Mean Young Mania Rating Scale score changes: CI indicates confidence interval; SMD, standardized mean difference. Mean rates of somnolence: CI indicates confidence interval. Mean rates of extrapyramidal adverse effects: Meta-analyses addressing the use of SGAs in the treatment of acute mania are lacking. The SGAs were significantly more efficacious than placebo. The analysis demonstrated that adding antipsychotic agents to MS treatment was significantly more effective than treatment with MSs alone.
Some SGAs seemed to induce more extrapyramidal symptoms than placebo. The SGAs were also associated with higher rates of somnolence than placebo.
Mood stabilizers MSs and first-generation antipsychotic agents have long been the mainstay of treatment of acute mania with and without psychotic features.
However, there are reports of first-generation antipsychotics inducing or worsening depressive symptoms in patients with bipolar disorder. In recent years, second-generation antipsychotic SGA agents have been developed and have proved to be effective in the treatment of bipolar mania.
The SGAs do not seem to induce depressive episodes, and recent studies 4 , 5 revealed that some SGAs may have antidepressant effects. Fountoulakis et al 6 recently reviewed treatment guidelines for bipolar disorder. Their investigation revealed that guidelines for the treatment of bipolar disorder vary significantly across committees or specialist groups.
In particular for the treatment of acute mania, some guidelines recommend monotherapy with an MS or an SGA drug as first-line treatment, whereas others recommend a combination of an MS and an antipsychotic agent. However, meta-analyses addressing the efficacy and effectiveness of SGAs in the treatment of acute mania are lacking. All published and unpublished randomized controlled trials that assessed the efficacy of SGAs aripiprazole, amisulpride, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zotepine in the treatment of mania were searched for in the PsiTri database http: PsiTri is a register of controlled trials that compiles the registers of all Cochrane review groups in the field of mental health.
The registers of the single Cochrane review groups are compiled by means of regular searches of numerous electronic databases and conference abstract books and hand searches of major journals the exact search strategies of the individual review groups are listed in The Cochrane Library The abstracts, titles, and index terms of studies were searched using the following key words: They were also contacted for the provision of missing data necessary for the meta-analysis. A rating based on the 3 quality categories described in The Cochrane Collaboration Handbook 11 was given for each trial: A indicates low risk of bias adequate allocation concealment ; B, moderate risk of bias some doubt about the results, mainly studies said to be randomized but without an explanation of the method ; and C, high risk of bias clearly inadequate allocation concealment, eg, alternate randomization.
Only trials belonging to categories A and B were included. Two of us H. Any disagreement was discussed, and the decisions were documented. Further outcome parameters were the rate of response and effectiveness criteria, such as the number of participants leaving the study early dropouts for any reason, dropouts due to adverse events, dropouts due to inefficacy, mean weight gain, rate of somnolence, and EPSs. For response, the definition used by the authors of the original studies was adopted by the reviewers.
In a once randomized—analyzed approach last observation carried forward method we assumed in the case of dichotomous data that participants who dropped out before completion had no change in their condition unless otherwise stated. Continuous data had to be reported as presented in the original studies without any assumptions about those lost to follow-up. The outcome data were combined in a meta-analysis. When standard deviations were not indicated we either derived them from P values or used the mean standard deviations of the other studies.
Whereas many meta-analysts preferred to use odds ratios some years ago, it has been shown that the RR is more intuitive 14 and that odds ratios tend to be interpreted as RRs by physicians. The random-effects model of DerSimonian and Laird 16 was used in all cases. Random-effects models are, in general, more conservative than fixed-effects models because they take heterogeneity among studies into account, even if this heterogeneity is not statistically significant.
Results of the pooled analyses, which were statistically significantly heterogeneous, were noted in the results. In the case of significant differences between groups, the number of participants needed to treat NNT and the number of participants needed to harm NNH were calculated.
For this purpose we calculated risk differences RDs in addition to RRs. Studies with negative results are less likely to be published than studies with significant results.
The possibility of such publication bias was examined using the funnel plot method described by Egger and colleagues. The exact formulas were reported there. We conducted 4 comparisons: In addition, in each comparison SGAs were entered in an exploratory pooled analysis. The latter results are detailed only in cases in which they were not heterogeneous. A total of 24 studies dealing with all the SGAs except zotepine and amisulpride were included eTable 1 and eTable 2. These studies could be classified according to 4 different comparisons Table 1: The baseline mania scores were similar in all the trials except 2 studies with more 25 or less 33 severely manic patients.
The duration of most studies was 3 weeks; however, 3 studies investigated a 4-week period 21 , 31 , 32 and 2 a 6-week period. The 3-week data were used for the analysis.
Each of these trials was matched for episode type. Given the small number of studies, the use of funnel plots a method based on symmetry was appropriate only for SGAs vs placebo. The plots on the primary efficacy outcomes did not suggest publication bias. The plot on dropouts regardless of reason was the only asymmetrical one, but it remains unclear whether a study was unpublished in case an SGA failed to prove superiority in terms of dropout rate.
Figure 1 displays the results of the primary outcome YMRS score changes , and Table 2 gives the pooled results of the secondary outcome parameters. Each individual SGA agent was significantly superior to placebo in treating acute manic symptoms Figure 1. Response rates were significantly higher in the aripiprazole, olanzapine, risperidone, and ziprasidone trials but not in the quetiapine trials.
The analysis revealed a significantly lower global dropout rate in patients treated with olanzapine and risperidone but not with aripiprazole, quetiapine, and ziprasidone. Dropout due to adverse events did not differ between treatments. Except for aripiprazole, the dropout rate due to inefficacy was lower for SGAs and for the pooled data compared with placebo.
Weight gain was significantly greater in patients treated with olanzapine and quetiapine but not with the other SGAs. All the SGAs exhibited significantly higher rates of somnolence Figure 2.
In addition, increased EPS rates were found for ziprasidone. There were no overall differences in the symptom severity of EPS measures using the Simpson Angus Scale or the Extrapyramidal Symptom Rating Scale in the aripiprazole, olanzapine, risperidone, and ziprasidone trials. Akathisia, however, assessed using the Barnes Akathisia Scale, proved to be significantly more pronounced in patients treated with aripiprazole and ziprasidone. Five studies investigated olanzapine, quetiapine, and risperidone vs the MSs valproate sodium 29 , 30 or lithium 22 , 31 , 32 Table 1.
Figure 4 displays the results of the primary outcome YMRS score changes , and Table 3 gives the pooled results of the secondary outcome parameters. Olanzapine compared with valproate showed greater symptom improvement Figure 4. In no other trials were differences between the comparative treatments found.
Response rates were reported in 2 trials only. In the quetiapine vs lithium comparison, no difference was observed. As to the global dropout rate and the dropout rates due to adverse events or inefficacy, no differences between SGAs and MSs could be discerned. Patients treated with olanzapine and quetiapine had greater weight gain and a greater rate of somnolence than those treated with lithium or valproate data for risperidone were not available.
In these studies, the rates of EPS were not reported. One trial 38 did not report previous treatment. Figure 5 displays the results of the primary outcome YMRS score changes , and Table 4 gives the pooled results of the secondary outcome parameters.
Compared with placebo as add-on medication to MSs, statistically significant superiority in improving manic symptoms was found for olanzapine, quetiapine, and risperidone but not for ziprasidone Figure 5. Considered as a group, the SGAs were significantly superior. The percentage of patients with a response was much higher in groups of patients who received add-on treatment with olanzapine and quetiapine but not with risperidone data for ziprasidone were not available.
Analysis of all the trials showed a significant advantage for combination therapy. The global dropout rate was significantly lower in patients treated with MSs plus quetiapine or risperidone than in those treated with MSs plus placebo. No difference was found for olanzapine and ziprasidone. Analysis of all the trials showed a significantly reduced global dropout rate in patients treated with combination therapy.
In studies with quetiapine, risperidone, and ziprasidone, adverse event dropout rates were not different; they were, however, higher for olanzapine than for placebo add-on treatment. There was no overall difference between the active treatment and placebo groups. Regarding the dropout rate due to inefficacy, a significant advantage for combination therapy was shown in the olanzapine study but not for quetiapine and risperidone data for ziprasidone were not available. The combined dropout rate due to inefficacy was significantly lower in patients treated with combination therapy.
Mean weight change was increased in patients treated with olanzapine, risperidone, and quetiapine data for ziprasidone were not available. The rate of somnolence was significantly higher in patients treated with olanzapine, quetiapine, and ziprasidone but not with risperidone. The pooled analysis revealed a significantly higher rate of somnolence in patients treated with MSs plus SGAs.
Data on EPS rates were reported only in the risperidone and ziprasidone trials. The incidence of EPSs was higher with ziprasidone than with placebo but not with risperidone vs placebo. We included 2 studies investigating aripiprazole 39 and olanzapine 40 vs haloperidol and the branches of 3 further studies analyzing quetiapine 23 and risperidone 26 , 32 vs haloperidol Table 1.
Figure 6 displays the results of the primary outcome YMRS score changes , and Table 5 gives the pooled results of the secondary outcome parameters. Reduction in manic symptoms was similar for aripiprazole and risperidone compared with haloperidol. The response rates did not differ between SGAs and haloperidol. The analysis revealed a significantly lower global dropout rate in patients treated with aripiprazole and a trend toward a higher rate in patients treated with quetiapine.
For olanzapine and risperidone, no difference was observed.More...