Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis

• Published in: The Lancet (British edition) 2019-09, Vol.394 (10202), p.939-951
• Main Authors: Huhn, Maximilian, Nikolakopoulou, Adriani, Schneider-Thoma, Johannes, Krause, Marc, Samara, Myrto, Peter, Natalie, Arndt, Thomas, Bäckers, Lio, Rothe, Philipp, Cipriani, Andrea, Davis, John, Salanti, Georgia, Leucht, Stefan
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adults; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - adverse effects; Antipsychotic Agents - therapeutic use; Antipsychotics; Balances (scales); Biomedical research; Clinical decision making; Clinical trials; Clozapine; Comparative Effectiveness Research - methods; Confidence; Control methods; Decision making; Disorders; Drug dosages; Drugs; Effectiveness; Emotional behavior; Evidence-based medicine; Flupenthixol; Health services; Humans; Illnesses; Medical research; Mental depression; Mental disorders; Meta-analysis; Moderators; Patients; Prolactin; Prolongation; Psychotropic drugs; Quality of life; Randomization; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenia - drug therapy; Sensitivity analysis; Side effects; Signs and symptoms; Statistical analysis; Sulpiride; Systematic review; Treatment Outcome; Treatment resistance; Ziprasidone
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(19)31135-3

Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials. We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919. We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from −0·89 (95% CrI −1·08 to −0·71) for clozapine to −0·03 (−0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from −0·69 (95% CrI −0·86 to −0·52) for amisulpride to −0·17 (−0·31 to −0·04) for brexpiprazole, for negative symptoms (32 015 participants) from −0·62 (−0·84 to −0·39; clozapine) to −0·10 (−0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from −0·90 (−1·36 to −0·44; sulpiride) to 0·04 (−0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause dis