Comparative Effectiveness of Long-Acting Injectable Versus Oral Antipsychotics in Older Adults with Schizophrenia: Insights from Hong Kong’s Population-Based Study

Introduction

Schizophrenia is a chronic mental disorder that significantly impacts individuals’ functioning and quality of life. In older adults, typically aged 65 years and above, managing schizophrenia presents unique challenges due to age-related cognitive decline, polypharmacy, and increased vulnerability to treatment non-adherence. Effective long-term treatment strategies aim not only to control symptoms but also to reduce relapse rates and prevent mortality. Traditionally, oral antipsychotics have been the mainstay of treatment, yet long-acting injectable (LAI) antipsychotics have emerged as an alternative, offering potential benefits in adherence and consistent drug levels. Despite their widespread use in younger populations, the evidence supporting LAI use in elderly patients remains limited, necessitating population-based studies to inform clinical decision-making.

Background and Rationale

Schizophrenia in the elderly is associated with high morbidity and mortality, partly due to increased treatment non-compliance and the risk of relapse. Non-adherence is often exacerbated by cognitive decline, complex medication regimens, and social factors. LAI antipsychotics could potentially address adherence issues by reducing the frequency of dosing, but concerns about adverse effects, including extrapyramidal symptoms and other lab aberrations, have limited their widespread adoption in this age group. The need for robust evidence comparing the safety and efficacy of LAI versus oral antipsychotics in older patients is pressing, especially in diverse populations like Hong Kong, which has a significant aging demographic.

Study Design and Methods

The Hong Kong population-based study utilized the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority, capturing electronic health records from 1993 to 2023. The inclusion criteria focused on individuals aged 65 and above diagnosed with schizophrenia based on ICD-9-CM code 295, who were prescribed either LAI or oral antipsychotics between 2004 and 2023. The primary outcome was disease relapse, operationalized as hospitalization for schizophrenia. Secondary outcomes assess mortality and adverse events, including cardiovascular hospitalizations, extrapyramidal symptoms, and laboratory-confirmed injuries such as acute liver and kidney damage. The study employed a self-controlled case series design, comparing periods of LAI versus oral antipsychotic use within the same individuals, adjusting for time-dependent confounders such as age and concomitant medications. Cox regression analyses evaluated mortality risk.

Major Findings and Results

From the total cohort of 24,985 older individuals with schizophrenia, 4,696 (18.8%) received either LAI or oral antipsychotics. The analysis revealed that LAI antipsychotics were associated with a 29% reduction in hospital admission for schizophrenia compared to oral formulations (IRR 0.71; 95% CI 0.64-0.78; p<0.0001). Importantly, mortality was markedly lower in the LAI group, with an observed hazard ratio of 0.23 (95% CI 0.12-0.44; p<0.0001), translating to nearly a 77% decrease in all-cause mortality risk. The safety profile indicated no significant differences in cardiovascular hospitalizations, acute liver injury, or kidney injury between treatment modalities. However, LAI use was associated with a higher risk of extrapyramidal symptoms (IRR 2.17; 95% CI 1.24-3.80; p=0.0068), specifically linked to first-generation LAI medications (IRR 2.86; 95% CI 1.41-5.84; p=0.0038), whereas second-generation LAIs did not show a similar risk increase.

Interpretation and Clinical Implications

This large, population-based study suggests that in older adults with schizophrenia, LAI antipsychotics confer significant benefits in reducing relapse and mortality without increasing most adverse events. The exception is a notable increase in extrapyramidal symptoms associated primarily with first-generation LAIs, highlighting the need for cautious selection. The findings support a broader consideration of LAI medications, particularly second-generation formulations, early in the disease course to enhance adherence, prevent relapses, and improve survival outcomes. These implications align with the evolving treatment paradigm favoring personalized, adherence-promoting strategies tailored to the elderly population.

Limitations and Future Directions

While the study’s large sample size and methodology strengthen its findings, certain limitations warrant discussion. The observational design cannot establish causality, and unmeasured confounders such as cognitive status, social support, and detailed medication adherence were not captured. Data on ethnicity were unavailable, potentially affecting generalizability. Additionally, the higher risk of extrapyramidal symptoms with first-generation LAIs emphasizes the need for ongoing monitoring and individualized treatment plans. Future research should explore quality-of-life outcomes, cognitive effects, and the role of patient preferences in treatment choices. Randomized controlled trials targeting older populations are desirable to confirm these findings and optimize treatment guidelines.

Conclusion and Practice Takeaways

The evidence demonstrates that LAI antipsychotics are associated with improved relapse prevention and lower mortality in older patients with schizophrenia, with a manageable safety profile predominantly when second-generation formulations are used. Clinicians should consider patient-specific factors, including susceptibility to extrapyramidal symptoms, when selecting treatment modalities. Integrating LAI options into comprehensive care plans may enhance long-term outcomes and support active aging in this vulnerable population.

Funding and Disclosures

This study was funded by the National Natural Science Foundation of China. No conflicts of interest were declared.

References

Wei Y, Yan VKC, Castle DJ, Huang C, Deng EK, Leung SM, Yiu HHE, Lee KJ, Lui SSY, Ng VWS, Hayes JF, Lai FTT, Wang H, Yan EWC, Chan EW. Disease relapse, all-cause mortality, and adverse events associated with long-acting injectable antipsychotics versus oral antipsychotics in older people with schizophrenia in Hong Kong: a population-based within-subject analysis. Lancet Psychiatry. 2025 Nov;12(11):830-840. doi: 10.1016/S2215-0366(25)00268-8

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