Long‐acting injectable antipsychotics as maintenance therapy for schizophrenia during the COVID‐19 pandemic: A micro‐narrative review

Abstract The coronavirus disease pandemic has presented healthcare systems with unprecedented challenges globally and substantially impacted the management of chronic diseases such as schizophrenia. This narrative review highlights the usefulness of long‐acting injectable antipsychotics (LAIs) as maintenance therapy for patients with schizophrenia during the pandemic. The analysis of relevant literature and psychiatric survey data revealed diverse trends in LAIs prescription and patient adherence with oral antipsychotics. Although some studies have reported a decrease in LAIs prescriptions owing to pandemic‐related disruptions, others have suggested stable patient adherence with oral antipsychotics. Approximately 70% of Japanese psychiatrists reported an increase in schizophrenia relapse rates in a survey, underscoring the critical role of LAIs in maintaining therapeutic stability. The potential benefits of LAIs with extended dosing intervals have been highlighted, including improving oral medication adherence and reducing the frequency of hospital visits. In conclusion, this review emphasizes the continued need for uninterrupted LAIs therapy in conjunction with community and home‐based care despite the disruptions caused by the coronavirus disease pandemic. Further development of LAIs maintenance therapy strategies considering the ongoing pandemic and potential future public health emergencies are required.

health insurance system, revised its reimbursement procedures to cover LAIs fees for hospitalized patients and thereby promote LAIs use nationwide. 3Simultaneously, the ongoing coronavirus disease (COVID-19) pandemic necessitated an examination of LAIs prescribing trends in Japan and beyond to understand the status of schizophrenia maintenance therapy during this global crisis.This narrative review aims to present the findings of various studies on LAIs prescribing trends during the COVID-19 pandemic.This review also discusses the significance of LAIs for patients with schizophrenia during the pandemic, their usefulness in conjunction with community social resources, and the potential benefits of extended LAIs dosing intervals.

| ME THODS
Relevant studies on LAIs prescriptions during the COVID-19 pandemic were sourced from PubMed on October 7, 2023, using the following search strategy: ("Long-acting inject*" or "LAI") AND Eight of the retrieved studies were not relevant to the topic of this study.18 were related to LAIs prescriptions during the COVID-19 pandemic; however, three were reviews for which no parameters were presented; thus, and 15 were ultimately included for in-depth analysis.

| L AIS PRE SCRIP TI ON S DURING THE COVID -19 PANDEMIC
Following the implementation of lockdown measures after the declaration of COVID-19 as a pandemic by the World Health Organization (WHO) in March 2020, access to several medical facilities was temporarily restricted.Psychiatric facilities also implemented various preventive measures in prescribing LAIs. 4

| LAIs prescribing trends before and after the COVID-19 pandemic: A decrease in LAI prescriptions
Our review identified four retrospective observational studies, including one mirror-image study (Table 1).A significant decline in LAIs prescriptions in Romania was observed following the COVID-19 pandemic declaration on March 11, 2020.This is likely due to the considerable impact COVID-19 has had on the entire healthcare system, including export restrictions on drugs and supply delays in pharmacies. 5,6Recent literature has suggested other factors, such as patient reluctance to leave home and a reduction in the number of injections due to shorter working hours of clinics. 7Barlati et al. 4 reported that the decrease in new LAIs prescriptions in Italian civilian hospitals was related to a switch to oral medications aimed to prevent reduced number of visits during the COVID-19 pandemic and interactions with drugs administered for severe cases.

| LAIs prescribing trends before and after the COVID-19 pandemic: LAIs prescriptions remain stable or increase
Four retrospective observational studies, including one mirrorimage study, suggested that LAIs prescriptions remained stable or increased during the pandemic (Table 2).Studies conducted in the United States (US; Pittsburgh) 8 and Australia 9 attributed the stable LAIs prescription rates to thorough infection control measures and successful communication with patients and families regarding the importance of continued LAIs treatment.A Canadian study suggested that LAIs prescriptions continued during the pandemic due to persistent needs, despite the potential selection bias owing to its pharmacy database-based design. 10A survey of psychiatric providers in the United States indicated that LAIs prescriptions were expected to remain stable or increase in 2021. 11

| Parameter changes related to LAIs during the COVID-19 pandemic
We identified several studies using parameter changes related to LAIs during the COVID-19 pandemic (Table 3).These studies highlighted that LAIs treatment was associated with the risk of infection, limited clinic access, and increased frequency of LAIs non-adherence during the COVID-19 pandemic. 12,13To counter these issues, strategies such as switching to oral medications 12,14,15 and less frequent LAIs administration 12,15,16 were adopted.Other infection control measures included home visits 12 and LAIs administration at community pharmacies. 17tably, no difference was observed in the readmission rates between patients taking oral antipsychotics and those receiving LAIs during the pandemic. 18However, more LAIs prescribers reported worsened adherence with oral antipsychotic prescriptions and symptom control in patients with schizophrenia during the pandemic. 15

| MAINTENAN CE THER APY FOR SCHIZOPHRENIA US ING L AIS DURING THE COVID -19 PANDEMIC
Despite the prescribing trends during the pandemic, LAIs remained in demand.According to Zhdanava et al., approximately half of LAIs prescribers in the United States observed no changes in oral medication adherence during the pandemic. 15Nevertheless, oral medication adherence remained a concern, as highlighted in other studies. 15,19 a survey of Japanese psychiatrists, approximately 70% reported an increase in relapses during the pandemic. 20Schizophrenia necessitates continuous drug treatment, 1 and medical interruptions owing to the pandemic potentially resulted in decreased oral antipsychotic TA B L E 1 LAI prescribing trends before and after the COVID-19 pandemic (LAI decreasing).

Ifteni et al., 2020
Observational  • Participants emphasized several benefits of switching to PP3M; convenience was the most reported (93.5%), followed by more excellent quality of life (58.7%),reduced stigma (39.1%), and better adherence (28.3%).Additionally, 93.5% of respondents reported no drawbacks, while 6.5% spoke about worsening symptoms or side effects • Only one patient stopped using PP3M after a year, and the total number of hospitalizations decreased within that time frame relative to the year before switching prescriptions.This, in turn, negatively impacted oral medication adherence in patients with schizophrenia.Zhdanava et al. 15 demonstrated that switching from oral medication to LAIs was a strategy to improve antipsychotic oral medication adherence during the pandemic.
Online medical care has grown in popularity; however, our previous study showed that psychiatrists rated the usefulness of online care as low owing to difficulties in evaluating psychopathology and accessibility issues in certain areas such as rural and underpopulated regions. 20Because a decrease in LAIs prescriptions was observed during the early stages of the COVID-19 pandemic because of fewer face-to-face consultations, satisfactory access to LAIs became crucial. 21In 2020, the American Psychiatric Association recommended that physicians avoid interrupting LAIs treatment for high-risk patients with schizophrenia. 22cLaurin et al. 12  The pandemic has resulted in increased anxiety and depression in patients with schizophrenia, as noted in a Turkish study. 25Therefore, considering LAIs as maintenance therapy options for schizophrenia during the COVID-19 pandemic has been crucial, not only to prevent patients from isolating themselves or interrupting their visits but also for direct patient treatment through visits.

| OP TIMAL US E OF L AIS DURING THE COVID -19 PANDEMIC
Based on our survey, psychiatrists deemed LAIs as effective during the COVID-19 pandemic. 20Several previous studies have supported this view, suggesting that LAIs with extended dosing intervals are advantageous. 6,8,12,20,26Patients have shared similar views. 16Given that the COVID-19 pandemic is ongoing and considering future global health emergencies, considering LAIs with even longer dosing intervals may be beneficial.This may facilitate the recovery of patients with schizophrenia by improving oral medication adherence and reducing the frequency of hospital visits.

| LIMITATI ON S AND FUTURE PER S PEC TIVE S
This is a narrative review, not a systematic review.Therefore, a systematic review should be conducted in the future.It would be clinically appropriate to examine how LAIs use has changed before and after unforeseen events such as recent wars, earthquakes, and other disasters.

| CON CLUS ION
LAIs are essential for maintenance therapy for schizophrenia before
patients with schizophrenia treated with LAI in the Freedom Trail Clinic of North Suffolk Mental Health Association From January to May 2020 (COVID-19 pandemic) Number of LAI prescriptions • Twenty-three individuals switched to an outside injector between January and May 2020, with visiting nurses providing injections most of the time.Three patients shifted treatment, and six switched to oral drugs.The clinic's LAI program was continued for the remaining 45 patients.15 percent (7 patients) of 45 patients shifted to lengthier formulations of their respective LAIs and visited less frequently • Concerning the prescribed LAIs, 30 patients were taking aripiprazole, 18 were receiving paliperidone, 12 were receiving haloperidol, three were receiving risperidone, and one received fluphenazine • For skipping their injection or having their prescription switched, no patients needed to be admitted to a mental health facility Miron AA et al., 2022 Observational study Twenty-seven individuals with schizophrenia who had been treated with OLZ-LAI for a long time and remained in remission at Brasov, Romania's Clinical Hospital of Psychiatry and Neurology From April 2020 to March 2021 (COVID-19 pandemic) • Proportion of switches from olanzapine-LAI to oral olanzapine • Recurrence rate • Of 27 patients, 21 (77.77%)preferred to convert to oral olanzapine.Only 6 patients continued the longacting formulation • After switching from olanzapine LAI to OA, 15 patients (71.42%) relapsed during the subsequent 12 months, and 12 were hospitalized at the emergency psychiatric ward Mascari et al.-based pharmacy • Eighty-two percent of patients strongly agreedthat they felt at ease having this service at the neighborhood pharmacy and that the service's privacy was satisfactory• Only 18% of patients strongly agreed that the community-based pharmacy was close to their place of employment or residence• 71 percent of patients who received this service elsewhere strongly agreed that the LAI medication administration service was more convenient than a similar service received elsewhere data from US-based healthcare practitioners (LAI prescribers) with a specialty in psychiatry.COVID-19 pandemicPrescriber's perspective: The proportion of switches from LAI to oral tablets medication adherence symptom control/relapse frequency • Of the 401 LAI prescribers who met survey requirements, 64.6% reported that their LAI prescribing has not changed (update: 19.2%; decrease: 14.0%) • The majority of prescribers shifted the same proportion of patients from OAPs to LAIs during the pandemic as in previous practice (65.1%).None shifted to oral antipsychotics (OAP; 63.3%) or LAI formulations with lower frequency of administration (68.1%) • Antipsychotic adherence was unchanged for most patients according to 50.1% of LAI prescribers, and treatment was effective for 44.6% based on symptom control and relapse frequency Forster et al., 2022 Observational study Electronic medical data of 101 patients with severe mental illness receiving LAI-As in the United States COVID-19 pandemic Pandemic-related barriers to LAI-A adherence and/ or changes to LAI-A medications • For 33% of the patients, pandemic-related obstacles to LAI-A adherence and adjustments to LAI-A prescriptions were documented • Within-participant comparison of an adherence metric generated from electronic health record data showed that the incidence of missed or delayed LAI-A doses was slightly higher during the pandemic than it was before the pandemic • Only 2 of the 13 patients who were interviewed expected that worries about the epidemic would affect their ability to take their medications as prescribed Masterich et al., 2022 Retrospective study Participants with delusional conditions, schizophrenia, and illnesses like schizophrenia at the Clinic for Psychiatry of CHC Split COVID-19 pandemic Number of rehospitalizations of patients with schizophrenia Regarding whether they took oral antipsychotics or LAIs, there was no difference in the number of rehospitalizations of patients with schizophrenia, schizophrenia-like disorders, and delusional states Barnett et al., 2023 the 46 individuals who participated in the trial said they were satisfied (89.2%) and felt safer (93.5%) after switching to the three-monthly formulation during the COVID-19 pandemic cited the availability of community resources to support ongoing treatment as a critical factor in switching to LAIs during the COVID-19 pandemic.Notably, users of community services and their families who maintained optimal therapeutic relationships with experienced nursing teams received person-centered, ongoing care even during the COVID-19 pandemic. 23One major issue highlighted by Correll et al. is reduced access to psychiatric care for patients with severe mental illnesses owing to COVID-19 control restrictions. 21To this extent, Moreno et al. proposed a home treatment to improve access to care, 24 whereas Gannon et al. underscored the importance of regular in-person visits for LAIs and oral medication adherence for patients and their families.8 and during the COVID-19 pandemic.While a reduction in LAIs prescriptions was reported during the pandemic owing to distribution issues, some studies showed no significant change.The discrepancies in these findings can be attributed to the variations in the COVID-19 measures implemented in different regions or settings.Despite these challenges, continued uninterrupted LAIs treatment and community and home care through a multidisciplinary approach are vital in preventing patient isolation, which can exacerbate the symptoms of schizophrenia and pose additional barriers to treatment.Looking forward, the development of new LAIs formulations is eagerly anticipated, as is the continued refinement of LAIs maintenance therapy strategies in the face of unprecedented public health crises such as the COVID-19 pandemic.AUTH O R CO NTR I B UTI O N S Y.O., N.M., and K.A. conceived and designed the study.Y.O.drafted the manuscript.All authors have read and approved the final manuscript.