[Therapies for the Improvement of Stroke Recovery - Assessment of Clinical Trial Results]. / Therapien zur Verbesserung der Schlaganfall-Regeneration ­ Ergebnisse klinischer Studien im wissenschaftlichen Kontext.

Recovery processes after stroke include restoration or compensation of function initially lost or newly acquired after injury. Therapeutic interventions can either directly improve these processes and/or inhibit processes that impede regeneration. Numerous experimental studies suggested a great opportunity for such treatments, but the results from recent large clinical trials with neuromodulators such as dopamine and fluoxetine have been rather disappointing. The reasons for this are manifold and involve the extrapolation of results from animal models to humans. Given the differences between animals and humans in genetic and epigenetic background, brain size and anatomy, cerebral vascular anatomy, immune system, as well as clinical function, and behavior, direct extrapolation is unlikely to work. Backward blockades include the incompatible adaption of clinical trial objectives and outcomes in clinical trials with regard to previous preclinical findings. For example, the clinical recovery trial design widely varies and has been characterized by the selection of different clinical endpoints, the inclusion a wide spectrum of stroke subtypes and clinical syndromes, and different time windows for treatment initiation after onset of infarction. This review will discuss these aspects based on the results of the recent stroke recovery trials with the aim to contributing to the development of a therapy that improves the functional outcome of a chronic stroke patient.

Cost-minimization analysis of escitalopram, fluoxetine, and amitriptyline in the treatment of depression.

INTRODUCTION: Escitalopram, fluoxetine, and amitriptyline are the drugs commonly used in the treatment of depression. The pharmacoeconomic evaluation of these drugs becomes relevant as they are prescribed for a long period of time, and depression causes a significant economic burden. The cost-minimization study would contribute to bringing down the annual treatment costs, leading to better medication adherence and ultimately better patient outcomes. MATERIALS AND METHODS: All drug prices are mentioned in Indian National Rupee (INR). All expenses are based on 2022 pricing. No cost discounting was used because all expenditures were calculated over a year. We considered hypothetical scenarios where the patient was prescribed the lowest possible dose for depression, an equivalent antidepressant dose, a defined daily dose, and the maximum acceptable therapeutic dose for depression. RESULTS: Annual average treatment costs of amitriptyline, escitalopram, and fluoxetine in patients with depression at baseline with equivalent dosing as mono-drug therapy were 2765.53, 2914.78, and 1422.72 rupees (INR), respectively. Savings were high when the patient was shifted to fluoxetine from either escitalopram or amitriptyline. The savings from switching to fluoxetine were 50.66% and 56.42% from escitalopram and amitriptyline, respectively. CONCLUSION: The choice of an antidepressant depends on multiple aspects, among which the cost of treatment plays a crucial role. Among the drugs compared, fluoxetine seems to offer greater value for money. The study emphasizes that selective serotonin reuptake inhibitors are the most commonly prescribed antidepressants not only because of their favorable pharmacological profile but also because of their affordability.

Health outcomes and cost-effectiveness of treating depression in people with HIV in Sub-Saharan Africa: a model-based analysis.

High prevalence of depression among people living with HIV (PLHIV) impedes antiretroviral therapy (ART) adherence and viral suppression. We estimate the effectiveness and cost-effectiveness of strategies to treat depression among PLHIV in Sub-Saharan Africa (SSA). We developed a microsimulation model of HIV disease and care in Uganda which captured individuals' depression status and the relationship between depression and HIV behaviors. We consider a strategy of screening for depression and providing antidepressant therapy with fluoxetine at ART initiation or re-initiation (if a patient has dropped out). We estimate that over 10 years this strategy would reduce prevalence of depression among PLHIV by 16.0% [95% uncertainty bounds 15.8%, 16.1%] from a baseline prevalence of 28%, increase adherence to ART by 1.0% [1.0%, 1.0%], and decrease rates of loss to followup by 3.7% [3.4%, 4.1%]. This would decrease first-line ART failure rates by 2.5% [2.3%, 2.8%] and increase viral suppression rates by 1.0% [1.0%, 1.0%]. This strategy costs $15/QALY compared to the status quo, and was highly cost-effective over a broad range of sensitivity analyses. We conclude that screening for and treating depression among PLHIV in SSA with fluoxetine would be effective in improving HIV treatment outcomes and would be highly cost-effective.

Fluoxetine to improve functional outcomes in patients after acute stroke: the FOCUS RCT.

BACKGROUND: Our Cochrane review of selective serotonin inhibitors for stroke recovery indicated that fluoxetine may improve functional recovery, but the trials were small and most were at high risk of bias. OBJECTIVES: The Fluoxetine Or Control Under Supervision (FOCUS) trial tested the hypothesis that fluoxetine improves recovery after stroke. DESIGN: The FOCUS trial was a pragmatic, multicentre, parallel-group, individually randomised, placebo-controlled trial. SETTING: This trial took place in 103 UK hospitals. PARTICIPANTS: Patients were eligible if they were aged ≥ 18 years, had a clinical stroke diagnosis, with focal neurological deficits, between 2 and 15 days after onset. INTERVENTIONS: Patients were randomly allocated 20 mg of fluoxetine once per day or the matching placebo for 6 months via a web-based system using a minimisation algorithm. MAIN OUTCOME MEASURES: The primary outcome was the modified Rankin Scale at 6 months. Patients, carers, health-care staff and the trial team were masked to treatment allocation. Outcome was assessed at 6 and 12 months after randomisation. Patients were analysed by their treatment allocation as specified in a published statistical analysis plan. RESULTS: Between 10 September 2012 and 31 March 2017, we recruited 3127 patients, 1564 of whom were allocated fluoxetine and 1563 of whom were allocated placebo. The modified Rankin Scale score at 6 months was available for 1553 out of 1564 (99.3%) of those allocated fluoxetine and 1553 out of 1563 (99.4%) of those allocated placebo. The distribution across modified Rankin Scale categories at 6 months was similar in the two groups (common odds ratio adjusted for minimisation variables 0.951, 95% confidence interval 0.839 to 1.079; p = 0.439). Compared with placebo, patients who were allocated fluoxetine were less likely to develop a new episode of depression by 6 months [210 (13.0%) vs. 269 (16.9%), difference -3.78%, 95% confidence interval -1.26% to -6.30%; p = 0.003], but had more bone fractures [45 (2.9%) vs. 23 (1.5%), difference 1.41%, 95% confidence interval 0.38% to 2.43%; p = 0.007]. There were no statistically significant differences in any other recorded events at 6 or 12 months. Health economic analyses showed no differences between groups in health-related quality of life, hospital bed usage or health-care costs. LIMITATIONS: Some non-adherence to trial medication, lack of face-to-face assessment of neurological status at follow-up and lack of formal psychiatric diagnosis during follow-up. CONCLUSIONS: 20 mg of fluoxetine daily for 6 months after acute stroke did not improve patients' functional outcome but decreased the occurrence of depression and increased the risk of fractures. These data inform decisions about using fluoxetine after stroke to improve functional outcome or to prevent or treat mood disorders. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) (Australasia/Vietnam) and Efficacy oF Fluoxetine - a randomisEd Controlled Trial in Stroke (EFFECTS) (Sweden) trials recruited an additional 2780 patients and will report their results in 2020. These three trials have an almost identical protocol, which was collaboratively developed. Our planned individual patient data meta-analysis will provide more precise estimates of the effects of fluoxetine after stroke and indicate whether or not effects vary depending on patients' characteristics and health-care setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83290762. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 22. See the NIHR Journals Library website for further project information. The Stroke Association (reference TSA 2011101) funded the start-up phase.

Fluoxetine, sometimes referred to by the drug company name Prozac, has been used for many years to treat people who are depressed, including after a stroke. However, studies have suggested that treatment with fluoxetine started soon after a stroke might improve patients' physical recovery. The Fluoxetine Or Control Under Supervision (FOCUS) trial recruited 3127 volunteers who had had a stroke within the previous 2 weeks from 103 UK hospitals between 2012 and 2017. Participants were randomly allocated to take a 6-month course of fluoxetine or an identical placebo capsule containing no fluoxetine. They were followed up at 6 months and 12 months after recruitment. Patients completed questionnaires that indicated how much they had recovered, and also measured their mood, fatigue and quality of life. The results of the trial showed that the physical recovery of patients was very similar in both groups. This indicates that fluoxetine does not improve physical outcomes of stroke patients. However, participants receiving fluoxetine were less likely to develop depression after the stroke but once the fluoxetine was stopped these effects on mood disappeared. Unfortunately, patients on fluoxetine were slightly more likely to fall and fracture a bone than those on placebo. The FOCUS trial is the first of three large randomised controlled trials testing fluoxetine in stroke patients to be completed. The FOCUS trial results suggest that patients with stroke should not routinely be treated with fluoxetine. The other two trials will give us further information about the effects of fluoxetine after stroke and whether or not its effects differ between countries or ethnic groups.

A randomised controlled trial assessing the use of citalopram, sertraline, fluoxetine and mirtazapine in preventing relapse in primary care patients who are taking long-term maintenance antidepressants (ANTLER: ANTidepressants to prevent reLapse in dEpRession): study protocol for a randomised controlled trial.

BACKGROUND: Antidepressants are used both for treating acute episodes and for prophylaxis to prevent future episodes of depression, also called maintenance treatment. This article describes the protocol for a randomised controlled trial (ANTLER: ANTidepressants to prevent reLapse in dEpRession) to investigate the clinical effectiveness and cost-effectiveness in UK primary care of continuing on long-term maintenance antidepressants compared with a placebo in preventing relapse of depression in those who have taken antidepressants for more than 9 months and who are currently well enough to consider stopping maintenance treatment. METHODS/DESIGN: The ANTLER trial is an individually randomised, double-blind, placebo-controlled trial in which participants are randomised to remain on active medication or to take an identical placebo after a tapering period of 2 months. Eligible participants are those who: are between the ages of 18 and 74 years; have had at least two episodes of depression; and have been taking antidepressants for 9 months or more and are currently taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg but are well enough to consider stopping their medication. The participants will be followed up at 6, 12, 26, 39 and 52 weeks. The primary outcome will be the time in weeks to the beginning of the first episode of depression after randomisation. This will be measured using a retrospective version of the Clinical Interview Schedule-Revised administered at 12, 26, 39 and 52 weeks. Secondary outcomes will include depressive and anxiety symptoms, adverse effects, withdrawal symptoms, emotional processing tasks, quality of life and the resources and costs used. We will also perform a cost-effectiveness analysis based on results of the trial. DISCUSSION: The ANTLER trial findings will inform primary care prescribing practice by providing a valid and generalisable estimate of the clinical effectiveness and cost-effectiveness of long-term maintenance treatment with antidepressants in UK primary care. TRIAL REGISTRATION: Controlled Trials ISRCTN Registry, ISRCTN15969819. Registered on 21 September 2015.

Switching Selective Serotonin Reuptake Inhibitors in Adolescents with Selective Serotonin Reuptake Inhibitor-Resistant Major Depressive Disorder: Balancing Tolerability and Efficacy.

Objective: To guide clinicians in selecting the "next line" selective serotonin reuptake inhibitor (SSRI) for adolescents with treatment-resistant major depressive disorder, we sought to compare response rates among SSRIs in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study and to jointly model tolerability and efficacy for the specific SSRI comparisons. Methods: Efficacy and tolerability data for paroxetine, citalopram, and fluoxetine were extracted from the TORDIA study. Using a joint bivariate normal likelihood for response and tolerability (based on the maximum implied variance from the 95% credible intervals previously reported for the three SSRIs), a Monte Carlo pseudorandom sample (100,000 draws) was obtained, from which credible intervals, means, posterior tail probabilities, etc. were determined. Joint null hypotheses of no difference in efficacy and tolerability were then evaluated with regard to superiority of each SSRI over the others. Results: No significant differences in response were observed for citalopram compared with fluoxetine (p = 0.247) or for fluoxetine compared with paroxetine (p = 0.110), although citalopram trended toward being superior to paroxetine (mean difference: 0.2, p = 0.055). For efficacy-tolerability models, citalopram and fluoxetine were superior to paroxetine (p = 0.029 and p = 0.022, respectively) but did not differ between each other (p = 0.146). Conclusions: Joint efficacy-tolerability models suggest that citalopram and fluoxetine were statistically significantly superior to paroxetine while citalopram trended toward superiority over paroxetine in the efficacy model. These findings provide a more granular and practical evidence base for clinicians faced with treatment sequencing decisions in adolescents with SSRI-resistant depression.

Health care services and disease modifying therapies use in community-based multiple sclerosis patients: Evolution from 2013 to 2015 and demographic characteristics.

INTEREST OF THE WORK: Multiple sclerosis (MS) disease modifying therapies (DMT) utilization increased during the last decade with the approval of new drugs. Symptomatic treatments also play an important role. Describing time trends and demographic characteristics for DMT and symptomatic treatments utilization in population-based MS patients will lead to a better knowledge of the resources distribution. METHODS: Repeated cross-sectional analysis on each calendar year were implemented retrospectively on the health insurance claims database in France from 2013 until 2015 regarding DMT, fampridine, fluoxetine, psychiatrist office visits, and Physical therapy sessions to calculate an utilization rate defined as the number of MS patients (whenever the date of diagnosis) who filled at least 1 prescription or service within the studied calendar year per cent MS patients covered the same calendar year (number of users per cent MS population per annum). Beneficiaries with MS were identified by their exemption of co-payment for long-term disease (ALD). RESULTS: DMT utilization rate increased from 34.22% in 2013 to 38.73% in 2015. The increase was due to recently developed DMT as first-generation DMT utilization rate decreased from 30.20% to 20.06%. Rates were not different between genders but significantly decreased with age. The average age of users was significantly lower for DMT than for symptomatic treatments (recently developed DMT: 43.63, first-generation DMT: 45.84, psychiatrist office visits: 49.08, Fampyra®: 55.41, Physical therapy sessions: 55.88, fluoxetine: 58.26). Regional DMT utilization rates ranged from 31.68% in Auvergne-Rhône-Alpes to 42.58% in Normandie. They were not correlated to regional rates of MS prevalence (R-Square=0.0558; P=0.2556) nor to the presence of a MS reference centre in the region (Chi-Square=0.0190; P=0.8905). In 2015 the six DMTs with the highest rates were by decreasing orders: Tecfidera®, Avonex®, Gilenya®, Aubagio®, Copaxone®, and Rebif®. Half of them were recently developed orally-administered drugs. PERSPECTIVES: Complex factors may explain the interprovincial variability. Low DMT utilization rates in the most aged patients who also have the highest recourse rate to symptomatic treatments reflect the fact that the indication of disease modifying therapies do not address older patient's needs. New DMTs with medical indications for the late degenerative phase are needed.

Escitalopram para trastornos psiquiátricos / Escitalopram for psychiatric disorders

En el Perú se estima que en el 2012 los trastornos mentales y de comportamiento en el Perú́ concentraron el 17% del total de años saludables perdidos por discapacidad y muerte prematura siendo responsables de la pérdida de 1 millón 10 mil 594 años saludables, representando la primera carga de años saludables perdidos en el país. La familia de los inhibidores selectivos de la recaptación de serotonina (ISRS) es una de las más usadas en psiquiatría. El mecanismo de acción principal de los ISRS generalmente se explica simplemente por su inhibición selectiva del transportador de serotonina. - Escitalopram es un fármaco de la familia de los ISRS. Se trata del enantiómero levógiro (S) puro del citalopram. Como todos los ISRS actúa inhibiendo selectivamente la recaptación de serotonina en la hendidura sináptica interneuronal, incrementa la concentración sináptica de serotonina y activa las vías serotonérgicas neurales. Se postula que el escitalopram podría ser una opción de tratamiento eficaz y asociada a menos eventos adversos comparado con sertalina y fluoxetina. - Se identificaron 3 RS. Además, se identificó tres GPC que mencionaban a la tecnología. No se encontraron ETS, ni EE de la región. - La evidencia con respecto a escitalopram en trastornos psiquiátricos es abundante. Para depresión y ansiedad generalizada en adultos, se evidencia una adecuada respuesta a tratamiento de escitalopram versus placebo. En comparaciones indirectas se evidencia un beneficio de escitalopram por sobre fluoxetina para depresión, pero no se evidencia diferencia con sertralina. Basado también en comparaciones indirectas, en el caso de ansiedad generalizada no hay diferencias entre la tecnología de interés y los comparadores. En el caso de efectividad en niños con diagnóstico de depresión, se identifica escitalopram y fluoxetina como los medicamentos con mayor evidencia y que mostraron beneficio, sin embargo, no se tiene disponibilidad de estudios comparativos de escitalopram vs fluoxetina o sertralina. - Las guías de práctica clínica recabadas, en general, recomiendan el uso de inhibidores de la recaptación de serotonina indistintamente como primera línea mencionando que la decisión entre estos medicamentos depende de las características del paciente, interacciones con drogas y criterio clínico.

ECT Has Greater Efficacy Than Fluoxetine in Alleviating the Burden of Illness for Patients with Major Depressive Disorder: A Taiwanese Pooled Analysis.

Background: The burden of major depressive disorder includes suffering due to symptom severity, functional impairment, and quality of life deficits. The aim of this study was to compare the differences between electroconvulsive therapy and pharmacotherapy in reducing such burdens. Methods: This was a pooled analysis study including 2 open-label trials for major depressive disorder inpatients receiving either standard bitemporal and modified electroconvulsive therapy with a maximum of 12 sessions or 20 mg/d of fluoxetine for 6 weeks. Symptom severity, functioning, and quality of life were assessed using the 17-item Hamilton Rating Scale for Depression, the Modified Work and Social Adjustment Scale, and SF-36. Side effects following treatment, including subjective memory impairment, nausea/vomiting, and headache, were recorded. The differences between these 2 groups in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, quality of life, side effects, and time to response (at least a 50% reduction of 17-item Hamilton Rating Scale for Depression) and remission (17-item Hamilton Rating Scale for Depression ≤7) following treatment were analyzed. Results: Electroconvulsive therapy (n=116) showed a significantly greater reduction in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, and quality of life deficits and had significantly shorter time to response/remission than fluoxetine (n=126). However, the electroconvulsive therapy group was more likely to experience subjective memory impairment and headache. Conclusions: Compared with fluoxetine, electroconvulsive therapy was more effective in alleviating the burden of major depressive disorder and had a substantially increased speed of response/remission in the acute phase. Increased education and information about electroconvulsive therapy for clinicians, patients, and their families and the general public is warranted.

The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis.

BACKGROUND: Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients' functional outcome. METHODS/DESIGN: The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2-15 days after stroke onset. Patients are randomised centrally via each trials' web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months. DISCUSSION: Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020. TRIAL REGISTRATION: FOCUS: ISRCTN , ISRCTN83290762 . Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012. AFFINITY: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921 . Registered on 22 July 2011. EFFECTS: ISRCTN , ISRCTN13020412 . Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213 . Registered on 2 February 2016. EudraCT, 2011-006130-16 . Registered on 8 August 2014.

Análisis de impacto presupuestal de citalopram, clomipramina escitalopram, paroxetina, fluvoxamina, fluoxetina y sertralina para pacientes con Trastorno Obsesivo Compulsivo en Colombia / Budget impact analysis of citalopram, clomipramine escitalopram, paroxetine, fluvoxamine, fluoxetine and sertraline for patients with Obsessive Compulsive Disorder in Colombia

INTRODUCCIÓN: El análisis de impacto presupuestal (AIP) del citalopram, clomipramina, escitalopram, paroxetina, fluvoxamida, fluoxetina y sertralina para pacientes con trastorno obsesivo compulsivo (TOC) en Colombia, se desarrolló en el marco del mecanismo técnico-científico para la ampliación progresiva del Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) y la definición de la lista de exclusiones, establecido en el artículo 15 de la Ley 1751 de 2015 (1). Estas tecnologías fueron seleccionadas por la Dirección de Beneficios, Costos y Tarifas del Aseguramiento en Salud del Ministerio de Salud y Protección Social (MinSalud), y remitidas al Instituto de Evaluación Tecnológica en Salud (IETS) para su evaluación. El TOC es un trastorno de ansiedad que se caracteriza por pensamientos intrusivos, recurrentes (obsesiones) y persistentes, que producen inquietud, temor o preocupación y comportamientos repetitivos (compulsiones) dirigidos a reducir la ansiedad asociada. Afectan el rendimiento laboral, académico y las relaciones interpersonales, generando un deterioro en la calidad de vida de los pacientes, así como el desarrollo de ideas o comportamientos suicidas. Se estima que la prevalencia del TOC en la población general a nivel mundial es de 1,6%, siendo uno de los principales trastornos que afecta a niños y adolescentes (3). La prevalencia de TOC en Colombia oscila entre el 0,9% y el 2,4% (4); se ha observado una mayor incidencia de este trastorno en las mujeres que en los hombres, en quienes se evidencia una fuerte relación de episodios psicóticos con otros tipos de trastornos como la esquizofrenia (5,6).Según los reportes del Sistema Integral de Información de la Protección Social (SISPRO), entre los años 2009 y 2013, se diagnosticaron en promedio 1194 casos nuevos de pacientes con TOC en Colombia. Adicionalmente, se ha encontrado que el 55 % de los casos reportados han sido en pacientes entre los 27 a 59 años de edad. El DSM-IV establece como criterio para el diagnóstico de TOC, que las obsesiones y compulsiones resulten excesivas o irracionales para el paciente, aunque aclara que este criterio no es aplicable a los menores, ya que es frecuente que estos síntomas sean ego sintónicos para los niños e incluso para algunos adolescentes (8). En la actualidad, el TOC es entendido como un único trastorno sea cual sea la edad en el que aparezca, aunque en el 80% de los casos el inicio del trastorno ocurre antes de los 18 años. Este documento describe la metodología desarrollada para realizar el análisis de impacto presupuestal de citalopram y clomipramina para pacientes con TOC que requieren manejo farmacológico en Colombia. Este informe, sigue los lineamientos propuestos en el Manual para la Elaboración de Análisis de Impacto Presupuestal y en el Manual de Participación y Deliberación publicados por IETS. TECNOLOGÍAS EVALUADAS: En el escenario actual se incluyeron las tecnologías que se encuentran cubiertas por el Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) para el TOC. Así mismo, se definieron los tratamientos farmacológicos para primera y segunda línea del TOC a partir de consideraciones clínicas expuestas por los expertos temáticos. Los tratamientos farmacológicos con las tecnologías que se encuentran dentro del escenario actual son: Tratamiento de primera línea: sertralina y fluoxetina. Tratamiento de segunda línea: no se identificó ninguna tecnología. INSUMOS Y MÉTODOS: Esta sección presenta los supuestos, parámetros y métodos utilizados para el modelo de estimación del impacto presupuestal. Cada una de las fuentes de información, estructuración de casos tipo y supuestos de modelación que fueron discutidos con el grupo de expertos temáticos en espacios de participación promovidos por el IETS. DISTRIBUCIÓN DE LA POBLACIÓN EN EL ESCENARIO ACTUAL: De acuerdo a la Base de Datos Única de Afiliados del Sistema General en Salud (BDUA) para el año 2017 se registran 32.768.685 personas mayores de 18 años en Colombia; al aplicar la prevalencia de TOC identificada previamente, se estimaron 1.540.128,195 casos. Considerando que entre estos pacientes el 33% presentan comorbilidades, el número de casos que tendrían únicamente diagnóstico de TOC correspondería a 508.242 casos. Para establecer la probabilidad de requerir tratamiento farmacológico en los pacientes con diagnóstico de TOC, el consenso de expertos y el estudio publicado por Martin P, en el año 2003 establecen que aproximadamente el 68% de los pacientes con TAG requieren tratamiento farmacológico de primera línea (22); tomando esta probabilidad se estiman para Colombia 345.605 casos de TOC como población objetivo para el presente AIP. Para establecer la probabilidad de requerir tratamiento farmacológico de segunda línea en los pacientes con diagnóstico de TOC, se extrajeron las probabilidades de respuesta a los tratamientos de primera línea reportadas en el análisis de costo-efectividad de escitalopram comparado con paroxetina, fluoxetina, sertralina, fluvoxamina y clomipramina como terapia de mantenimiento para pacientes con trastorno obsesivo compulsivo en Colombia (21). Considerando este estudio, se estableció que la probabilidad de respuesta a los tratamientos de primera línea es de 0,515, por lo tanto, por propiedades de probabilidades complementarias, se estimó que el 48% (1-p) de los pacientes requerirían tratamiento de segunda línea, dando como resultado una estimación de 165.890 casos. MÉTODOS DE COSTEO Y COSTOS: Se obtuvo como primera medida los registros sanitarios vigentes por parte del INVIMA para el primer semestre del 2017. Para la valoración de los medicamentos se utilizó SISMED para el año 2016 (enero-diciembre), tomando como base el canal institucional laboratorio. Para cada tratamiento se identificó la dosis promedio recomendada para cada tecnología sugerida en la fuente de información Micromedex ® 2017 (23), la periodicidad y la duración del tratamiento. El precio promedio, mínimo y máximo por tableta o unidad calculada corresponde al precio ponderado de las diferentes presentaciones del medicamento, el cual comprende tanto los genéricos como las moléculas originales. Con lo anterior se buscó determinar un precio ponderado del principio activo, y no de una molécula en particular. Adicionalmente se revisaron las circulares de regulación de precios del Ministerio de Salud, con el fin de identificar si a la fecha existe un precio máximo regulado de alguna de las alternativas de comparación. El procedimiento para calcular los precios de los medicamentos siguió las recomendaciones del manual metodológico para la elaboración de evaluaciones económicas del IETS. RESULTADOS: Los resultados que se presentan en el informe corresponde al impacto presupuestal total e incremental obtenidos en los escenarios 1 y 2 para los tratamientos de TOC de primera y segunda línea.

A decline in depression treatment following FDA antidepressant warnings largely explains racial/ethnic disparities in prescription fills.

BACKGROUND: The Food and Drug Administration's 2004 antidepressant warning was followed by decreases in antidepressant prescribing for youth. This was due to declines in all types of depression treatment, not just the intended changes in antidepressant prescribing patterns. Little is known about how these patterns varied by race/ethnicity. METHOD: Data are Medicaid claims from four U.S. states (2002-2009) for youth ages 5-17. Interrupted time series analyses measured changes due to the warning in levels and trends, by race/ethnicity, of three outcomes: antidepressant prescription fills, depression treatment visits, and incident fluoxetine prescription fills. RESULTS: Prewarning, antidepressant fills were increasing across all racial/ethnic groups, fastest for White youth. Postwarning, there was an immediate drop and continued decline in the rate of fills among White youth, more than double the decline in the rate among Black and Latino youth. Prewarning, depression treatment visits were increasing for White and Latino youth. Postwarning, depression treatment stabilized among Latinos, but declined among White youth. Prewarning, incident fluoxetine fills were increasing for all groups. Postwarning, immediate increases and increasing trends of fluoxetine fills were identified for all groups. CONCLUSIONS: Antidepressant prescription fills declined most postwarning for White youth, suggesting that risk information may have diffused less rapidly to prescribers or caregivers of minorities. Decreases in depression treatment visits help to explain the declines in antidepressant prescribing and were largest for White youth. An increase in incident fluoxetine fills, the only medication indicated for pediatric depression at the time, suggests that the warning may have shifted prescribing practices.

Prescription Pattern of Antidepressants for Children and Adolescents in Korea Based on Nationwide Data.

Antidepressant prescription for youths has recently been on the increase. There is a growing concern over the increasing off-label usage of antidepressants. Current data on off-label antidepressant usage vary across countries and healthcare systems. Therefore, we examined the extent and pattern of antidepressant prescription for Korean children and adolescents using population-based data. Our data was retrieved from the Korean National Health Insurance Service National Sample Cohort of the year 2013. Among 0.2 million children and adolescents aged 6-18 years from the cohort, subjects who had received any antidepressant medication in the year 2013 were investigated for the prescribed medication, concomitant psychotropic medication, and the associated diagnosis. A total of 2,190 children and adolescents (boys, 55.4%) received antidepressant medication. The most common diagnosis was depressive disorders (n = 469, 21.4%), followed by attention-deficit/hyperactivity disorder (n = 442, 20.2%). Among the prescriptions (n = 3,370), escitalopram (n = 650, 24.1%) and fluoxetine (n = 553, 20.5%) were the two most frequently prescribed drugs. A majority of prescriptions (n = 2,039, 60.5%) included concomitant psychotropic agents, consisting of antipsychotics (n = 901, 26.7%), sedatives (n = 263, 26.3%), medication for attention-deficit/hyperactivity disorder (n = 822, 24.4%), and some others. Our study shows the prescription pattern of antidepressants for children and adolescents in Korea, of which a large proportion is off-label. The results call for close monitoring by clinicians treating this population.

Análisis de costo-efectividad del escitalopram comparado con paroxetina, sertralina, fluoxetina, imipramina y fluvoxamina como terapia de mantenimiento para pacientes con trastorno de pánico en Colombia / Cost-effectiveness analysis of escitalopram compared to paroxetine, sertraline, fluoxetine, imipramine and fluvoxamine as maintenance therapy for patients with panic disorder in Colombia

Problema de investigación: Describir los costos y la efectividad de escitalopram comparado con paroxetina, sertralina, fluoxetina, imipramina y fluvoxamina como terapia de mantenimiento en adultos con diagnóstico de trastorno de pánico en Colombia. Tipo de evaluación económica: Análisis de costo-efectividad. Población objetivo: Adultos colombianos con diagnóstico de trastorno de pánico. Intervención y comparadores: Intervención: escitalopram, Comparadores: paroxetina, sertralina, fluoxetina, imipramina y fluvoxamina. Horizonte temporal: 32 semanas. Perspectiva: SGSSS de Colombia. Tasa de descuento: No aplica. Estructura del modelo: Se estructuró un árbol de decisión, teniendo en cuenta modelos publicados en la literatura. Fuentes de datos de efectividad y seguridad: Reporte de efectividad y seguridad elaborado en diciembre de 2014 en el IETS, Ensayo s clínicos a leatorizados. Desenlaces y valoración: Ausencia de crisis de pánico, Semanas libres de crisis de pánico. Costos incluidos: Costo de los medicamentos, Costo de procedimientos, Costo de los eventos adversos. Fuentes de datos de costos: SISMED, Manual tarifario ISS 2001. Resultados del caso base: Para el caso base, escitalopram, fluvoxamina y fluoxetina e imipramina fueron tecnologías dominadas por sertralina y paroxetina. El costo adicional por crisis de pánico evitada en tratamiento con paroxetina comparado con trasertralina se estimó en $4.814.953. Análisis de sensibilidad: Los análisis de sensibilidad y el diagrama de tornado muestran a la probabilidad de lograr ausencia de crisis de pánico y la probabilidad de recaída, como a las variables con mayor impacto sobre las estimaciones de la razón de costo-efectividad. Conclusiones y discusión: De acuerdo con los hallazgos aquí presentados, paroxetina, ofrece mayor razón de costo-efectividad, respecto a sus comparadores. No obstante, es \r\nnecesario tener en cuenta que cualquiera de las alternativas aquí estudiadas, puede ser costo-efectiva, debido a que las pequeñas variaciones en la probabilidad de ausencia de crisis de pánico pueden cambiar el resultado. La principal limitación de este estudio es la ausencia de información roveniente de estudios de investigación clínica, que muestre el desempeño comparativo entre las tecnologías, así como el seguimiento de los participantes en los estudios, en escenarios de más largo plazo que los existentes al momento de elaborar este documento.(AU)

Análisis de impacto presupuestal de escitalopram, paroxetina, sertralina, fluoxetina, fluvoxamina y clomipramina como terapia de mantenimiento para pacientes adultos con trastorno obsesivo compulsivo en Colombia / Budget impact analysis of escitalopram, paroxetine, sertraline, fluoxetine, fluvoxamine and clomipramine as maintenance therapy for adult patients with obsessive-compulsive disorder in Colombia

Tecnologías evaluadas: Nuevas: escitalopram, paroxetina, fluvoxamina y clomipramina\r\nActuales: sertralina y fluoxetina. Población: Pacientes mayores\tde\t18 años\tcon trastorno\tobsesivo\r\ncompulsivo en Colombia. Perspectiva: La perspectiva del presente AIP corresponde al tercer pagador,\r\nque en este caso es el Sistema General de Seguridad Social en Salud (SGSSS) en Colombia. Horizonte temporal: El horizonte temporal de este AIP en el caso base es de un año. Adicionalmente, se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de la inclusión en el POS en el año 1. Costos incluídos: Costo por mg de los medicamentos. Fuente de costos: SISMED. Escenarios: En el escenario 1 se considera una igualación progresiva de las participaciones de mercado de todos los medicamentos analizados hasta llegar al año 3. En el escenario 2, además de una participación\tde\tmercado\tigual para\ttodos los medicamentos, se asume un precio común para las nuevas alternativas con base en la metodología de inclusión de grupos terapéuticos definida por el Ministerio de Salud y Protección\r\nSocia. Resultados: Para la inclusión en el POS de escitalopram, paroxetina, fluvoxamina y Clomipramina como terapia de mantenimiento para pacientes con diagnóstico de trastorno obsesivo ompulsivo en Colombia, se requeriría una inversión de $99.508.967.049 en el año 1 y de $136.213.036.626 en el año 3. En el caso que los medicamentos del escenario nuevo sean incluidos con un precio igual basado en las metodología de grupos terapéuticos del Ministerio de Salud y protección Social, el impacto presupuestal\r\nse reduciría a $13.170.025.624 en el año 1 y $19.887.249.147, en el año 3.(AU)

Análisis de costo-efectividad del escitalopram comparado con paroxetina, sertralina, fluoxetina, imipramina y fluvoxamina como terapia de mantenimiento para pacientes con trastorno de pánico en Colombia / nalysis cost-effectiveness of escitalopram compared to paroxetine, sertraline, fluoxetine, imipramine and fluvoxamine as maintenance therapy for patients with panic disorder in Colombia

PROBLEMA DE INVESTIGACIÓN: Describir los costos y la efectividad de escitalopram comparado con paroxetina, sertralina, fluoxetina, imipramina y fluvoxamina como terapia de mantenimiento en adultos con diagnóstico de trastorno de pánico en Colombia. TIPO DE EVALUACIÓN ECONÓMICA: Análisis de costo-efectividad. POBLACIÓN OBJETIVO: Adultos colombianos con diagnóstico de trastorno de pánico. INTERVENCIÓN Y COMPARADORES: Intervención: escitalopram; Comparadores: paroxetina, sertralina, fluoxetina, imipramina y fluvoxamina. HORIZONTE TEMPORAL: 32 semanas. PERSPECTIVA: SGSSS de Colombia. TASA DE DESCUENTO: No aplica. ESTRUCTURA DEL MODELO: Se estructuró un árbol de decisión, teniendo en cuenta modelos publicados en la literatura. FUENTES DE DATOS DE EFECTIVIDAD Y SEGURIDAD: Reporte de efectividad y seguridad elaborado en diciembre de 2014 en el IETS; Ensayos clínicos aleatorizados. DESENLACES Y VALORACIÓN: Ausencia de crisis de pánico; Semanas libres de crisis de pánico. COSTOS INCLUIDOS: Costo de los medicamentos; Costo de procedimientos; Costo de los eventos adversos. FUENTES DE DATOS DE COSTOS: SISMED; Manual tarifario ISS 2001. RESULTADOS DEL CASO BASE: Para el caso base, escitalopram, fluvoxamina y fluoxetina e imipramina fueron tecnologías dominadas por sertralina y paroxetina. El costo adicional por crisis de pánico evitada en tratamiento con paroxetina comparado contra sertralina se estimó en $4.814.953. ANÁLISIS DE SENSIBILIDAD: Los análisis de sensibilidad y el diagrama de tornado muestran a la probabilidad de lograr ausencia de crisis de pánico y la probabilidad de recaída, como a las variables con mayor impacto sobre las estimaciones de la razón de costo-efectividad. CONCLUSIONES Y DISCUSIÓN: De acuerdo con los hallazgos aquí presentados, paroxetina, ofrece mayor razón de costo-efectividad, respecto a sus comparadores. No obstante, es necesario tener en cuenta que cualquiera de las alternativas aquí estudiadas, puede ser costo-efectiva, debido a que las pequeñas variaciones en la probabilidad de ausencia de crisis de pánico pueden cambiar el resultado. La principal limitación de este estudio es la ausencia de información proveniente de estudios de investigación clínica, que muestre el desempeño comparativo entre las tecnologías, así como el seguimiento de los participantes en los estudios, en escenarios de más largo plazo que los existentes al momento de elaborar este documento.(AU)

Antidepressant prescribing in Irish children: secular trends and international comparison in the context of a safety warning.

BACKGROUND: In 2003, the Irish Medicines Board (IMB) warned against the treatment of childhood depression with selective serotonin reuptake inhibitors (SSRIs) due to increased risk of suicide. This study examined the effect of this warning on the prevalence of anti-depressants in Irish children and compared age and gender trends and international comparisons of prescription rates. METHODS: A retrospective cohort study of the Irish Health Service Executive (HSE) pharmacy claims database for the General Medical Services (GMS) scheme for dispensed medication. Data were obtained for 2002-2011 for those aged ≤ 15 years. Prevalence of anti-depressants per 1000 eligible population, along with 95% confidence intervals, were calculated. A negative binomial regression analysis was used to investigate trends and compare rates across years, sex and age groups (0-4, 5-11, 12-15 years). International prescribing data were retrieved from the literature. RESULTS: The prevalence of anti-depressants decreased from 4.74/1000 population (95% CI: 4.47-5.01) in 2002 to 2.61/1000 population (95% CI: 2.43-2.80) in 2008. SSRI rates decreased from 2002 to 2008. Prescription rates for contra-indicated SSRIs paroxetine, sertraline and citralopram decreased significantly from 2002 to 2005, and, apart from paroxetine, only small fluctuations were seen from 2005 onwards. Fluoxetine was the most frequently prescribed anti-depressant and rates increased between 2002 and 2011. Anti-depressant rates were higher for younger boys and older girls. The Irish prevalence was lower than the US, similar to the U.K. and higher than Germany and Denmark. CONCLUSIONS: The direction and timing of these trends suggest that medical practitioners followed the IMB advice.

The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: a study protocol for three multicentre randomised controlled trials.

BACKGROUND: Several small trials have suggested that fluoxetine improves neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials that aim to determine whether routine administration of fluoxetine (20 mg daily) for 6 months after acute stroke improves patients' functional outcome. METHODS/DESIGN: The three trial investigator teams have collaboratively developed a core protocol. Minor variations have been tailored to the national setting in the UK (FOCUS), Australia and New Zealand (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will subsequently provide the most precise estimate of the overall effect of fluoxetine after stroke and establish whether any effects differ between trials and subgroups of patients. The trials include patients ≥18 years old with a clinical diagnosis of stroke, persisting focal neurological deficits at randomisation between 2 and 15 days after stroke onset. Patients are randomised centrally via web-based randomisation systems using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Our primary outcome measure is the modified Rankin scale (mRS) at 6 months. Secondary outcomes include the Stroke Impact Scale, EuroQol (EQ5D-5 L), the vitality subscale of the Short-Form 36, diagnosis of depression, adherence to medication, adverse events and resource use. Outcomes are collected at 6 and 12 months. The methods of collecting these data are tailored to the national setting. If FOCUS, AFFINITY and EFFECTS combined enrol 6000 participants as planned, they would have 90 % power (alpha 5 %) to detect a common odds ratio of 1.16, equivalent to a 3.7 % absolute difference in percentage with mRS 0-2 (44.0 % to 47.7 %). This is based on an ordinal analysis of mRS adjusted for baseline variables included in the minimisation algorithm. DISCUSSION: If fluoxetine is safe and effective in promoting functional recovery, it could be rapidly, widely and affordably implemented in routine clinical practice and reduce the burden of disability due to stroke. FOCUS: ISRCTN83290762 (23/05/2012), AFFINITY: ACTRN12611000774921 (22/07/2011). EFFECTS: ISRCTN13020412 (19/12/2014).

Eficácia e segurança da venlafaxina, duloxetina e trazodona no tratamento da depressão / Efficacy and safety of venlafaxine, duloxetine and trazodone in the treatment of depression / Eficacia y seguridad de la venlafaxina, de la duloxetina y de la trazodona en el tratamiento de la depresíon

TECNOLOGIAS: Duloxetina, venlafaxina e trazodona. INDICAÇÃO: Depressão moderada ou grave. CARACTERIZAÇÃO DA TECNOLOGIA: A duloxetina e a venlafaxina fazem parte do grupo de antidepressivos inibidores da recaptação de serotonina e noradrenalina (IRSN). A trazodona é um antidepressivo atípico, atua inibindo a recaptação da serotonina e bloqueia os receptores adrenérgicos e histaminérgicos. Esses medicamentos aumentam a quantidade de serotonina e/ ou noradrenalina na fenda sináptica, aumentando, portanto, a estimulação sináptica e a atividade destas monoaminas no SNC. PERGUNTA: Os medicamentos duloxetina, venlafaxina e trazodona são mais eficazes e seguros para o tratamento da depressão maior em adultos do que a fluoxetina? BUSCA E ANÁLISE DE EVIDÊNCIAS CIENTÍFICAS: Foram pesquisadas as bases Medline (via Pubmed), Centre for Reviews and Dissemination (CRD), The Cochrane Library e LILACS. Buscaram-se revisões sistemáticas (RS) de ensaios clínicos que comparassem a eficácia e segurança dos medicamentos duloxetina, venlafaxina e trazodona comparados à fluoxetina para o tratamento do Transtorno Depressivo Maior, que utilizaram como critério de diagnóstico as classificações internacionais CID-10 e o DSM IV. A qualidade da evidência foi avaliada pelo sistema GRADE. Para avaliar desfechos secundários relacionados ao abandono do tratamento e efeitos adversos, dados de estudos observacionais presentes nas RS foram considerados. Avaliações de Tecnologias de Saúde e guias terapêuticos foram pesquisadas em sites de agências internacionais e na Rede Brasileira de Avaliação de Tecnologia em Saúde. RESUMO DOS RESULTADOS DOS ESTUDOS SELECIONADOS: Foram incluídas doze revisões sistemáticas (RS) com meta-análise. Na avaliação da eficácia, os resultados das RS demonstraram uma discreta superioridade da venlafaxina frente à fluoxetina. Na avaliação da segurança, ao verificar as taxas de abandono do tratamento e incidência de eventos adversos, grande parte dos estudos se mostrou inconclusiva ou levemente desfavorável à duloxetina ou venlafaxina comparados à fluoxetina. A maioria das RS apresentou evidência de baixa qualidade e todas contribuíram para uma recomendação fraca a favor da venlafaxina. Foram incluídos três guias terapêuticos que não fizeram distinção entre os medicamentos antidepressivos de segunda geração (ex. duloxetina, venlafaxina e trazodona) e os ISRS (ex. fluoxetina) para o desfecho de eficácia. RECOMENDAÇÕES: Os resultados de eficácia encontrados neste PTC apontam para a indicação da venlafaxina em caso de resposta inadequada ao tratamento com ISRS. Ao mesmo tempo em que o mecanismo de ação da venlafaxina parece estar relacionado à sua superioridade terapêutica, também estaria relacionado às suas limitações clinicas, principalmente em pacientes hipertensos ou com problemas cardíacos. A escolha inicial do medicamento deve ser pautada em vários critérios como: potenciais reações adversas e o custo do tratamento. Considerando a baixa qualidade da evidência dos resultados apresentados e o maior custo de tratamento frente às alternativas terapêuticas existentes, a fluoxetina ainda se apresenta como medicamento de primeira escolha para o tratamento do TDM em pacientes adultos, uma vez que sua eficácia é comparável às tecnologias avaliadas, com melhor tolerância. Ressalta-se que apesar de não ter sido objeto de comparação neste PTC outros ISRS, tais como: sertralina, citalopram ou escitalopram parecem possuir eficácia comparável entre si. Quanto a duloxetina e trazodona, não foram encontradas evidências de comparação direta com fluoxetina.(AU)

TECHNOLOGIES: duloxetine, venlafaxine and trazodone. INDICATION: moderate or major depression. CHARACTERIZATION OF THE TECHNOLOGY: Duloxetine and venlafaxine are part of the group of antidepressants reuptake of serotonin and norepinephrine (IRSR). Trazodone is an atypical antidepressant, works by inhibiting the reuptake of serotonin and blocks the adrenergic and histaminergic. These drugs increase the amount of serotonin and / or noradrenaline in the synaptic cleft, thereby increasing synaptic stimulation and the activity of these monoamines in the CNS. QUESTION: Are duloxetine, venlafaxine and trazodone more effective and safe than fluoxetine for the treatment of major depression in adults? SEARCH AND ANALYSIS OF SCIENTIFIC EVIDENCE: We searched Medline (via Pubmed) Centre for Reviews and Dissemination (CRD), The Cochrane Library and LILACS. Sought to systematic reviews (SR) clinical trials that compared the efficacy and safety of duloxetine drugs, venlafaxine and trazodone compared to fluoxetine for the treatment of Major Depressive Disorder, which used as a diagnostic criterion the international classifications ICD-10 and DSM IV. The quality of evidence was evaluated by the GRADE system. To evaluate secondary endpoints related to the abandonment of treatment and adverse effects data from observational studies present in the SR were considered. Health Technology Assessments and therapeutic guidelines were searched in international agency sites and the Brazilian Network for Health Technology Assessment. SUMMARY OF THE RESULTS OF THE SELECTED STUDIES: Twelve systematic reviews with meta-analysis were included. In assessing effectiveness, the results of SR showed a slight superiority of venlafaxine front of fluoxetine. In safety assessment, to check the dropout rates of treatment and incidence of adverse events, most studies proved inconclusive or slightly unfavorable to duloxetine or venlafaxine compared to fluoxetine. Most SR presented evidence of low quality and all contributed to a weak recommendation in favor of venlafaxine. Were included three therapeutic guides who didn't distinguish between second-generation antidepressant medications (eg, duloxetine, venlafaxine and trazodone) and SSRIs (eg, fluoxetine) for efficacy endpoint. RECOMMENDATIONS: Efficacy results of this study point to the indication of venlafaxine in case of inadequate response to treatment with SSRIs. While the mechanism of action of venlafaxine seems to be related to its therapeutic superiority it could also be related to its clinical limitations, especially in hypertensive patients or in patients with heart problems. The initial choice of drug should be based on various criteria such as potential adverse reactions and the cost of treatment. Given the low quality of the evidence and the higher cost of treatment in face of existing treatment alternatives, fluoxetine still presents itself as the first choice drug for the treatment of MDD in adult patients, since its effectiveness is comparable to the evaluated technologies and it is better tolerated. We emphasize that despite not having been the object of comparison in this study other SSRIs such as sertraline, citalopram or escitalopram seem to have comparable efficacy to each other. As for duloxetine and trazodone, we found no evidence of direct comparison with fluoxetine.(AU)

TECNOLOGÍA: Duloxetina, venlafaxina y trazodona. INDICACIÓN: Depresión moderada o grave. CARACTERIZACIÓN DE LA TECNOLOGÍA: La parte venlafaxina y duloxetina del grupo antidepresivos de la recaptación de serotonina y norepinefrina (IRSN). La trazodona es un antidepresivo atípico, actúa mediante la inhibición de la recaptación de serotonina y bloquea los receptores adrenérgicos e histamina. Estos fármacos aumentan la cantidad de serotonina y/o norepinefrina en la hendidura sináptica, lo que aumenta la estimulación sináptica y la actividad de estas monoaminas en el SNC. PREGUNTA: ¿Las drogasduloxetina, venlafaxina, trazodona y son más eficaces para el tratamiento de la depresión mayor en adultos que la fluoxetina? BÚSQUEDA Y ANÁLISIS DE LA EVIDENCIA CIENTÍFICA: Se hicieron búsquedas en las bases de datos Medline (viaPubmed), Centre for Reviews and Dissemination (CRD), The Cochrane Library y en LILACS. Mucha demanda hasta Revisiones Sistemáticas (RS) de ensayos clínicos que compararon la eficacia y seguridad de medicamentos duloxetina, venlafaxina, trazodona en comparación con la para el tratamiento de la depresión moderada o grave, que utiliza como criterio diagnóstico de las clasificaciones internacionales de la CID-10 y DSM IV. Para evaluar los objetivos secundarios relacionados con el abandono del tratamiento y los efectos adversos, se consideraron los datos de estudios observacionales presentes en el RS. La calidad de la evidencia se evaluaron utilizando el sistema GRADE. Evaluación de Tecnologías Sanitarias y las guias terapéuticas fueron encuestados en las agencias y sitios web internacionales de la Red Brasileña de Evaluación de Tecnologías Sanitarias. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Se incluyeron doce RS con y meta-análisis. En la evaluación de la eficacia, los resultados de RS mostraron una ligera superioridad de venlafaxina frente de la fluoxetina. Una evaluación de la seguridad, para comprobar las tasas de abandono del tratamiento y la incidencia de eventos adversos, la mayoría de los estudios demostró inconclusa o ligeramente desfavorable a la duloxetina o venlafaxina en comparación con la fluoxetina. La mayoría de RS mostraron evidencia de baja calidad y contribuyeron a una recomendación débil a favor de la venlafaxina. Se incluyeron tres guías terapéuticas que no hacía distinciones entre los antidepresivos de segunda generación (por ejemplo, duloxetina, venlafaxina y trazodona) y los ISRS (por ejemplo fluoxetina) para los resultados de eficacia. RECOMENDACIONES: Los resultados de eficacia de este estudio apuntan para la indicación de la venlafaxina en caso de respuesta inadecuada al tratamiento con ISRS. Mientras que el mecanismo de acción de la venlafaxina parece estar relacionada con su superioridad terapéutica también se relacionó con sus limitaciones clínicas, especialmente en pacientes hipertensos o con problemas del corazón. La elección inicial de drogas debe basarse en diversos criterios, tales como reacciones adversas potenciales y el costo del tratamiento. Dada la baja calidad de la evidencia de los resultados presentados y el mayor costo del tratamiento en frente a de las alternativas de tratamiento existentes, la fluoxetina todavía presentase como el fármaco de primera elección para el tratamiento del trastorno depresivo mayor en adultos, ya que su eficacia es comparable a las tecnologías evaluadas con mejor tolerancia. Es de destacar que a pesar de no haber sido objeto de comparación en este estudio otros ISRS tales como sertralina, citalopram o escitalopram parecen tener una eficacia comparable entre ellos. Cuanto a la duloxetina y la trazodona, no se encontraron pruebas de comparación directa con la fluoxetina.(AU)

Current landscape, unmet needs, and future directions for treatment of bipolar depression.

BACKGROUND: Depression is the predominant pole of illness disability in bipolar disorder and, compared with acute mania, has less systematic research guiding treatment development. The aim of this review is to present the therapeutic options currently available for managing bipolar depression and to highlight areas of unmet need and future research. METHODS: Literature search of PubMed, PsycINFO, and Cochrane databases and bibliographies from 2000 to August 2013 for treatments that have regulatory approval for bipolar depression or early controlled preliminary data on efficacy. RESULTS: Treatment options for bipolar depression have increased over the last decade, most notably with regulatory approval for olanzapine/fluoxetine combination, quetiapine, and lurasidone. Conventional mood stabilizers lamotrigine and divalproex have meta-analyses suggesting acute antidepressant response. Manual-based psychotherapies also appear to be effective in treating bipolar depression. The therapeutic utility of unimodal antidepressants, as a class, for the treatment of patients with bipolar depression, as a group, remains to be confirmed. There is a substantially unmet need to develop new interventions that are efficacious, effective, and have low side effect burden. LIMITATIONS: Additional compounds are currently being developed that may ultimately be applicable to the treatment of bipolar depression and early open-trial data encourage further studies, but both of these topics are beyond the scope of this review. CONCLUSION: Future registrational trials will need to establish initial efficacy, but increasing interest for personalized or individualized medicine will encourage further studies on individual predictors or biomarkers of response.