Background: La mania è 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 più adatto nella fase maniacale acuta del disturbo bipolare. L’obiettivo del presente lavoro è stato quello di condurre una revisione sistematica della letteratura per confrontare i farmaci più comunemente utilizzati in ambito clinico per il trattamento della mania, sia in termini di efficacia che di tollerabilità. 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 – RCT) in doppio cieco, che confrontavano un farmaco antimaniacale (antipsicotico o stabilizzante dell’umore) 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 più 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’efficacia comparativa tra farmaci antimaniacali, l’aloperidolo è risultato essere il farmaco più 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 più 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 tollerabilità, l’aloperidolo ha mostrato rispetto all’olanzapina un maggior tasso di drop-out dopo 3 settimane di trattamento. Il litio è risultato peggio di olanzapina, risperidone e quetiapina; la lamotrigina peggio di olanzapina e risperidone; il topiramato è stato peggio tollerato di molti altri trattamenti antimaniacali, come aloperidolo, olanzapina, risperidone, quetiapina, aripiprazolo, carbamazepina e valproato. Conclusioni: Questa multiple treatments meta-analysis è 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 –with 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 guidelines
COMPARATIVE EFFICACY AND ACCEPTABILITYOF PHARMACOLOGICAL TREATMENTSFOR ACUTE MANIA:A MULTIPLE TREATMENTS META-ANALYSIS
PURGATO, Marianna
2012-01-01
Abstract
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 –with 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 guidelinesFile | Dimensione | Formato | |
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