APPRAISE-RS: Automated, updated, participatory, and personalized treatment recommender systems based on GRADE methodology

Attention deficit hyperactivity disorder; Evidence-based medicine; Meta-analysisTrastorn per dèficit d'atenció amb hiperactivitat; Medicina basada en l'evidència; MetaanàlisiTrastorno por déficit de atención con hiperactividad; Medicina basada en la evidencia; MetanálisisPurpose: Clinical practice guidelines (CPGs) have become fundamental tools for evidence-based medicine (EBM). However, CPG suffer from several limitations, including obsolescence, lack of applicability to many patients, and limited patient participation. This paper presents APPRAISE-RS, which is a methodology that we developed to overcome these limitations by automating, extending, and iterating the methodology that is most commonly used for building CPGs: the GRADE methodology.Method: APPRAISE-RS relies on updated information from clinical studies and adapts and automates the GRADE methodology to generate treatment recommendations. APPRAISE-RS provides personalized recommendations because they are based on the patient's individual characteristics. Moreover, both patients and clinicians express their personal preferences for treatment outcomes which are considered when making the recommendation (participatory). Rule-based system approaches are used to manage heuristic knowledge.Results: APPRAISE-RS has been implemented for attention deficit hyperactivity disorder (ADHD) and tested experimentally on 28 simulated patients. The resulting recommender system (APPRAISE-RS/TDApp) shows a higher degree of treatment personalization and patient participation than CPGs, while recommending the most frequent interventions in the largest body of evidence in the literature (EBM). Moreover, a comparison of the results with four blinded psychiatrist prescriptions supports the validation of the proposal.Conclusions: APPRAISE-RS is a valid methodology to build recommender systems that manage updated, personalized and participatory recommendations, which, in the case of ADHD includes at least one intervention that is identical or very similar to other drugs prescribed by psychiatrists.This work was supported by European Regional Development Fund (ERDF), the Spanish Ministry of the Economy, Industry and Competitiveness (MINECO) and the Carlos III Research Institute [PI19/00375], Fundació Pascual i Prats & Campus Salut, UdG [AIN2018E], Generalitat de Catalunya [2017 SGR 1551]

Placebo response and its predictors in Attention Deficit Hyperactivity Disorder: a meta-analysis and comparison of meta-regression and MetaForest

BACKGROUND: High placebo response in attention deficit hyperactivity disorder (ADHD) can reduce medication-placebo differences, jeopardizing the development of new medicines. This research aims to (1) determine placebo response in ADHD, (2) compare the accuracy of meta-regression and MetaForest in predicting placebo response, and (3) determine the covariates associated with placebo response. METHODS: A systematic review with meta-analysis of randomized, placebo-controlled clinical trial investigating pharmacological interventions for ADHD was performed. Placebo response was defined as the change from baseline in ADHD symptom severity assessed according to the 18-item, clinician-rated, DSM-based rating scale. The effect of study design-, intervention-, and patient-related covariates in predicting placebo response was studied by means of meta-regression and MetaForest. RESULTS: Ninety-four studies including 6614 patients randomized to placebo were analyzed. Overall, placebo response was -8.9 points, representing a 23.1% reduction in the severity of ADHD symptoms. Cross-validated accuracy metrics for meta-regression were R2 = 0.0012 and root mean squared error = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response among ADHD patients increased by 63% between 2001 and 2020 and was larger in the United States than in other regions of the world. CONCLUSIONS: Strong placebo response was found in ADHD patients. Both meta-regression and MetaForest showed poor performance in predicting placebo response. ADHD symptom improvement with placebo has markedly increased over the last 2 decades and is greater in the United States than the rest of the world

Guía de práctica clínica para el tratamiento farmacológico y psicológico de los pacientes adultos con trastorno bipolar y un diagnóstico comórbido de trastorno por uso de sustancias

This review synthesizes the pharmacological and psychosocial interventions that have been conducted in comorbid bipolar disorder (BD) and substance use disorders (SUDs) while also providing clinical recommendations about which intervention elements are helpful for addressing substance use versus mood symptoms in patients with these co-occurring conditions. The best evidence from randomized controlled trials was used to evaluate treatment options. The strength of recommendations was described using the GRADE approach. Very few of the randomized trials performed so far have provided consistent evidence for the management of both mood symptoms and substance use in patients with a BD. No clinical trials are available for bipolar patients using cannabis. Some treatments have shown benefit for mood symptoms without benefits for alcohol or illicit substance use. Our results suggest that 1) we can (weakly) recommend the use of adjuvant valproate or naltrexone to improve symptoms of alcohol use disorder; 2) Lamotrigine add-on therapy seems to reduce cocaine-related symptoms and is therefore recommended (moderate strength); and 3) Varenicline is (weakly) recommended to improve nicotine abstinence. Integrated group therapy is the most-well validated and efficacious approach on substance use outcomes if substance use is targeted in an initial treatment phaseEsta revisión resume las intervenciones farmacológicos y psicosociales que se han realizado en trastorno bipolar (TB) y un diagnóstico comórbido de trastorno por uso de sustancias (TUS) y además proporciona recomendaciones clínicas respecto de cuáles elementos de intervención son útiles para hacer frente a los síntomas del uso de sustancias versus los síntomas de estado de ánimo en pacientes con estas afecciones concurrentes. Se utilizó la mejor evidencia de ensayos controlados aleatorizados para evaluar las opciones de tratamiento. La fuerza de las recomendaciones se describió mediante el enfoque GRADE. Muy pocos de los ensayos aleatorizados realizados hasta la fecha han proporcionado evidencia consistente para el manejo tanto de los síntomas de estado de ánimo como del uso de sustancias en pacientes con TB. No hay disponibilidad de ensayos clínicos para pacientes con TB que utilizan el cannabis. Algunos tratamientos han mostrado beneficios para los síntomas de estado de ánimo sin beneficios para el uso de alcohol o sustancias ilícitas. Nuestros resultados sugieren que 1) podemos (débilmente) recomendar el uso de ácido valproico o naltrexona adyuvante para aliviar los síntomas del trastorno por consumo de alcohol; 2) el tratamiento complementario con lamotrigina parece reducir los síntomas relacionados con la cocaína y, por tanto, es recomendable (fuerza moderada); y 3) la vareniclina es recomendable (débilmente) para mejorar la abstinencia de la nicotina. La terapia grupal integrada es el enfoque con más validación y eficacia sobre los resultados en el uso de sustancias cuando este uso es abordado durante la fase inicial de tratamientoS

Eficàcia, seguretat i abandonament del tractament farmacològic del trastorn per dèficit d’atenció amb hiperactivitat en pacients adults

There are concerns about the benefit-risk ratio of pharmacologic interventions for ADHD in adults, especially in patients with ADHD and substance use disorder (SUD). Four systematic reviews of randomized placebo-controlled clinical trials in adult patients with ADHD and in patients with ADHD and SUD were performed. Data were combined using meta-analysis. Pharmacological treatment for ADHD was moderately efficacious in improving ADHD symptom severity, but it was associated with more frequent adverse events and a slightly higher treatment discontinuation compared to placebo. The results were more favourable when treatment was administered with psychotherapy, when psychostimulant drugs were used, when efficacy was assessed by investigators, when previously-treated patients were included, in short-term studies and in studies that included a lead-in phase. In patients with ADHD and SUD pharmacological treatment reduced ADHD symptom severity but did not improve neither drug abstinence nor treatment discontinuationExisteixen dubtes sobre la seva relació benefici-risc dels medicaments per al tractament del TDAH en adults, sobretot en pacients amb TDAH i trastorn per ús de substàncies (TUS). S’han realitzat quatre revisions sistemàtiques metanalítiques d’assajos clínics aleatoritzats de pacients adults amb TDAH i de pacients amb TDAH i TUS. Els medicaments pel TDAH disminueixen moderadament la gravetat dels símptomes, però s’associen a una major aparició d’efectes adversos i a un petit augment de l’abandonament del tractament en comparació amb el placebo. Els resultats són més favorables quan els medicaments s’administren amb psicoteràpia, quan s’utilitzen psicoestimulants, quan l’avaluador de l’eficàcia és l’investigador, en pacients que han estat prèviament tractats amb psicoestimulants, en els estudis de curta durada i en els que fan servir un període de preinclusió. En pacients amb TDAH i TUS els medicaments pel TDAH milloren la gravetat del TDAH, però no l’abstinència de substàncies ni l’abandonament del tractamen

Psychostimulant drugs for cocaine dependence.

Objective: To ascertain the efficacy of psychostimulants for cocaine dependence on cocaine use, sustained cocaine abstinence and retention in treatment. The influence of type of drug, comorbid disorders and clinical trial reporting quality over psychostimulants efficacy has also been studied. Cocaine dependence is a frequent disorder for which no medication has clearly proved to be efficacious. Substitution therapy involves the replacement of abused drug, which is often illegal, used several times a day, by a legal, orally administered one. A substitutive drug has similar effects to the abused one, but with a lower addictive potential therefore leading to drug abstinence and involving patients to follow medical and psychological assistance. This strategy has proved to be efficacious for heroin and nicotine dependence. In this review we investigated if psychostimulant substitution was efficacious for cocaine dependence. We found that sixteen studies that had enrolled 1,345 patients investigated the efficacy of psychostimulants against placebo for cocaine dependence. Seven drugs with psychostimulant effect or metabolized to a psychostimulant have been investigated: bupropion, dexamphetamine, methylphenidate, modafinil, mazindol, methamphetamine and selegiline. Psychotherapy was provided in all clinical trials. Study length ranged from 6 to 24 weeks. Psychostimulants did not improve cocaine use, had an unclear beneficial effect over sustained cocaine abstinence and were not associated with higher retention in treatment. Psychostimulants did not increase risk of serious adverse events. It was found that psychostimulants could be efficacious for some groups of patients, such as methadone maintained dual heroin-cocaine addicts. Therefore, psychostimulants, though have not proved yet their efficacy for cocaine dependence, deserve further investigation

Placebo Response and Its Predictors in Attention Deficit Hyperactivity Disorder: A Meta-Analysis and Comparison of Meta-Regression and MetaForest

Transtorn per dèficit d'atenció i hiperactivitat; MetaForest; Aprenentatge automàticDesorden hiperactivo y deficit de atencion; MetaForest; Aprendizaje automáticoAttention Deficit Hyperactivity Disorder; MetaForest; Machine learningHigh placebo response in ADHD can reduce medication-placebo differences, jeopardizing the development of new medicines. This research aims to 1) determine placebo response in ADHD, 2) compare the accuracy of meta-regression and MetaForest in predicting placebo response, and 3) determine the covariates associated with placebo response. A systematic review with meta-analysis (SRMA) of RPCCTs investigating pharmacological interventions for ADHD was performed. Placebo response was defined as the change from baseline in ADHD symptom severity assessed according to the 18-item, clinician-rated, DSM-based rating scale. The effect of study design-, intervention- and patient-related covariates in predicting placebo response was studied by means of meta-regression and MetaForest. Ninety-four studies including 6,614 patients randomized to placebo were analysed. Overall, placebo response was -8.9 points, representing a 23.1% reduction in the severity of ADHD symptoms. Cross-validated accuracy metrics for meta-regression were R 2 = 0.0012 and RMSE = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response amongst ADHD patients increased by 63% between 2001 and 2020 and was larger in the US than in other regions of the world. Strong placebo response was found in ADHD patients. Both meta-regression and MetaForest showed poor performance in predicting placebo response. ADHD symptom improvement with placebo has markedly increased over the last two decades and is grater in the US than the rest of the world.This study was funded in part by a grant from the Instituto de Salud Carlos III (PI19/00375). Caspar van Lissa is supported by a NWO Veni grant (NWO grant no. VI.Veni.191G.090)

Placebo response and its predictors in Attention Deficit Hyperactivity Disorder: a meta-analysis and comparison of meta-regression and MetaForest

BACKGROUND: High placebo response in attention deficit hyperactivity disorder (ADHD) can reduce medication-placebo differences, jeopardizing the development of new medicines. This research aims to (1) determine placebo response in ADHD, (2) compare the accuracy of meta-regression and MetaForest in predicting placebo response, and (3) determine the covariates associated with placebo response. METHODS: A systematic review with meta-analysis of randomized, placebo-controlled clinical trial investigating pharmacological interventions for ADHD was performed. Placebo response was defined as the change from baseline in ADHD symptom severity assessed according to the 18-item, clinician-rated, DSM-based rating scale. The effect of study design-, intervention-, and patient-related covariates in predicting placebo response was studied by means of meta-regression and MetaForest. RESULTS: Ninety-four studies including 6614 patients randomized to placebo were analyzed. Overall, placebo response was -8.9 points, representing a 23.1% reduction in the severity of ADHD symptoms. Cross-validated accuracy metrics for meta-regression were R2 = 0.0012 and root mean squared error = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response among ADHD patients increased by 63% between 2001 and 2020 and was larger in the United States than in other regions of the world. CONCLUSIONS: Strong placebo response was found in ADHD patients. Both meta-regression and MetaForest showed poor performance in predicting placebo response. ADHD symptom improvement with placebo has markedly increased over the last 2 decades and is greater in the United States than the rest of the world

Clinical practice guideline on pharmacological and psychological management of adult patients with depression and a comorbid substance use disorder

Data de publicació electrònica: 12-03-2021La concurrencia de depresión y un trastorno por uso de sustancias (TUS) en pacientes que presentan patología dual ha sido reconocida desde hace mucho tiempo como una consideración importante en la práctica clínica. Esta revisión sintetiza la evidencia de intervenciones farmacológicas y psicosociales para trastornos comórbidos de depresión y uso de sustancias y además proporciona recomendaciones clínicas respecto de las mejores intervenciones para tratar a estos pacientes. Se utilizó la mejor evidencia de ensayos controlados aleatorizados para evaluar las opciones de tratamiento. La fuerza de las recomendaciones se describió mediante el enfoque GRADE. Nuestros resultados sugieren que: 1) en pacientes con depresión y consumo de alcohol, se recomienda la administración de antidepresivos inhibidores de la recaptación de serotonina (ISRS) no selectivos en lugar de los ISRS para mejorar los síntomas depresivos (recomendación fuerte). No se recomiendan antidepresivos ISRS (recomendación fuerte) ni antidepresivos no ISRS (recomendación débil) para reducir el consumo de alcohol; 2) en pacientes con depresión y consumo de cannabis, no se recomienda el uso de venlafaxina (recomendación débil); 3) en pacientes con depresión y consumo de cocaína, no se recomienda el uso de antidepresivos ISRS para mejorar los síntomas depresivos (recomendación débil) o para reducir el consumo de cocaína (recomendación fuerte). El uso de antidepresivos no ISRS solo se recomienda para mejorar los síntomas depresivos (recomendación fuerte); 4) no se recomienda la administración de bupropión para reducir el consumo de nicotina (recomendación fuerte), y 5) en cuanto al tratamiento psicológico, en pacientes con depresión y trastorno de alcohol concurrente, tanto la farmacoterapia como la terapia cognitivo-conductual tienen efectos positivos en la internalización de los síntomas y en la reducción del consumo de alcohol (recomendación débil). Nuestra revisión sugiere la necesidad de realizar más investigaciones en esta área y de estudios aleatorizados, multisitio y más grandes para proporcionar más evidencia definitiva.Co-occurrence of depression and a substance use disorder (SUD) in patients who present dual diagnoses has been long recognized as an important consideration in clinical practice. This review synthesizes the evidence of pharmacological and psychosocial interventions for comorbid depressive disorders and SUDs while providing clinical recommendations about the best interventions to address these patients. The best evidence from randomized controlled trials was used to evaluate treatment options. The strength of recommendations was described using the GRADE approach. Our results suggest that 1) In patients with depression and alcohol consumption, the administration of non-selective serotonin reuptake inhibitor (SSRI) antidepressants instead of SSRI is recommended for improvement of depressive symptoms (strong recommendation). Neither SSRI (strong recommendation) nor non-SSRI (weak recommendation) antidepressants are recommended for reduction in alcohol consumption. 2) In patients with depression and cannabis use, the use of venlafaxine is not recommended (weak recommendation). 3) In patients with depression and cocaine consumption, the use of SSRI antidepressants for improving depressive symptoms (weak recommendation) or to reduce cocaine use is not recommended (strong recommendation). The use of non-SSRI antidepressants is only recommended for improving depressive symptoms (strong recommendation). 4) The administration of bupropion to reduce nicotine consumption is not recommended (strong recommendation). 5) Regarding psychological treatment, in patients with depression and co-occurring alcohol disorder, both pharmacotherapy and cognitive behavioural therapy have positive effects on internalizing symptoms and in reducing alcohol consumption (weak recommendation). Our review suggests the need for more research in this area and for larger, multisite, randomized studies to provide more definite evidence