Objectives: To systematically identify and assess economic evaluations of interventions for schizophrenia, examine their methodological characteristics, and synthesize key drivers of cost-effectiveness to inform healthcare decision-making.

Methods: A systematic literature review was conducted following PICOS criteria. Comprehensive searches were performed in Medline, Cochrane Library, PubMed, and grey literature for studies published from 1990 to 2024. Search terms combined schizophrenia-related keywords with economic terms (e.g., "cost", "economic", "burden"). Eligible studies were full-text articles in English or Greek evaluating any schizophrenia-related intervention, while abstracts, conference presentations, reviews, and editorials were excluded. Screening and data extraction followed PRISMA guidelines.

Results: A total of 110 studies met the inclusion criteria. Second-generation antipsychotics (SGAs) generally outperformed first-generation agents (FGAs) in terms of both clinical outcomes and economic value. SGAs such as olanzapine, paliperidone, and clozapine were frequently associated with improved relapse prevention and reduced inpatient costs, contributing to favorable cost-effectiveness profiles compared to haloperidol or other FGAs. Newer agents, including lurasidone and brexpiprazole, appeared in a limited number of recent studies. Early findings suggest promising cost-effectiveness, particularly in maintenance treatment, though further evidence is needed to support their broader economic value. Across evaluations, QALYs were consistently used as primary effectiveness outcomes. Reported ICERs varied considerably depending on model assumptions and local healthcare contexts, but several SGAs demonstrated dominant or cost-effective under commonly accepted willingness-to-pay (WTP) thresholds. Despite considerable methodological heterogeneity (e.g., model type, time horizon, perspective), key drivers of cost-effectiveness consistently included improved adherence, relapse prevention, and reduced hospitalization.

Conclusions: This review reinforces the long-term value of schizophrenia interventions, particularly SGAs, and underscores the need for consistent methodological standards. These findings contribute to a more robust evidence base for HTA submissions, inform pricing and reimbursement decisions, and support the development of sustainable, value-based mental health policies.