CNS Drugs

, Volume 28, Issue 11, pp 989–1003 | Cite as

Mood Stabilizers and Antipsychotics for Acute Mania: A Systematic Review and Meta-Analysis of Combination/Augmentation Therapy Versus Monotherapy

  • Yusuke Ogawa
  • Aran Tajika
  • Nozomi Takeshima
  • Yu Hayasaka
  • Toshi A. Furukawa
Systematic Review



Pharmacotherapy remains the mainstay of treatment for acute bipolar mania, but there are many choices, including mood stabilizers (MSs) and antipsychotics (APs).


To provide an up-to-date and comprehensive review of the efficacy, acceptability and adverse effects of MSs and APs as combination or augmentation therapy versus monotherapy with either drug class for the treatment of acute mania.

Data Sources

The Cochrane Central Register of Controlled Trials, MEDLINE, PsycINFO, Scopus, and clinical trial databases were searched for articles published between the inception of the databases and July 1, 2014. The following keywords were used: [bipolar disorder, mania, manic, mixed bipolar, schizoaffective] combined with the names of MSs and APs. The reference lists of all the identified randomized controlled trials (RCTs), articles that cited the identified trials, and recent systematic reviews were also checked.

Study Selection

Double-blind RCTs comparing MS and AP as combination or augmentation therapy with either monotherapy during the acute phase treatment of mania were included in the present study. The electronic search yielded 6,445 potential articles in September 2013 and 264 new references in an updated search performed in July 2014. Finally, 19 RCTs were considered eligible for our meta-analyses: MS plus AP combination or augmentation therapy was compared with MS monotherapy in 14 trials (n = 3,651) and with AP monotherapy in 6 trials (n = 606) [one study compared combination therapy versus both MS monotherapy and AP monotherapy].

Data Extraction

The primary outcomes were the mean change scores on validated rating scales for mania and all-cause discontinuation at 3 weeks. The secondary outcomes included response, remission, the mean change scores for depression, dropouts due to adverse events and to inefficacy, and adverse events at 3 weeks and mean change scores on validated rating scales at 1 week. Using random-effects models, standardized mean difference (SMD), risk ratio (RR) and numbers needed to treat with their 95 % confidence intervals (CIs) were calculated.


Most patients included in trials comparing combination/augmentation therapy versus MS monotherapy had prior treatment with an MS, while more than 70 % of participants in trials comparing combination/augmentation therapy versus AP monotherapy had not been on medications or were washed out from their previous medication before randomization. MS plus AP combination/augmentation therapy was more effective than MS monotherapy in terms of change in scores on mania rating scales at 3 weeks (SMD −0.26; 95 % CI −0.36 to −0.15) and at 1 week (SMD −0.17, −0.29 to −0.04). MS plus AP combination/augmentation therapy was more effective than AP monotherapy at 3 weeks (SMD −0.31, −0.50 to −0.12), but not at 1 week (SMD −0.22, −0.84 to 0.40). No significant differences were seen between the combination/augmentation therapy and either monotherapy group in study withdrawal for any reason (MS + AP vs. MS monotherapy: RR 0.99, 0.88–1.12; MS + AP vs. AP monotherapy: RR 0.70, 0.47–1.04) or adverse events (MS + AP vs. MS monotherapy: RR 1.39, 0.97–1.99; MS + AP vs. AP monotherapy: RR 0.62, 0.27–1.40). The combination/augmentation therapy was associated with more side effects, especially with somnolence, while it did not increase treatment-emergent depression.


Combining MS and AP is more efficacious and more burdensome than, but overall as acceptable as, the continuation of MS or AP monotherapy, when either monotherapy has not been successful. There is currently no robust evidence to judge whether MS and AP combination therapy is more efficacious than MS monotherapy as the initial therapy for acutely manic patients without prior medication.


Risperidone Risk Ratio Quetiapine Aripiprazole Ziprasidone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



YO, AT and NT have received honoraria for speaking at meetings sponsored by Eli Lilly. YH has no conflicts of interest. TAF has received lecture fees from Eli Lilly, Meiji, Mochida, MSD, Pfizer and Tanabe-Mitsubishi, and consultancy fees from Sekisui and Takeda Science Foundation. He is diplomate of the Academy of Cognitive Therapy. He has received royalties from Igaku-Shoin, Seiwa-Shoten and Nihon Bunka Kagaku-sha. The Japanese Ministry of Education, Science, and Technology, the Japanese Ministry of Health, Labor and Welfare, and the Japan Foundation for Neuroscience and Mental Health have funded his research projects. No sources of funding were used to assist with the preparation of the manuscript.


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Yusuke Ogawa
    • 1
  • Aran Tajika
    • 1
  • Nozomi Takeshima
    • 1
  • Yu Hayasaka
    • 1
  • Toshi A. Furukawa
    • 1
  1. 1.Department of Health Promotion and Human BehaviorKyoto University Graduate School of Medicine/School of Public HealthKyotoJapan

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