Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis
Britta Galling
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
Search for more papers by this authorAlexandra Roldán
Department of Psychiatry, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Search for more papers by this authorKatsuhiko Hagi
Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA
Sumitomo Dainippon Pharma Co., Tokyo, Japan
Search for more papers by this authorLiz Rietschel
University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
Search for more papers by this authorFrozan Walyzada
Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA
Search for more papers by this authorWei Zheng
Guangzhou Brain Hospital, Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Search for more papers by this authorXiao-Lan Cao
Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorYu-Tao Xiang
Unit of Psychiatry, Faculty of Health Sciences, University of Macao, Taipa, Macao, SAR, China
Search for more papers by this authorMathias Zink
Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Search for more papers by this authorJohn M. Kane
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
Search for more papers by this authorJimmi Nielsen
Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Search for more papers by this authorStefan Leucht
Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universität München, Munich, Germany
Search for more papers by this authorChristoph U. Correll
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
Search for more papers by this authorBritta Galling
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
Search for more papers by this authorAlexandra Roldán
Department of Psychiatry, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Search for more papers by this authorKatsuhiko Hagi
Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA
Sumitomo Dainippon Pharma Co., Tokyo, Japan
Search for more papers by this authorLiz Rietschel
University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
Search for more papers by this authorFrozan Walyzada
Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA
Search for more papers by this authorWei Zheng
Guangzhou Brain Hospital, Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Search for more papers by this authorXiao-Lan Cao
Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China
Search for more papers by this authorYu-Tao Xiang
Unit of Psychiatry, Faculty of Health Sciences, University of Macao, Taipa, Macao, SAR, China
Search for more papers by this authorMathias Zink
Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Search for more papers by this authorJohn M. Kane
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
Search for more papers by this authorJimmi Nielsen
Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Search for more papers by this authorStefan Leucht
Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universität München, Munich, Germany
Search for more papers by this authorChristoph U. Correll
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
Search for more papers by this authorAbstract
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.
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