Elsevier

The Lancet

Volume 378, Issue 9799, 8–14 October 2011, Pages 1306-1315
The Lancet

Articles
Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis

https://doi.org/10.1016/S0140-6736(11)60873-8Get rights and content

Summary

Background

Conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirect comparisons, to assess the effects of all antimanic drugs.

Methods

We systematically reviewed 68 randomised controlled trials (16 073 participants) from Jan 1, 1980, to Nov 25, 2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the mean change on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks. Analysis was done by intention to treat.

Findings

Haloperidol (standardised mean difference [SMD] −0·56 [95% CI −0·69 to −0·43]), risperidone (–0·50 [–0·63 to −0·38), olanzapine (–0·43 [–0·54 to −0·32], lithium (–0·37 [–0·63 to −0·11]), quetiapine (–0·37 [–0·51 to −0·23]), aripiprazole (–0·37 [–0·51 to −0·23]), carbamazepine (–0·36 [–0·60 to −0·11], asenapine (–0·30 [–0·53 to −0·07]), valproate (–0·20 [–0·37 to −0·04]), and ziprasidone (–0·20 [–0·37 to −0·03]) were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD −0·19 [95% CI −0·36 to −0·01]), quetiapine (–0·19 [–0·37 to 0·01]), aripiprazole (–0·19 [–0·36 to −0·02]), carbamazepine (–0·20 [–0·36 to −0·01]), asenapine (–0·26 [–0·52 to 0·01]), valproate (–0·36 [–0·56 to −0·15]), ziprasidone −0·36 [–0·56 to −0·15]), lamotrigine (–0·48 [–0·77 to −0·19]), topiramate (–0·63 [–0·84 to −0·43]), and gabapentin (–0·88 [−1·40 to −0·36]). Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin.

Interpretation

Overall, antipsychotic drugs were significantly more effective than mood stabilisers. Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines.

Funding

None.

Introduction

Mania is a condition of excessively raised mood that affects about 1% of the population, usually occurs in association with episodes of depression, and defines the diagnosis of bipolar disorder. Bipolar disorder is a recurring illness, and one of the leading causes of worldwide disability, especially in those aged 15–44 years.1 Mood stabilisers and antipsychotic drugs have long been the mainstay of treatment of acute mania with and without psychotic features.2 These medicines have been shown to be individually more effective than placebo, but guidelines have not usually attempted to rank the effectiveness of these drugs.3, 4, 5, 6, 7

We report a systematic review of randomised controlled trials that compared efficacy and acceptability of antimanic drugs, either against placebo or against one another, in the treatment of acute mania. We used the method of multiple-treatments meta-analysis, to allow the integration of data from direct and indirect comparisons.8, 9 We had previously compared the effectiveness of antidepressants in unipolar depression in this way.10 This method comprehensively synthesises data to provide a clinically useful summary that can guide treatment decisions.

Section snippets

Study protocol

At the beginning of this project, we drafted a study protocol and subsequently made it freely available to the public on our institutional website before doing the final analyses (webappendix p 1). Furthermore, with the publication of this Article, the overall dataset will be in the public domain for anyone who would be interested to use it.

Search strategy and selection criteria

We searched Medline, Embase, Cumulative Index to Nursing and Allied Health (CINAHL), PsycINFO, the Cochrane Central Register of Controlled Trials, and the

Results

In total, we included 68 trials in the multiple-treatments meta-analysis (figure 1, webappendix pp 15–20 for references to included studies and study characteristics). 14 treatments were analysed: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, paliperidone, quetiapine, risperidone, topiramate, ziprasidone, and placebo. Most trials (54 [79%] of 68) were two-grouped studies and the rest were three-grouped studies in which one active

Discussion

This study shows both statistically and clinically significant differences between treatments of acute mania. In terms of efficacy, haloperidol, risperidone, and olanzapine outperformed other drugs. In terms of drop-outs, olanzapine, risperidone, and quetiapine were better than haloperidol. These results have potential clinical implications that should be considered in the development of clinical practice guidelines.2, 4, 22, 23, 24 Strikingly, antipsychotic drugs were, overall, significantly

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