The Year in Psychiatry: Studies Not to Miss From 2011

Christoph U. Correll, MD; Maren Carbon, MD


November 23, 2011

In This Article

Update on Antimanic Treatments: An Efficacy Comparison

Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36:375-389.

Which agent is best suited to treat mania? Although many drugs have empirically been used for this purpose, not all have been FDA approved and little is known about their comparative efficacy.

This meta-analysis included data from over 10,800 patients from 38 short-term, randomized, placebo-controlled studies of antimanic agents for acute mania in manic or mixed states in bipolar I disorder, yielding 56 drug/placebo comparisons of 17 agents. Their pooled effect size for mania improvement was 0.42 (95% confidence interval [CI], 0.36-0.48), indicating a moderate effect size. The pooled responder rate difference was 17% (drug: 48%, placebo: 31%), yielding an estimated number-needed-to-treat (NNT) of 6 (moderate effect size). All 8 second-generation antipsychotics (SGAs) tested (aripiprazole, asenapine, cariprazine, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone), as well as haloperidol, tamoxifen (a central protein kinase C inhibitor), lithium, and the 2 antiepileptics, carbamazepine and valproate, showed clear superiority compared with placebo. Although there was a class effect for all D2-blocking agents, the effects of antiepileptics were highly heterogeneous, with strong efficacy of carbamazepine (NNT: 3.9; smaller NNT indicating greater efficacy) and a moderate efficacy of valproate (NNT: 5.9) but no greater efficacy of licarbazepine, lamotrigine, and topiramate compared with placebo. Of all agents, tamoxifen showed the highest response rates (NNT: 2.6), but these data result from 2 small trials (n = 74) only, indicating that more experience with this agent is needed. Estimates of NNT benefit values ranked haloperidol directly behind tamoxifen, followed by carbamazepine or valproate and oral SGAs. However, the 95% CIs of the effect sizes of all other medications that outperformed placebo overlapped, indicating similar efficacy in this indirect, placebo-controlled comparison. Moreover, in some pooled analyses, SGAs seemed superior to conventional mood stabilizers for acute mania, but both of these antimanic medication classes had similar pooled effect sizes compared with placebo, provided that only lithium, valproate, and carbamazepine were entered as conventional mood stabilizers into the analyses.

Taken together, these data support recent guidelines for bipolar mania that have suggested to rank certain antimanic agents in the treatment selection first based on the safety and tolerability profile, assuming roughly equal efficacy, at least when analyzing groups of patients.

Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378:1306-1315.

In an effort to expand the scope of a classical meta-analysis, such as the one performed by Yildiz and colleagues described above, the authors of the current study used a multiple-medications network analysis to assess acute antimanic treatment efficiency. In addition to comparisons with placebo, inferences of class comparisons were calculated. Moreover, augmentation studies, ie, the addition of a second mood stabilizer or antipsychotic to ongoing mood stabilizer therapy, compared with placebo addition, were also included in this meta-analysis. Notably, response or remission was not used as a primary efficacy endpoint. Instead, the percent reduction in the Young-Mania Rating Scale (YMRS) at 3 weeks of treatment was used as the primary efficacy measure, and treatment discontinuation due to any cause was used as a general measure of treatment "acceptability." The authors assigned up to 50 points each to the "efficacy" and "acceptability" outcomes, and by adding up these scores, they ranked antimanic agents along their efficacy-acceptability dimension. On the basis of their criteria, the authors ranked the highest as haloperidol, risperidone, and olanzapine, followed by lithium, quetiapine, aripiprazole, and carbamazepine, arguing that these findings should influence treatment guidelines. Like in the meta-analysis by Yildiz and colleagues, lamotrigine and topiramate, as well as gabapentin -- which was only studied in augmentation trials -- did not separate from placebo.

Several limitations complicate the interpretation of these results and the conclusions of the authors. First, treatment recommendations were based on 3-week data only, although long-term and maintenance effects might even be more relevant for the overall treatment effectiveness. Second, the measure of all-cause discontinuation is hardly a good measure of acceptability. This might have been assessed better by analyzing rates of discontinuation due to intolerability, nonadherence, or individual adverse effects that have relevant short-term and, especially, long-term implications, such as parkinsonian side effects, weight gain, sexual dysfunction, tardive dyskinesia, and metabolic and endocrine abnormalities. Third, the 95% CIs for the effect sizes of acute symptom reduction and for the response rates were largely overlapping among the agents that were more effective than placebo, calling into question the singling out of haloperidol, risperidone, and olanzapine. Finally, the validity of class comparisons that includes indirect comparisons across different cohorts studied under different conditions and at different times, as done in a network meta-analysis, is not entirely clear. For example, the 3 purportedly most effective agents were studied earlier than most of the other agents. Because effect sizes of clinical trials have systematically declined over the last decades, due to larger dropout and placebo response rates, comparisons spanning multiple decades can be biased by a cohort effect that can lead to a potentially unjustified conclusion that older medications are superior to newer ones.


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