Findings We identified 14 687 records, of which 137 studies (397 319 patients) met the inclusion criteria (32 RCTs [23?4%; 8577 patients], 65 cohort studies [47?4%; 377 447 patients], and 40 pre?post studies [29?2%; 11 295 patients]) and were analysed. The quality of studies in terms of risk of bias varied across study designs and within each study design from low to high. LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs (RCTs: 29 studies, 7833 patients, RR 0?88 [95% CI 0?79?0?99], p=0?033; cohort studies: 44 studies, 106 136 patients, RR 0?92 [0?88?0?98], p=0?0044; pre?post studies: 28 studies, 17 876 patients, RR 0?44 [0?39?0?51], p<0?0001). This association was maintained across the study designs when we reversed the preferential order to risk of relapse over hospitalisation, and in individual analysis of hospitalisation risk. The association was maintained only in pre?post studies for relapse risk alone. In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18?3%) of 328 comparisons, not different in 252 (76?8%) comparisons, and less beneficial in 16 (4?9%) comparisons when analysed by study design. Significant heterogeneity was observed across all three study designs. Publication biases were apparent in cohort and pre-post studies, but effect sizes were similar after trim-and-fill analyses. Interpretation Although study designs have strengths and weaknesses, including potential low quality of observational studies, we consistently identified significant benefit with LAIs versus oral antipsychotics in preventing hospitalisation or relapse, in settings ranging from restricted research (RCTs) to real-word application (cohort and pre?post studies). Our findings suggest that increased clinical use of LAIs could improve outcomes in schizophrenia. Summary Background Evidence of comparative benefits of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics for schizophrenia has been inconsistent across study designs. The aim of this study was to evaluate the comparative benefits of LAIs versus oral antipsychotics in three study designs to inform clinical decision making. Methods We did a comprehensive systematic review and meta-analysis comparing LAIs versus oral antipsychotics for schizophrenia covering three study designs: randomised controlled trials (RCTs), cohort studies, and pre-post studies. Our literature search was without language restrictions, in MEDLINE and PubMed, the Cochrane Library, Scopus, and Embase, for studies published from database inception up to a last search on March 13, 2020. We also searched for unpublished studies and ClinicalTrials.gov. We included studies lasting at least 6 months that targeted adults with schizophrenia and related disorders (>80% of participants). Studies on penfluridol (neither an LAI or daily oral antipsychotic), case reports, and case series with fewer than 20 patients were excluded. Two investigators independently extracted study-level data and resolved disagreement by consensus, or via a third investigator. Study authors were contacted to obtain additional information as needed. For our primary outcome we meta-analysed the risk ratio (RR) for hospitalisation or relapse with LAIs versus oral antipsychotics by a random-effects model, with hospitalisation used preferentially over relapse. As secondary analyses, we reversed the preferential order to relapse over hospitalisation, and assessed hospitalisation risk and relapse risk individually. Other secondary outcomes included all meta-analysable data, classed by relevance to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, and analysed by study design. Dichotomous outcomes were expressed as pooled RR and continuous outcomes as standardised mean difference (SMD). The protocol is registered with PROSPERO (CRD42019142094). Findings We identified 14 687 records, of which 137 studies (397 319 patients) met the inclusion criteria (32 RCTs [23middot4%; 8577 patients], 65 cohort studies [47middot4%; 377 447 patients], and 40 pre-post studies [29middot2%; 11 295 patients]) and were analysed. The quality of studies in terms of risk of bias varied across study designs and within each study design from low to high. LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs (RCTs: 29 studies, 7833 patients, RR 0middot88 [95% CI 0middot79-0middot99], p=0middot033; cohort studies: 44 studies, 106 136 patients, RR 0middot92 [0middot88-0middot98], p=0middot0044; pre-post studies: 28 studies, 17 876 patients, RR 0middot44 [0middot39-0middot51], p<0middot0001). This association was maintained across the study designs when we reversed the preferential order to risk of relapse over hospitalisation, and in individual analysis of hospitalisation risk. The association was maintained only in pre-post studies for relapse risk alone. In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18middot3%) of 328 comparisons, not different in 252 (76middot8%) comparisons, and less beneficial in 16 (4middot9%) comparisons when analysed by study design. Significant heterogeneity was observed across all three study designs. Publication biases were apparent in cohort and pre-post studies, but effect sizes were similar after trim-and-fill analyses. Interpretation Although study designs have strengths and weaknesses, including potential low quality of observational studies, we consistently identified significant benefit with LAIs versus oral antipsychotics in preventing hospitalisation or relapse, in settings ranging from restricted research (RCTs) to real-word application (cohort and pre-post studies). Our findings suggest that increased clinical use of LAIs could improve outcomes in schizophrenia.
