INTRODUCTION
Bipolar disorder is a chronic illness, and a higher number of previous episodes implies a greater likelihood of future ones, emphasizing the necessity of consistent medication therapy [1]. Therefore, patient adherence to medication regimens is crucial in predicting long-term treatment outcomes, as medication non-adherence increases hospitalization rates and the incidence of suicide attempts and mortality [2,3]. However, in a South Korean study, the discontinuation rate over 1 year among 275 patients with bipolar disorder I or II was 33.8%, reaching 50.2% over 3 years [4]. Considering that maintenance treatment for at least 1 year is necessary for patients with bipolar disorder [5], it can be inferred that at least one-third of patients do not receive adequate maintenance treatment.
Moreover, the side effects of mood stabilizers commonly prescribed for bipolar disorder can have serious implications for the patients. For example, patients may experience thyroid dysfunction after taking lithium, or complain about significant weight gain and metabolic issues after taking valproate. These side effects can lead to medication discontinuation and an increasing trend of substituting with antipsychotic medications that have mood-stabilizing effects [6]. In 2004, aripiprazole was approved by the US Food and Drug Administration for the treatment of mania and mixed episodes, and was found to be effective overall regardless of the severity of symptoms or the presence of psychotic features, showing efficacy even in rapid cycling [7]. In a study comparing aripiprazole with haloperidol in patients with bipolar disorder, the aripiprazole group showed a higher treatment response rate and fewer study discontinuations, particularly in the management of acute mania [8]. Furthermore, a study of South Korean patients with acute mania and mixed episodes showed that the combination of aripiprazole and valproate significantly reduced symptoms from the first week of administration [9]. As the mood-stabilizing effects of antipsychotic medications with fewer serious side effects become increasingly recognized, monotherapy with atypical antipsychotic medications and combination therapy with mood stabilizers are being evaluated as first-line treatments for mania [10].
According to the Korean Bipolar Disorder Pharmacotherapy Algorithm 2022 [11], long-acting injectable antipsychotics (LAIs) are considered after third-line treatment. In a meta-analysis on bipolar disorder [12] analyzing a total of seven randomized controlled trials (n=1,192) compared with placebos, LAIs showed superior effects in terms of relapse and discontinuation rates for all causes. Aripiprazole once monthly (AOM) is approved for the maintenance treatment of bipolar I disorder in patients stabilized with oral aripiprazole [13]. While its official indications are limited to bipolar I disorder, AOM is frequently utilized in clinical practice for bipolar II disorder, particularly in cases where medication compliance is poor or where patients are sensitive to side effects of oral therapies. Bipolar disorder is characterized not only by manic symptoms but also by depressive and anxiety symptoms, which significantly contribute to patients’ distress. Anxiety symptoms in bipolar disorder are particularly prominent in episodes with mixed features, where they often present as a cluster along with irritability and agitation [14]. The effectiveness of aripiprazole in managing episodes with mixed features suggests potential benefits for anxiety symptoms included with irritability and agitation. Furthermore, evidence indicates that AOM may have therapeutic effects for not only manic-related symptoms but also depressive and anxiety symptoms in bipolar disorder [15]. However, research on the broader efficacy of AOM, particularly in bipolar II disorder and in addressing depressive and anxiety symptoms, remains limited, warranting further investigation.
Second-generation LAIs enhance medication adherence and maintain more stable serum drug levels by avoiding first-pass metabolism [16]. Their effectiveness has been well documented in schizophrenia, including studies from South Korea showing improvements in symptoms and reduced polypharmacy [17-20]. However, research on LAIs for the treatment of bipolar disorder in South Korea remains scarce, highlighting the need for real-world evidence on their efficacy through naturalistic observational studies.
Building on this context, the present study aimed to investigate whether the use of AOM in patients with bipolar disorder improves symptoms and functioning while reducing medication dosage and pill burden. The hypotheses were as follows:
• AOM usage enhances overall symptom management and functional outcomes in patients with bipolar disorder.
• AOM demonstrates efficacy in alleviating not only manic symptoms but also depressive and anxiety symptoms in bipolar disorder.
• AOM simplifies treatment regimens by reducing the required medication dosage and pill burden for patients with bipolar disorder.
METHODS
Participants
This is a retrospective, longitudinal, naturalistic observation, and medical record analysis study. The starting point for analysis was the initiation of AOM treatment in a general treatment setting. Data were collected from medical records at baseline and at intervals of 1, 3, 6, 9, and 12 months thereafter, with a permissible window of ±2 weeks for each visit. Medical records of patients who met the selection criteria from December 23, 2015 (when AOM was approved in South Korea) to December 31, 2023 were analyzed. The selection criteria included individuals who: 1) were diagnosed with bipolar disorder according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition; 2) were 18 to under 75 years; 3) switched to AOM treatment for symptom control, functional improvement, maintenance therapy, or issues related to nonadherence based on the judgment of the psychiatrist; and 4) received at least three AOM injections. Participants who did not meet the selection criteria or who had compliance issues, despite receiving AOM injections three or more times, were considered dropouts, and evaluations were not conducted after the dropout point. A total of 24 participants who received AOM treatment thrice or more were selected, and 17 participants (70.8%) completed the 12-month observation period (Figure 1).
All study procedures were approved by the Institutional Review Board of Kangbuk Samsung Hospital (approval number: KBSMC 2023-08-061-001) and adhered to the latest version of the Declaration of Helsinki and principles of Good Clinical Practice. The requirement for informed consent was waived because only de-identified data were used.
Clinical assessments
Medical records were used to collect data on age, sex, years of education, type of bipolar disorder (I/II), family history of major psychiatric disorders (yes/no), comorbidities (yes/no), duration of illness (months), number of psychiatric hospitalizations, number of treatment failures, types and doses of mood stabilizers and antipsychotics, and number of pills. The doses of mood stabilizers and antipsychotics were converted into lithium-equivalent doses [21] and chlorpromazine-equivalent doses [22] based on previous studies [23-25]. In addition, AOM injections were also converted into chlorpromazine-equivalent doses and combined with oral antipsychotics to evaluate the overall reduction in antipsychotic dosage. Information on the duration of adjunctive aripiprazole from the starting point, AOM dosage, and total AOM injection numbers during 12 months was also collected. Adjunctive aripiprazole was defined as the use of aripiprazole for safety evaluation purposes up to 2 months prior to the initiation of AOM treatment. Safety evaluations were conducted for all adverse reactions documented in the medical records, assessing severity and seriousness.
The primary outcome measure was the change in the average Global Assessment of Functioning (GAF) score over the 12-month period [26], while the secondary outcome measures included changes in the average Clinical Global Impression-Bipolar-Severity (CGI-BP-S) [27], Young Mania Rating Scale (YMRS) [28], Korean version of the Montgomery-Åsberg Depression Rating Scale (K-MADRS) [29], and Hamilton Anxiety Rating Scale (HAM-A) [30] scores over 12 months, as well as changes in the average doses and number of pills of mood stabilizers and antipsychotics.
Statistical analysis
Frequency analysis and descriptive statistics were used to examine participants’ demographic and clinical characteristics. Demographic information and clinical characteristics such as age, educational level, duration of illness, psychiatric hospitalization frequency, treatment failure frequency, dosage and number of tablets of antipsychotic medication, duration of adjunctive aripiprazole from baseline, AOM dosage, and total AOM injection frequency over 12 months were presented with descriptive statistics such as means and standard deviations for continuous variables, and frequencies and proportions for categorical variables. Functional and clinical symptom severity represented by the GAF, CGI-BP-S, YMRS, K-MADRS, and HAM-A scores at evaluation periods (1, 3, 6, 9, and 12 months) from baseline were presented as continuous variables with descriptive statistics such as means and standard deviations.
To compare changes in clinical outcomes and medication from AOM initiation to 12 months later, the Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons was performed. The same analysis was additionally conducted specifically for patients with bipolar I disorder. R version 4.3.1 (R Foundation for Statistical Computing) was used for statistical analyses, conducted with a two-tailed significance level of 0.05.
RESULTS
Demographic characteristics
Table 1 displays the participants’ demographic characteristics. The mean age was 34.42±9.46 years, and six participants (25.0%) were male. The average duration of illness was 87.67 ±63.34 months. At the start of the study, 16 individuals (66.7%) were diagnosed with bipolar I disorder and 8 (33.3%) with bipolar II disorder. After 12 months, a total of 17 participants remained in the study, of whom only 3 (17.6%) were diagnosed with bipolar II disorder. The mean duration of concurrent oral aripiprazole use at baseline was 12.67±23.89 months, with a mean concurrent dosage of 5.25±3.66 mg. The initial dosage of AOM for all participants was 400 mg, and the mean dosage of AOM during the study period was 392.42±22.01 mg, with an average of 10.46±4.00 injections administered over a 12-month period. The mean GAF, YMRS, K-MADRS, and HAM-A score at baseline was 49.38±14.36, 6.88±8.19, 15.17±9.28, and 14.67±9.91, respectively.
The average of the total number of pills taken by the participants at baseline was 8.71±4.16, the average of the mood stabilizer dosage calculated in lithium equivalent was 651.50±577.42, and the number of pills was 2.12±1.89. Antipsychotic drugs were standardized based on chlorpromazine equivalence, and the average dosage, total dosage per month, and number of pills was 272.83±278.98, 15,971.3±7,811.80, and 2.23±1.54, respectively. The lorazepam-equivalent dosage of benzodiazepines taken by patients was 1.33±1.05, the number of pills was 1.88±1.27, and the number of pills for Z-drugs, anticholinergics, and beta blockers was 0.15±0.35, 0.21±0.39, and 1.53±0.92, respectively.
Changes in function and symptom severity over time
Figure 2 shows the mean changes in GAF, CGI-BP-S, YMRS, K-MADRS, and HAM-A scores at baseline, 1, 3, 6, 9, and 12 months. The GAF score significantly increased by 25.7% from baseline to 12 months (p=0.001). Significant improvement in GAF scores was observed at each time point compared with baseline. Scores on the CGI-BP-S, YMRS, K-MADRS, and HAM-A decreased significantly by 24.4% (p=0.001), 81.2% (p=0.001), 36.2% (p=0.002), and 36.1% (p=0.003), respectively, from baseline to 12 months. Significant reduction in symptom severity scores were observed at each time point compared with baseline.
Supplementary Figure 1 shows the mean changes in GAF, CGI-BP-S, YMRS, K-MADRS, and HAM-A scores at baseline, 1, 3, 6, 9, and 12 months in patients with bipolar I disorder. The GAF score significantly increased by 21.6% from baseline to 12 months (p=0.016), with significant improvement observed at each time point except at the sixth month compared with baseline. Scores on the CGI-BP-S, YMRS, K-MADRS, and HAM-A decreased significantly by 28.9% (p=0.010), 91.4% (p=0.013), 39.5% (p=0.031), and 47.3% (p=0.017), respectively, from baseline to 12 months. Significant reductions in symptom severity scores were observed at each time point, except for K-MADRS scores at the third month, compared with baseline.
Changes in prescribed medications over time
Figure 3 shows the mean changes in prescribed medications at baseline, 1, 3, 6, 9, and 12 months. The number of pills taken decreased by 20.7% from 8.7 at baseline to 6.9 at 12 months, but this was not statistically significant. However, the dosage of mood stabilizers, calculated as lithium-equivalent doses, was significantly reduced by 40.1% from 651.5 to 390.2 mg over 12 months (p=0.006), showing a significant decrease at each time point. Likewise, the dose of antipsychotic medication previously taken decreased by 49.2% from 272.8 to 138.6 mg (p=0.047), significantly decreasing at each time point. Additionally, when the dosage of AOM was calculated in chlorpromazine-equivalent doses and combined with oral antipsychotics, a 27.0% reduction was observed over 12 months, decreasing from 16,207.06 mg to 11,838.24 mg (p=0.07) (Figure 4).
Supplementary Figure 2 shows the mean changes in prescribed medications at baseline, 1, 3, 6, 9, and 12 months in patients with bipolar I disorder. There was a significant decrease in the dosage of mood stabilizers, calculated as lithium-equivalent doses, by 41.1%, from 742.9 mg at baseline to 431.6 mg at 12 months (p=0.027). Additionally, the dosage of antipsychotics, calculated as chlorpromazine-equivalent doses, decreased significantly by 39.9% at 1 month and 46.9% at 3 months compared with baseline (p=0.033 and p=0.033, respectively).
When the dosage of AOM was calculated in chlorpromazine-equivalent doses and combined with oral antipsychotics for patients with bipolar I disorder only, a decreasing trend was observed, though it did not reach statistical significance (p=0.14). The dosage decreased from 16,805.71 to 12,505.71 mg over 12 months (Supplementary Figure 3).
Discontinuation and adverse events
Among the participants, 17 (70.8%) maintained AOM treatment for 1 year. Three (12.5%) discontinued by the third month, 5 (20.8%) by the sixth month, 6 (25.0%) by the ninth month, and 7 (29.2%) by 1 year (Figure 1). Reasons for discontinuation included non-compliance (n=4) and adverse events (n=3). Adverse events such as akathisia, tremors, weight gain, and headache were reported by six patients, three of whom switched from AOM to oral medication owing to oculogyric crisis (n=1), akathisia (n=1), and dizziness (n=1). All adverse events were mild or moderate, with no serious events reported.
DISCUSSION
In this study, after 1 year of AOM treatment in patients with bipolar disorder, there was an improvement in functioning compared with baseline, and the severity of symptoms, including those related to affect and anxiety, improved. Additionally, the total pill count showed a non-significant trend-level decrease, while the dosage of mood stabilizers and antipsychotics significantly decreased over time compared with baseline. Even when analyzed exclusively within the bipolar I disorder group, there was significant improvement in function, a reduction in symptom severity, and a decrease in the dosage of mood stabilizers and antipsychotics over time compared with baseline.
After 1 year of use, there were improvements in functioning and reductions in the severity of manic, depressive, and anxiety symptoms in patients with bipolar disorder, consistent with previous findings. A case report [31] on a patient with bipolar I disorder showed that switching from oral aripiprazole to AOM improved quality of life and psychosocial functioning within 4 months. A multicenter, placebo-controlled study [32] revealed that AOM significantly delayed mood episode recurrence, reduced hospitalization risk by over 85%, and improved functioning over 1 year. A 52-week open-label trial [33] further confirmed stable manic symptoms during maintenance treatment. Previous studies [34,35] have reported reductions in manic/hypomanic episodes with AOM, while evidence on depressive episode recurrence has been mixed. One study [36] noted decreased depressive relapses with aripiprazole and valproate combination therapy. The reduction in symptom severity observed in this study may be due to an increased duration of euthymic states as mood episode recurrence decreases, consistent with previous findings. In this study, patients with both types of bipolar disorder were included. In patients with bipolar I disorder, significant improvements were observed in function, affective symptoms, and anxiety symptoms over a year. Although the number of participants with bipolar II disorder was small, the overall results, which included these participants, demonstrated significant improvement. This highlights the potential utility of AOM in managing symptoms and providing maintenance treatment across bipolar disorders, including bipolar II disorder. Further research with larger sample sizes is warranted to confirm these findings.
An intriguing finding is that AOM usage led to a trend-level decrease in total pill count, albeit not statistically significantly. Additionally, the dosages of antipsychotics (measured in chlorpromazine equivalents) and mood stabilizers (measured in lithium equivalents) significantly decreased over 1 year. While limited research suggests a reduction in pill count with the use of LAIs, a previous study [37] supports this finding. Simplifying drug regimens through improved polypharmacy has been shown to enhance medication adherence and compliance. Although a statistically significant reduction in pill count was not observed in this study, a decreasing trend consistent with previous findings suggests that AOM may positively impact drug adherence and compliance in patients with bipolar disorder. Furthermore, this study demonstrated a significant decrease in the dosages of both antipsychotics and mood stabilizers over the course of 1 year following the introduction of AOM. This reduction may be attributed to the consistent and stable blood levels of antipsychotics achieved through regular administration, enhancing therapeutic efficacy owing to antipsychotic accumulation in the brain [38]. Stable blood levels likely contributed to symptom improvement, facilitating a reduction to maintenance treatment doses [39]. The decrease in medication dosage may reduce side effects, thereby improving adherence, while a reduced pill count can alleviate the burden of taking medications and reduce stigma, further enhancing compliance [40,41]. These findings suggest that AOM usage plays a crucial role in improving symptom relief and functional outcomes by increasing medication adherence. Furthermore, AOM administration was found to be safe and well tolerated in patients with bipolar disorder. Over the course of 1 year, 29.2% (n=7) of the patients discontinued AOM, with only 12.5% discontinuing owing to adverse events, including oculogyric crisis, akathisia, and dizziness. Additional adverse events, such as tremors, weight gain, and headache, were reported by six patients, though all were classified as mild to moderate, with no serious events recorded. These findings, along with a reduction in polypharmacy, suggest that AOM is a well-tolerated option that may enhance adherence to maintenance therapy for patients with bipolar disorder while posing a low risk of intolerability.
This study had several limitations. First, owing to the small sample size and single-hospital setting in South Korea, the study may not represent the broader bipolar disorder population, reducing statistical power and generalizability. Future research should involve larger and more diverse samples to validate these findings. Second, only patients who received AOM at least three times and had 1-year follow-up records were included, potentially introducing selection bias by excluding those with early discontinuation or inconsistent follow-up. Third, as an observational study without a control group, causal inference is limited, and improvements cannot be attributed solely to AOM; unmeasured clinical or psychosocial factors may also have contributed. Therefore, the results should be interpreted cautiously, emphasizing associations rather than causality. Fourth, although AOM is officially approved for bipolar I disorder, our study also included patients with bipolar II disorder. In clinical practice, AOM is sometimes prescribed to bipolar II patients who are treatment-resistant or who experience significant adverse effects from oral medications, such as weight gain or hyperprolactinemia. However, the small number of bipolar II cases in our study limits firm conclusions. Future studies should expand the sample size of patients with bipolar II disorder and directly compare treatment responses between bipolar I and bipolar II disorders. Lastly, as a retrospective study, it may be subject to biases such as recall bias in rating scales.
To the best of the researchers’ knowledge, this is the first study to demonstrate that the use of AOM in patients with bipolar disorder not only reduces the dosages of both antipsychotics and mood stabilizers but also leads to significant improvements in manic, depressive, and anxiety symptoms, along with overall functional enhancement. This study uniquely integrates these findings to provide a comprehensive view of AOM’s therapeutic benefits over 1 year. These findings were consistent regardless of whether the analysis included patients with only bipolar I disorder or patients with both types, suggesting the potential efficacy of AOM in managing symptoms and improving outcomes even in bipolar II disorder. Although six patients reported mild side effects such as akathisia, tremors, weight gain, and headache, no severe adverse effects were observed. These results indicate that AOM may be a promising maintenance treatment option for bipolar disorder, warranting further research to confirm its efficacy and safety, particularly in bipolar II disorder.
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