Abstract
Background
Schizophrenia spectrum disorders (SSD) are chronic psychiatric conditions with high rates of medication nonadherence, relapse, and hospitalization. Long-acting injectable antipsychotics (LAIs) aim to improve adherence; their real-world use in inpatient settings is not yet well understood.
Objective
To investigate prescription patterns of LAI antipsychotics in a real-life setting among psychiatric inpatients with SSD in Australia.
Methods
This retrospective cross-sectional study was conducted at a major Australian tertiary center. It investigated prescription trends, demographics, hospitalization outcomes, and substance use among inpatients with SSD who received oral, LAI, or combined oral–LAI treatment. Readmission rates were also analyzed in patients with a history of medication nonadherence.
Results
Among the total of 510 inpatients with SSD, 26.6% received LAIs, 40% were treated with combined oral–LAI therapy, and 33.3% were prescribed oral antipsychotics alone. Second-generation LAIs were most prevalent (87.5%), with paliperidone being the most frequently used (53.7%). The combined oral–LAI therapy group had the highest rates of nonadherence (83.8%) and substance use (82.8%). Among patients with a history of medication nonadherence, those receiving LAIs had lower 30-day readmission rates compared with the oral antipsychotic treatment group.
Conclusions
Findings align with global trends favoring second-generation LAIs and highlight the rising yet understudied use of combined oral–LAI therapy. High nonadherence and substance use in the combined oral–LAI therapy group call for targeted interventions. While LAIs may reduce readmissions in nonadherent patients, further research is needed to assess combined therapy’s effectiveness and optimize prescribing. These insights reinforce the role of LAIs in relapse prevention and the need for tailored adherence strategies.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40801-025-00511-z.
Key Points
| Real-world data from an Australian psychiatric inpatient setting show frequent use of long-acting injectable (LAI) antipsychotics and a marked increase in combining them with oral medication. |
| Patients receiving combined oral and LAI therapy had particularly high rates of nonadherence and substance use, highlighting the need for more targeted support. |
| Among individuals with a history of not following treatment, LAIs were linked to fewer short-term hospital readmissions than oral therapy alone. |
Introduction
Schizophrenia spectrum disorders (SSD) encompass a group of persistent, debilitating psychotic illnesses that can profoundly affect all aspects of patients’ lives [1]. Globally, SSDs affect over 21 million people [2], with an estimated prevalence of approximately 4 individuals per 1000 in Australia [3]. Comorbid substance use is highly prevalent among patients with SSD. A systematic review of 165,811 patients reported a 42% prevalence of substance use disorder [4]. Notably, patients with SSD with persistent substance use are more likely to experience negative consequences, such as higher rates of hospitalization, homelessness, aggression, violence, incarceration, suicidality, and premature mortality compared with those without comorbid substance use disorders [4–10].
Even though antipsychotics are the cornerstone of SSD treatment, medication nonadherence remains a major challenge, further increasing relapse, hospitalization, and suicide risk [11–13]. To address these concerns, first- and second-generation long-acting injectable antipsychotics (LAIs) were specifically developed to enhance adherence among patients who struggle with consistent medication use, while also enabling healthcare professionals to intervene promptly in cases of treatment discontinuation [14, 15]. The efficiency of LAIs in improving adherence is demonstrated across multiple study designs, including a randomized controlled trial [16], a retrospective comparative study [17], and a meta-analysis [18]. In addition, a large-scale nationwide cohort study found that LAIs were associated with a 67% lower likelihood of treatment interruption compared with oral antipsychotics [19]. A recent meta-analysis also showed the risk for all-cause discontinuation was lower in patients receiving LAIs than in patients receiving oral antipsychotics [20].
While LAIs have a similar level of efficacy and tolerability compared with traditional oral antipsychotic agents [20], emerging research indicates that LAIs may offer additional advantages. These include fewer side effects [20], lower relapse rates [16, 21], preventing hospitalization, decreasing the number of hospitalizations in patients with SSD [17, 18, 22, 23], and an approximately 30% lower risk of death compared with oral agents [24]. In addition, LAIs are also associated with a lower number of police arrests and incarceration rates [25]. Acknowledging the advantages of LAIs, recent guidelines recommend LAIs not only for patients with adherence challenges but also for those who actively prefer them, reflecting a broader recognition of their role in psychiatric treatment [26–28].
Despite its benefits and recommendations, LAI prescribing rates remain low and vary widely across countries, ranging roughly between 10 and 30%, according to epidemic reports [29–32]. However, real-world data on LAI prescribing patterns in inpatient settings remain scarce, with no such studies conducted in Australia. The available studies from the USA and Europe show high variability in inpatient LAI prescribing rates. In the USA, it ranges from 9 to 44%, with higher rates in a hospital serving low-income populations [17, 33]. Similarly, in a Swiss psychiatric hospital, 13.9% of all patients received an LAI, with 28.1% of eligible patients being prescribed one [34].
Although it has historically low prescribing rates, LAI use is steadily increasing. A community-based study of the French healthcare system (2007–2014) found LAI prescriptions rose from 8.9 to 9.6%, with a notable increase in second-generation LAIs [35]. A similar trend was seen in Australia (2000–2021), where first-generation LAIs had an average prescription rate of 2.65% and second-generation LAIs of 5.59% [36]. However, growth rates differed significantly, with a 1.99% increment for first-generation LAIs versus 14.73% for second-generation LAIs [36]. Moreover, although LAIs are traditionally prescribed as monotherapy, there is some evidence suggesting that they are increasingly used alongside oral antipsychotics, raising important questions about the clinical implications of combined therapy [37]. The only Australian study on this topic highlighted an increasing trend of concurrent oral and LAI use, particularly among elderly patients; however, no data are yet available regarding its impact on clinical outcomes [36].
With the rise in LAI prescriptions and more LAI options emerging, understanding their real-world use is essential. However, data on their use in acute psychiatric inpatient settings, particularly in Australia, remain scarce. Uncertainty also persists regarding the hospitalization benefits of second-generation LAIs over first-generation agents [38], as well as the impact of combining oral and LAI therapy on treatment outcomes. Therefore, this single-institution descriptive retrospective cross-sectional study investigated prescription patterns of LAI antipsychotics in a real-life setting among psychiatric inpatients at a major academic tertiary center in Australia. Specifically, it aimed to explore the demographic, medication, and hospitalization patterns, along with substance use prevalence, among patients being prescribed oral antipsychotics only, LAI only, and a combination of these. In addition, this study explores whether the history of medication nonadherence affects the readmission rates in patients receiving either oral, LAI, or combined oral and LAI antipsychotic treatment. By analyzing these factors, the study aims to provide insights into prescribing trends and clinical outcomes in antipsychotic treatment.
Methods
Study Design, Setting, and Population
This cross-sectional study was conducted at the Princess Alexandra Hospital, a major public tertiary teaching hospital in Queensland, Australia, with data collected between 1 January 2019 and 31 December 2019. It included patients aged 18 years and older who were discharged from the psychiatric inpatient unit during this period with either a pre-existing or new diagnosis of an SSD (schizophrenia, schizotypal disorder, delusional disorder, acute and transient psychotic disorder, or schizoaffective disorder) on the basis of the International Classification of Diseases [39] and were either prescribed LAI, oral antipsychotics, or a combination of these. This study was approved by the Metro South Health Human Research Ethics Committee (HREC/2024/QMS/105491).
Sample Size Determination
The LAI prescription rate was estimated to range between 10 and 30% on the basis of previous research data [29–31]. A priori sample size estimation was performed using the standard formula for cross-sectional prevalence studies [40]. On the basis of an average expected LAI antipsychotic prescription prevalence of 20%, a 95% confidence level, and a precision of 4%, the minimum required sample size was calculated to be 384. After adjusting for an anticipated 5% rate of missing or incomplete data, the final minimum sample size was calculated as 404 participants.
Data Collection
Access to electronic medical records from patients meeting the inclusion criteria was requested from the hospital. Data were manually extracted from the PowerChart integrated electronic medical record and Consumer Integrated Mental Health and Addiction application. Extracted data included demographic characteristics (age and sex), SSD diagnosis subtype (schizophrenia, schizoaffective disorder, acute and transient psychotic disorder, delusional disorder, and schizotypal disorder), experiencing an SSD episode for the first time, antipsychotic treatment information (agent type, formulation type, and LAI generation), hospitalization metrics (length of stay; readmission within 30, 60, and 90 days), history of medication nonadherence, and co-occurring substance use disorders.
The age category was determined using the median value in the total population. The total number of readmissions was calculated by summing readmissions within 30, 60, and 90 days. Similarly, total substance use was computed as the combined total of tobacco, cannabis, alcohol, cocaine, synthetic cannabis, and methamphetamine use. The total number of antipsychotic agents prescribed and the rate of antipsychotic agents available in both LAI and oral forms were also calculated. Patients were categorized into three groups on the basis of their antipsychotic treatment: those receiving LAI only (LAI group), oral antipsychotics only (oral group), or a combination of oral antipsychotics and LAI (combined group).
Statistical Analyses
Statistical analyses were conducted using SPSS 27 (IBM Corp, Armonk, NY, USA). Descriptive statistics were used to summarize baseline characteristics for patient demographics, SSD diagnosis, and comorbid substance use disorders for the total sample and the three antipsychotic treatment subgroups. Frequencies and proportions were calculated for categorical variables and mean (or medians) for continuous variables.
Comparative analyses between the three antipsychotic treatment groups (LAI, oral, and combined) were performed using chi-squared tests for categorical data and one-way analysis of variance (ANOVA) for continuous data to assess differences between the three medication groups. Additional exploratory chi-squared analyses were conducted within the subgroup of patients with a history of medication nonadherence to evaluate the readmission rates between the three antipsychotic treatment groups.
p-values were corrected using Bonferroni corrections. If the assumptions were not met, Fisher’s exact test was used for categorical data, and the Kruskal–Wallis test was used for continuous data. Normality of continuous variables was assessed using the Shapiro–Wilk test. Statistical significance was defined as p ≤ 0.05. Subjects with missing data or not having been prescribed any antipsychotics were excluded from the analysis.
Results
Descriptive Statistics
All descriptive statistics for the total sample, the antipsychotic treatment subgroups, and the SSD diagnostic subgroups are detailed in Tables 1 and 2.
Table 1.
Demographics and clinical data by treatment group
| Characteristic | Total (N = 510) | Oral (n = 170) | LAI (n = 136) | Combined (n = 204) |
|---|---|---|---|---|
| Sex, n (%) | ||||
| Male | 316 (62.0%) | 86 (50.6%) | 89 (65.4%) | 141 (69.1%) |
| Age, years | ||||
| Mean (SD) | 45.89 (14.49) | 50.02 (16.59) | 46.53 (14.64) | 42.03 (11.18) |
| Median (range) | 43 (21–88) | 48 (21–83) | 44 (24–88) | 40 (23–75) |
| Age category | ||||
| ≤ 43 years | 259 (51.8%) | 70 (41.2%) | 67 (49.3%) | 122 (59.8%) |
| SSD diagnosis, n (%) | ||||
| Schizophrenia | 362 (71%) | 102 (60.0%) | 102 (75.0%) | 158 (77.5%) |
| Schizotypal disorder | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Delusional disorder | 23 (4.5%) | 14 (8.2%) | 5 (3.7%) | 4 (2.0%) |
| Acute transient psychotic disorder | 22 (4.3%) | 17 (10.0%) | 4 (2.9%) | 1 (0.5%) |
| Schizoaffective disorder | 103 (20.2%) | 37 (21.8%) | 25 (18.4%) | 41 (20.1%) |
| First SSD episode, n (%) | 62 (12.2%) | 36 (21.2%) | 18 (13.2%) | 8 (3.9%) |
| Length of stay (days) | ||||
| Mean (SD) | 26.09 (38.46) | 23.95 (31.90) | 24.81 (24.81) | 28.72 (49.34) |
| Readmission, n (%) | ||||
| ≤ 30 days | 42 (8.2%) | 18 (10.6%) | 5 (3.7%) | 19 (9.3%) |
| ≤ 60 days | 23 (4.5%) | 9 (5.3%) | 6 (4.4%) | 8 (3.9%) |
| ≤ 90 days | 17 (3.3%) | 5 (2.9%) | 2 (1.5%) | 10 (4.9%) |
| Number of readmissions | ||||
| Median (range) | 0 (0–3) | 0 (0–3) | 0 (0–1) | 0 (0–2) |
| Number of antipsychotics used | ||||
| Median (range) | 1 (1–3) | 1 (1–3) | 1 (1–2) | 2 (2–3) |
| Antipsychotics exist in both forms, n (%) | 442 (86.7%) | 122 (70.9%) | 121 (89.0%) | 199 (97.5%) |
| Medication nonadherence, n (%) | 372 (72.9%) | 90 (52.9%) | 111 (81.6%) | 171 (83.8%) |
| Substance use disorder, n (%) | ||||
| Tobacco | 308 (60.4%) | 77 (45.3%) | 76 (55.9%) | 155 (76.0%) |
| Cannabis | 190 (37.3%) | 35 (20.6%) | 55 (40.4%) | 100 (49.0%) |
| Alcohol | 214 (42.0%) | 59 (34.7%) | 62 (45.6%) | 93 (45.6%) |
| Cocaine | 8 (1.6%) | 2 (1.2%) | 4 (2.9%) | 2 (1.0%) |
| Synthetic cannabinoids | 1 (0.2%) | 0 (0%) | 0 (0%) | 1 (0.5%) |
| Methamphetamine | 164 (32.2%) | 30 (17.6%) | 47 (34.6%) | 87 (42.6%) |
| Any substance | 368 (72.2%) | 101 (59.4%) | 98 (72.1%) | 169 (82.8%) |
| Total substance use | ||||
| Median (range) | 2 (0–5) | 1 (0–5) | 2 (0–5) | 2 (0–5) |
LAI long-acting injectable antipsychotic, SD standard deviation, SSD schizophrenia spectrum disorder
Table 2.
Demographics and clinical data by diagnosis subgroup
| Characteristic | Total | Schizophrenia | Schizotypal | Delusional | Acute transient psychotic disorder | Schizoaffective disorder |
|---|---|---|---|---|---|---|
| n (%) | 510 (100%) | 362 (71.0%) | 0 (0%) | 23 (4.5%) | 22 (4.3%) | 103 (20.2%) |
| Sex, n (%) | ||||||
| Male | 316 (62%) | 248 (68.5%) | 0 (0%) | 9 (39.1%) | 7 (31.8%) | 52 (50.5%) |
| Age, years | ||||||
| Mean (SD) | 45.89 (14.49) (14.47) | 45.03 (13.62) | 0 (0%) | 61.78 (17.56) | 39.27 (14.68) | 46.80 (14.49) |
| Median (range) | 43 (21–88) | 43 (23–88) | 0 (0%) | 60 (25–84) | 35 (21–81) | 44 (23–85) |
| Age category | ||||||
| ≤ 43 years | 259 (51.8%) | 190 (52.5%) | 0 (0%) | 4 (17.4%) | 16 (72.7%) | 50 (48.5%) |
| First SSD episode, n (%) | 62 (12.2%) | 33 (9.1%) | 0 (0%) | 10 (43.5%) | 18 (81.8%) | 2 (1.9%) |
| Length of stay (days) | ||||||
| Mean (SD) | 26.09 (38.46) | 25.89 (35.69) | 0 (0%) | 26.09 (24.55) | 10.32 (5.94) | 30.15 (51.61) |
| Readmission, n (%) | ||||||
| ≤ 30 days | 42 (8.2%) | 29 (8.0%) | 0 (0%) | 2 (8.7%) | 1 (4.5%) | 10 (9.7%) |
| ≤ 60 days | 23 (4.5%) | 14 (3.9%) | 0 (0%) | 0 (0%) | 0 (0%) | 9 (8.7%) |
| ≤ 90 days | 17 (3.3%) | 10 (2.8%) | 0 (0%) | 0 (0%) | 0 (0%) | 7 (6.8%) |
| Number of readmissions | ||||||
| Median (range) | 0 (0–3) | 0 (0–2) | 0 (0%) | 0 (0–1) | 0 (0–1) | 0 (0–3) |
| Number of antipsychotics used | ||||||
| Median (range) | 1 (1–3) | 1 (1–3) | 0 (0%) | 1 (1–2) | 1 (1–2) | 1 (1–3) |
| Antipsychotics exist in both forms, n (%) | 442 (86.7%) | 313 (86.5%) | 0 (0%) | 22 (95.7%) | 22 (100%) | 85 (82.5%) |
| LAI group, n (%) | ||||||
| First generation | 17 (12.5%) | 14 (13.7%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (12.0%) |
| Second generation | 119 (87.5%) | 88 (86.3%) | 0 (0%) | 5 (100%) | 4 (100%) | 22 (88.0%) |
| Flupenthixol | 2 (1.5%) | 2 (2.0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Zuclopenthixol | 14 (10.3%) | 11 (10.8%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (12.0%) |
| Haloperidol | 1 (0.7%) | 1 (1.0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Paliperidone | 73 (53.7%) | 54 (52.9%) | 0 (0%) | 3 (60.0%) | 2 (50.0%) | 14 (56.0%) |
| Aripiprazole | 31 (22.8%) | 22 (21.6%) | 0 (0%) | 2 (40.0%) | 1 (25.0%) | 6 (24.0%) |
| Risperidone | 5 (3.7%) | 3 (2.9%) | 0 (0%) | 0 (0%) | 1 (25.0%) | 1 (4.0%) |
| Olanzapine | 12 (8.8%) | 11 (10.8%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (4.0%) |
| LAI prescribed during index hospital stay, n (%) | ||||||
| Yes | 86 (63.2%) | 66 (64.7%) | 0 (0%) | 66 (64.7%) | 4 (100%) | 12 (48.0%) |
| Medication nonadherence n (%) | 372 (72.9%) | 280 (77.3%) | 0 (0%) | 10 (43.5%) | 1 (4.5%) | 82 (79.6%) |
LAI long-acting injectable antipsychotic, SD standard deviation, SSD schizophrenia spectrum disorder
During the study period, 12,342 patients were admitted to the hospital and were assessed for eligibility. Among the 530 patients hospitalized for SSD and discharged from the inpatient unit, 510 patients met the inclusion criteria and were included in the study. Inclusion required a confirmed SSD diagnosis, prescription of at least one antipsychotic medication at discharge, and complete clinical and prescription data. Patients were excluded if they were under 18 years of age or if their primary diagnosis did not fall within the SSD category (i.e., those admitted for other psychiatric conditions).
The sample comprised 316 males (62%) and 194 females (38%), with a mean age of 45.89 years (standard deviation [SD] = 14.49, range 21–88, median = 43).
Among the total sample, most patients with SSD were diagnosed with schizophrenia (71%), followed by schizoaffective disorder (20.2%). A smaller proportion was diagnosed with either delusional disorder (4.5%) or acute transient psychotic disorder (4.3%), while no patients with schizotypal disorder were identified during the data collection period. In addition, 12.2% of patients experienced their first SSD episode during the index hospital stay.
The mean length of index hospital stay was 26.09 days (SD = 38.46, range 1–491). Readmission rates were 8.2% within 30 days, 4.5% within 60 days, and 3.3% within 90 days, and the median number of readmissions was 0 (range 0–3). A history of medication nonadherence was reported in most patients (72.9%), being most common among patients with schizoaffective disorder (79.6%) and schizophrenia (77.3%).
The median number of antipsychotic agents used was 1 (range 1–3). In the total sample, 33.3% were treated with oral agents only (oral group), 26.7% received LAI agents only (LAI group), and 40% received a combined oral–LAI antipsychotic treatment (combined group). Notably, antipsychotic agents that exist in both oral and LAI forms were prescribed to 86.7% of the total sample. Within the combined treatment group, the vast majority (97.5%) were prescribed antipsychotics that exist in both formulations; however, only 11.3% received the same molecule in both oral and LAI forms, while 88.7% patients were prescribed different antipsychotics in oral and LAI forms. The most common same-molecule combinations were aripiprazole (7.8%) and olanzapine (2.5%) (Supplementary Table 2). A detailed breakdown of prescribing patterns in the LAI group is provided in the next subsection, and further information on the oral and combined groups is presented in Supplementary Tables 1 and 2, respectively.
Substance use was common, with a median of two substance types (range 0–5), and 72.2% of the patients used at least one substance. Tobacco was the most frequently reported substance (60.4%), followed by alcohol (42.0%), cannabis (37.3%), and methamphetamine (32.2%).
LAI Subgroup Characteristics
Most patients in the LAI group (63.2%) received an LAI prescription during their index hospital stay (Table 2). Second-generation LAI agents were prescribed more frequently (87.5%) than first-generation agents (12.5%). Among second-generation LAIs, paliperidone was the most commonly used (53.7%), followed by aripiprazole (22.8%), olanzapine (8.8%), and risperidone (3.7%). Among first-generation LAI agents, zuclopenthixol was the most prescribed (10.3%), while flupenthixol (1.5%) and haloperidol (0.7%) were used less frequently.
A similar pattern was observed across all SSD diagnostic subgroups prescribed LAIs exclusively, with second-generation LAIs consistently accounting for most prescriptions, particularly among patients with schizophrenia (86.3%) and schizoaffective disorder (88.0%) (Table 2). Paliperidone was the most prescribed LAI agent across all SSD subgroups, with usage rates of 52.9% in schizophrenia and 56.0% in schizoaffective disorder.
Groupwise Comparisons
Demographic Characteristics
Between-group comparisons revealed significant differences in demographic characteristics (Tables 1, 3). Age varied significantly across the three antipsychotic treatment groups (p < 0.001), with post hoc tests indicating that patients in the combined treatment group were significantly younger than those in the oral and LAI groups (p < 0.05). Similarly, age category comparisons showed significant differences (p < 0.05), with a higher proportion of patients aged ≤ 43 years in the combined group (59.8%) compared with the oral group (41.2%; p < 0.05).
Table 3.
Group comparisons between the treatment groups
| Variables | Statistical test | p-value | Post hoc comparisons |
|---|---|---|---|
| Age, median | 21.410a | < 0.001 | Combined < oral**, LAI* |
| Age category, n (%) | |||
| ≤ 43 years | 12.983b | 0.001 | Combined > oral* |
| > 43 years | Combined < oral* | ||
| Sex, n (%) | |||
| Female | 14.461b | 0.001 | Oral < LAI*, combined* |
| Male | Oral < LAI*, combined* | ||
| Length of stay, mean (SD) | 0.815c | 0.443 | N/A |
| Readmission, n (%) | |||
| ≤ 30 days | 5.300b | 0.071 | N/A |
| ≤ 60 days | 0.410b | 0.815 | N/A |
| ≤ 90 days | 3.292b | 0.212 | N/A |
| Number of readmissions, median | 3.443a | 0.179 | N/A |
| Number of antipsychotics used, median | 393.681a | < 0.001 | Combined > oral**, LAI** |
| Antipsychotics exist in both forms | 54.221b | < 0.001 | Combined* > oral*, LAI* |
| Medication nonadherence (%) | 51.881b | < 0.001 | Combined* > LAI* > oral* |
| Substance use (%) | |||
| Tobacco | 38.080b | < 0.001 | Combined > oral*, LAI* |
| Cannabis | 32.871b | < 0.001 | Oral < LAI*, combined* |
| Alcohol | 5.551b | 0.064 | N/A |
| Cocaine | 2.087d | 0.351 | N/A |
| Synthetic cannabinoids | N/A | N/A | N/A |
| Methamphetamine | 27.055b | < 0.001 | Oral < LAI*, combined* |
| Any substance | 25.341b | < 0.001 | Oral < combined* |
| Total substance use, median | 43.357a | < 0.001 | Oral < LAI**, combined** |
LAI long-acting injectable antipsychotic, N/A not applicable, SD standard deviation
*p < 0.05, **p < 0.001
aKruskal–Wallis test
bChi-squared test
cOne-way ANOVA
dFisher’s exact test
Sex differences were also significant (p < 0.05), with a higher proportion of male patients in both the combined (69.1%; p < 0.05) and LAI (65.4%; p < 0.05) treatment groups compared with the oral group (50.6%). In contrast, the highest proportion of females was found in the oral group (49.4%).
Hospitalization Metrics
Hospitalization metrics, including length of index hospital stay and readmission rates within 30, 60, and 90 days, showed no significant differences across the three treatment groups (Tables 1, 3). While the length of index hospital stay was the shortest in the oral group (mean = 23.95, SD = 31.90) and the longest in the combined group (mean = 28.72, SD = 49.34), the difference was nonsignificant. A similar trend was observed in readmission rates, with the LAI group consistently exhibiting the lowest rates within 30 days (3.7%), 60 days (4.4%), and 90 days (1.5%). However, these differences were also not statistically significant. The median number of readmissions was consistent at 0 for all three treatment groups, with no significant difference between groups.
Additional exploratory analyses were conducted on the subsample of patients with SSD with a history of medication nonadherence (n = 372), comparing the readmission rates in the oral (n = 90), LAI (n = 111), and combined (n = 171) treatment groups (Table 4). Within 30 days after the index hospital stay, a significant overall group difference was revealed (p < 0.05), with readmission rates being significantly lower in the LAI (4.5%) compared with the oral group (16.7%) (p < 0.05). However, no significant differences were found between the three treatment groups regarding hospital readmission rates at 60 days (p = 0.420) or 90 days (p = 0.109).
Table 4.
Group comparisons between patients with a history of medication nonadherence in the treatment groups
| Variables | Total = 372 | Statistical test | p-value | Post hoc comparisons | ||
|---|---|---|---|---|---|---|
| Oral (n = 90) | LAI (n = 111) | Combined (n = 171) | ||||
| Readmission, n (%) | ||||||
| ≤ 30 days | 15 (16.7%) | 5 (4.5%) | 16 (9.4%) | 8.448b | 0.015 | LAI < oral* |
| ≤ 60 days | 7 (7.8%) | 6 (5.4%) | 7 (4.1%) | 1.660d | 0.420 | N/A |
| ≤ 90 days | 5 (5.6%) | 1 (0.9%) | 9 (5.3%) | 4.458d | 0.109 | N/A |
LAI long-acting antipsychotic, N/A not applicable, SD standard deviation
*p < 0.05, **p < 0.001
bChi-squared test
dFisher’s exact test
Medication Metrics
Significant group differences were observed regarding medication metrics (Tables 1, 3). The total number of antipsychotics used differed significantly across groups (p < 0.001), with the combined group (median = 2, range 2–3) being prescribed more agents than the oral group (median = 1, range 1–3; p < 0.05) or LAI group (median = 1, range 1–2; p < 0.05).
Antipsychotics that exist in both oral and LAI formulations were commonly prescribed across all three groups, with the combined group showing the highest rates (97.5%), followed by the LAI group (89.0%) and the oral group (70.9%). A significant group difference was identified (p < 0.001), and post hoc pairwise comparisons revealed significant differences among all three groups (p < 0.05). The proportion of patients with a history of medication nonadherence also differed between the treatment groups (p < 0.001), as it was significantly higher in the combined group (83.8%) than in both the oral (52.9%; p < 0.05) and LAI (81.6%; p < 0.05) groups.
Co-occurring Substance Use
Substance use patterns varied significantly among the three groups, with the combined group consistently exhibiting the highest rates of substance use regardless of substance type (Tables 1, 3).
The total number of substances used differed between the treatment groups (p < 0.001), being significantly lower in the oral group (median = 1, range 0–5) than in both the LAI (median = 2, range 0–5, p < 0.001) and the combined (median = 2, range 0–5, p < 0.001) group. A significant group difference was also revealed regarding the proportion of individuals reporting any substance use (p < 0.001), with significantly higher rates in the combined group (82.8%) than in the oral group (59.4%, p < 0.05). A similar significant pattern was observed for tobacco use (p < 0.001), with the combined group (76.0%) showing significantly higher rates than both the LAI group (55.9%, p < 0.05) and the oral group (45.3%, p < 0.05). Cannabis use also showed significant group differences (p < 0.001), with higher rates in the combined group (49.0%, p < 0.05) and the LAI group (40.4%, p < 0.05) than in the oral group (20.6%). Similarly, significant group differences were revealed for methamphetamine use (p < 0.001), as rates were significantly higher in the combined (42.6%, p < 0.05) and LAI (34.6%, p < 0.05) groups than in the oral group (17.6%). In contrast, no significant differences were observed for alcohol or cocaine use, while synthetic cannabinoid use was exclusive to the combined group, disabling group comparisons.
Discussion
This study highlights the evolving prescription patterns and clinical outcomes linked to LAI and combined oral and LAI treatments within an Australian psychiatric inpatient setting. It showed that a significant proportion of patients with SSD received LAIs (26.6%), with second-generation agents (87.5%), particularly paliperidone (53.7%), being the most used. This pattern is in line with the well-documented shift toward LAI utilization, particularly the increasing preference for second-generation agents [35, 36]. It also aligns with global real-world data, which show a growing preference for second-generation LAIs across various healthcare systems [33–36]. Similarly, previous Australian studies have reported steady growth in second-generation LAI prescriptions over the past two decades [36, 41].
As for the large proportion of patients with SSD receiving combined oral and LAI treatment observed in the current setting (40%), comparative data are limited. While LAIs are conventionally monotherapeutic alternatives to improve medication adherence, real-world prescribing patterns often diverge from clinical guidelines and controlled trial protocols [37]. There is some evidence showing that concurrent use of oral and LAI antipsychotic medication does occur. For instance, Shi et al. found that 68% of patients on fluphenazine or haloperidol decanoate also received oral antipsychotics over a year, with a median overlap of 144 days [42]. Similarly, Aggarwal et al. reported that 46% of low-income patients prescribed LAI also received oral antipsychotics, typically matching their LAI formulation [43]. Doshi et al. further found that 75.9% of patients with initiated LAI treatment had a concurrent oral antipsychotics prescription 6 months post discharge, usually receiving an oral formulation of their LAI medication [37]. While Taylor et al. [41] emphasized that antipsychotic polypharmacy was uncommon in Australia with less than 10%, the study by Radha Krishnan et al. revealed a growing trend of combining oral and LAI treatment, particularly among elderly patients [36]. In contrast, the current study observed a much higher prevalence of combined oral–LAI prescribing, affecting 40% of the sample. Critically, only 11.3% of patients in the combined group received the same antipsychotic molecule in both oral and LAI formulations (e.g., aripiprazole or olanzapine), whereas 88.7% were treated with different agents, indicating a high rate of polypharmacy with distinct antipsychotics. This pattern is clinically concerning, as combining different antipsychotics can increase the risk of adverse effects, including sedation, extrapyramidal symptoms, metabolic complications, and medication burden, without consistent evidence for improved efficacy [44, 45].
Concurrent prescription of oral antipsychotics with LAI is usually prompted by patient relapse, which can occur for several reasons, including co-occurring single or multiple substance use disorder, low plasma concentrations, or life-event-induced temporary increase in psychotic symptoms [46–48]. Additional reasons behind these prescribing patterns may include serving as a safeguard against logistical barriers, such as missed injections owing to transportation issues, and allowing flexible dose adjustments that can be quickly reversed if adverse effects occur [37, 43]. Moreover, some patients may benefit from taking daily oral medication alongside LAIs, as it can reinforce self-care habits and provide a sense of control over their treatment [37]. However, the frequent use of combined therapy may also reflect a lack of pharmacokinetic guidance in Australian psychiatric practice, as plasma concentrations of antipsychotics are not routinely measured. This absence of routine monitoring limits clinicians’ ability to detect subtherapeutic levels, identify nonresponse due to pharmacokinetics, or tailor dose adjustments accordingly [48, 49]. As a result, clinicians may default to compensatory strategies such as unnecessary oral augmentation, which could undermine the intended benefits of LAIs. These findings underscore the need to examine the clinical rationale, duration, and clinical outcomes for this specific type of antipsychotic polypharmacy more closely.
As a starting point toward this goal, the current study was the first attempt to explore the demographic, medication, and hospitalization patterns, along with substance use prevalence, among Australian patients with SSD being prescribed oral antipsychotics only, LAI only, and a combination of these. Regarding demographics, this study found significant differences between the three antipsychotic treatment groups, with patients in the combined treatment group being significantly younger, with a higher proportion of male patients in both the combined and LAI groups than in the oral group. While no comparative data are available for the combined group specifically, current findings align with results of the two similar real-life setting studies regarding the LAI and oral treatment groups [33, 34]. Olayinka et al. also reported a high proportion of males in the LAI group (77%) and younger patients (≤ 41 years) being more likely to receive LAI treatment in a psychiatric hospital in a lower-income region of the USA [33]. Reymann et al. [34] also found that LAIs are more commonly prescribed to younger males (74%) but reported lower overall LAI prescription rates (13.9%) in a Swiss hospital setting, likely due to healthcare system differences. In line with current findings, a recent large cohort study also found that LAIs were more frequently initiated in men (58.1%) and younger patients (42% aged 18–34 years), particularly those who were previously nonadherent to oral antipsychotics [50].
A history of medication nonadherence was common in the current setting (72.9%), with the significantly highest proportion in the combined group (83.8%) and the lowest in the oral group (52.9%). While the relatively high number of nonadherent patients in the combined group cannot be compared given the lack of related studies, nonadherence is a general issue among patients with SSD, ranging between 40 and 90% [48]. Poor adherence is consistently linked to prolonged hospital stays, worse symptom outcomes, and increased relapse risk [51–53]. Although current findings showed no significant differences in hospitalization duration or readmission rates between the three treatment groups, within the subgroup of patients with a history of medication nonadherence, those receiving LAIs had significantly lower 30-day readmission rates compared with those on oral antipsychotics. While the combined group showed slightly higher readmission rates than the LAI group, the difference was not statistically significant. These findings align with previous research demonstrating the superiority of LAIs in preventing relapse and reducing hospitalizations, particularly among nonadherent patients [16–18]. A recent large-scale mirror-image study in France similarly reported a 20–26% reduction in psychiatric hospitalizations following LAI initiation among younger, nonadherent patients [50]. However, their study also pointed out that LAIs had only such benefits for the nonadherent patients, while using the LAI form of risperidone and paliperidone was even associated with increased psychiatric hospitalization duration in compliant patients [50]. Such a comparison should also be made regarding the oral–LAI combined treatment outcomes.
Substance use was highly prevalent in the current setting, with tobacco, alcohol, and cannabis being the most reported substances. Notably, the highest rates of substance use were observed in the combined treatment group, followed by the LAI treatment group. The latter finding is consistent with prior studies suggesting that patients with co-occurring substance use disorders are more likely to receive LAIs owing to concerns regarding medication adherence [34]. In Switzerland, similar trends were observed, with higher LAI usage among patients with substance use comorbidities [34]. This reinforces the notion that clinicians may preferentially prescribe LAIs in populations at higher risk for treatment discontinuation and relapse. Our finding that the combined group included a higher proportion of young males may at least partially explain the higher medical nonadherence and substance use rates in this treatment group, as young men reflect a subgroup with greater illness severity and behavioral complexity [12, 54]. This demographic is also disproportionately affected by substance use disorders and tobacco smoking, both of which are known to reduce medication adherence, while smoking can also alter antipsychotic metabolism [9, 55–58]. These factors may partially explain the clinical rationale for combining oral and LAI formulations in this group as a strategy to improve adherence and symptom control in a population at elevated risk for poor outcomes. While not a primary objective of the study, exploratory analyses were performed to examine differences in readmission rates across treatment groups among patients with comorbid substance use (Supplementary Tables 3–9). Overall, readmission rates were low, mirroring trends seen in the subgroup with a history of medical nonadherence, and no significant differences were observed between treatment groups, except among methamphetamine users, where the 30-day readmission rate was significantly higher in the Oral group (23.3%) than in the LAI group (4.3%).
These findings suggest the potential benefits of the LAIs in this high-risk group; however, the limited availability of specific studies examining the combined use of LAIs and oral antipsychotics in patients with concurrent substance use disorders highlights the need for further research to understand the efficacy and outcomes of such treatment strategies in this population.
Overall, the study’s strength lies in its comprehensive analysis of real-world prescribing patterns, demographic factors, hospitalization outcomes, and substance use prevalence among psychiatric inpatients in Australia. It highlights the growing preference for second-generation LAIs, particularly among younger males and nonadherent patients, and the significant presence of combined oral–LAI therapy. The findings reinforce the role of LAIs in reducing readmission rates, supporting their clinical utility in relapse prevention. Shedding light on the high number of patients receiving combined treatment, their antipsychotic usage patterns, along with high medication nonadherence rates and concurrent substance use rates in this specific group of patients, is also an important finding of the current study. However, the study’s retrospective design limits its ability to control for potential confounding variables such as illness severity, number of previous hospitalizations, and comorbid psychiatric conditions, all of which may have influenced both prescribing decisions and clinical outcomes. The absence of these clinical details restricts the interpretability of the findings and the ability to draw causal conclusions and warrants future investigation.
Taken together, while LAIs are linked with improved adherence, their real-world use remains inconsistent owing to clinician biases, patient preferences, and healthcare barriers [59]. Moreover, despite their benefits, second-generation LAIs may not be suitable for all patients with SSD [50, 60]. Further research is needed to determine whether LAIs should be recommended for all patients or primarily for those considered at higher risk, such as individuals with a history of poor adherence or repeated hospitalizations. In addition, the benefits, drawbacks, and long-term consequences of prescribing oral and LAI antipsychotics in combination should be systematically evaluated. Future studies should build on current findings by adopting prospective research designs and including larger, multisite samples to improve the generalizability of results.
To strengthen the clinical significance of such research, it would also be crucial to include more detailed clinical variables, including prior treatment history, symptom progression, functional outcomes, and confounding factors such as illness severity, number of previous hospitalizations, and comorbid psychiatric conditions, along with a clinical rationale for treatment choices. Greater attention should be given to distinguishing between short-term oral augmentation with the same antipsychotic and long-term polypharmacy involving different agents, which carries greater risks and remains controversial.
Given the high prevalence of substance use among individuals with schizophrenia, future studies should also explore how specific patterns of use, including the type and severity of substance use and the presence of multiple substances, affect treatment outcomes. Well-powered subgroup analyses will be essential to assess whether LAIs are effective in reducing relapse among patients with co-occurring substance use disorders. Finally, integrating pharmacokinetic assessment into psychiatric care and increasing access to therapeutic drug monitoring could support more informed and precise prescribing practices. Collecting additional data on the types of combination regimens used in routine care, particularly whether the same or different antipsychotic molecules are involved, would offer valuable insights for developing more rational and personalized treatment approaches for complex patient populations.
Conclusions
This real-world study demonstrated an increasing trend in the use of long-acting injectable (LAI) antipsychotics as well as the use of a combination of oral and LAI therapies in an Australian inpatient setting, suggesting that clinicians may be addressing concerns about nonadherence or other complex clinical profiles. In line with this, there was a high rate of medication nonadherence and substance use in the combined therapy group in our study, indicating a greater need for focused intervention in this group. Furthermore, while there were no significant differences in overall hospitalization metrics, LAI therapy was associated with fewer short-term readmissions among patients with a history of nonadherence. Our findings strengthen the value of LAIs in preventing relapse, especially in high-risk groups and, in addition, also point to the growing and underexamined practice of combining oral and LAI agents. Notably, this combined treatment approach most often involved the use of different antipsychotic molecules rather than the same formulation, highlighting a form of polypharmacy that may carry increased risks without consistent evidence of improved efficacy. Prospective studies will be needed to assess the long-term benefits and potential harm that may arise from combined oral–LAI regimens, as well as strategies to address the needs of these high-risk patients with co-occurring substance use disorders. In addition, future research should distinguish between short-term oral bridging or augmentation with the same agent versus long-term use of distinct antipsychotic combinations, given the differing risk profiles. Integrating therapeutic drug monitoring and collecting more in-depth clinical data, such as illness severity and functional outcomes, could support more personalized and evidence-based prescribing strategies.
Supplementary Information
Below is the link to the electronic supplementary material.
Funding
No funding was received for conducting this study or preparing this manuscript.
Declarations
Conflict of interest
All authors declare that they have no conflicts of interest.
Availability of data
The data supporting the results reported in this article are available upon reasonable request. Contact the corresponding author for further information.
Ethics approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Metro South Health Human Research Ethics Committee (HREC/2024/QMS/105491).
Consent to participate
A waiver of consent was granted by the Metro South Health Human Research Ethics Committee to enable access to retrospective data from patient medical records.
Consent for publication
Not applicable.
Code availability
Not applicable.
Author contributions
All authors contributed to the conception and design of the study. Tumilara Akindele was responsible for material preparation and data collection. Tumilara Akindele and Kanchana De Alwis were responsible for data analysis and results analysis. Tumilara Akindele wrote the first draft of the manuscript. All authors contributed to writing the manuscript. All authors have read and approved the final manuscript.
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