The LAI-Oral Antipsychotic Efficacy-Effectiveness Paradox in Schizophrenia.

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Abstract

<i>Background and Objectives</i>: Long-acting injectable (LAI) antipsychotics are associated with reduced hospitalization and relapse in real-world observational studies of schizophrenia; however, randomized controlled trials (RCTs) demonstrate no statistically significant advantage over oral antipsychotics for relapse prevention. This efficacy-effectiveness paradox has remained unresolved in the literature for decades and has directly contributed to the persistent underutilization of LAIs in clinical practice. <i>Objective</i>: To examine the methodological sources of the LAI efficacy-effectiveness paradox and to propose four conceptual, precision-medicine-informed methodological solutions, including artificial intelligence (AI)-supported neuroimaging, to guide the design of future comparative effectiveness research. <i>Materials and Methods</i>: This report comprises two components: Part I, a scoping review of existing comparative studies, conducted and reported in accordance with the PRISMA extension for scoping reviews (PRISMA-ScR); and Part II, a conceptual methodological framework proposed by the authors on the basis of gaps identified in Part I, which is not itself a product of systematic scoping-review methodology. For Part I, we searched PubMed, EMBASE, PsycINFO, and the Cochrane Library from January 2000 to March 2026. Search terms included 'long-acting injectable antipsychotics,' 'oral antipsychotics,' 'schizophrenia,' 'medication adherence,' 'confounding by indication,' 'pharmacogenomics,' 'CYP2D6,' 'digital medicine,' 'pragmatic trials,' 'positron emission tomography,' 'functional magnetic resonance imaging,' 'neuroimaging,' 'machine learning,' and 'artificial intelligence. <i>Results:</i> The paradox is primarily explained by confounding by indication in observational studies and inadequate adherence measurement across all study designs (Part I). On this basis, we propose, as a conceptual framework rather than a validated finding, four methodological solutions (Part II): (1) objective digital adherence monitoring via ingestible sensor or equivalent technology, subject to explicit informed consent and comprehensive ethical safeguards; (2) pharmacogenomic stratification using CYP2D6, CYP3A4, and CYP2C19 metaboliser phenotyping to control for pharmacokinetic confounding specific to antipsychotic drug metabolism; (3) pragmatic RCT designs with real-world eligibility criteria and objective primary adherence endpoints; and (4) artificial intelligence-supported neuroimaging positron emission tomography (PET)-derived dopamine receptor occupancy and machine learning analysis of functional magnetic resonance imaging (fMRI) connectivity data as an objective pharmacodynamic and predictive complement to the three adherence- and pharmacokinetics-focused solutions. <i>Conclusions:</i> Current evidence on LAI versus oral antipsychotic superiority cannot be considered definitive. Integration of digital monitoring, pharmacogenomics, pragmatic trial design, and AI-supported PET and fMRI neuroimaging into future research represents a necessary methodological correction that could resolve decades of contradictory findings and provide clinicians with genuinely actionable, patient-centered evidence.

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