Optimizing Treatment With Aripiprazole Monohydrate: Pharmacokinetic Advantages of Long-Acting Injectable Formulations, A Consensus Panel Report.

BackgroundFrench clinical recommendations suggest prescribing long-acting injectable (LAI) antipsychotics to patients with a maintenance treatment indication in schizophrenia. Despite this, and due to their relatively high acquisition and administration costs, LAIs are still underused in clinical practice in France, thus highlighting the need for pharmacoeconomic evaluations.ObjectiveOur objective was to estimate the cost effectiveness of paliperidoneLAI (or paliperidone palmitate), a once-monthly second-generation LAI antipsychotic, compared with the most common antipsychotic medications for the maintenance treatment of schizophrenia in France.MethodsA Markov model was developed to simulate the progression of a cohort of schizophrenic patients through four health states (stable treated, stable non-treated, relapse and death) and to consider up to three lines of treatment to account for changes in treatment management. Paliperidone LAI was compared with risperidone LAI, aripiprazole LAI, olanzapine LAI, haloperidol LAI (or haloperidol decanoate) and oral olanzapine. Costs, quality-adjusted life-years (QALYs) and number of relapses were assessed over 5 years based on 3-month cycles with a discount rate of 4 % and from a French health insurance perspective. Patients were considered to be stabilised after a schizophrenic episode and would enter the model at an initiation phase, followed by a prevention of relapse phase if successful. Data (e.g. relapse or discontinuation rates) for the initiation phase came from randomised clinical trials, whereas relapse rates in the prevention phase were derived from hospitalisation risks based on real-life French data to capture adherence effects. Safety and utility data were derived from international publications. Additionally, costs were retrieved from French health insurance databases and publications. Finally, expert opinion was used for validation purposes or in case of gaps in data. The robustness of results was assessed through deterministic and probabilistic sensitivity analyses.ResultsAll LAI antipsychotics were found to have similar costs over 5 years: approximatively €55,000, except for paliperidone LAI which had a discounted cost of €50,880. Oral olanzapine was less costly than LAIs (i.e. €50,379 after 5 years) but was associated with fewer QALYs gained and relapses avoided. Paliperidone LAI dominated aripiprazole LAI, olanzapine LAI and haloperidol LAI in terms of costs per QALY, and it was associated with slightly fewer QALYs when compared with risperidone LAI (i.e. 3.763 vs 3.764). This resulted in a high incremental cost-effectiveness ratio (ICER) (i.e. €4,770,018 per QALY gained) for risperidone LAI compared with paliperidone LAI. Paliperidone LAI was more costly than olanzapine oral but associated with more QALYs (i.e. ICER of €2411 per QALY gained for paliperidone LAI compared with oral olanzapine). Paliperidone LAI had a probability of being the optimal strategy in more than 50 % of cases for a willingness-to-pay threshold of €8000 per QALY gained.ConclusionThis analysis, to the best of our knowledge, is the first of its kind to assess the cost effectiveness of antipsychotics based on French observational data. Paliperidone LAI appeared to be a cost-effective option in the treatment of schizophrenia from the French health insurance perspective.

BackgroundPatients undergoing antipsychotic treatment for psychiatric disorders may experience challenges in functioning, either stemming from the severity of the illness or from the tolerability issues of prescribed medications.ObjectivesThe aims of this cross-sectional study are to investigate the impact of adverse effects of antipsychotic drugs on patients’ daily life functioning, comparing oral and long-acting injectable (LAI) antipsychotics, and further dividing antipsychotics by receptor-binding profiles based on recently defined data-driven taxonomy.MethodsThis study involved patients with schizophrenia and bipolar spectrum disorders taking oral or LAI antipsychotics. Disability and functioning levels were assessed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS), and the adverse effects of medications were evaluated using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and its subscales.ResultsThe total sample consisted of 126 participants with a diagnosis of schizophrenia-spectrum or bipolar disorder, and included 54 males and 72 females ranging from 18 to 78 years of age (mean 45.1, standard deviation 14); 78 patients were taking oral antipsychotics and 48 were taking LAI antipsychotics, with subcategories of muscarinic (31), adrenergic/low dopamine (25), serotonergic/dopaminergic (23), dopaminergic (1), LAI muscarinic (15), LAI adrenergic (6), and LAI serotonergic/dopaminergic (25). The UKU total score for adverse effects showed significant correlations with WHODAS total score (ρ = 0.475; p < 0.001). Compared with oral antipsychotics, LAIs showed significantly lower scores in psychological (p = 0.014), autonomic (p = 0.008), other (p = 0.004), and sexual adverse effects (p = 0.008), as well as the UKU total score (p = 0.002). The Kruskal–Wallis test showed a significant difference in adverse effects between LAI and oral muscarinic subgroups, with LAIs having lower scores compared with antipsychotics binding to muscarinic receptors (p = 0.043).ConclusionThese findings indicate clinically relevant differences in adverse effects among formulations, warranting further investigation for future observational studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-024-01391-x.

BackgroundTo overcome nonadherence in patients with psychosis switch to long-acting injectable (LAI) antipsychotic formulations is adopted. Most oral versus LAI comparisons showed similar antipsychotic responses. Psychoses often overlap with substance use disorder (SUD). Head-to-head LAI comparisons have hitherto focused only on non-comorbid populations.ObjectiveThe objective of this study was to compare two LAIs, administered for 12 months, in initially hospitalized patients with psychosis comorbid with SUD in their clinical and quality of life (QoL) outcomes.Patients and methodsInpatients were recruited during 2016 and switched randomly to 400 mg intramuscular aripiprazole monohydrate (AM) (N=50) or to 100 mg intramuscular paliperidone palmitate (PP) once-monthly (N=51); patients were discharged and followed up for 12 months. Patients were rated at baseline and after 1 year through the Clinical Global Impression scale – severity (CGIs), substance craving intensity was rated through a visual analog scale for substance craving, and QoL through the World Health Organization (WHOQOL-BREF) scale. We addressed confounders with backward stepwise logistic regression and three-way analysis of variance.ResultsPP were older and had more cases of schizophrenia spectrum and less bipolar disorders than AM, but AM had a stronger craving for substances at baseline. Both LAIs were associated with significant improvements in all outcomes, with AM displaying stronger effect sizes than PP. The two groups did not differ on baseline WHOQOL-BREF scores in any domain, but at the 1-year follow-up, AM fared better on all domains. The two groups did not differ in final severity, but PP scored higher than AM in craving at the 1-year endpoint.Limitation: The CGIs is not a refined tool for severity and the substance craving may be subject to recall bias.Conclusion1-year AM and PP was followed by improved clinical status and QoL and reduced substance craving in a population with psychosis and SUD comorbidity. AM, compared to PP, improved craving and QoL at the 1-year follow-up.

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

Objective Long-acting injectable (LAI) antipsychotics are recommended in the treatment non-adherence. Despite the widespread use of LAI antipsychotics, there is limited data on clinical outcomes in bipolar I disorder (BD-I) patients with real-world data. We aimed to compare BD-I patients treated with LAI and oral antipsychotics (OAP) in terms of treatment effectiveness in a 1-year follow-up period. Methods The study was conducted retrospectively with electronic health records of 116 BDI patients. The primary outcomes were whether patients in the LAI group and the OAP group differed in relapse, rehospitalization, emergency room (ER) visits, and all-cause treatment discontinuation at 1-year follow-up after a mania episode. Cox regression modeling was used to predict the recurrence of any mood episode and all-cause treatment discontinuation during follow-up. The secondary outcomes evaluated were the effects of sociodemographic and clinical parameters and concomitant psychotropic medications on the course of the illness and treatment adherence. Results Of all 116 patients, 33 (28.4%) were under LAI, and 83 (71.6%) were under OAP treatment. LAI users had a history of more hospitalizations and total mood episodes. Patients in the LAI group had more treatment non-adherence before the index hospitalization. At 1-year follow-up, there was no difference between the groups in terms of any mood relapse, rehospitalization, ER visits, and all-cause treatment discontinuation. As a secondary outcome, lithium users were found to have fewer new episodes and discontinuations of treatments. Conclusions In real-world data, there is no evidence that LAI antipsychotics (compared to OAP) are superior in the maintenance treatment of BD. These results are important in terms of reflecting clinical practices for the treatment of BD-I. These results do not devalue the use of LAI therapy in BD; however, more studies are needed to identify positive predictors for LAI treatments in BD.

Improving medication adherence is critical to improving outcomes in patients with schizophrenia. A long-acting injectable (depot) antipsychotic is one of the most effective methods for improving treatment adherence and decreasing rehospitalization rates in patients with schizophrenia. Until recently, only three second-generation antipsychotics were available in a long-acting injectable formulation (risperidone, paliperidone, and olanzapine). In this respect, the emergence of long-acting aripiprazole injection (ALAI), approved by the US Food and Drug Administration for the treatment of schizophrenia in 2013, is timely. ALAI is a lyophilized powder of aripiprazole, and the aripiprazole molecule is unmodified. The initial and target dosage of ALAI is 400 mg once monthly, but it could be reduced to 300 mg if adverse reactions occur with 400 mg. When first administering ALAI, it is recommended to continue treatment with oral aripiprazole (10–20 mg/day) or another oral antipsychotic for 2 weeks in order to maintain therapeutic antipsychotic concentrations. The primary clearance route for ALAI is hepatic, ie, cytochrome P450 (CYP)2D6 and CYP3A4, so dose adjustment is required in poor CYP2D6 metabolizers. The efficacy of ALAI was demonstrated in three studies. A randomized controlled trial that formed the basis for approval of ALAI in the treatment of schizophrenia showed that ALAI significantly delayed time to impending relapse when compared with placebo (P<0.0001, log-rank test). An open-label, mirror study demonstrated that total psychiatric hospitalization rates were significantly lower after switching from oral antipsychotics to ALAI. Another randomized controlled trial presented in poster form suggested that ALAI 400 mg was comparable with oral aripiprazole 10–30 mg in preventing relapse. ALAI was generally well tolerated during both short-term and long-term studies. Its tolerability profile, including extrapyramidal symptoms and clinically relevant metabolic parameters, was similar to placebo. However, insomnia, headache, anxiety, akathisia, weight gain, injection site pain, and tremor need clinical attention. These studies suggest that ALAI is a viable treatment option for patients with schizophrenia, but direct head-to-head comparisons between ALAI and other long-acting injectable antipsychotics are needed to elucidate its risk–benefit profile.

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.

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.

Aripiprazole is a second-generation partial dopamine D₂ receptor agonist antipsychotic approved for the treatment of schizophrenia and maintenance treatment of bipolar I disorder. As the only partial dopamine D₂ receptor agonist available in both oral and long-acting injectable (LAI) formulations, it provides flexibility for tailoring treatment across different phases of the illness. Two LAI formulations of aripiprazole monohydrate are available: aripiprazole once-monthly 400 mg and aripiprazole 2-month ready-to-use 960 mg, offering options to accommodate patient needs and preferences and support adherence. The aripiprazole monohydrate LAIs are well-supported options for early intervention and maintenance treatment, with evidence demonstrating clinical effectiveness in reducing relapse and hospitalizations while supporting enhanced adherence. LAI antipsychotics, including aripiprazole monohydrate, offer practical benefits for patients with schizophrenia, particularly those at risk for nonadherence or recurrent episodes. However, these formulations are often underutilized due to lingering stigma and misperceptions, leading many clinicians to defer use of these agents until later in the treatment course. To support earlier and more informed use of aripiprazole monohydrate LAIs, a panel of psychiatric experts convened to review the latest evidence and share clinical strategies for integrating this agent into a comprehensive treatment plan. This Academic Highlights section presents the main points of their consensus recommendations, offering practical guidance for prescribers seeking to optimize outcomes in patients with schizophrenia.

Introduction Long-acting injectable (LAI) formulations of second-generation antipsychotics (SGA) are a mainstay in the treatment of schizophrenia-spectrum patients, and their use improves adherence and reduces relapse risk. Personalizing LAI-based therapy involves tailoring the transition from oral to LAIs based on individual and drug-related pharmacokinetic peculiarities. Areas covered We discuss pharmacokinetic considerations as a cornerstone of a smooth transition from oral to LAI SGAs based on works identified using an updated search in PubMed and Embase in February 2023. Establishing the extent of antipsychotic exposure during oral SGA-treatment from the patient’s SGA levels is often a more appropriate orientation method to choose the equivalent LAI dose than population-based data. Oral dose adjustment during LAI transition can also be guided by checking SGA levels before the LAI injection. Expert opinion LAI SGAs may dominate the maintenance treatment of schizophrenia-spectrum disorders with increased use for other severe mental illnesses such as bipolar disorder. Spurring this trend is the development of newer formulations with longer injection intervals and increased administration ease, but transitioning from oral SGA remains a challenge. By understanding the pharmacokinetics of LAI formulations and measuring SGA levels during oral therapy, one can personalize/optimize the switch from oral SGAs to LAI counterparts.

1152 – Formalized consensus guidelines for use and management of antipsychotic depots

Long-acting injectable (LAI) antipsychotics improve patient outcomes and are recommended by treatment guidelines for patients with limited medication adherence in schizophrenia spectrum, bipolar, and other psychotic disorders. Reports of LAI antipsychotic use in these disorders and if use aligns with treatment guidelines are lacking. This study aimed to report patient characteristics associated with LAI antipsychotic use in these disorders. Retrospective observational study of patients ≥18-years-old with bipolar or psychotic disorders at a large, integrated, community-based health system. Patient demographic and clinical characteristics served as exposures for the main outcome of adjusted odds ratio (aOR) for LAI versus oral antipsychotic medication use from January 1, 2017 to December 31, 2023. There were N = 2685 LAI and N = 31 531 oral antipsychotic users. Being non-white (aOR = 1.3-2.0; P < .0001), non-female (aOR = 1.5; P < .0001), from a high deprivation neighborhood (NDI, aOR = 1.3; P < .0007), having a higher body mass index (BMI, aOR = 1.3-1.7; P < .0009), having a schizophrenia/schizoaffective (aOR = 5.8-6.8; P < .0001), psychotic (aOR = 1.6, P < .0001), or substance use disorder (aOR = 1.4; P < .0001), and outpatient psychiatry (aOR = 2.3-7.5; P < .0001) or inpatient hospitalization (aOR = 2.4; P < .0001) utilization in the prior year with higher odds and age ≥40 (aOR = 0.4-0.7; P < .0001) or bipolar disorder (aOR = 0.9; P < .05) were associated with lower odds of LAI use. Non-white, non-female, age 18-39, and high NDI patients had higher LAI use regardless of treatment adherence markers. Smoking and cardiometabolic markers were also associated with LAI use. Demographic and clinical factors are associated with increased LAI use irrespective of treatment adherence. Research on utilization variation informing equitable formulation use aligned with treatment guideline recommendations is warranted.

Long-acting injectable (LAI) antipsychotics were developed as a way to decrease pill burden and simplify medication regimens by allowing less frequent administration to assist with medication adherence. The purpose of this study was to determine whether LAI antipsychotics prevent or delay hospital readmission in patients with a known history of medication non-adherence. The study is a retrospective evaluation of 240 men and women 18-65 years of age diagnosed with bipolar disorder, schizophrenia, or schizoaffective disorder discharged from an inpatient state hospital over a 2 year period of time on a LAI antipsychotic (fluphenazine LAI, haloperidol LAI, risperidone LAI or paliperidone LAI) or oral antipsychotic. Patients on LAIs were matched to patients on an equivalent oral dose, psychiatric diagnosis, number of prior hospital admissions, and length of stay. Those who received a LAI (N = 120) had a significantly longer survival time (mean 278.0 days) without readmission compared to those who did not (N = 120; mean 243.6 days). There was no statistically significant difference in the frequency of one-year readmission between those who did receive a LAI (43.1%) and those who did not (56.9%). Those who received a LAI with administration frequency of a month or longer had a significantly longer survival time without readmission (mean 307.9 days) when compared to those with a shorter administration frequency (mean 245.0 days). This study revealed the use of LAI antipsychotics in those with a history of medication non-adherence, particularly those with longer administration frequency, have potentially promising outcomes.

The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, and in maintenance treatment. The authors critically reviewed 3 types of data: (1) positron emission tomography data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, (2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and (3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics. Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations because these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including comedications and comorbidities. Reported data combined with positron emission tomography evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges. Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.

Antipsychotic medications are a central component of effective treatment for schizophrenia, but nonadherence is a significant problem for the majority of patients. Long-acting injectable (LAI) antipsychotic medications are a recommended treatment option for nonadherent patients, but evidence regarding their potential advantages has been mixed. Observational data on newer, second-generation LAI antipsychotic medications have been limited given their more recent regulatory approval and availability. To examine antipsychotic medication nonadherence, discontinuation, and rehospitalization outcomes in Medicaid patients receiving oral versus LAI antipsychotic medications in the 6 months after a schizophrenia-related hospitalization. The 2010-2013 Truven Health Analytics MarketScan Medicaid research claims database was used to identify adult patients with a recent history of nonadherence (prior 6 months) who received an oral or LAI antipsychotic medication within 30 days after an index schizophrenia-related hospitalization. Primary outcome measures were nonadherence (proportion of days covered less than 0.80), discontinuation (continuous medication gap ≥ 60 days), and schizophrenia-related rehospitalization, all in the 6 months after discharge. Descriptive analyses compared users of oral versus LAI antipsychotic medication on sociodemographic, clinical, and treatment characteristics. Logistic regressions were used to examine associations between use of oral versus LAI antipsychotics and each study outcome while controlling for observed differences in sample characteristics. All outcomes were compared at 3 levels of analysis: overall LAI class, LAI antipsychotic generation (first-generation [FGA] or second-generation [SGA] antipsychotics), and individual LAI agent (fluphenazine decanoate, haloperidol decanoate, risperidone LAI, and paliperidone palmitate). Of the final sample, 91% (n = 3,428) received oral antipsychotics, and 9.0% (n = 340) received LAI antipsychotics after discharge. Slightly over half (n =183, 53.8%) of LAI users used an SGA LAI. A smaller percentage of patients receiving LAIs were nonadherent (51.8% vs. 67.7%, P less than 0.001); had a 60-day continuous gap in medication (23.8% vs. 39.4%, P less than 0.001); and were rehospitalized for schizophrenia (19.1% vs. 25.3%, P = 0.01) compared with patients receiving oral medications. The size of these differences was magnified when comparing SGA LAI users with users of oral antipsychotics for nonadherence. After controlling for all differences in measured covariates, LAI initiators had lower odds of being nonadherent (adjusted odds ratio [AOR] = 0.35, 95% CI = 0.27-0.46, P less than 0.001) and of having continuous 60-day gaps (AOR = 0.45, 95% CI = 0.34-0.60, P less than 0.001) when compared with patients receiving oral medications. Both FGA and SGA LAI users had lower odds of nonadherence compared with patients receiving oral antipsychotics. Similarly, FGA LAI users (AOR = 0.58, 95% CI = 0.40-0.85, P = 0.005) and SGA LAI initiators (AOR = 0.34, 95% CI =0.23-0.51, P less than 0.001) had lower odds of a 60-day continuous gap compared with patients receiving oral antipsychotics. Compared with those receiving oral antipsychotics, LAI initiators also had lower odds of rehospitalization (AOR = 0.73, 95% CI = 0.54-0.99, P = 0.041); however, when examined separately, only patients receiving SGA LAIs (AOR = 0.59, 95% CI = 0.38-0.90, P = 0.015) and not FGA LAIs (AOR = 0.90, 95% CI = 0.60-1.34, P = 0.599) had a statistically significant reduction in odds of rehospitalization. Among individual LAIs, odds of rehospitalization only among initiators of paliperidone palmitate were statistically different from those among users of oral antipsychotics (AOR = 0.53, 95% CI = 0.30-0.94, P = 0.031). While odds of rehospitalization were 33% lower among patients receiving risperidone LAI compared with those receiving oral antipsychotics, the estimate did not reach statistical significance (AOR = 0.67, 95% CI = 0.37-1.22, P = 0.194). This claims-based analysis of posthospitalization adherence and rehospitalization outcomes in Medicaid patients with schizophrenia adds to the growing real-world evidence base of the benefits of LAI antipsychotic medications in routine clinical practice, particularly with regard to second-generation LAIs. As new SGA formulations become available for long-acting use, real-world studies with larger sample sizes will be needed to further delineate their potential advantages in terms of clinical outcomes and costs.