title: Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis.
abstract: Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random effects meta-analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co-primary outcomes were total symptom reduction and study-defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N=694, standardized mean difference, SMD=-0.53, 95% CI: -0.87 to -0.19, p=0.002). However, superiority was only apparent in open-label and low-quality trials (both p<0.001), but not in double-blind and high-quality ones (p=0.120 and 0.226, respectively). Study-defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N=938, risk ratio = 1.19, 95% CI: 0.99 to 1.42, p=0.061), being clearly non-significant in double-blind and high-quality studies (both p=0.990). Findings were replicated in clozapine and non-clozapine augmentation studies. No differences emerged regarding all-cause/specific-cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N=931, SMD=-0.38, 95% CI: -0.63 to -0.13, p<0.003), but only in studies augmenting with aripiprazole (8 studies, N=532, SMD=-0.41, 95% CI: -0.79 to -0.03, p=0.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p=0.028), but more prolactin elevation (p=0.015), while aripiprazole augmentation was associated with reduced prolactin levels (p<0.001) and body weight (p=0.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double-blind/high-quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation.
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatic Medicine and Psychotherapy, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Galling
authors.affiliation: Department of Psychiatry, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Roldán
authors.affiliation: Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA.|Sumitomo Dainippon Pharma Co., Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hagi
authors.affiliation: 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: Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA.
authors.forename: Frozan
authors.initials: F
authors.lastname: Walyzada
authors.affiliation: Guangzhou Brain Hospital, Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Cao
authors.affiliation: Unit of Psychiatry, Faculty of Health Sciences, University of Macao, Taipa, Macao, SAR, China.
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Xiang
authors.affiliation: Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Zink
authors.affiliation: Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, USA.|Feinstein Institute for Medical Research, Manhasset, NY, USA.|Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Kane
authors.affiliation: Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Jimmi
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universität München, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Leucht
authors.affiliation: Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, USA.|Feinstein Institute for Medical Research, Manhasset, NY, USA.|Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Christoph U
authors.initials: CU
authors.lastname: Correll
keywords: Antipsychotics; aripiprazole; augmentation; clozapine; monotherapy; polypharmacy; schizophrenia