Comparative effectiveness of long-acting injectable versus oral antipsychotic medication after a first episode of psychosis

Switching to long-acting injectable (LAI) antipsychotic therapy as compared with continuation of oral therapy after a first episode of psychosis (FEP) may reduce the risk of relapse and hospitalization, as reported in some randomized trials. However, other trials and network meta-analyses reported no risk reduction. We emulated two target trials using data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts of people with FEP. The first target trial was designed to ask a similar question as the European Long-Acting Antipsychotics in Schizophrenia Trial (EULAST) trial, which compared the 18-month hospitalization risk between patients assigned to LAI therapy (aripiprazole, risperidone or paliperidone) and those on continuation of oral therapy. We benchmarked the observational estimates to those from the actual trial. The second target trial extended the first to examine the 3-year risks of psychotic relapses and in subgroups (prior relapses, non-adherence, substance use disorder). Of 2,228 individuals with FEP, 1,067 were eligible for the benchmarking analyses. Both our target trial emulation and EULAST showed little effect of LAI therapy initiation on the 18-month hospitalization risk. In the extended analysis (1,193 individuals), the 3-year risk difference of psychotic relapse comparing LAI therapy initiation with oral continuation was –7.0% (95% CI: –12.1, –0.7). The risk difference was substantially lower in subgroups with a prior relapse (–15.5%, 95%CI: –24.1, –5.5) or prior non-adherence (–21.9, 95% CI: –41.9, –2.0). We estimated that, compared with oral therapy continuation, LAI therapy initiation reduced psychotic relapses over 3 years. LAI therapy initiation may be particularly beneficial in vulnerable subgroups. This study reveals that in people with first episode of psychosis receiving oral antipsychotic medication, switching to long-acting injectable antipsychotic therapy may reduce psychotic relapses, especially in vulnerable subgroups, such as those with prior relapses or non-adherence to antipsychotic medication.