Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Pharmacological interventions for acute bipolar mania: systematic review of randomized placebo-controlled trials. Bipolar Disord 9: 551-560

Medical Research Matters, Eynsham, UK.
Bipolar Disorders (Impact Factor: 4.97). 09/2007; 9(6):551-60. DOI: 10.1111/j.1399-5618.2007.00468.x
Source: PubMed


We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials in acute bipolar mania to summarize available data on drug treatment of mania.
We included trials of medications licensed in the USA or UK for the treatment of any phase of bipolar disorder. Outcomes investigated were changes in mania scores, attrition, extrapyramidal effects and weight change. Data were combined through meta-analyses.
We included 13 studies (involving 3,089 subjects) and identified 2 studies for each of the following medications: carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone, valproate semisodium and aripiprazole. All drugs showed significant benefit compared with placebo for reduction in mania scores. Compared with placebo, for all antipsychotics pooled, response to treatment (> or =50% reduction in Young Mania Rating Scale scores) was increased more than 1.7 times [relative risk (RR) = 1.74, 95% confidence interval (CI) = 1.54, 1.96]; for all mood stabilizers pooled, response to treatment was doubled (RR 2.01, 95% CI = 1.66, 2.43). Overall withdrawals were 34% fewer (24-43%) with antipsychotics, and 26% fewer (10-39%) with mood stabilizers. However, for carbamazepine, aripiprazole and lithium an increase in risk of withdrawal could not be excluded. Small but significant increases in extrapyramidal side effects occurred with risperidone and aripiprazole.
Antipsychotics and mood stabilizers are significantly more effective than placebo for the treatment of acute mania. Their effect sizes are similar. Small differences between effect sizes may be due to differences in the patients included in the studies or to chance. Carbamazepine and lithium may be more poorly tolerated, and antipsychotics cause more extrapyramidal side effects.

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    • "Leucht et al (2009) in a metaanalytic review of 38 studies reported a difference of only nine points on the brief psychiatric rating scale between SGAs and placebo in patients diagnosed with schizophrenia. The few previous meta-analytic assessments of relative efficacy of treatments for mania usually involved selective consideration of agents of particular interest, and none has considered outcomes of all available RCTs, as identified through clinical trial registries (Emilien et al, 1996; Perlis et al, 2006b; Scherk et al, 2007; Smith et al, 2007; Tohen et al, 2001). Indeed, bias toward reporting favorable trials, as well as alleged delays or failure to report details of trials not showing separation of a novel treatment from placebo, probably have limited or biased information available (Vieta and Cruz, 2008). "

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    • "In a recent meta-analysis of randomized controlled studies comparing one active antimanic drug with another one or with placebo including combination and augmentation studies, risperidone, olanzapine, and haloperidol have shown the best efficacy profile in the treatment of acute mania while lamotrigine, topiramate, and gabapentin were not significantly better than placebo (Cipriani et al., 2011). In another meta-analysis of co-therapy and monotherapy in acute bipolar mania, Smith et al. (2007) analyzed 8 RCTs including 1124 patients and found that significant reductions in mania (>50% reduction from baseline at YMRS scores) were shown for haloperidol, olanzapine, risperidone, and quetiapine as co-therapy combined with a mood stabilizer even if combination was less well tolerated as compared with monotherapy. Goodwin et al. (2009), during the ECNP consensus meeting, suggested that conventional two-arm trial designs could benefit form adding a third antipsychotic monotherapy arm in order to improve data from studies which compare and quantify the efficacy of antipsychotics in monotherapy or in combination. "
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    • "While older clinical trials for mania medications were conducted with less rigorous methodological requirements and did not necessarily satisfy current scientific criteria (comparative, randomized, doubleblind design), more recent studies have validated the efficacy of a variety of anti-manic drugs (Grunze et al., 2009). It is relevant to note, however, that treatment efficacy is most commonly defined as a 50% improvement on subjective measures such as the Young Mania Rating Scale (YMRS) (Smith et al., 2007), while objective quantification of manic symptoms such as motor hyperactivity is rarely assessed (Henry et al., 2010). Recent investigations indicate that genetic variation in BD could also play a important role in treatment effects; the response to lithium therapy may relate to variants in genes that code for the serotonin transporter, glycogen synthase kinase 3 (GSK-3) and inositol monophosphatase (IMPase) proteins (Cruceanu et al., 2006). "
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