The Early Use of Long-acting Injectable Antipsychotic Drugs in the Treatment of Bipolar Disorder: A Call for Action

Bipolar disorder (BD) is a severe, recurring mental illness. Pharmacotherapy is crucial in the treatment of patients with BD, supplemented by social and psychological interventions. Traditionally, monotherapy with mood stabilizers such as lithium, carbamazepine, and valproic acid was recommended as the first-line medications for BD in 1994, but the routine use of antipsychotics (neuroleptics) was not recommended [1]. But in recent decades, recommendations from CANMAT guidelines in 2013 suggest mood stabilizers and certain antipsychotics to be the first-line medications during different phases of illness course [2], with most second-generation antipsychotics (SGAs) being indicated for treating patients with BD in the manic phase. Data from Taiwan’s National Health Insurance Research Database on discharged patients with BD revealed that the use of mood stabilizers was 79.4%, antipsychotics was 74.1%, and combined use was 52% from 2000 to 2007 [3]. In a survey conducted across Asian countries in 2019 involving 2003 subjects, the rates were 80.8%, 82.1%, and 48.9%, respectively, with monotherapy using antipsychotics reported at 13.4% [4]. The use rate of SGAs was 67.6%, first-generation antipsychotics was 6.9%, and a combination of both was 7.6% in this study. These results suggest that the use of antipsychotics in the treatment of patients with BD has become increasingly popular in recent decades. Monotherapy with antipsychotics to treat patients with BD was scarcely reported until the emergence of SGAs. In this systematic review [5], the authors suggested that the use of SGAs, such as aripiprazole, olanzapine, lurasidone, risperidone, and quetiapine, has been found to be adequate for their use in monotherapy as maintenance treatment for patients with BD, according to randomized and controlled clinical trials. Long-acting injectable antipsychotics (LAIs) have been proven to be a better treatment regimen than oral antipsychotics for schizophrenia in many well-designed clinical trials and national cohort reports [6]. But LAIs are rarely prescribed to treat patients with BD unless a patient has experienced multiple relapses, severe symptoms, and poor adherence to oral medications [7]. In a review using mirror-image design studies, the authors suggested that the use of LAIs is an effective strategy to improve major clinical outcomes in patients with BD [8]. Six studies were analyzed in this review, and two of which were reports from Taiwan [9,10]. In the Finnish nationwide cohort study done from 1996 to 2018, with a mean follow-up of 9.3 years, LAIs have been reported to have better efficacy in the treatment of BD, using rehospitalization as an indicator [11]. But the use rate was only 1.8% (1,065/60,045), with only 1% of patients receiving LAIs as monotherapy [12]. Interestingly, a report from a public psychiatric hospital in southern Taiwan revealed that the LAIs’ prescription rate for patients with BD was increased remarkably from 2.2% in 2006 to 11.6% in 2018, with the use of LAI of SGAs gradually increasing [13]. This study has also shown greater efficacy in reducing the risk of rehospitalization. Another report from a psychiatric hospital in northern Taiwan also suggested that LAIs were associated with a reduced risk of rehospitalization within one-year postdischarge compared with oral medications from 2006 to 2017 [14]. However, the rate of LAIs use was only 4.6% by person-time. In a recent survey done across 10 Asian countries [15], the investigators of the study analyzed 2,029 prescription records for patients with BD and identified 103 cases involving the use of LAIs. The highest LAIs’ prescription rates have been observed in Sri Lanka and Malaysia, while no use was reported in Myanmar, India, and Japan (Table 1). These findings show remarkably different rates but align with the results of a survey on LAIs use in schizophrenia across Asian countries [16]. These two surveys on LAIs use in Asian countries reflect differences that may stem from the distinct challenges each country faces regarding healthcare regulations and resources, clinicians’ training backgrounds and attitudes, and patient adherence. BD is a lifelong condition characterized by recurrence and relapse, making medication adherence crucial for effective management.Table 1: Distribution of long-acting injectable antipsychotics treatment prescriptions for bipolar disorder across different Asian countries (this table is reprinted from [15])In the latest CANMAT guidelines, published in 2023, the use of LAI aripiprazole has been recommended as a first-line treatment, while LAI risperidone is suggested as a second-line medication for maintenance therapy in patients with BD [17]. Notably, in an open-label study, LAIs such as aripiprazole, paliperidone, and risperidone were given to 116 adolescent patients with bipolar mania or schizoaffective disorder bipolar type. Over the course of one year, these treatments have shown to have remarkable efficacy and tolerability [18]. The repeated recurrence of manic or depressive phases may result in neurodegeneration in patients with BD, leading to cognitive and functional impairment, as well as increased mortality, which underscores the necessity of early prophylaxis [19]. In an expert consensus, the benefits of LAIs in the management of patients with BD were highlighted, and their early use has been strongly advocated [20]. In Taiwan, the government officials have encouraged the use of LAIs in patients with schizophrenia, who have compliant problems with oral antipsychotic drugs [21]. In this context of the cost versus benefit, I am calling for action to consider the early use of LAIs even in patients with BD, either as monotherapy or in combination with mood stabilizers. Data Sharing Statement Data sharing is not available to this editorial because no datasets were generated and/or analyzed during the writing of this editorial. Financial Support and Sponsorship The author denies any source of funding or any sponsorship in writing the editorial. Conflicts of Interest The author declares no potential conflicts of interest in writing this editorial.