title: Mood stabilizers and antipsychotics for acute mania: a systematic review and meta-analysis of combination/augmentation therapy versus monotherapy.
abstract: BACKGROUND
  Pharmacotherapy remains the mainstay of treatment for acute bipolar mania, but there are many choices, including mood stabilizers (MSs) and antipsychotics (APs).
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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].
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan, ogawa.yusuke.2u@kyoto-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Aran
authors.initials: A
authors.lastname: Tajika
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takeshima
authors.forename: Yu
authors.initials: Y
authors.lastname: Hayasaka
authors.forename: Toshi A
authors.initials: TA
authors.lastname: Furukawa
mesh_terms: D000208:Acute Disease; D018692:Antimanic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000523:psychology; D004359:Drug Therapy, Combination; D006801:Humans; D016896:Treatment Outcome
chemical_list: D018692:Antimanic Agents; D014150:Antipsychotic Agents