptoms (p = 0.0063), or global symptoms (p = 0.0003). The most frequent adverse events were somnolence (17%) and weight gain (13%). The mean dose of olanzapine at the end of the 43-week follow-up was 8.1 mg/day. Olanzapine may be a useful medication for the long-term adjunctive treatment of patients with bipolar disorder who exhibit a poor response to mood stabilizers, such as lithium, valproate, or carbamazepine. These results suggest mood-stablizing properties of olanzapine.

Fluoxetine in the prevention of depressive recurrences: a double-blind study.

Optimal outcomes from depression treatment are long-term recovery and, in the case of recurrent depression, prevention of new episodes. However, few data are available concerning the long-term efficacy of antidepressants in prophylactic treatment to prevent recurrences of depression. The efficacy and safety of fluoxetine 20 mg/day was evaluated in reducing the number of depressive episodes and in extending the time free of symptoms in patients with recurrent unipolar major depression. Patients with recurrent unipolar major depression according to DSM-III-R criteria and who responded to 32 weeks of open-label fluoxetine were randomly assigned to receive fluoxetine 20 mg/day (N = 70) or placebo (N = 70) for 48 weeks of double-blind maintenance treatment. Outcome measures were the percentage of recurrences and time to recurrence. Safety assessments included treatment-emergent adverse events, reasons for discontinuation, vital signs, and laboratory measures. Fluoxetine was associated with a statistically significantly smaller percentage of patients who had a recurrence compared with placebo (20% vs. 40%; chi2 analysis, p = 0.010). The symptom-free period was significantly longer for patients treated with fluoxetine versus placebo (295 vs. 192 days; Kaplan-Meier estimates, log-rank test, p = 0.002). Treatments were well tolerated during maintenance treatment. The only statistically significant difference in adverse events between treatment groups was anxiety, which was more frequent in the placebo group (fluoxetine, 12.9% vs. placebo, 30%; chi2 analysis, p = 0.013). Two placebo-treated patients and no fluoxetine-treated patients were withdrawn because of adverse events. In conclusion, fluoxetine at 20 mg/day was effective and well tolerated for the prophylactic treatment of recurrent unipolar major depression.

Augmentation of fluoxetine's antidepressant action by pindolol: analysis of clinical, pharmacokinetic, and methodologic factors.

In a controlled trial, the beta-adrenoceptor/5-hydroxytryptamine-1A (5-HT1A) receptor antagonist pindolol accelerated and enhanced the antidepressant effect of fluoxetine. The median times to sustained response (> or = 50% reduction of baseline severity maintained until endpoint) were 19 days for fluoxetine plus pindolol (N = 55) and 29 days for fluoxetine plus placebo (N = 56) (p = 0.01). The response rate at endpoint was 16% greater in patients treated with the combination. The plasma concentration of pindolol remained stable between 3 days (first blood sampling) and 6 weeks. Mean values were approximately 26 nM, a concentration higher than the Ki of (-)pindolol for human 5-HT1A autoreceptors (11 nM). Plasma fluoxetine and norfluoxetine concentrations increased steadily until the fourth week of treatment. Fluoxetine concentrations were lower in patients receiving the combination (p = 0.043), but there was no significant relationship to the clinical response in either group. A reanalysis of the data using a survival analysis revealed that significant differences in the time to sustained response between both groups would have also been detected (1) in a 2-week trial, (2) without a placebo lead-in phase, and (3) with less frequent visits. However, the use of "response" instead of "sustained response" as measure of clinically relevant change would have greatly diminished the difference between treatment arms (p = 0.08 instead of p = 0.01). This emphasizes the need of using stringent outcome criteria in antidepressant drug trials. A comparison of the data of all sustained responders (N = 27) in the fluoxetine-plus-placebo group with the first 27 responders in the fluoxetine-plus-pindolol group (of a total of 38) revealed a highly significant difference in the time to sustained response (18 and 10 days, respectively; p = 0.0002). This indicates that the faster response in the fluoxetine-plus-pindolol group is not a result of the greater proportion of responders.

Estudio abierto con fluoxetina en niños con autismo / An open study of fluoxetine in children with autism

Introducción: La disfunción serotoninérgica ha sido implicada en la fisiopatología del autismo. Los ISRS han mostrado eficacia en la mejoría de algunos síntomas en niños con autismo. Objetivos: Evaluar, en un estudio piloto, la eficacia y seguridad de la fluoxetina en niños con autismo. Método: Se realizó un estudio abierto de un año con fluoxetina en 12 niños (entre 3 y 13 años) con Trastorno Generalizado del Desarrollo. Pa ra la medida de la severidad y la mejoría de los síntomas se utilizó el ICG de severidad. La mejoría individual de los síntomas fue evaluada tanto por los padres como por los terapeutas. La fluoxetina fue dosificada en todos los pacientes desde 1,2 ml/día hasta alcanzar una dosis final de 3,6 o 5 ml/día en cuatro semanas. La tolerancia fue evaluada mediante la recogida de los efectos adversos espontáneos. Resultados: 11 niños completaron el estudio. Los niños experimentaron una mejoría moderada o marcada (puntuación final de ICG de mejoría de 3 a 5). Mejora ron la comunicación y la capacidad de atención. Disminuyeron también los rituales, las estereotipias y los comportamientos repetitivos. Los efectos adversos más frecuentes fueron la impulsividad e inquietud, también aparecieron trastornos del sueño y pérdida de apetito. Seis niños necesitaron a lo largo del estudio medicación concomitante con carbamacepina y uno levopromacina. Conclusiones: Estos resultados señalan que la fluoxetina a dosis de 5 ml/día (20 mg/d) pueden ayudar a mejora r algunos síntomas del Trastorno Generalizado del Desarrollo y permitir aumentar la efectividad de otros abordajes terapéuticos que se realizan con estos pacientes. Más estudios son necesarios para confirmar estos resultados. (AU)

Cost-effectiveness of fluoxetine plus pindolol in patients with major depressive disorder: results from a randomized, double-blind clinical trial.

Some preliminary studies have suggested that the beta-adrenoceptor 5-HT1A antagonist pindolol (PIN) could increase the effect of selective serotonin reuptake inhibitors (SSRIs). We prospectively estimated the cost-effectiveness of fluoxetine and pindolol versus fluoxetine plus placebo, using results from the first double-blind randomized clinical trial comparing both treatments. Efficacy and medical care resource utilization were collected prospectively in a parallel, randomized, double-blind clinical trial conducted in a single centre in Spain. Average cost-effectiveness (cost/% response and cost/% remission) as well as the incremental cost-effectiveness were calculated for both treatments. A 'bootstrap' method was used to calculate confidence limits around the incremental cost-effectiveness ratio. A significantly greater percentage of patients (one-tailed P < 0.05) in the fluoxetine FLX + PIN group than in the FLX + PLA group had experienced a therapeutic response (74.5% versus 58.97%) at 6 weeks. Direct medical costs were lower in the FLX + PIN group (mean 2508 pesetas per patient) than in the FLX + PLA group (mean 31870 pesetas per patient). Hospital admissions due to worsening of depressive symptoms were significantly lower (P < 0.05) in the FLX + PIN group (0/55) than in the FLX + PLA group (4/56). The observed differences in average costs and percentage response in the study were -29362 pesetas (< 0) and 15.6% (> 0), respectively, and the resulting cost-effectiveness ratio was negative. These outcomes indicate that the FLX + PIN option completely dominates FLX + PLA. These results suggest that, over a course of 6 weeks of treatment, the combination of fluoxetine and pindolol incurs lower direct medical costs than treatment with fluoxetine placebo. Despite their limitations, economic assessments in addition to clinical trials allow a 'dynamic assessment' on the potential success of the drug, both from a clinical and an economic point of view, allowing decisions on priorities to be made earlier.