Review
Comparative efficacy and acceptability of mood stabilizer and second generation antipsychotic monotherapy for acute mania — A systematic review and meta-analysis

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Abstract

Background

All treatment guidelines for acute mania recommend monotherapy with either mood stabilizers (MS) or antipsychotics. The objective of this analysis was to compare the efficacy and acceptability of both drug classes in an expanded set of clinical trials in acute mania.

Method

Randomized double-blind trials comparing MS vs second generation antipsychotics (SGA) in acute mania were identified in a systematic literature search. Change in mania rating scale, responder rates and dropout rates were compared by treatment assignment using Review Manager version 5.0.

Results

Nine studies totaling 1631 patients that compared the MS lithium or valproate against a number of SGAs, and which reported one or more analysis endpoints were identified. Statistically significant advantages were noted in favour of SGA over MS for standardized mean difference (SMD) for change in mania scores (− 0.22 [95% CI − 0.33 to − 0.11]; p < 0.0001), responder rate risk difference (7% [95% CI 1% to 13%]; p = 0.02), and dropout risk difference (− 5% [95% CI − 10% to − 1%]; p = 0.02). This change in SMD for mania scores is equivalent to a 2.5–3 point difference in Young Mania Rating Scale score. Similar trends for SMD were noted when comparing subgroups of lithium and valproate studies against SGAs.

Limitations

Over half the included studies included olanzapine, and the applicability of these findings, especially to first generation antipsychotic drugs, requires confirmation. This analysis could not assess the relative efficacy of combined MS/SGA vs individual monotherapies.

Conclusion

In acute mania, monotherapy with SGAs demonstrates statistically significant advantages over MS in terms of both efficacy and acceptability, and may be preferable for initial choice of treatment.

Introduction

Acute mania is a disorder characterized by an abnormal elevation of mood along with impaired judgment, and disinhibition (American Psychiatric Association, 1994). In general urgent pharmacological management is required to normalize mood, along with hospitalization, as patients are at risk of behaviour that may harm themselves or others (Belmaker, 2004). A number of pharmacological interventions have been shown to be effective in acute mania, including mood stabilizers (MS) such as sodium valproate, lithium and carbamazepine, and both first and second generation antipsychotics (SGAs), as well as combinations of SGA and MS (Fountoulakis and Vieta, 2008). Monotherapy with SGAs or MS are both recommended for acute mania in all recent treatment guidelines (Goodwin, 2009, Yatham et al., 2009, Grunze et al., 2009, Scottish Intercollegiate Guidelines Network, 2005, Suppes et al., 2005, National Institute for Health Clinical Excellence, 2006, American Psychiatric Association, 2002, Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Bipolar Disorder, 2004), although the process for deriving these guidelines has been criticized (Fountoulakis et al., 2005). Comparing the relative efficacy of these drug classes has been limited by a paucity of head-to-head studies. Whereas monotherapy with SGAs or MS is clearly more efficacious than placebo (Scherk et al., 2007, Perlis et al., 2006, Smith et al., 2007), comparison of monotherapy with MS vs SGA reported similar effect sizes for responder rates (Smith et al., 2007). Another analysis of studies which directly compared MS and SGA monotherapy reported no statistically significant difference between these classes (Scherk et al., 2007). Since these analyses, additional large comparative studies of MS vs SGAs have been completed. The objective of this structured review and meta-analysis was to re-evaluate the comparative efficacy and acceptability of MS and SGA monotherapy in acute mania.

Section snippets

Methods

In this meta-analysis we aimed to identify all drug treatment trials comparing MS and SGA as monotherapy in DSM-IV (American Psychiatric Association, 1994) acute mixed or manic episodes. We selected only those studies that were double blinded, and used randomized allocation to study treatment arms. Studies between 1/1/1950 and 1/12/2009 were included. We attempted to include both published and unpublished studies, through electronic database searches, searches of clinical and pharmaceutical

Results

Fig. 1 summarizes the study selection process. The initial search strategy resulted in 5424 references. This was reduced to 135 studies, on the basis of the title and abstract review. These 135 papers were retrieved and examined. Of these 135 papers a further 126 were excluded, resulting in 9 papers being included in the analysis. The main reasons for exclusion included presentation of duplicate data, and comparison of MS or SGA against placebo or combination therapy (Fig. 1).

Nine studies were

Discussion

This systematic review and meta-analysis has identified that in acute mania, monotherapy with SGAs provides modest but statistically significant advantages over the mood stabilizers valproate and lithium, both in terms of efficacy (greater decrease in mania rating scores score and increased responder rate) and acceptability (lower dropout rate). This effect appears to be independent of type of mood stabilizer. To put the SMD from the present analysis (− 0.22) into a clinical context, this would

Role of the funding source

All authors are employees of the University of Otago. There was no external funding for this analysis.

Conflicts of interest

Professor Herbison and Mr Tarr have no conflicts of interest to report. Professor Glue was employed by Pfizer until 2008.

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