Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment.

BACKGROUND AND PURPOSE: The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed ß-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. EXPERIMENTAL APPROACH: We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS: DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS: DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.

Guías y algoritmos clínicos de tratamiento de la depresión en atención primaria: ¿son todos iguales? / Evaluation of clinical guidelines and algorithms for treatment of depression in primary care: are they all the same?

Objetivo. La consulta por depresión ocupa el 40% de las consultas al médico de asistencia primaria. Se buscan maneras de reorganizar el proceso de atención a la depresión integrando herramientas como el uso de guías y algoritmos clínicos. Objetivo. Ante la diversidad de opciones es importante conocer una o dos herramientas para aplicarlas adecuadamente. El objetivo es analizar y comparar las guías de tratamiento de la depresión con mayor difusión que incluyan la consulta de atención primaria. Material y métodos. Se realiza una revisión de la bibliografía encontrada en PubMed y en publicaciones de Sociedades Científicas. Las guías se comparan aplicando el instrumento «Appraisal of Guidelines Research and Evaluation Colaboration» (AGREE). Resultados. Los algoritmos de tratamiento tienen unas características comunes respecto el contenido, la secuenciación del tratamiento y la elección del antidepresivo. Se prefiere elegir la opción más sencilla, más eficaz y con menor riesgo. Existen diferencias en cuanto al rigor, participación de los implicados y aplicabilidad. Conclusiones. Las guías presentan más similitudes que diferencias. Las diferencias se hallan en las dimensiones rigor y participación. Ante el creciente número de guías y algoritmos se recomienda elegir uno y adaptarlo al territorio donde se interviene (AU)

Objective. Depression accounts for 40% of family doctor consultations. Ways of reorganising the process of care for depression are being looked for by integrating tools such as the use of clinical guidelines and algorithms. It is important to know of one or two tools and to implement them properly. The aim is to analyse and compare the guidelines for the treatment of depression in Primary Care cjinics. Material and methods. We reviewed of the literature found on PubMed and in publications of scientific societies. The guidelines are compared using the Appraisal of Guidelines Research and Evaluation Colaboration. Results. The processing algorithms have some common features regarding the content, sequencing of treatment and choice of antidepressant. The preferred choice should be easier, more efficient and less risk. There are differences in the rigor of the implications and applications. Conclusions. The guidelines have more similarities than differences. The differences are in size and participation rigor. With the increasing number of guidelines and algorithms it is recommended to choose one and adapt it to the area where it will be used (AU)

Estudio naturalístico: 100 episodios de agitación psicomotriz consecutivos en urgencias psiquiátricas / A naturalistic study: 100 consecutive episodes of acute agitation in a psychiatric emergency department

Introducción. La agitación psicomotriz es una situación frecuente en urgencias de psiquiatría con una prevalencia aproximada del 10 %. No hay un consenso total respecto a su manejo; benzodiazepinas, antipsicóticos típicos y, más recientemente, los atípicos han demostrado una eficacia similar. El objetivo del presente estudio es describir las características epidemiológicas y el manejo clínico de los pacientes agitados en la práctica clínica en un servicio de urgencias psiquiátricas.Métodos. Estudio naturalístico de los episodios de agitación psicomotriz recogidos consecutivamente en un servicio de urgencias psiquiátricas. Se recogieron variables demográficas, clínicas y terapéuticas. Las variables de eficacia fueron determinadas mediante la escala Excitement Component of the Positive and Negative Syndrome Scale (PANSS-EC) y la Agitation-Calmness Evaluation Scale (ACES). Se analizaron variables pragmáticas como la necesidad de sucesivas intervenciones farmacológicas o la necesidad de contención física.Resultados. Fueron incluidos 100 episodios de agitación psicomotriz. La edad media fue de 36,2 años y el 54% eran mujeres. Los diagnósticos más frecuentes fueron de trastorno psicótico (48 %) y de trastorno de la personalidad (24 %). El 39 % requirió contención física y el 52 % aceptó el tratamiento por vía oral. El haloperidol fue el fármaco más utilizado por vía oral y la olanzapina por vía intramuscular.Conclusiones. Una aproximación naturalística permite obtener datos de la práctica real en los servicios de urgencias psiquiátricas. Los estrictos diseños de investigación de los ensayos clínicos de eficacia implican sesgos de selección de la muestra y se suelen alejar de la realidad clínica. Los antipsicóticos atípicos se están convirtiendo en fármacos de primera línea en el tratamiento de la agitación

Introduction. Psychomotor agitation is a common event in psychiatric emergency services (PES) with a prevalence of approximately 10 %. There is no general consensus on to how to manage psychomotor agitation; benzodiazepines, typical antipsychotics and now atypical antipsychotics have demonstrated similar efficacy. The aim of our study was to describe the epidemiology and clinical management of agitation in «real-life» in a psychiatric emergency service. Methods. A naturalistic study was performed in acutely agitated patients recruited consecutively in a psychiatric emergency service. Demographics, clinical and therapeutic characteristics were analyzed. Efficacy was assessed by the Excitement Component of the Positive and Negative Syndrome Scale (PANSS-EC) and the Agitation-Calmness Evaluation Scale (ACES). Pragmatic variables such as the need for second pharmacological intervention and the need for physical restraints were assessed. Results. The study included 100 patients with psychomotor agitation. Mean age was 36.2 % and 54% were women. The most prevalent diagnoses were psychotic disorder (48 %) and personality disorder (24 %). Physical restraint was required in 39 % of patients and 52 % accepted oral treatment. Haloperidol was the most frequent oral treatment and olanzapine was the most frequent intramuscular treatment. Conclusions. A naturalistic approach provides data based on clinical reality in psychiatric emergency services. Strict research designs of clinical trials of efficacy imply sample selection biases and are generally distanced from the clinical reality. Atypical antipsychotics have become the first-line treatment in acute agitation

[A naturalistic study: 100 consecutive episodes of acute agitation in a psychiatric emergency department]. / Estudio naturalístico: 100 episodios de agitación psicomotriz consecutivos en urgencias psiquiátricas.

INTRODUCTION: Psychomotor agitation is a common event in psychiatric emergency services (PES) with a prevalence of approximately 10 %. There is no general consensus on to how to manage psychomotor agitation; benzodiazepines, typical antipsychotics and now atypical antipsychotics have demonstrated similar efficacy. The aim of our study was to describe the epidemiology and clinical management of agitation in "real-life" in a psychiatric emergency service. METHODS: A naturalistic study was performed in acutely agitated patients recruited consecutively in a psychiatric emergency service. Demographics, clinical and therapeutic characteristics were analyzed. Efficacy was assessed by the Excitement Component of the Positive and Negative Syndrome Scale (PANSS-EC) and the Agitation-Calmness Evaluation Scale (ACES). Pragmatic variables such as the need for second pharmacological intervention and the need for physical restraints were assessed. RESULTS: The study included 100 patients with psychomotor agitation. Mean age was 36.2 % and 54% were women. The most prevalent diagnoses were psychotic disorder (48 %) and personality disorder (24 %). Physical restraint was required in 39 % of patients and 52 % accepted oral treatment. Haloperidol was the most frequent oral treatment and olanzapine was the most frequent intramuscular treatment. CONCLUSIONS: A naturalistic approach provides data based on clinical reality in psychiatric emergency services. Strict research designs of clinical trials of efficacy imply sample selection biases and are generally distanced from the clinical reality. Atypical antipsychotics have become the first-line treatment in acute agitation