title: Safety and tolerability of antipsychotic co-treatment in patients with schizophrenia: results from a systematic review and meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  Antipsychotic co-treatment is common in schizophrenia, despite lacking evidence for its efficacy and safety. Areas: We conducted a systematic search of PubMed/PsycInfo/CJN/WangFan/CBM without language restrictions from database inception until 05/25/2015 for randomized trials comparing antipsychotic monotherapy with antipsychotic co-treatment in ≥20 adults with schizophrenia reporting meta-analyzable adverse events (AEs) data. Meta-analyzing 67 studies (n=4,861, duration=10.3±5.2 weeks), antipsychotic co-treatment was similar to monotherapy regarding intolerability-related discontinuation (risk ratio (RR)=0.84, 95% confidence interval (CI)=0.53-1.33, p=0.455). While incidence of ≥1 AE was lower with antipsychotic co-treatment (RR=0.77, 95%CI=0.66-0.90, p=0.001), these results were solely driven by open-label and efficacy-focused studies. Adjunctive D2-antagonists lead to less nausea (RR=0.220, 95%CI=0.06-0.87, p=0.030) and insomnia (RR=0.26, 95%CI=0.08-0.86, p=0.028), but higher prolactin (SMD=2.20, 95%CI=0.43-3.96, p=0.015). Conversely, adjunctive partial D2-agonists (aripiprazole=100%) resulted in lower electrocardiogram abnormalities (RR=0.43, 95%CI=0.25-0.73, p=0.002), constipation (RR=0.45, 95%CI=0.25-0.79, p=0.006), drooling/hypersalivation (RR=0.14, 95%CI=0.07-0.29, p<0.001), prolactin (SMD=-1.77, 95%CI=-2.38, -1.15, p<0.001), total and LDL-cholesterol (SMD=-0.33, 95%CI=-0.55, -0.11, p=0.003; SMD=-0.33, 95%CI=-0.54, -0.10, p=0.004).
  
  
  CONCLUSIONS
  No double-blind evidence for altered AE burden associated with antipsychotic co-treatment was found. However, AEs were insufficiently and incompletely reported and follow-up duration was modest. Adjunctive partial D2-agonists might be beneficial for counteracting several AEs. High-quality, long-term studies that comprehensively assess AEs are needed.
authors.affiliation: a The Zucker Hillside Hospital , Psychiatry Research, Northwell Health , Glen Oaks , NY , USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Galling
authors.affiliation: b Department of Psychiatry, Institut d'Investigació Biomédica-Sant Pau (IIB-SANT PAU) , Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB) , Barcelona , Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Roldán
authors.affiliation: c University Hospital of Child and Adolescent Psychiatry and Psychotherapy , University of Bern , Bern , Switzerland.
authors.forename: Liz
authors.initials: L
authors.lastname: Rietschel
authors.affiliation: a The Zucker Hillside Hospital , Psychiatry Research, Northwell Health , Glen Oaks , NY , USA.|d Sumitomo Dainippon Pharma Co., Ltd., Medical Affairs , Tokyo , Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hagi
authors.affiliation: a The Zucker Hillside Hospital , Psychiatry Research, Northwell Health , Glen Oaks , NY , USA.
authors.forename: Frozan
authors.initials: F
authors.lastname: Walyzada
authors.affiliation: e Department of Psychiatry, Guangzhou Brain Hospital (Guangzhou Huiai Hospital), Affilated Hospital of Guangzhou Medical University , Guangzhou , China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: f Department of Psychiatry , Chinese University of Hong Kong , Hong Kong , China.
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Cao
authors.affiliation: g Unit of Psychiatry, Faculty of Health Sciences , University of Macau , Macao , China.
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Xiang
authors.affiliation: a The Zucker Hillside Hospital , Psychiatry Research, Northwell Health , Glen Oaks , NY , USA.|h Hofstra North Shore LIJ School of Medicine , Hempstead , NY , USA.|i The Feinstein Institute for Medical Research , Manhasset , NY , USA.|j Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Kane
authors.affiliation: a The Zucker Hillside Hospital , Psychiatry Research, Northwell Health , Glen Oaks , NY , USA.|h Hofstra North Shore LIJ School of Medicine , Hempstead , NY , USA.|i The Feinstein Institute for Medical Research , Manhasset , NY , USA.|j Albert Einstein College of Medicine , Bronx , NY , USA.
authors.forename: Christoph U
authors.initials: CU
authors.lastname: Correll
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D054333:Drug Partial Agonism; D004359:Drug Therapy, Combination; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2
keywords: Antipsychotics; adverse effects; augmentation; combination; cotreatment; metaanalysis; monotherapy; polypharmacy; safety; schizophrenia; tolerability