COMPARATIVE EFFICACY AND ACCEPTABILITYOF PHARMACOLOGICAL TREATMENTSFOR ACUTE MANIA:A MULTIPLE TREATMENTS META-ANALYSIS

Background: La mania \ue8 la caratteristica clinica che contraddistingue il disturbo bipolare. Ad oggi, non vi sono in letteratura evidenze forti e indicazioni chiare rispetto a quale trattamento farmacologico sia pi\uf9 adatto nella fase maniacale acuta del disturbo bipolare. L\u2019obiettivo del presente lavoro \ue8 stato quello di condurre una revisione sistematica della letteratura per confrontare i farmaci pi\uf9 comunemente utilizzati in ambito clinico per il trattamento della mania, sia in termini di efficacia che di tollerabilit\ue0. I risultati degli studi inclusi sono stati inoltre analizzati utilizzando la tecnica della multiple treatments meta-analysis, che permette di effettuare una stima complessiva con confronti diretti e indiretti tra farmaci, ed arrivare ad avere una gerarchia dei trattamenti basata sulle evidenze. Metodi: Sono stati inclusi studi clinici controllati e randomizzati (randomized controlled trial \u2013 RCT) in doppio cieco, che confrontavano un farmaco antimaniacale (antipsicotico o stabilizzante dell\u2019umore) con un altro farmaco antimaniacale o placebo, come terapia in acuto della mania. Sono state raccolte evidenze per 14 farmaci, oltre al placebo: aripiprazolo, asenapina, carbamazepina, valproato, gabapentin, aloperidolo, lamotrigina, litio, olanzapina, paliperidone, quetiapina, risperidone, topiramato e ziprasidone. Sono stati inclusi solo studi che confrontassero trattamenti somministrati per via orale, sia in monoterapia che in associazione tra loro. Risultati: Delle 582 referenze potenzialmente rilevanti, in totale 68 trial (tra cui 9 RCT non pubblicati) sono stati inclusi nella multiple treatments meta-analysis. Tutti i farmaci studiati sono risultati in maniera statisticamente significativa pi\uf9 efficaci rispetto al placebo, ad eccezione di gabapentin, lamotrigina e topiramato. In termini di acceptability, solo olanzapina, risperidone e quetiapina sono risultati significativamente meglio del placebo. Riguardo l\u2019efficacia comparativa tra farmaci antimaniacali, l\u2019aloperidolo \ue8 risultato essere il farmaco pi\uf9 efficace, rispetto a litio, quetiapina, aripiprazolo, carbamazepina, asenapina, valproato, ziprasidone, lamotrigina, topiramato e gabapentin. Risperidone e olanzapina hanno mostrato un profilo di efficacia molto simile, essendo entrambi pi\uf9 efficaci di valproato, ziprasidone, lamotrigina, topiramato e gabapentin. Topiramato e gabapentin hanno rivelato una minore efficacia rispetto a tutti gli altri farmaci antimaniacali. Riguardo alla tollerabilit\ue0, l\u2019aloperidolo ha mostrato rispetto all\u2019olanzapina un maggior tasso di drop-out dopo 3 settimane di trattamento. Il litio \ue8 risultato peggio di olanzapina, risperidone e quetiapina; la lamotrigina peggio di olanzapina e risperidone; il topiramato \ue8 stato peggio tollerato di molti altri trattamenti antimaniacali, come aloperidolo, olanzapina, risperidone, quetiapina, aripiprazolo, carbamazepina e valproato. Conclusioni: Questa multiple treatments meta-analysis \ue8 il primo lavoro che effettua confronti diretti e indiretti tra trattamenti farmacologici per la mania acuta. I risultati di questa analisi hanno importanti implicazioni cliniche che dovrebbero essere considerate nella costruzione di linee-guida e raccomandazioni sui trattamenti farmacologici.Background: Mania is the hallmark feature of bipolar disorder. Clinically, mania can quickly escalate out of control, and cause severe disruption to the lives of individuals with the disorder. This is particularly important as mania can result in disturbed behavior that, when extreme, can be a risk to the safety of the patient and others. Mood stabilizers and antipsychotic agents have long been the mainstay of treatment of acute mania. In recent years several atypical antipsychotics agents have been licensed to treat mania (aripiprazole, olanzapine, risperidone and quetiapine). However, conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. The aim of this study was to compare the efficacy and acceptability of pharmacological treatments for acute mania, in order to inform clinical practice and mental health policies. We carried out a multiple-treatments meta-analysis (MTM), a statistical technique that allows both direct and indirect comparisons to be undertaken, even when two of the treatments have not been directly compared. Methods: Double-blind randomized controlled trials (RCTs) comparing one active drug (antipsychotic, mood stabiliser or benzodiazepine) with another active drug (antipsychotic, mood stabiliser or benzodiazepine) or placebo as oral therapy in the treatment of acute mania were included. All combination and augmentation studies were included as well. Participants were patients aged 18 or older of both sexes with a primary diagnosis of acute mania or bipolar disorder (manic or mixed episode) according to the standardised diagnostic criteria used by the study authors. Overall efficacy was primarily measured as the mean change of the total score of the Young Mania Rating Scale (YMRS) from baseline to endpoint. We also estimated efficacy as the proportion of patients who responded to treatment (reduction of at least 50% on the total score between baseline and endpoint on a standardized rating scale for mania possibly YMRS). Acceptability was defined as the proportion of patients who left the study early for any reason, out of the total number of randomized patients. Results: We systematically reviewed 68 RCTs (16 073 participants) from 1980 to 2010, which compared any of the following 14 drugs at therapeutic dose range: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. 15 673 patients contributed to the efficacy analysis as continuous outcome (63 studies), 15 626 to the acceptability analysis (65 studies); for secondary outcome 12 649 patients (47 studies) contributed to efficacy analysis as dichotomous data. All anti-manic drugs \u2013with exception of topiramate and gabapentin- showed significant efficacy than placebo. Antipsychotic drugs were significantly more effective than mood stabilizers. In terms of efficacy, haloperidol, risperidone, and olanzapine outperformed other drugs. In terms of dropouts, olanzapine, risperidone, and quetiapine were better than haloperidol. Risperidone, olanzapine, and haloperidol seem to be the best of the available options for the treatment of manic episodes. Conclusions: This MTM is the first analysis that incorporates direct and indirect comparisons between pharmacological treatments for acute mania. These findings have potential clinical implications that should be considered in the development of clinical practice guideline

Epigallocatechin-3-gallate Delivered in Nanoparticles Increases Cytotoxicity in Three Breast Carcinoma Cell Lines

The anticancer act i v i t y of epigallocatechin-3-gallate (EGCG), orally administrated, is limited by poor bioavailabi l i t y , absorption, and unpredictable distribution in human tissues. EGCG charged nanoparticles may represent an opportunity to overcome these limitations. We assayed two different kinds of lipid nanoparticles (LNPs and LNPs functionalized with folic acid) charged with EGCG on three breast carcinoma cell lines (MCF-7, MDA-MB-231, and MCF-7TAM) and the human normal MCF10A mammary epithelial cells. Both LNPs loaded with EGCG, at low concentrations, induced a significant cytotoxicity in the three breast carcinoma cells but not in MCF10A cells. In view of a future application, both LNPs and LNPs-FA were found to be very suitable for in vitro studies and usef u l to improve EGCG administration in vivo. Since they are produced by inexpensive procedures using bioavailable, biocompatible, and biodegradable molecules, t h e y represent an applicable tool for a more rationale use of EGCG as an anti-cancer agent

Forty-five years of schizophrenia trials in Italy: a survey

<p>Abstract</p> <p>Background</p> <p>Well-designed and properly executed randomized controlled trials (RCTs) provide the best evidence on the efficacy of healthcare interventions. Mental health has a strong tradition of using trial to evaluate treatments, but the translation of research to clinical practice is not always easy. Even well-conducted trials do not necessarily address the needs of every day care and trials can reflect local needs and the specific culture in which they are undertaken. Generalizing results to other contexts can become problematic but these trials may, nevertheless, be very helpful within their own context. Moreover, pathways for drug approval can be different depending on local regulatory agencies. Local trials are helpful for decision-making in the region from which they come, but should not be viewed in isolation. National quantity and quality of trials may vary across nations.</p> <p>The aim of this study is to quantify trialing activity in Italy from 1948 until 2009 and to describe characteristics of these trials. In addition, we evaluated change over time in three keys aspects: sample size, follow-up duration, and number of outcomes.</p> <p>Methods</p> <p>We used the Cochrane Schizophrenia Group's register that contains 16,000 citations to 13,000 studies relating only to people with schizophrenia or schizophrenia-like illness. Randomized controlled trials and controlled clinical trials undertaken in Italy and involving pharmacological interventions were included.</p> <p>Results</p> <p>The original search identified 155 records of potentially eligible studies, 74 of which were excluded because do not meet inclusion criteria. A total of 81 studies were included in the analysis. The majority of trials were conducted in north Italy, and published in international journals between 1981 and 1995. The majority of studies (52 out of 81) used standardized diagnostic criteria for schizophrenia disorder. They were defined as randomized and used blind methods to administer treatment. However, most failed to report detail regarding methodological procedures and it is difficult to ascertain which studies are associated with a low risk of bias.</p> <p>Conclusions</p> <p>Trials should be designed to address the needs of everyday care with the aim of following large samples of typical patients in the long term. The Italian tradition in the area of trialing treatments for people with schizophrenia is not as strong as in many other similar countries and Italy should be producing more, better, independent, and clinically relevant trials.</p

Which psychotherapy is effective in panic disorder? And which delivery formats are supported by the evidence? Study protocol for two systematic reviews and network meta-analyses

Introduction Panic disorder is among the most prevalent anxiety diseases. Although psychotherapy is recommended as first-line treatment for panic disorder, little is known about the relative efficacy of different types of psychotherapies. Moreover, there is little evidence concerning the effectiveness of different formats of major psychotherapeutic types, such as cognitive-behavioural therapy (CBT). In this protocol, we present an overarching project consisting of two systematic reviews and network meta-analyses (NMA) to shed light on which psychotherapy (NMA-1), and specifically, which CBT delivery format (NMA-2) should be considered most effective for adults suffering from panic disorder with or without agoraphobia. Methods and analyses Starting from a common pool of data, we will conduct two systematic reviews and NMA of randomised controlled trials examining panic disorder. A comprehensive search will be performed in electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Register of Controlled Trials - CENTRAL from database inception to 1 January 2021 to identify relevant studies. A systematic approach to searching, screening, reviewing and data extraction will be applied. Titles, abstract and - whenever necessary - full texts will be examined independently by at least two reviewers. The quality of the included studies will be assessed using the revised Cochrane risk of bias tool V.2. The primary efficacy outcome will be anxiety symptoms at study endpoint. The primary acceptability outcome will be all-cause discontinuation, as measured by the proportion of patients who had discontinued treatment for any reason at endpoint. Data will be pooled using a random-effects model. Pairwise and NMA will be conducted. Ethics and dissemination No ethical approval is necessary for these two studies, as there will be no collection of primary data. The results will be disseminated through peer-reviewed publications and presentations at national and international conferences and meetings

A network meta-analysis of psychosocial interventions for refugees and asylum seekers with PTSD

Introduction Refugees and asylum seekers are vulnerable to common mental disorders, including post-traumatic stress disorder (PTSD). Using a network meta-analysis (NMA) approach, the present systematic review compared and ranked psychosocial interventions for the treatment of PTSD in adult refugees and asylum seekers. Methods Randomised studies of psychosocial interventions for adult refugees and asylum seekers with PTSD were systematically identified. PTSD symptoms at postintervention was the primary outcome. Standardised mean differences (SMDs) and ORs were pooled using pairwise and NMA. Study quality was assessed with the Cochrane Risk of Bias (RoB) tool, and certainty of evidence was assessed through the Confidence in Network Meta-Analysis application. Results A total of 23 studies with 2308 participants were included. Sixteen studies were conducted in high-income countries, and seven in low-income or middle-income countries. Most studies were at low risk of bias according to the Cochrane RoB tool. NMA on PTSD symptoms showed that cognitive behavioural therapy (CBT) (SMD=-1.41; 95% CI -2.43 to -0.38) and eye movement desensitisation and reprocessing (EMDR) (SMD=-1.30; 95% CI -2.40 to -0.20) were significantly more effective than waitlist (WL). CBT was also associated with a higher decrease in PTSD symptoms than treatment as usual (TAU) (SMD -1.51; 95% CI -2.67 to -0.36). For all other interventions, the difference with WL and TAU was not significant. CBT and EMDR ranked best according to the mean surface under the cumulative ranking. Regarding acceptability, no intervention had less dropouts than inactive interventions. Conclusion CBT and EMDR appeared to have the greatest effects in reducing PTSD symptoms in asylum seekers and refugees. This evidence should be considered in guidelines and implementation packages to facilitate dissemination and uptake in refugee settings

Adverse childhood experiences and global mental health: avenues to reduce the burden of child and adolescent mental disorders

Mental disorders are one of the largest contributors to the burden of disease globally, this holds also for children and adolescents, especially in low- and middle-income countries. The prevalence and severity of these disorders are influenced by social determinants, including exposure to adversity. When occurring early in life, these latter events are referred to as adverse childhood experiences (ACEs).In this editorial, we provide an overview of the literature on the role of ACEs as social determinants of mental health through the lenses of global mental health. While the relation between ACEs and mental health has been extensively explored, most research was centred in higher income contexts. We argue that findings from the realm of global mental health should be integrated into that of ACEs, e.g. through preventative and responsive psychosocial interventions for children, adolescents and their caregivers. The field of global mental health should also undertake active efforts to better address ACEs in its initiatives, all with the goal of reducing the burden of mental disorders among children and adolescents globally

Comparative efficacy and acceptability of psychotherapies for panic disorder with or without agoraphobia: Systematic review and network meta-Analysis of randomised controlled trials

Background Psychotherapies are the treatment of choice for panic disorder, but which should be considered as first-line treatment is yet to be substantiated by evidence. Aims To examine the most effective and accepted psychotherapy for the acute phase of panic disorder with or without agoraphobia via a network meta-Analysis. Method We conducted a systematic review and network meta-Analysis of randomised controlled trials (RCTs) to examine the most effective and accepted psychotherapy for the acute phase of panic disorder. We searched MEDLINE, Embase, PsycInfo and CENTRAL, from inception to 1 Jan 2021 for RCTs. Cochrane and PRISMA guidelines were used. Pairwise and network meta-Analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO (CRD42020206258). Results We included 136 RCTs in the systematic review. Taking into consideration efficacy (7352 participants), acceptability (6862 participants) and the CINeMA confidence in evidence appraisal, the best interventions in comparison with treatment as usual (TAU) were cognitive-behavioural therapy (CBT) (for efficacy: standardised mean differences s.m.d. =-0.67, 95% CI-0.95 to-0.39; CINeMA: moderate; for acceptability: relative risk RR = 1.21, 95% CI-0.94 to 1.56; CINeMA: moderate) and short-Term psychodynamic therapy (for efficacy: s.m.d. =-0.61, 95% CI-1.15 to-0.07; CINeMA: low; for acceptability: RR = 0.92, 95% CI 0.54-1.54; CINeMA: moderate). After removing RCTs at high risk of bias only CBT remained more efficacious than TAU. Conclusions CBT and short-Term psychodynamic therapy are reasonable first-line choices. Studies with high risk of bias tend to inflate the overall efficacy of treatments. Results from this systematic review and network meta-Analysis should inform clinicians and guidelines

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Publicat a La Voz de Asturias