Long-Acting Injectable Antipsychotic Initiation in Child and Adolescent Patients with Psychiatric Disorders.

The availability of long-acting injectable (LAI) antipsychotics for the treatment of schizophrenia provides clinicians with options that deliver continuous drug exposure and may improve adherence compared with daily oral antipsychotics. However, all LAI antipsychotics have unique formulations and pharmacokinetic characteristics that have implications for medication selection, administration interval, and injection site. This review outlines key differences in drug formulations and pharmacokinetics among LAI antipsychotics. A systematic search of the PubMed database was conducted to identify physical and formulation properties and pharmacokinetic data of commercially available LAI antipsychotics, including flupentixol decanoate, fluphenazine decanoate, haloperidol decanoate, zuclopenthixol decanoate, aripiprazole monohydrate, aripiprazole lauroxil, olanzapine pamoate, paliperidone palmitate, risperidone microspheres, and risperidone polymeric microspheres. Additional information was obtained from package inserts and product monographs. Relevant data on drug properties, administration details, pharmacokinetic parameters, and oral dose equivalencies of LAI antipsychotics are summarized. Based on our analysis, formulation characteristics (e.g., vehicle medium) and administration characteristics (e.g., injection site) can affect rate of absorption and adverse effects and may factor into whether oral supplementation or an additional injection is needed. Dose adjustments may be necessary based on potential drug–drug interactions, and approximate dose equivalence with oral formulations can help inform titration when switching from oral to LAI formulations. Clinicians administering LAI antipsychotics should consider these formulation and pharmacokinetic factors to maximize clinical impact and to adjust to an individual patient’s needs and treatment goals.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-020-00779-5.

Objectives: Current literature shows a benefit in clinical outcomes when long-acting injectable antipsychotics (LAIAs) are utilized in adult patients with psychiatric disorders such as schizophrenia, schizoaffective disorder, and bipolar disorder. Literature regarding LAIA use in pediatric patients is sparse. The objective of this study is to compare the number of acute psychiatric admissions, psychiatric emergency services (PES) visits, and total number of days admitted to an acute psychiatric hospital 1 year prior to and 1-year post-mirror point of index hospitalization and LAIA initiation. Methods: This was a single-site retrospective mirror-image review of patients <18 years of age initiated on an LAIA during an acute psychiatric hospitalization between October 1, 2015, and October 31, 2022. The number of admissions to the acute psychiatric hospital, number of PES visits, and total number of days hospitalized at the acute psychiatric hospital were captured 1-year pre-index hospitalization admission and 1-year post-index hospitalization discharge, with LAIA administration during index hospitalization being the mirror point. Descriptive statistics and a two-tailed paired t-test were utilized to analyze the data. Results: There were 45 unique pediatric patients initiated on an LAIA during the specified timeframe. Across these 45 patients, there were 47 psychiatric admissions 1-year pre-index hospitalization and 38 psychiatric admissions 1-year post-index hospitalization discharge (p = 0.37). Additionally, there were 24 PES visits 1-year pre-index hospitalization admission and 16 PES visits 1-year post-index hospitalization discharge (p = 0.25). Finally, across the 45 patients, there were a total of 1040 days admitted to the acute psychiatric hospital in the 1-year prior to index hospitalization admission compared with 774 days admitted to the acute psychiatric hospital in the 1-year post-index hospitalization discharge (p = 0.48). Conclusions: In this cohort of pediatric patients initiated on an LAIA, there was a positive trend favoring LAIA therapy over oral antipsychotic therapy with LAIA injection as the mirror point; however, there was no statistically significant difference in the number of psychiatric admissions, number of PES visits, or total number of days admitted to an acute psychiatric hospital. Further studies are required to fully understand the impact of LAIA therapy on clinical outcomes for child and adolescent patients with psychiatric disorders.

Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. Several trials of antipsychotics suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in preventing non-adherence, partial adherence, and in reducing relapse in BD. Various long-acting injectable (LAI) antipsychotics are available, including fluphenazine decanoate, haloperidol decanoate, olanzapine pamoate, risperidone microspheres, paliperidone palmitate, and aripiprazole monohydrate. Due to the increasing number of BD patients receiving LAI antipsychotics, treatment guidelines have been developed. However, the clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Expert physicians from Taiwan participated in a consensus meeting, which was held to review key areas based on both current literature and clinical practice. The purpose of this meeting was to generate a practical and implementable set of recommendations for LAI antipsychotic use to treat BD; target patient groups, dosage, administration, and adverse effects were considered. Experts recommended using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotic use was recommended in BD patients with the following characteristics: multiple episodes and low adherence; seldom yet serious episodes; low adherence potential per a physician’s clinical judgment; preference for injectable agents over oral agents; and multiple oral agent users still experiencing residual symptoms.

Prescription patterns in patients with schizophrenia who discontinued long-acting injectable antipsychotics: A chart-review.

How Would You Like to Take Your Medicine 2 Times a Year? Paliperidone Palmitate Every 6 Months for the Maintenance Treatment of Schizophrenia

Antipsychotics exhibit different profiles of efficacy and safety in patients with schizophrenia. It has recently been reported that the risk of rehospitalization was the lowest with paliperidone palmitate (PP), a long-acting injectable (LAI), when compared with other LAIs (of zuclopenthixol, perphenazine, and olanzapine). We aimed to investigate whether treating patients with PP was also associated with improved real-life treatment persistence. We conducted a retrospective observational study of the LAI antipsychotics (LAIAs) dispensed in French retail pharmacies. Treatment persistence was defined as the non-discontinuation of LAIAs for ≥5 months after LAIA initiation (and was also analyzed by Kaplan-Meier persistence curves). A total of 4,492 patients were included in the study. The persistence rate was significantly greater for LAI-PP (64.5%) than for either LAI haloperidol decanoate (HD) or LAI risperidone microspheres (R) (46.4% and 35.4%, respectively). Multivariate Cox analyses illustrated that LAIA initiation with HD or R significantly increased the risk of discontinuation when compared with PP. PP demonstrated a significantly higher persistence rate than HD or R. Moreover, LAIA initiation with HD or R significantly increased the risk of treatment discontinuation relative to PP. Further comparative studies are required to comprehensively determine whether PP has a better efficacy and/or safety profile than other LAIs.

Five long-acting injectable (LAI) antipsychotics are currently available in the United States for the treatment of schizophrenia: fluphenazine decanoate, haloperidol decanoate, risperidone microspheres, paliperidone palmitate, and olanzapine pamoate. Additionally, aripiprazole LAI is currently under FDA review. However, research into the safety and tolerability of these LAIs, with particular regard to the development of postinjection delirium/sedation syndrome (PDSS), is limited and has been focused mainly on olanzapine pamoate. This proposal seeks to review data regarding all currently available LAI antipsychotics to determine if a significant association exists between these depot formulations and the development of PDSS. A review of all published literature from 2005 to the present was obtained via a PubMed search for current data regarding the topic of LAIs and the development of PDSS. Keywords used for the search were "long-acting injectable antipsychotics" in association with one of the following: "post-injection delirium/sedation syndrome," "PDSS, " "side effects, " and "tolerability." References to key articles were further explored for relevancy to this proposal. A case analysis based on all 8 olanzapine LAI clinical trials conducted between August 2000 and October 2008 showed an occurrence of PDSS in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). A second case analysis reviewing the clinical trial databases for 15 completed studies and the postmarketing safety database for risperidone LAI versus 10 completed clinical trials of paliperidone palmitate failed to demonstrate an occurrence of PDSS events in patients receiving either LAI treatment. However, one case of PDSS was identified in a placebo group. In 4 randomized, double-blind, placebo-controlled trials, treatment-emergent adverse events leading to treatment discontinuation were similar for paliperidone palmitate and placebo; however, among the most frequently occurring treatment-emergent adverse events was somnolence/sedation (5%-7% paliperidone palmitate group vs 3% placebo). Postinjection delirium/sedation syndrome is a potentially serious adverse event that has been shown to be associated with one currently available LAI antipsychotic, olanzapine pamoate. However, further data are still needed to both support this conclusion and determine if an association exists among other currently available LAIs and PDSS. With the bulk of current evidence coming from registration studies, head-to-head comparison studies between 2 LAIs would help to determine whether the risk of postinjection complications differs among different agents. Further observational studies are also needed to address the incidence, severity, and optimal clinical management of this syndrome.

This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia initiating LAIs January 2015–December 2016 were enrolled from the French National Health Data System (SNDS). Standardized mean differences (SMD > 0.1 deemed clinically significant) were calculated for psychiatric healthcare resource utilization measures assessed one year before (during oral AP treatment) and one year after LAI initiation. LAI effectiveness was analyzed overall and by age group, gender and compliance to oral AP, defined as exposure to an AP for at least 80% of the year before LAI initiation. 12,373 patients were included. LAIs were more frequently initiated in men (58.1%), young (18–34 years, 42.0%) and non-compliant (63.7%) patients. LAI initiation was effective in reducing the number and duration of psychiatric hospitalizations and psychiatric emergency department (ED) admissions in non-compliant patients (SMD = −0.19, −0.26 and −0.12, respectively), but not in compliant patients. First-generation LAIs, paliperidone and aripiprazole LAIs reduced psychiatric hospitalizations (SMD = −0.20, −0.24, −0.21, respectively) and ED admissions (SMD = −0.15, −0.13, −0.15, respectively). No differences in effectiveness were found for age or gender. In compliant patients, only aripiprazole LAI reduced the number of psychiatric hospitalizations (SMD = -0.13). Risperidone and paliperidone LAIs increased hospitalization duration (SMD = 0.15 and 0.18, respectively). The prescription of LAIs (except risperidone) should be recommended in all non-compliant patients, even in women and patients aged 35 or older. The lower frequency of administration of LAIs than of oral APs may improve compliance and hence reduce the risk of relapse. Aripiprazole LAI may represent a treatment of choice for compliant patients that should be further investigated.

Current guidelines for the treatment of patients with schizophrenia advocate that patients receive treatment with a long-acting injectable (LAI) antipsychotic medication if they prefer such treatment or if they have a history of poor or uncertain adherence. Available LAI formulations in the United States include first-generation antipsychotics (fluphenazine decanoate and haloperidol decanoate), risperidone/paliperidone containing products (risperidone microspheres, paliperidone palmitate, and risperidone subcutaneous), aripiprazole containing products (aripiprazole monohydrate and aripiprazole lauroxil), and olanzapine pamoate. LAI antipsychotics can address the guesswork about adherence status and patients may prefer them if they are offered this as a choice, including individuals early in their disease course. Additional approved indications in the United States for LAI antipsychotics include bipolar I disorder maintenance treatment for risperidone microspheres and aripiprazole monohydrate, and schizoaffective disorder for paliperidone palmitate once monthly. Differences and similarities among the different products are discussed, including guidance regarding optimal treatment selection. Tips are provided to enhance effective patient communication to maximize the likelihood of acceptance of this treatment modality.

ABSTRACTIntroduction: Long-acting injectable (LAI) antipsychotics are a useful but underutilized option in the management of schizophrenia.Areas covered: This is a narrative review of newer LAI antipsychotics approved by the US Food and Drug Administration and is an update to a previously published review from 2013. Emphasized are new indications and new dosing intervals.Expert commentary: Ensuring that persons receiving oral antipsychotics are aware that LAI antipsychotics are available is important. The use of LAI antipsychotics can decrease the risk of relapse in both first-episode and chronic schizophrenia. Available treatments differ in terms of specific indications, approved injection sites, needle gauge, injection volume, injection interval, requirements for oral supplementation, availability of pre-filled syringes, storage needs, and post-injection observation period, as well as potential drug-drug interactions and commonly encountered adverse reactions. Approved indications have expanded beyond schizophrenia to also include bipolar maintenance (risperidone microspheres and aripiprazole monohydrate) and schizoaffective disorder (paliperidone palmitate monthly). Intervals between injections can be longer than one month (six-week or two-month aripiprazole lauroxil, and three-month paliperidone palmitate). After a review of the evidence-base, guidance is offered on the appropriate selection among the LAI formulations of both first and second-generation antipsychotics.

The use of long-acting injectable antipsychotics (LAIs) is considered to be an important treatment option, especially in early stages of schizophrenia. The aim of this study was to evaluate the efficacy, safety and sustained remission in schizophrenia patients treated with three of the available LAIs substances: olanzapine pamoate, risperidone microspheres and aripiprazole monohydrate. A retrospective chart review study evaluating the efficacy of LAIs compared to oral antispychotics during a five years period was performed. Of the 102 patients included in the study, 52 (50.9%) continued LAIs: olanzapine pamoate (n = 20, 38.4%), risperidone microsphere (n = 22, 42.3%), aripiprazole monohydrate (n = 10, 19.3%). In the LAIs group the number of relapses was smaller than in the oral antipsychotics group (12 vs. 23, P [ 0.05) as well as the number of admissions (15 vs. 30, P [ 0.05). In conclusion, relapse in schizophrenia is strongly related to nonadherence. LAIs prescription overall was underutilized despite their efficacy. Future randomized studies are needed to evaluate the long term efficacy of LAIs compared to oral treatment.

To quantify and explain variation in use of long-acting injectable antipsychotics (LAIs) in the United States, and understand the relationship between patient characteristics, drug reimbursement policies, and LAI prescribing after relapse. A cohort of recently relapsed patients with schizophrenia ages 18 to 64, were identified immediately after discharge from a related inpatient hospitalization, partial hospitalization, or emergency room visit, drawn from 2004 to 2006 Medicaid claims, and followed for 90days until LAI initiation. Data on state-level Medicaid prior authorization (PA) policies for LAIs were collected. Sequential longitudinal Poisson regression models were developed to understand the relationship between patient and PA policy variables and LAI prescribing, including prior adherence to oral antipsychotics, demographics, clinical variables, and presence of PA policy for LAI. Among 36282 patients, 3.1% received risperidone LAI, and 3.8% received a first-generation (FGA) LAI with wide variation across states. Prior adherence ranged from 29% to 89% but was marginally associated with initiation and did not explain variation for LAI prescribing. FGA initiation was associated with geography and race/ethnicity but not PA policy. For risperidone LAI initiation, demographics and clinical factors explained, respectively, 5.0% and 3.0% of the variation; PA policy had a large negative association with initiation (RR=0.41; 95%CI 0.20-0.87) and explained 8.4% of the variation. PA policies may represent a major treatment barrier for risperidone LAI among relapsed patients. Non-adherence plays a little role in predicting which patients receive LAIs. Policy makers and health insurers will need to consider these findings when guiding the use of LAIs. KEY POINTS Among a nationwide cohort of relapsed schizophrenia patients enrolled in US Medicaid, 3.1% received Risperdal Consta, a long-acting injectable antipsychotic (LAI), and 3.8% initiated a first-generation first-generation LAI within 90days after discharge. During 2004 to 2006, there was marked variation in 90day post-relapse initiation of Risperdal-Consta-a newly marketed medication during this period-and also marked variation in 90day post-relapse initiation of any first-generation LAI, which appeared to be associated with race/ethnicity and geography. Prior authorization policies were associated with substantially lower initiation of Risperdal Consta in this cohort of relapsed patients even after accounting for clinical indication (non-adherence), relapse history, demographics, adjunctive medication, and mental health service use.

PMH46 Treatment Patterns With Aripiprazole Lauroxil Versus Other Atypical Long-Acting Injectable Antipsychotics in Patients With Schizophrenia: A Retrospective Electronic Health Records Database Study

Effect of long-acting injectable antipsychotics on emergency department visits and hospital admissions in people with bipolar disorder: A retrospective mirror-image analysis from the Northern Milan Area Cohort (NOMIAC) study

Schizophrenia is a chronic, debilitating psychiatric disorder with a high risk of relapse. Nonadherence to medication is a significant contributor to poor outcomes. Although long-acting injectable (LAI) antipsychotics prevent the relapse of schizophrenia, several factors present obstacles to the use of LAI antipsychotics, and clinical guidelines for LAI antipsychotics remain limited. To provide clinical recommendations, the Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN) developed consensus statements for the effectiveness, target populations, initiation timing, and particular clinical situations for the use of LAI antipsychotics in patients with schizophrenia. After a systematic literature review, a working group drafted consensus statements for the selected clinical topics and determined the levels of evidence-based recommendation based on the latest World Federation of Societies of Biological Psychiatry grading system. A scientific committee evaluated the draft statements and decided the final recommendations regarding the grades by anonymous voting after incorporating clinical experience and practice into the evidence from research. The TSBPN proposed ten consensus statements for the application of LAI antipsychotics. The current evidence supported that LAI antipsychotics could be a treatment option for all schizophrenia patients, including first-episode patients. LAI antipsychotics could be initiated both during an acute psychotic episode and when patients are stable. The consensus also gave recommendations for particular clinical situations with insufficient scientific data, such as for use in elderly or adolescent patients, patients with treatment-resistant schizophrenia, and breakthrough psychosis, and strategies to assist patients/caregivers with decision making. The consensus statements developed by the TSBPN provide evidence-based clinical recommendations and could give clinicians more confidence when prescribing LAI antipsychotics to treat schizophrenia, thereby improving treatment outcomes.