Efficacy and Effectiveness of Antipsychotics in Schizophrenia: Combining Evidence from Randomised Controlled Trials and Real-World.

Abstract

Background: There is debate about the generalisability of results from randomised clinical trials (RCTs) to ‘real-world’ (RW) settings. Studying outcomes of treatments for schizophrenia can shed light on this issue and inform treatment guidelines. We therefore compared the efficacy (RCT) and effectiveness (RW) of antipsychotics for relapse prevention in schizophrenia and estimated overall treatment effects utilizing all available RCT and RW evidence. Methods: We conducted network meta-analyses (NMAs) using individual participant data from Swedish and Finnish national registries and aggregate data from RCTs. The target population was people with schizophrenia and schizoaffective disorder with stabilized symptoms. We analysed each registry separately to obtain hazard ratios (HRs) and 95% Confidence Interval (CI) for relapse within 6 months post-antipsychotic initiation as our main outcome. Interventions were antipsychotics, no antipsychotic use, and placebo. We compared HRs vs a reference drug (oral haloperidol) between registries, and between registry individuals who would be eligible and ineligible for RCTs, using the ratio of HRs (RHR). We synthesized evidence using NMA and compared results from our RW-NMA with our RCT-NMA, including oral vs long-acting injectable (LAI) formulations. Finally, we conducted a joint RW/RCT-NMA. Findings: We included 90,469 individuals from the Swedish and Finnish registries (mean age 45·9 (SD 14·6) years; of whom N=43,025 (48%) were women) and 10,091 individuals from 30 RCTs (mean age 39·6 years (SD 11·7); N=3,724 (36·9%) women). Ethnicity data were unavailable in the registries. We found good agreement in effectiveness of antipsychotics between Swedish and Finnish registries (RHR 0·97, 95%CI [0·88; 1·08]). Drug effectiveness vs no antipsychotic was larger in RCT-eligible than RCT-ineligible individuals (RHR 1·40 [1·24; 1·59]). Efficacy vs 4 placebo in RCTs was larger than effectiveness vs no antipsychotic in RW (RHR 2·58 [2·02; 3·30]). We found no evidence of differences between effectiveness and efficacy for between-drug comparisons (RHR vs haloperidol oral 1·17 [0·83; 1·65], where RHR>1 means superior effectiveness in RW to RCTs), except for LAI vs oral comparisons (RHR 0·73 [0·53; 0·99], indicating superior effectiveness in RW relative to RCTs). The RW-NMA showed clozapine was most effective, followed by olanzapine LAI. The RCT-NMA exhibited heterogeneity and inconsistency. The RW/RCT-NMA identified olanzapine as the most efficacious antipsychotic amongst those present in both RCTs and RW. Interpretation: LAI antipsychotics perform slightly better in RW than according to RCTs. Otherwise, RCT evidence was in line with RW evidence for most between-drug comparisons, but RCTs ma overestimate effectiveness of antipsychotics observed in routine care settings. Our results further the understanding of the generalisability of RCT findings to clinical practice and may inform preferential prescribing guidelines.