Schizophrenia is a chronic and often relapsing psychotic disorder characterized by a rare achievement of complete remission and a progressive decline in function. The development of new therapeutic drugs has allowed for better outcomes than in the past, yet schizophrenia remains among the top 10 causes of disability worldwide. Patients with schizophrenia experience disabilities in cognitive functions, social functions, occupational functions, and other psychosocial aspects, leading to a decreased quality of life. The chronic nature of schizophrenia imposes direct and indirect economic burdens on patients, caregivers, and society at large, including hospitalization costs and loss of productivity [1]. One of the significant obstacles in treating patients with schizophrenia is low disease awareness, leading to poor medication adherence. Various methods have been employed, one of which is the use of long-acting injectable (LAI) antipsy-chotics. Unlike oral medications that must be taken daily, LAIs are administered intramuscularly once a month or even more extended periods, maintaining the drug’s efficacy throughout this time. This approach has shown remarkable therapeutic effects, particularly in patients with low adherence, and recent studies argue for the benefits of LAI formulations not only in patients with chronic schizophrenia but also in first-episode patients and those with bipolar disorder [2,3].

Another benefit of LAIs that has attracted interest is their ability to reduce healthcare expenses potentially. While the drug costs for LAIs are generally much higher than for equivalent oral formulations, the increased adherence resulting from LAI use can lead to more stable maintenance of schizophrenia symptoms, reducing the chances of relapse and hospitalization [4,5]. Given the nature of schizophrenia, where each acute exacerbation can worsen the disease, reducing relapses leads to a long-term decrease in the disease burden. It can prevent healthcare expenditures due to hospitalizations, which can be catastrophic depending on the country. Still, the high prices of LAIs are not justified in all circumstances, especially in patients who are already stable on oral regimens [6]. Therefore, it is challenging to determine the balance between the increased medication costs associated with switching to LAIs and the reductions in healthcare expenses and improved quality of life resulting from their use. South Korea, where every citizen is covered by a national health insurance system with centrally controlled medical costs applied uniformly across the country, presents an ideal context to verify the impact of LAI usage on the healthcare expenditures of patients with schizophrenia [7]. We, therefore, decided to conduct more in-depth research on this topic to aid future decisions on the use of LAIs.

A retrospective review was performed for patients visiting the psychiatry department of Korea University Guro Hospital. This study included patients who were diagnosed with schizophrenia by a board-certified psychiatrist between January 2017 and July 2022, were adults aged 18 and over and had a history of receiving LAI antipsychotics. The LAIs in focus were monthly injectable paliperidone palmitate (PAL) and aripiprazole monohydrate (ARP). Patients who had not received treatment at Korea University Guro Hospital for at least one year before the initial LAI injection and after their initial LAI treatment were excluded from the study. For those meeting the criteria, the year before their first LAI dose was designated as the pre-LAI period, and the year following the first dose, including the day of administration, was marked as the post-LAI period. The hospital’s administrative department collaborated to investigate the total medical costs spent in the psychiatry department incurred during the pre-and post-LAI periods. Additionally, the number of outpatient department (OPD) visits and inpatient department (IPD) admissions during each period was recorded to calculate the total OPD and IPD costs and the average cost per OPD visit and per IPD admission.

Paired t tests were performed to compare the number of OPD visits, the cost per OPD visit, the total annual OPD costs, the number of IPD admissions, the cost per IPD admission, the total annual IPD costs, and the overall psychiatric medical costs combining both OPD and IPD services before and after LAI treatment. Further comparisons of medical costs between PAL and ARP user groups were also performed for periods before and after LAI treatment initiation using student’s t tests.

All statistical analyses were performed using SPSS version 23 (IBM Corp.). The significance level was set at p ≤ 0.05. The Institutional Review Board of the Korea University Guro Hospital (2024GR0077) approved the research processes. All research methods were performed following the relevant guidelines and regulations.

A total of 164 patients (71 males, 93 females) were included in the final analysis. The mean age of all participants was 38.52 ± 13.34 years. Out of all participants, 70 patients experienced at least one IPD admission before their first LAI administration, while 12 patients had at least one IPD admission after LAI. The PAL user group consisted of 113 patients (57 males, 56 females) with a mean age of 38.93 ± 12.47 years. From the PAL group, 46 patients experienced pre-LAI admissions, while seven patients experienced post-LAI admissions. The ARP group consisted of 51 patients (14 males, 37 females) with a mean age of 37.63 ± 15.19 years. Within ARP users, 24 patients experienced pre-LAI admissions, and five patients experienced post-LAI admissions. The results are presented in Table 1.

OPD visits per year increased from 7.63 ± 5.74 to 12.71 ± 3.28 times after LAI administration. Both total annual OPD costs (1,437.44 ± 1,127.60 to 4,015.42 ± 1,204.59; units: 1,000 KRW) and costs per OPD visit (203.38 ± 104.51 to 326.97 ± 104.08; units: 1,000 KRW) increased post-LAI. IPD admissions per year decreased from 0.54 ± 0.72 to 0.12 ± 0.68 times. Annual IPD costs decreased from 3,826.06 ± 5,500.63 to 698.06 ± 3,619.38 (units: 1,000 KRW), and IPD costs per admission decreased from 3,314.31 ± 4,860.24 to 465.76 ± 1,997.75 (units: 1,000 KRW). Total annual medical costs decreased from 5,263.49 ± 5,333.11 to 4,713.48 ± 3,625.89 (units: 1,000 KRW) after LAI administration, but this was not statistically significant. The results are presented in detail in Tables 2 and 3.

PAL and ARP groups did not show many statistically significant differences in healthcare cost variables. The only significance was the ARP group having lower post-LAI costs per OPD visit than the PAL group (338.85 ± 113.91 vs. 300.65 ± 72.27; units: 1,000 KRW). Although statistically unsignificant, the ARP group showed lower post-LAI total healthcare and OPD costs while showing higher IPD costs when compared to the PAL group. The results are presented in detail in Table 4.

Our research enabled us to compare healthcare expenditures before and after initiating LAI regimens. The start of LAI treatment was connected to an initial increase in the annual number of OPD visits and a significant increase in the average cost per OPD visit. Consequently, using LAIs was associated with an increase in the total annual OPD costs. Conversely, after the initiation of LAIs, the number of IPD admissions decreased significantly, as did the cost spent per admission. As a result, the total annual cost of IPD admissions decreased drastically, outweighing the increase in OPD costs. However, this reduction in total annual healthcare costs did not reach statistical significance.

The increase in OPD visits following LAI initiation could be attributed to the need for patients to receive injections at specified intervals every four weeks to maintain the antipsychotic efficacy of the regimen. The increased cost per OPD visit and total annual OPD costs are likely due to the increased medication expenditures. In South Korea, where national health insurance applies uniformly, the price of a 75 mg dose of PAL, administered every four weeks, is 170,955 KRW. The price is more than three times higher than the dose equivalent of a 6 mg oral paliperidone tablet (1,713 KRW per tablet, 47,964 KRW for four weeks) [8,9]. Similarly, the price of one monthly 400 mg dose of ARP 400 mg is 185,548 KRW, whereas the equivalent 20 mg oral form would cost 122,584 KRW (2,189 KRW per 10 mg tablet) [10,11]. The prices mentioned are based on rates as of February 8, 2024. Although the use of LAIs may have led to a net decrease in the use of other psychiatric medications, offsetting the substantial increase in the cost of the main antipsychotic would have been challenging. From the perspective of OPD costs alone, LAIs may seem like something other than an attractive option. However, this changes when it comes to IPD admissions. After the initiation of LAIs, there was a significant decrease in the average number of admissions, with the number of admitted patients dropping from 70 to 12, marking a substantial change. The cost per admission was also reduced by about 85% compared to costs before the LAI administration. The proven decrease in relapse rates of schizophrenia patients due to LAI usage likely contributed to the reduced need for hospital admissions and shorter durations of stay, which are thought to be the main reasons behind this drastic cost reduction [12-14]. From the perspective of hospital admission costs, LAIs offer significant economic benefits in terms of cost per admission and total annual costs. There was little difference in the analysis of PAL and ARP subgroups. Past studies support this finding. Although there are mixed reports, most studies showed that the LAI forms of the two medications have similar properties [15,16].

LAIs may not demonstrate immediate cost-saving effects for schizophrenia patients in the first year, but the reduction of admissions rate and cost is very significant and promising. Considering that hospital admissions constitute a significant portion of healthcare costs when treating schizophrenia, this downward trend of hospitalization costs promises to increase economic benefits over a long time [17]. In addition to these direct cost reductions, it is imperative to consider secondary savings. As of 2024, the minimum wage in Korea is 9,860 KRW per hour. Assuming a worker engages in labor for eight hours a day, five days a week, they would receive a weekly wage of 394,400 KRW and a monthly income of 2,760,800 KRW. The average hospitalization period for patients with schizophrenia per admission is approximately 74 days in Korea [18]. Using LAIs can reduce the annual admissions from 0.54 to 0.12, equating to roughly 31 days of hospitalization time. This reduction in hospitalization duration effectively eliminates a month of inability to work. When considering the consequent wage earnings (2,760,000 KRW), the disparity in medical costs between the LAI user and non-user groups will likely increase over time. In-deed, previous studies have argued that the societal costs associated with productivity losses far outweigh the direct medical expenses of schizophrenia treatment [19]. How-ever, it is essential to note that these calculations are based on the healthcare system of Korea, suggesting a need for further health economic studies tailored to the healthcare realities of other nations.

Despite variations in specific methodologies, similar studies to ours have been conducted across various countries to investigate the economic impacts of using LAIs in patients with schizophrenia. Lin et al. [20] in the United States analyzed Medicare data to compare the costs of LAIs with oral antipsychotics over 12 months, finding that both hospitalization and outpatient care costs were lower for LAIs. Similarly, findings from Croatia indicated that LAIs incurred lower costs and improved clinical outcomes compared to oral medications [21]. In contrast, a French study evaluating the cost-effectiveness of LAIs versus oral antipsychotics over five years, based on three-month cycles, revealed that although LAIs were more expensive, they were associated with more significant gains in quality-adjusted life years (QALY) [22]. Consistent outcomes were observed in Germany, while research from Sweden demonstrated that LAIs provided both cost savings and higher QALY gains [23,24]. These diverse studies further illustrate how variations in healthcare systems across different countries can influence the economic viability of LAIs.

Our study had some limitations. First, we only analyzed data from one year before and after the initiation of LAI treatment. A more extended analysis could have improved the accuracy of our data. The second limitation is the inability to account for medical expenses incurred at other healthcare institutions. While most patients in South Korea, especially those with psychiatric conditions, prefer to continue treatment at a single facility, this cannot be guaranteed. Future research could minimize this issue by utilizing national health insurance data. The third limitation is the small sample size and the analysis conducted at a single local institution. The fourth limitation is the absence of a control group taking oral antipsychotics, which would have allowed for a clearer comparison of the economic effects of LAIs.

Despite these limitations, our study demonstrates that the economic benefits of using LAI are robust enough to be evident in a small study at a single institution and provides evidence to support the feasibility of using LAI. Regional characteristics might have influenced healthcare expenditure patterns, suggesting a need for multi-institutional data analysis in the future.

In conclusion, the battle against the economic burden that schizophrenia imposes on individuals and society continues in real time. With the medical justification for the use of LAIs becoming increasingly established, ours and prior research have shown that expanding the use of LAIs could also offer economic benefits. As more LAI formulations of various medications are developed in the future, and advancements in pharmaceutical technologies may reduce the cost of drug delivery, these advantages are expected to be further maximized.

No potential conflict of interest relevant to this article was reported.

Conceptualization: SuHyuk Chi, Jeong Kyung Ko. Data acquisition: Hyung-Ghang Jeong, Changsu Han. Formal analysis: SuHyuk Chi, Jeong Kyung Ko. Supervision: Hyung-Ghang Jeong, Changsu Han, Moon-Soo Lee. Writing—original draft: SuHyuk Chi. Writing—review & editing: Moon-Soo Lee.